Novel Routes of Synthesis for the Preparation of Suvorexant

The present invention relates to a process for the preparation of a compound of formulae

(Ila') and (II)

and a compound of formulae (II), and (Ha') as such, as well as obtained or obtainable by said process. Further, the present invention relates to processes for the preparation of intermediate compounds useful in the synthesis of compounds of formula (A) and (Aa) and of suvorexant.

BACKGROUND OF THE INVENTION

Orexin is a neurotransmitter that regulates wakefulness and appetite. Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness. Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies such as depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behavior disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; eating disorders such as anorexia, bulimia, cachexia, and obesity; addictive feeding behaviors; binge/purge feeding behaviors; cardiovascular diseases; diabetes; appetite/taste disorders; emesis, vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia; hypophysis tumor/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric dyskinesia; gastric ulcers; Froehlich's syndrome; adenohypophysis disease; hypophysis disease; adenohypophysis hypofunction; adenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischemic or hemorrhagic stroke; subarachnoid hemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection, e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, and angina; migraine; urinary bladder incontinence, e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet lag syndrome; and neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism- amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy; seizure disorders and other diseases related to general orexin system dysfunction.

Some orexin receptor antagonists are capable of influencing at least some of the above described pathological conditions. In particular, orexin receptor antagonists capable of promoting sleep in animals and humans are described in the art. One example for such an orexin receptor antagonist is [(7R)-4-(5-chloro-l,3-benzoxazol-2-yl)-7-methyl-l,4- diazepan-l-yl][5-methyl-2-(2H-l ,2,3-triazol-2-yl)phenyl]methanone which has the structure according to Formula I

and which is, e.g., described in US 2008/0132490, WO 2008/069997 and Cox et al. (2010) Journal of Medicinal Chemistry, 53(14): 5320-5332. Alternative names for this compound are 5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-l,2,3-thiazol-2- yl)benzoyl]-l,4- diazepan- 1 -yl} - 1 ,3-benzobenzoxazol and [(R)-4-(5-chloro-benzooxazol-2-yl)-7-methyl- [ 1 ,4]diazepan- 1 -yl]-(5-methyl-2-[ 1 ,2,3]triazol-2-yl-phenyl)-methanone.

The synthesis of [(7R)-4-(5-chloro-l,3-benzoxazol-2-yl)-7-methyl-l,4-diazepan -l-yl][5- methyl-2-(2H-l,2,3-triazol-2-yl)phenyl]methanone (herein also referred to as "Suvorexant" or "orexin receptor antagonist") is described in WO 2008/069997. There, a synthesis that is based on a chiral resolution by chiral HPLC (high performance liquid chromatography) is described. The first step of this synthesis involves a 1 ,4-addition of Boc-ethylenediamine to methyl vinylketone followed by a Cbz-protection of the free amine to give a Boc- protected intermediate. The Boc-protecting group is then cleaved with HCI and a 7- membered ring is closed by a reductive amination reaction sequence to give a racemic compound which after re-protection of the free amine with a Boc-protective group is resolved by preparative chiral HPLC. The resulting enantiomerically pure amine is then coupled with a triazole benzoic acid derivative under standard peptide coupling conditions. Hydrogenation cleaves the Cbz-protecting group and the resulting amine is then finally coupled with a benzoxazole derivative to give Suvorexant. However, in this linear sequence a large number of steps is needed to provide Suvorexant with only rather low yields. Further, the synthesis is disadvantageous in that a chiral resolution by preparative HPLC is needed, a process which is costly and thus not suitable for the preparative scale.

A further synthesis of Suvorexant is described in WO 2012/148553. This process patent discloses a different route towards Suvorexant. According to WO 2012/148553, chloroaminophenol is condensed with thiophosgene to give mercaptobenzoxazole which is then converted into a ketone by treatment with oxalyl chloride/DMF followed by a one -pot reaction with mono Boc-protected ethylenediamine and vinylketone. The Boc-protecting group is then cleaved to give an intermediate which is then cyclized by a transfer hydrogenation with a costly and very specific ruthenium catalyst to give an enantiomerically pure compound comprising a free amine group. The amine is then coupled with the acid chloride of a triazole benzoic acid derivative to give Suvorexant.

A stereoselective Suvorexant synthesis includes a tandem enantioselective transamination/ring formation and is described in WO2013/169610. The synthesis starts with the preparation of a mesylate under standard conditions which is then converted into an amine in the presence of a (R)-selective sitagliptin transaminase and the intermediately formed amine cyclizes to give the seven-membered diazepane ring. This step requires a strict control of process parameters to suppress the formation of an undesired impurity (regioisomer). Further, a very specific and sensitive enzyme needs to be employed which again renders the process disadvantageous for the preparative scale.

Thus, there is still the need for an improved synthesis of Suvorexant which provides Suvorexant in high yields and which overcomes the disadvantages of the processes described in the prior art, such as the use of costly and complex catalyst systems and sensitive enzymes.

SUMMARY OF THE INVENTION

Surprisingly, it was found that this object can be solved by intermediates of formula (II), (Ila) and (Ha') and by process for preparing the same.

Hence, the present invention regards a process for preparing a compound of formula (Ila')

(Ila') the process comprising

(al) reacting a compound of formula (ΠΓ)

Ri b

N

_R ia' " NHR 2a with a compound of formula (IV)

to give a compound of formula V)

(a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V), to give a compound of formula (Ila')

wherein at each occurrence

R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl

R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la and R ^lb is H, or

R ^la is H and R ^lb is H, R ¹ , PG ¹ , R ^A or PG ^la ,

or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido roup of formula (p)

and succinimido group of formula (s)

R ^2a is H, R ² , PG ² , R ^B or PG ^2a ,

PG ^la and PG ^2a are, independently of each other, suitable protecting groups,

R ¹ is selected from the group consisting of H, PG ¹ and R ^A ,

R ² is selected from the group consisting of H, PG ² and R ^B ,

PG ¹ and PG ² are, independently of each other, suitable protecting groups,

R ^A is

R is

In a further embodiment the present invention relates to a process for preparing a compound of formula (Ila)

comprising

(al) reacting a compound of formula (III)

R ^1a HN^ _NHR2a with a compound of formula (IV)

to give a compound of formula (V)

wherein R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la and wherein R ^2a is H, PG ² , R ^B or PG ^2a and wherein PG ^la and PG ^2a are, independently of each other, suitable protecting groups,

(a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V),

to give the compound of formula (Ha).

In a further embodiment the present invention is directed to a process for the preparation of a compound of formula (II),

comprising the steps (al) to (a3) as disclosed above, the process further comprising in formula (Ha') when a compound of formula (Ha') is obtained in (a3)

(a4) replacing R ^2a with R ² and/or R ^la with R ¹ , preferably being R ^lb =H, or

replacing R ^2a with R ² and/or R ^lb with R ¹ , preferably being R ^la =H, or

replacing R ^2a with R ² and/or when R ^la and R ^lb are taken together to form a cyclic imide group optionally replacing the cyclic imide group with R ¹ and H

in formula (Ila), when a compound of formula (Ila) is obtained in (a3)

(a4) replacing R ^2a and/or R ^la with R ¹ and/or R ² ,

to give the compound of formula (II).

In another embodiment, the present invention regards a process for the preparation of a compound of formula (Ila')

comprising (a-i) reacting a compound of formula (1)

with a compound of formula (2)

R ^{1 b} O

and obtaining a compound of formula (Ha') and

(a-ii) optionally purifying the compound of formula (Ila'),

wherein at each occurrence

R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably R ^E is alkyl, more preferably R ^E is methyl, ethyl or propyl, more preferably R ^E is methyl,

R ^la is R ¹ , PG ¹ , R ^A or PG ^la ' and R ^lb is H, in this case preferably R ¹ not being H, or

R ^la is H, and R ^lb is R ¹ , PG ¹ , R ^A or PG ^la in this case preferably R ¹ not being H, or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido roup of formula (p)

and succinimido group of formula s)

R ^2a is H, PG ² , R ^B or PG ^2a '

PG ^la and PG ^2a are, independently of each other, suitable protecting

R ¹ is selected from the group consisting of H, PG ¹ and R ^A

R ² is selected from the group consisting of H, PG ² and R ^B

R ^A is

R is

In a further embodiment the present invention is directed to a process for the preparation of a compound of formula (II),

comprising the steps (a-i) to (a-ii) as disclosed above, the process further comprising

(a4) replacing R ^2a with R ² and/or R ^la with R ¹ , preferably being R ^lb =H, or

replacing R ^2a with R ² and/or R ^lb with R ¹ , preferably being R ^la =H, or

replacing R ^2a with R ² and/or when R ^la and R ^lb are taken together to form a cyclic imide group optionally replacing the cyclic imide group with R ¹ and H and obtaining a compound of formula (II).

The invention further regards compounds of formula (Ila') obtained or obtainable according to the process as disclosed above.

The invention further regards compound of formula (Ila') as such.

The invention further regards a compound of formula (Ila) obtained or obtainable according to the process as disclosed above.

The invention further regards a compound of formula (Ila) as such.

The invention further regards a compound of formula (II) obtained or obtainable according to the process as disclosed above.

The invention further regards a compound of formula (II) as such.

The invention further regards the use of a compound of formula (II) or of formula (Ila) or of formula (Ila') in the preparation of a compound of formula (A) or (Aa), preferably of suvorexant of formula (IX). DETAILED DESCRIPTION

The present invention is directed to two processes for the preparation of compound (Ila') or (Ila) which can be further reacted to obtain a compound (II).

The first process uses a ethylenediamine and derivative thereof as the staring material, the second process uses homoalanine and ester thereof as the starting material.

Compounds (ΙΙα') (Ha) and (II) and Compound (Ila'*) (Ila) and (II*)

As mentioned above, the compound of formula (Ila') provided in step (a3) of the ethylendiamine based process or in (a-ii) of the homoalanine based process has the structure

The structure

means that compound (Ila') has either the structure

or consists of a mixture of

R ^b O (Ila'*) and R ^b O (Ha'**)

wherein R ^la , R ^lb , R ^2a and R ^E are as defined above.

As mentioned above, the compound of formula (Ila) provided in step (a3) of the ethylendiamine process has the structure

means that compound (Ila) has either the structure

or consists of a mixture of

wherein R ^la , R ^2a and R ^E are as defined above.

As mentioned above, the compound of formula (II) provided in step (a4) has the structure

The structure

means that compound (II) has either the structure

or consists of a mixture of

(IP) and R ^E 0^0 (II**)

wherein R ¹ , R ² and R ^E are as defined above

Alternatively, in (a3), (a-ii) and in (a4), the compound of formula (Ila*), (Ila' *) (II*) are respectively provided, thus the "single (isolated) isomer" with R configuration is provided. The term "single isomer" in this context is denoted to mean that the compound of formula (Ila' *) or the compound of formula (Ila*) or the compound of formula (II*) comprises less than 1 % by weight of compound (Ila' **) or (Ila**) or (II**), respectively, preferably less than 0.5 % by weight, more preferably less than 0.1 % by weight, more preferably less than 0.05 % by weight, more preferably less than 0.01 % by weight, more preferably essentially no, more preferably no compound of formula (Ila' *), (Ila*) or (II**) respectively based on the total weight of (Ila'*) and (Ila'**) or, (Ila*) and (Ila**), or (II*) and (II**) respectively.

In case the compound of formula (Ila' *) or (Ila*) is provided in step (a3), the provision preferably either comprises a chiral resolution step or an enantioselective reaction step, such as enantioselective reduction of the double bond present in compound (V')/(V).

In case the compound of formula (II*) is provided in step (a4), the provision preferably either comprises a chiral resolution step or an enantioselective reaction step, such as enantioselective reduction of the double bond present in compound (V')/(V).

The chiral resolution may be carried out by any suitable method known to those skilled in the art, such as resolution by crystallization or by chiral chromatography, such as chiral HPLC. Preferably, the chiral resolution during step (a3) or (a4) is carried out by crystallization employing an optical pure resolving agent, preferably an optical pure chiral acid. Preferably, the chiral resolution of compound (Ila') or (II), if carried out, is carried out with a tartaric acid as chiral acid, preferably with tartaric acid.

Residue R ^E

As described above, R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably R ^E is selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl. It is preferred that R ^E is alkyl, preferably Ci-C ₆ alkyl, more preferably R ^E is methyl, ethyl or propyl, more preferably R ^E methyl.

Regarding R ^E , when R ^E is alkyl, it is preferred that alkyl is Ci-C ₆ alkyl, more preferably R ^E is methyl, ethyl or propyl, even more preferably R ^E methyl. R ^la , R ^lb and R ¹

As disclosed above in the ethyldiamine based process R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la and R ^lb is H, or R ^la is H and R ^lb is H, R ¹ , PG ¹ , R ^A or PG ^la , or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the grou consisting of phthalimido group of formula (p)

and succinimido group of formula (s)

As disclosed above in the homoalanine based process R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la ' and R ^lb is H, or R ^la is H, and R ^lb is H, R ¹ , PG ¹ , R ^A or PG ^la wherein preferably,

R ^la is R ¹ , PG ¹ , R ^A or PG ^la ' and R ^lb is H, in this case preferably R ¹ not being H, or

R ^la is H, and R ^lb is R ¹ , PG ¹ , R ^A or PG ^la in this case preferably R ¹ not being H,

or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group of formula

and succinimido group of formula (s)

The cyclic imide formed by R ^la and R ^lb taken together with the N atom to which they are attached is an amino protecting group having the same role of group PG ¹ or PG ^la as disclosed below. As mentioned above, in compound (Ila) R ^la is defined as H, PG ¹ , R ^A or PG ^la in this case R ^lb is H.

PG ^la and PG ^2a in the compound of formula (Ila') or (Ila) are independently of each other, suitable protecting groups.

In the context of the invention, the term "suitable protecting group" as used herein is denoted to encompass any amino protecting group. The term "protecting group" as such refers to a chemical moiety that can be selectively attached to and removed from a particular chemically reactive functional group in a molecule to prevent it from participating in undesired chemical reactions. The protecting group will vary depending on reaction conditions to be employed and the presence of additional reactive or protecting groups in the molecule. It is understood that the term "amino protecting group" is a chemical moiety being attached to a former amino group. After removal of the protecting group, the free amine is regained. Representative protecting groups for amino groups are well known to those skilled in the art and are described, for example, in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, N.Y., 1999, and references cited therein.

An "amino-protecting group" preferably includes both acyclic as well as cyclic protecting groups. A "cyclic protecting group" is a group which, together with the N to which it is bound, forms a cyclic group. Preferred protecting groups for PG ¹ include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl, PNZ, trifluoroacetate, phtalimide and the like; cyclic imide derivatives, such as succinimide and phthalimide; amides, such as formyl, (un)substituted acetyl, and benzoyl; and trialkyl silyl groups, such as t-butyldimethylsilyl and triisopropylsilyl. Particularly preferred amino-protecting groups include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl, Cbz, PNZ, Alloc, Trifluoroacetate, Phthalimide and the like. Most preferably, PG ¹ is wherein PG ¹ is selected from the group consisting of benzyl, t-butyloxycarbonyl (Boc), Cbz, PNZ, Alloc, Trifluoroacetate and Phthalimide, more preferably PG1 is a Boc group or a Cbz group, more preferably Boc.

Preferred protecting groups for PG ^la include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl and the like; cyclic imide derivatives, such as succinimide and phthalimide; amides, such as formyl, (un)substituted acetyl, and benzoyl; and trialkyl silyl groups, such as t- butyldimethylsilyl and triisopropylsilyl. Particularly preferred amino-protecting groups include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl and the like. Most preferably, PG ^la is a Boc group or a Cbz group, more preferably Boc. As disclosed above, R ¹ is selected from the group consisting of H, PG ¹ and R ^A . PG ¹ is as defined above.

R ^A is

R ^2a and R ²

As disclosed above R ^2a is H, R ² , PG ² , R ^B or PG ^2a wherein R ² is selected from the group consisting of H, PG ² and R ^B .

PG ^2a is suitable protecting groups, wherein "suitable protecting group" is as defined above.

PG ² is suitable protecting groups, wherein "suitable protecting group" is as defined above.

Preferred protecting groups for PG ^2a include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl and the like; cyclic imide derivatives, such as succinimide and phthalimide; amides, such as formyl, (un)substituted acetyl, and benzoyl; and trialkyl silyl groups, such as t-butyldimethylsilyl and triisopropylsilyl. Particularly preferred amino-protecting groups include Boc, Cbz (CBZ), Fmoc, benzyl, acetyl, benzoyl, trityl and the like. Most preferably, PG ^2a is a Boc group or a Cbz group, more preferably Cbz.

Preferred protecting groups for PG ² include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl, PNZ, trifluoroacetate, phtalimideand the like; cyclic imide derivatives, such as succinimide and phthalimide; amides, such as formyl, (un)substituted acetyl, and benzoyl; and trialkyl silyl groups, such as t-butyldimethylsilyl and triisopropylsilyl. Particularly preferred amino-protecting groups include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl, Cbz, PNZ, Alloc, Trifluoroacetate, Phthalimide and the like. Most preferably, PG ¹ is wherein PG ² is selected from the group consisting of Benzyl, t-butyloxycarbonyl (Boc), Cbz, PNZ, Alloc, Trifluoroacetate and Phthalimide, more preferably PG ² is a Boc group or a Cbz group, more preferably Cbz.

R ^B is

Compound (IIP) and compound (III)

As disclosed above compound (ΠΓ) and (III) of formulae

_R 1 b

_R ⁱ _a " ^NHR ^2a _(m)) ^MN ^^NHR ^2a (HI) are intermediates in the ethyldiamine process.

R ^la , R ^lb and R ^2a are as defined above.

It is preferred that in compound (III) when R ^2a is H then R ^la is not H or wherein when R ^la is H then R ^2a is not H.

It is preferred that in compound (ΠΓ) when R ^2a is H then R ^la or R ^lb is not H or wherein when R ^la is H and R ^lb and then R ^2a is not H.

It is hence preferred that at most one primary amino group is present in compound (III).

Compound (V) and compound (V)

Re arding compound of formula (V), preferably of formula (V)

it is an intermediate in the synthesis of compound (Ha') or (Ha). Specifically the double bond is reduced to single bond with the creation of a stereocenter as disclosed above in compounds (Ila*), (Ila**), (Ila'*) and (Ila'**). In compound (V) and (V), R ^la R ^lb , R ^2a and R ^E are as defined above

Compound (1)

Compound (1) is an homoalanine derivative of formula used in the homoalanine based process according to the present invention. Compound (1) has formula (1)

wherein R ^2a and R ^E are as defined above.

Compound (2)

Compound (2) is an intermediate of the homoalanine based process according present invention. It has formulae

wherein R ^la and R ^lb are as defined above.

In particular, R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la ' and R ^lb is H, or

R ^la is H, and R ^lb is H, R ¹ , PG ¹ , R ^A or PG ^la

preferably,

R ^la is R ¹ , PG ¹ , R ^A or PG ^la ' and R ^lb is H, in this case preferably R ¹ not being H, or

R ^la is H, and R ^lb is R ¹ , PG ¹ , R ^A or PG ^la in this case preferably R ¹ not being H,

or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group of formula

and succinimido group of formula (s)

The cyclic imide formed by R ^la and R ^lb taken together with the N atom to which they are attached is an amino protecting group having the same role of group PG ¹ or PG ^la as disclosed below. Process for preparing compound (Ila') and (II) from ethylenediamine (III) or (III') as the staring material (ethylenediamine based process).

The process of the present invention is directed to a process for preparing compounds (Ila'), (Ila) and compound (II). In the present context the process steps for the preparation of a compound of formula (II) are in some instances referred to as step "(a) providing a compound of formula (II)" or similar expressions.

Hence, the present invention is directed to a process for preparing a compound of formula

(Ila')

the process comprising

(al) reacting a compound of formula (ΠΓ)

R 1b

I

^' NHR 2a

(ΙΙΓ)

with a compound of formula (IV

to give a compound of formula (V)

(a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V), to give a compound of formula (Ila')

wherein at each occurrence

R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la and R ^lb is H, or R ^la is H and R ^lb is H, R ¹ , PG ¹ , R ^A or PG ^la ,

or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido roup of formula (p)

and succinimido group of formula s)

R ^2a is H, R ² , PG ² , R ^B or PG ^2a ,

PG ^la and PG ^2a are, independently of each other, suitable protecting groups,

R ¹ is selected from the group consisting of H, PG ¹ and R ^A ,

R ² is selected from the group consisting of H, PG ² and R ^B ,

PG ¹ and PG ² are, independently of each other, suitable protecting groups,

R ^A is

Preferably in the above describe process, R is H and hence the compound of formula (Ila') is a compound of formula (Ha).

The compound of formula (ΠΓ) is a compound of formula (III)

^R ' ^aHN - NHR- and the compound of formula (V) is a com ound of formula (V)

The process of the invention further optionally comprises

(a4) replacing R ^2a with R ² and/or R ^la with R ¹ , preferably being R ^lb =H, or

replacing R ^2a with R ² and/or R ^lb with R ¹ , preferably being R ^la =H, or

replacing R ^2a with R ² and/or when R ^la and R ^lb are taken together to form a cyclic imide group optionally replacing the cyclic imide group with R ¹ and H

to give the compound of formula II)

In particular step (a4) is optional when R ^2a is the same as R ² and/or R ^la is the same as R , and/or R ^lb is the same as R ¹ as it is explained below.

The present invention is hence, further directed to a process for the preparation of a compound of formula (II) and a compound obtained or obtainable by a method as disclosed above.

Alternatively, the method comprises

(al) reacting a compound of formula III)

with a compound of formula (IV)

to give a compound of formula V)

wherein R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la and wherein R ^2a is H, PG ² , R ^B or PG ^2a and wherein PG ^la and PG ^2a are, independently of each other, suitable protecting groups,

(a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V),

(a4) optionally replacing R ^2a and/or R ^la with R ¹ and/or R ² ,

and obtaining the compound of formula (II).

It is preferred that in any of the embodiments disclosed above R ^2a is H and R ^la or R ^lb is not H or when R ^la and R ^lb is H, R ^2a is not H.

It is further preferred a process for the preparation of a compound of formula (II), wherein the process further comprises (a4) replacing R ^2a and/or R ^la with R ¹ and/or R ² , to give the

compound of formula (II)

It is further preferred a process wherein in compounds (ΠΓ), (III), (V), (V), (Ha') and (Ila) R ^la is PG ¹ , R ^A or PG ^la with R ^A bein

It is further preferred a process wherein in compounds (ΠΓ), (III), (V), (V), (Ila') and (Ila) R ^la is PG ¹ , R ^A or PG ^la with R ^A bein

R ^a is H. It is preferred a process wherein in compounds (ΠΓ), (III), (V), (V), (Ha') and (Ila) R ^a is H and R ^la is Boc.

It is further preferred a process wherein in (al) R ^la is PG ^la and R ^2a is H, wherein PG ^la is a suitable protecting group, preferably a Boc group, R ^lb is H; in (a3) R ^la is PG ^la and R ^2a is H wherein PG ^la is a suitable protecting group, preferably a Boc group, R ^lb is H; and in (a4) R ^lb is H and R ^2a is replaced with

by reacting a compound of formula (Ila' with a compound of formula (XI)

wherein E is -COOH or a reactive carboxy group, and replacing R ^la with H by removing the rotecting group PG ¹ to give the compound of formula (II) in which R ¹ is H and R ² is

. In this case preferably, R ^E is meth l, R ² is

and R ¹ is H.

It is further preferred, a process wherein in compounds (ΠΓ), (III), (V), (V), (Ila') and (Ila) R ^la is PG ¹ , R ^A or PG ^la with R ^A bein

and in compound (II) R ² is

and R ¹ is H or Boc, preferably Boc and at each occurrence R ^E is preferably methyl.

It is further disclosed a process wherein in compounds (ΙΙΓ), (V) and (Ila'), R ^la is PG ¹ , preferably Boc and R ^lb is H, or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of hthalimido group of formula (p)

and succinimido roup of formula (s)

In this case, it is preferred that in step (a4 R ^a =H is replaced with

by reacting a compound of formula (Ila' with a compound of formula (XI)

wherein E is -COOH or a reactive carboxy group, and R ^la is replaced with H 1) by removing the protecting group PG ¹ or 2) by replacing R ^la and R ^lb , taken together to form a cyclic imide, with hydrogens, and the compound of formula (II) in which R ¹ is H and R ² is

is obtained.

It is preferred that at each occurrence R ^E is methyl,

It is further disclosed a process

-wherein in (a3) in compound (Ha') R ^la is PG ^la , preferably Boc and R ^lb is H, or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group (p) and succinimido group (s) and R ^2a is H, wherein the process comprises

(a4) replacing R ^2a =H with PG ² , wherein PG ² is preferably Boc or Cbz and

replacing R ^la , or R ^la taken together with R ^lb with hydrogens, and obtaining the compound of formula (II) in which R ¹ is H and R ² is PG ² wherein PG ² is preferably Boc or Cbz, wherein PG ^la and PG ² are orthogonal protecting groups, or

-wherein in (a3) in compound (Ila) R ^la is PG ^la , preferably Boc or Cbz, and R ^2a is H, wherein the process comprises

(a4') replacing R ^2a =H with PG ² , wherein PG ² is preferably Boc or Cbz and

replacing R ^la with H, and obtaining the compound of formula (II) in which R ¹ is H and R ² is PG ² wherein PG ² is preferably Boc or Cbz, wherein PG ^la and PG ² are orthogonal protecting groups.

It is preferred that (a4) or (a4') comprises

(a4-l) replacing R ^2a =H with PG ² wherein PG ² is preferably Boc or Cbz and

obtaining an intermediate compound and wherein PG ^la or the cyclic imide group and PG ² are orthogonal protecting groups and

( ^a 4-2) replacing R ^la or R ^la and R ^lb of the intermediate compound obtained in (a4-l) with hydrogens and obtaining the compound of formula (II) in which R ¹ is H and R ² is PG ² wherein PG ² is preferably Boc or Cbz.

In this specific embodiment it is further preferred that R ^la is Boc or R ^la and R ^lb taken together with the N atom to which they are attached form phthalimido group or a succinimido group and R ² is PG ² wherein PG ² is selected from the group consisting of Cbz, Bn, Boc and Fmoc, more preferably PG ² is Cbz, wherein PG ^la and PG ² are selected to be orthogonal protecting groups

Step ( al )

In step (al), a compound of formula (III) or (ΠΓ) is reacted with a compound of formula (IV) or to give the compound of formula (V) or (V). Preferably, in step (al), a compound of formula (III) is reacted with a compound of formula (IV) to give the compound of formula (V).

Preferably, step (al) is carried out at a temperature in the range of from 0 to 80 °C, more preferably in the range of from 10 to 50 °C, more preferably in the range of from 20 to 35 °C. During the reaction, the temperature may be varied or held essentially constant.

Preferably, an organic solvent is used in step (al), more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t- butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof. Most preferably, the reaction is carried out in dichloromethane.

Preferably, (al) is carried out in the presence of a catalysing agent, such as a dehydrating reagent or an acidic catalyst. The term "dehydrating agent" is denoted to mean an agent which removes water from the reagents such as by absorption. Such dehydrating agents are known to those skilled in the art. Preferably, the catalysing agent is Si0 ₂ or a molecular sieve or a mixture thereof. More preferably, the catalysing agent Si0 ₂ .

Step (al)

Preferably, the reaction mixture obtained in step (al) is subjected to a suitable work-up in step (a2), such as an isolation of the respective compound of formula (V) or (V). Such working up may comprise one or more stages wherein preferably at least one stage comprises a purification step, such as an extraction and/or a precipitation and/or filtration and/or chromatography or the like. Preferably, the reaction mixture is filtered to remove the Si0 ₂ and the solvent is removed, such as under reduced pressure.

More preferably, compound (V) or (V) is further purified, e.g. by distillation.

Step (a3)

In step (a3), the compound of formula (V), preferably of formula (V) is reduced to give a compound having the structure (H _a ).

Hence, the present invention also relates to a process for the preparation of a compound of formula (Ila), and a compound obtainable or obtained by said process, the process comprising

(al) reacting a compound of formula (III)

R ^1a HN.

^' NHR ^2a (HI)

with a compound of formula IV)

to give a compound of formula V)

wherein R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la and wherein R ^2a is H, PG ² , R ^B or PG ^2a and wherein PG ^la and PG ^2a are, independently of each other, suitable protecting groups,

(a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V), and obtaining the compound of

formula (Ila).

In case the reduction is carried out in a non-stereoselective manner, compound (Ila') or (Ila) consists of a mixture of (Ila'*) and (Ila'**) or, (Ila*) and (Ila**) as shown below

(Ila'**) or,

The reduction may be carried out by any suitable manner known to those skilled in the art. Preferably, a metal catalyst and hydrogen is used. The metal catalyst is preferably selected from the group consisting of a catalyst comprising Pd, Fe, Ir, Rh or a mixture of two or more thereof. Preferably, the catalyst comprises Pd and/or Fe and/or Rh, wherein the Fe, if present, is preferably present as part of a catalyst ligand. According to one preferred embodiment, the catalyst is a palladium catalyst, more preferably Pd/C. In case of Pd/C, the reaction is preferably carried out in a non-stereoselective manner. The term "non- stereoselective manner" is denoted to mean that a racemic mixture of compounds (Ila'*) and (Ila'**) or, (Ila*) and (Ila**) is obtained. Thus, the present invention also relates to a process, as described above, comprising the steps (al) to (a4), as described above, and wherein in step (a3), the compound is reduced with Pd/C.

The reaction is preferably carried out at a hydrogen pressure in the range of from 1 to 25 bar, more preferably, 2.5 to 10 bar. During the reaction, the pressure may be varied or held essentially constant.

Preferably, the reaction is carried out at a temperature in the range of from 10 to 1000 °C, of from 10 to 100 °C, more preferably in the range of from 20 to 60 °C, more preferably at 40 to 60 °C. During the reaction, the temperature may be varied or held essentially constant.

The reaction may be carried out in any suitable solvent known to those skilled in the art. Preferably, the cyclization reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof. Preferably, the solvent is methanol or TFE.

It is to be understood that in case in step (a4) as disclosed below a mixture of (II*) and (II**) is provided, compound (IIa')/(IIa) also consists of a racemic mixture, i.e. a mixture of the com ounds (IIa'*)(IIa*) and (IIa'**)(IIa**)

According to a preferred embodiment, in step (a3), the compound (V) is stereoselectively reduced to give a compound of formula (Ila'*)

According to a further preferred embodiment, in step (a3), the compound (V) is stereoselectively reduced to give a compound of formula (Ila*)

In this reduction reaction, preferably a chiral catalyst, i.e. a metal catalyst comprising a chiral ligand is employed. As mentioned above, preferably a metal catalyst and hydrogen is used. The metal catalyst is preferably selected from the group consisting of a catalyst comprising Pd, Fe, Ir, Rh and mixtures of two or more thereof. In case of a stereoselective reduction, the metal catalyst is preferably selected from the group consisting of a catalyst comprising Pd, Fe, Ir, Rh, and mixtures of two or more thereof. Preferably, the catalyst comprises Fe and/or Rh.

The reaction is preferably carried out at a hydrogen pressure in the range of from 1 to 25 bar, more preferably, 2.5 to 10 bar. During the reaction, the pressure may be varied or held essentially constant.

Preferably, the reaction is carried out at a temperature in the range of from 10 to 100 °C, more preferably in the range of from 20 to 60 °C, more preferably at 25 to 40 °C. During the reaction, the temperature may be varied or held essentially constant.

The reaction may be carried out in any suitable solvent known to those skilled in the art. Preferably, the cyclization reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof. Preferably, the solvent is methanol or TFE.

Preferably in compound (Ila), R ^la is Boc, R ^lb is H and R ^2a is H.

According to a preferred embodiment of the ethylenediamine based process, the process of the invention e.g. comprises reacting a compound of formula (III)

R ^1a HN

NHR' (III)

with a compound of formula IV)

to give a compound of formula (V)

wherein R ^la is PG ^la and wherein R ^2a is H, wherein PG ^la is a suitable protecting group, preferably a Boc group,

optionally purifying the compound of formula (V),

reducing the compound of formula (V) to give a compound of formula (Ila), wherein R ^la is PG ^la and wherein R ^2a is H

replacing R ^2a with

by reacting a compound of formula Ila) with a compound of formula (XI)

wherein E is -COOH or a reactive carboxy group, and replacing R ^la with H by removing the protecting group PG ^la .

Further, the present invention relates to the preparation of a compound of formula (Ila') and to a compound (Ila') obtained or obtainable by said method, the method comprising

the process comprising

(al) reacting a compound of formula (ΠΓ)

1 b

I

a

R ⁱ a - ^{' Ι} N ^Π HR 2

Κ ^" (ΠΓ) with a compound of formula IV)

to give a compound of formula V)

(a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V), to give a compound of formula (Ila')

wherein at each occurrence

R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la ,

R ^lb is H,

or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido roup of formula (p)

and succinimido group of formula (s)

R ^2a is H, R ² , PG ² , R ^B or PG ^2a ,

PG ^la and PG ^2a are, independently of each other, suitable protecting groups,

R ¹ is selected from the group consisting of H, PG ¹ and R ^A ,

R ² is selected from the group consisting of H, PG ² and R ^B ,

PG ¹ and PG ² are, independently of each other, suitable protecting groups,

R ^A is

R ^B is

R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl.

Further, the present invention relates to the preparation of a compound of formula (Ila) and to a compound (Ila) obtained or obtainable by said method, the method comprising

(al) reacting a compound of formula (III)

R ^1a HN ^ _{N HR2a} with a compound of formula (IV)

to give a compound of formula (V)

wherein R ^la is PG ^la and wherein R ^2a is H, wherein PG ^la is a suitable protecting group, preferably a Boc group, (a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V) to give a compound of formula (Ila), wherein R ^la is PG a and wherein R ^2a is H.

Further, the present invention relates to a compound of formula (Ila), in which R ^la is PG ^la and wherein R ^2a is H, preferably R ^la is Boc.

Further, the present invention also relates to the preparation of a compound of formula (II) and to a compound (II) obtained or obtainable by said method, the method comprising

(al) reacting a compound of formula (III)

with a compound of formula (IV)

to give a compound of formula (V)

wherein R ^la is PG a and wherein R ^2a is H, wherein PG ^la is a suitable protecting group, preferably a Boc group,

optionally purifying the compound of formula (V),

reducing the compound of formula (V) to give a compound of formula (Ila), wherein R ^la is PG ¹ and wherein R ^2a is H,

replacing R ^2a with

by reacting a compound of formula (Ila) with a compound of formula (XI)

(XI)

wherein E is -COOH or a reactive carboxy group, and replacing R ^la with H by removing the protecting group PG ^la ,

to give the compound of formula (II).

Further, the present invention relates to a compound of formula (Ila), in which R ^la is H and wherein R ^a is

According to a further preferred embodiment, the process of the to the invention comprises (al) reacting a compound of formula (III)

R ^{1 a} HN ^ _{NHR2a (m)} with a compound of formula (IV)

to give a compound of formula (V)

wherein R ^la is PG ^la and wherein R ^2a is H, PG ^la is a suitable protecting group, preferably a Boc group,

(a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V) to give a compound of formula (Ila),

wherein R ^la is PG ^la and wherein R ^2a is H replacing R ^2a with a protecting group PG ² and replacing R ^2a with H by removing the protecting group PG ^la .

to give the compound of formula (II), in which R ¹ is H and R ² is PG ² .

Process for preparing compound (Πα') and (II) from homoalanine as the starting material (homoalanine based process)

The present invention is further directed to a process for preparing compound of formula (Ila') and (II) using an homoalanine derivative as the stating material. Advantageously, homoalanine is a commercially available starting material. It can be purchased both as a racemic compound or as enantiomerically pure compound. In the latter case the correct stereochemistry of the methyl group of compound (II) or (Ila') can be introduced since the beginning into the synthesis of compound of formula (Ila'*) or (Ila'**). Alternatively, the compound of formula (Ila') or (II) can be separated into the two enantiomers as disclosed above in connection with the ethylenediamine based process of the invention. The homoalanine based process comprises only two steps that can be advantageously carried out in one pot.

Hence, the present invention is directed to a process for the preparation of a compound of formula (Ila')

comprising

reacting a compound of formula 1)

with a compound of formula (2)

R ^{1 b} O

R 1a' H

(2)

and obtaining a compound of formula (Ila') and

optionally purifying the compound of formula (Ila'),

wherein at each occurrence R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably R ^E is alkyl, more preferably R ^E is methyl, ethyl or propyl, more preferably R ^E is methyl,

R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la ' and R ^lb is H, or

R ^la is H, and R ^lb is H, R ¹ , PG ¹ , R ^A or PG ^la

preferably,

R ^la is R ¹ , PG ¹ , R ^A or PG ^la ' and R ^lb is H, in this case preferably R ¹ not being H, or

R ^la is H, and R ^lb is R ¹ , PG ¹ , R ^A or PG ^la in this case preferably R ¹ not being H,

or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group of formula

and succinimido group of formula s)

2a,

R ^2a is H, PG ² , R ^B or PG

PG ^la and PG ^2a are, independently of each other, suitable protecting groups,

R ¹ is selected from the group consisting of H, PG ¹ and R ^A

R ² is selected from the group consisting of H, PG ² and R ^B

PG ¹ and PG ² are, independently of each other, suitable protecting groups,

R is

In an embodiment, the process further comprises

(a4) in the compound obtained in (a-ii)

replacing R ^2a with R ² and/or R ^la with R ¹ , preferably being R ^lb =H, or

replacing R ^2a with R ² and/or R ^lb with R ¹ , preferably being R ^la =H, or

replacing R ^2a with R ² and/or when R ^la and R ^lb are taken together to form a cyclic imide group optionally replacing the cyclic imide group with R ¹ and H

and obtaining the compound of formula II)

Step (a4) is carried out as disclosed below.

Regarding R ^la , R ^lb , R ¹ , R ² , R ^A , PG ^la , PG ¹ , PG ² , PG ^2a , and R ^E they are defined as above and in the ethyldiamine based process of the invention.

Regarding R ^la and R ^lb preferabl R ^la is PG ¹ , R ^A or PG ^la with R ^A being

or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group of formula

and succinimido group of formula (s)

Regarding R ^la and R ^lb taken together, preferably they form a phthalimido group or a succinimido group.

Preferably, R ^la is PG ^la and R ^2a is H, and PG ^la is a suitable protecting group, preferably a Boc group or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group or succinimido group.

In an embodiment of the homoalanine process, it is preferred that in compound (Ila') R ^la is PG ¹ or PG ^la . More preferably, PG ¹ or PG ^la is Boc. In this case R ^lb is H. Alternatively, it is preferred that R ^lb is PG ¹ or PG ^la , more preferably, PG ¹ or PG ^la is Boc. In this case R ^la is H. Alternatively it is preferred that R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of hthalimido group of formula (p)

and succinimido group of formula (s)

In this case it is preferred that R ^a is H, and that (a4) is carried out by replacing R ^a being H with

by reacting a compound of formula (Ila') with a compound of formula (XI)

wherein E is -COOH or a reactive carboxy group. Either R ^la or R ^lb being PG ¹ or PG ^la are replaced with H by removing the protecting group PG ¹ or PG ^la or by replacing R ^la and R ^lb , taken together to form a cyclic imide, with hydrogens. The compound of formula (II) in which R ¹ is H and R ² is

is therefore obtained.

In another embodiment it is preferred that in compound (Ha') R ^la is PG ^la or PG ¹ , preferably Boc and R ^lb is H, or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group and succinimido group and R ^2a is H. In this case it is preferred that in (a4) R ^2a =H is replaced with PG ² , wherein PG ² is preferably Boc or Cbz and R ^la is replaced with H or R ^la taken together with R ^lb is replaced with hydrogens. In this case a compound of formula (II) in which R ¹ is H and R ² is PG ² wherein PG ² is preferably Boc or Cbz, is obtained. In this case an intermediate compound wherein PG ^la or PG ¹ on one hand and PG ² on the other hand are present. In this case PG ^la or PG ¹ on one hand and PG ² on the other hand are chosen to be orthogonal protecting groups that can be removed in different deprotection conditions. In this case it is preferred that step (a4) comprises

(a4-l) replacing R ^2a =H with PG ² wherein PG ² is preferably Boc or Cbz and

obtaining an intermediate compound and wherein PG ^la or the cyclic imide group and PG ² are orthogonal protecting groups and

(a4-2) replacing R ^la or R ^la and R ^lb of the intermediate compound obtained in (a4-l) with hydrogens and obtaining the compound of formula (II) in which R ¹ is H and R ² is PG ² wherein PG ² is preferably Boc or Cbz.

In step (a4-l), a compound is obtained wherein R ^2a is PG ² and wherein PG ² is preferably Boc or Cbz. PG ² is chosen to be orthogonal to R ^la being PG ¹ or PG ^la or to the imide group formed by R ^la and R ^lb taken together. This assures that in step (a4-2) when R ^la , or R ^la taken together with R ^lb is replaced with hydrogens, PG ² is not removed. In this embodiment it is further preferred that in (a4-l) a compound is obtained wherein PG ^la or PG ¹ is Boc or R ^la and R ^lb taken together with the N atom to which they are attached form phthalimido group or a succinimido group and PG ² is Cbz.

Step (a-i)

Regarding the reacting of (a-i), the reaction is a reduction. Preferably the reacting of (a-i) is selected from a reductive amination and hydrogenation, preferably reductive amination.

Regarding the reductive amination of (a-i), the reductive amination preferably is carried out using a reagent selected form the group consisting of NaBH ₄ , NaBH ₃ CN, NaBH(OAc) ₃ , LiAlH ₄ , more preferably NaBH(OAc) ₃

Regarding the reductive amination of (a-i), it is carried out at temperature in the range of - 30 to 70 °C, more preferably in the range of from -10 to 50 °C, even more preferably in the range of from 10 to 30°C.

Regarding the reductive amination of (a-i), it is carried out in an organic solvent, more preferably in an organic solvent is selected from the group consisting of tetrahydrofuran (THF), methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof, even more preferably in a solvent selected from the group consisting of tetrahydrofuran (THF), methyltetrahydrofurane, methyltertbutylether, dichloromethane .

The reacting of (a-i) can be a hydrogenation reaction.

Regarding hydrogenation of (a-i), it is carried out at a temperature in the range of- 10 to 1000 C, -10 to 100 C, more preferably in the range of from 10 to 70°C, even more preferably in the range of from 20 to 50°C.

Regarding hydrogenation of (a-i), is carried out in an organic solvent, more preferably the organic solvent is selected from the group consisting tetrahydrofuran (THF), methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile , ethyl acetate, isopropyl acetate and mixtures of two or more thereof, more preferably in tetrahydrofuran, ethyl acetate, methanol, ethanol, acetic acid and mixtures of two or more thereof, even more preferably in a solvent selected from the group consisting of tetrahydrofuran (THF), methyltetrahydrofuran, methyltertbutyleter, dichlormethane Regarding (a-i) it is preferred that R ^la or R ^lb is PG ^la and R ^2a is H, and PG ^la is a suitable protecting group. It is preferred that PG ^la is Boc or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consistin of phthalimido group of formula (p)

and succinimido group of formula (s)

Step (a-ii)

As disclosed above in step (a-ii) compound of formula (Ila') is purified. Any purification method such as crystallization and distillation method is suitable for the purification of compound of formula (IF a). It is preferred that the obtained compound (Ila') is purified via distillation.

Steps in common to the two processes

Step (a4)

In step (a3) of the first process and in step (a-i) or (a-ii) of the second process compound (Ila') is obtained. Compound (Ila') obtained according to (a3) of the first ethylediamine process or according to (a-i) (a-ii) can be further reacted to compound (II) according to step (a4).

It is to be understood that R ^la of compound (Ila') may be different from R ¹ or may be the same. Similarly, R ^2a in compound (Ila') may be different from R ² or may be the same. In case R ¹ differs from R ^la or in case R ² differs from R ^2a or in case both R ^la and R ^2a differ from R ^la and R ^2a , respectively, step (a4) is carried out. In case R ¹ is equal to R ^la and R ² is equal to R ^2a , step (a4) is omitted.

It is thus to be understood that compound (Ila') or (Ila) may correspond to compound (II), compound (Ila'*) or (Ila*) may correspond to (II*) and compound (Ila'**) or (Ila**) may correspond to (II**) in case R ^la is equal to R ¹ and in case R ² is equal to R ^2a .

In case R ^la is different from R ¹ and/or R ^2a is different from R ² , R ^la and/or R ^2a is transformed in step (a4) to R ¹ and R ² , wherein this transformation may be carried out in one or in multiple steps, to give compound (II) or (II*), respectively. It is to be understood that in case (II) corresponds to (Ha') or (Ila) or, (II*) corresponds to (Ila'**) or (Ila'**), step (a4) is omitted.

As mentioned above in formula (Ila') obtained in the ethylenamine based process or in the homoalanine based process of the invention step (a4) comprises

(a4) replacing R ^2a with R ² and/or R ^la with R ¹ , preferably being R ^lb =H, or

replacing R ^2a with R ² and/or R ^lb with R ¹ , preferably being R ^la =H, or

replacing R ^2a with R ² and/or when R ^la and R ^lb are taken together to form a cyclic imide group optionally replacing the cyclic imide group wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group of formula (p) oe a succinimido group of formula (s) with R ¹ and H

to give the compound of formula (II).

As mentioned above the ethylenediamine based process when a compound of formula (Ila) is obtained step (a4) comprises.

(a4) ) replacing R ^2a and/or R ^la with R ¹ and/or R ² ,

to give the compound of formula (II).

As mentioned above, R ^la may be different from R ¹ and/or R ^2a may be different from R ² . articular, the following embodiments are mentioned by way of example:

In the above mentioned table PG is preferably Boc and PG is preferably Cbz

In step (a4) protecting groups are removed or attached to the molecule. Methods for attaching and removing of a protecting group are known to those skilled in the art and depend on the respective protecting group employed. Representative protecting groups for amino groups are well known to those skilled in the art and methods for attaching them to amino groups as well as removing them are described, for example, in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, N.Y., 1999, and references cited therein. In case, the protecting group is a Boc group, the removal is preferably carried out under acidic conditions. More preferably, the removal is carried out with HC1 or TFA. The removal of such protecting groups may be carried out in any suitable solvent known to those skilled in the art. Preferably, the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof. Preferably, the removal is carried out at a temperature in the range of from 0 to 40 °C, more preferably in the range of from 10 to 30°C, more preferably at room temperature. During the reaction, the temperature may be varied or held essentially constant.

In case, the protecting group is a Cbz group, the removal is preferably carried out under reductive conditions. More preferably, the removal is carried out with hydrogen and a metal catalyst, preferably a palladium catalyst, more preferably the protecting group is removed with Pd/C. The removal of such a protecting group may be carried out in any suitable solvent known to those skilled in the art. Preferably, the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof, and mixtures of two or more thereof. Preferably, the removal is carried out at a temperature in the range of from 0 to 60 °C, more preferably in the range of from 10 to 50 °C, more preferably at room temperature. During the reaction, the temperature may be varied or held essentially constant. In case hydrogen is used, the reaction is preferably carried out at a pressure in the range of from 1 to 3 bar, more preferably, 1.5 to 2.5 bar.

In case in step (a4) the respective compound is reacted, i.e. coupled, with a compound of formula (XI), wherein E is -COOH or a reactive carboxy group, the coupling is preferably carried out in the presence of a suitable base, preferably an organic base, most preferably an amino group comprising base, most preferably a base selected from the group consisting of diisopropylamine (DIEA), triethylamine (TEA), N-methylmorpholine, N-methyl- imidazole, l,4-diazabicyclo[2.2.2]octane (DABCO), N-methylpiperidine, N- methylpyrrolidine, 2,6-lutidine, collidine, pyridine, 4-dimethylaminopyridine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU). As regards the reaction conditions used in this coupling step, preferably, the reaction is carried out in an organic solvent, such as N- methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile, acetone, dimethyl acetamide (DMA), dimethyl formamide (DMF), formamide, tetrahydrofuran (THF), 1,4- dioxane, diethyl ether, tert.-butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, tetrachloromethane and mixtures of two or more thereof. More preferably, the reaction is carried out in dichloromethane.

The temperature of the coupling reaction is preferably in the range of from 0 to 100 °C, more preferably in the range of from 5 to 50 °C, and especially preferably in the range of from 15 to 30 ^o0 C. During the course of the reaction, the temperature may be varied, preferably in the above given ranges, or held essentially constant.

With respect to preferred groups E, reference is made to the respective details given above

In case R ¹ differs from R ^la or in case R ² differs from R ^2a or m case both R ^la and R ^2a differ from R ^la and R ^2a , respectively, step (a4) is carried out. Depending on the respective groups to be replaced, step (a4) comprises one or multiple steps, such a deprotection step and/or a protection step and/or a coupling step with a com ound of formula

and/or a coupling step with a com ound of formula

to give the compound of formula (II)

Chiral resolution of compound of formula (Ha*) or (Ha)

Steps (al) to (a3), (al) to (a4), (a-i) to (a-ii), (a-i) to (a4) are indicated below in general as step (a) unless otherwise specified.

In an embodiment in case a compound having the structure (IIa'*)/(IIa*) is provided as single (isolated) isomer, as mentioned above, the process preferably comprises

a chiral resolution of the compound of formula (IIa')/(IIa) to give the compound of formula (IIa'*)/(IIa*),

a chiral resolution of the compound of formula (II) to give the compound of formula (II*), and/or

an enantio selective reduction in step (a3) of the first process as disclosed above to give the compound of formula (Ila' *)/(IIa*) or (II*), respectively. In case in step (a), a compound having the structure (II*) is provided as single (isolated) isomer, as mentioned above, step (a) preferably comprises

a chiral resolution of the compound of formula (IIa')/(IIa) to give the compound of formula (IIa*)/(IIa'*),

a chiral resolution of the compound of formula (II) to give the compound of formula (II*), and/or

an enantio selective reduction in step (a3) of the first process as disclosed above to give the compound of formula (IIa'*)/(IIa*) or (II*), respectively.

Chiral resolution of the compound of formula (II)

As mentioned above, compound (II) may comprise a mixture of compounds (II*) and (II**)

In this case, a chiral resolution of (II) may be carried out. More preferably, in case a chiral resolution is carried out at this stage, R ² is H, and R ¹ is Boc. R ^E is preferably methyl.

Preferably, the compound (II) contains of from 20 to 75 % by weight of the compound of formula (II*) based on the total weight of the sum of (II*) and (II**). This mixture is then resolved by chiral resolution to finally give, optionally after further steps, the compound

(II*).

Preferably, this is carried out by

(i) adding a single stereoisomer of a chiral acid and precipitating, preferably crystallizing, a chiral acid salt (S) of compound (II), thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (S) and the solvent,

(ii) preferably separating the precipitated, preferably crystallized, chiral acid salt (S) of the compound of formula (II) from the mixture obtained in (i), wherein the chiral acid salt (S) contains at least 80 % by weight of the chiral acid salt of the compound of formula (II*) based on the total weight of the chiral acid salt of the compound of formula (II),

(iii) converting the chiral acid salt (S) to the free base.

Preferably, in step (i), upon addition of the chiral acid in a suitable solvent, a chiral acid salt (S*) of at least part of the compound of formula (II) is formed and at least part of this chiral acid salt (S*) formed is precipitated, preferably crystallized, thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (S) and the solvent.

The chiral acid is preferably tartaric acid or a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, more preferably, the chiral acid is tartaric .

Step ( i)

The compound of formula (II) employed in (i) contains of from 20 to 75 % by weight, more preferably of from 40 to 60 % by weight, of the compound of formula (II*) based on the total weight of the sum of (II*) and (II**).

In step (i), at least part of the compound of formula (II) is transformed into the corresponding chiral acid salt, preferably tartaric acid salt (S*). The chiral acid salt (S*) contains the chiral acid salt of the compound of formula (II*), e.g. in an amount in the range of from 1 to 80 % by weight, such as in the range of from 10 to 70 % by weight, or in the range of from 30 to 60 % by weigh, or in the range of from 45 to 55 % by weight, based on the total amount of the chiral acid salt (S*).

Subsequently, at least part of (S*) is precipitated, preferably crystallized. This is preferably achieved by contacting (treating) the compound of formula (II) in a suitable solvent with the chiral acid. Thereby, a mixture comprising the crystallized chiral acid salt (S) of the compound of formula (II*) and the solvent is formed. As mentioned above, the precipitated, preferably crystallized, tartaric acid salt (S) of the compound of formula (II) contains at least 80 % by weight of chiral acid salt of the compound of formula (II*) based on the total weight of the chiral acid salt of the compound of formula (II).

It is to be noted that the mixture obtained in step (i) may comprise further compounds, in particular non crystalline forms of the compound of formula (II) and salts thereof. Preferably, the mixture obtained in (i) comprises non-crystalline forms of the compound of formula (II**) and chiral acids salts thereof.

The chiral acid salt (S*) of the compound of formula (II) is denoted to encompass all chiral acid salts of compound (II) formed in step (i) including the chiral acid salt (S) which precipitates as well as all chiral acid salts formed which remain dissolved (S*-S). Thus, the chiral acid salt (S) may comprise a mixture of chiral acid salt of compounds of formula (II*) and (II**).

As to the solvent used in step (i), any suitable organic solvent in which the compound of formula (II) is sufficiently soluble may be used. In particular, the solvent is selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH2C12, ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, isopropyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketon, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof. More preferably, the solvent comprises methylisobutylketon, preferably is methylisobutylketon.

It is to be understood that in step (i) a further solvent may be added in order to precipitate, preferably crystallize, the chiral acid salt (S). In this case, the mixture obtained in (i) preferably additionally comprises the further solvent.

This further solvent may be added prior to, together with or after the addition of the chiral acid to the compound of formula (II). According to a preferred embodiment, the compound of formula (II) is dissolved in the suitable solvent mentioned above and a mixture, preferably a solution of the chiral acid, in a further solvent is added to the solution, wherein the further solvent and the suitable solvent may be the same or may be different.

In particular, the further solvent is selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH ₂ CI ₂ , ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, isopropyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketone, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof. . More preferably, the suitable solvent and the further solvent are the same, in particular, they both comprise methylisobutylketone, , preferably both are methylisobutylketone.

Thus, the present invention also relates to a process for the preparation of a chiral acid salt (S) of a compound of formula (II), as described above, and a chiral acid salt (S) of compound of formula (II), obtained or obtainable by said process, wherein step (i) comprises dissolving the compound of formula (II) in the suitable solvent and adding a solution of the chiral acid dissolved in a further solvent to the solution, wherein the further solvent and the suitable solvent are preferably the same, more preferably methylisobutylketone .

Preferably, the compound of formula (II) is dissolved in the suitable solvent and the mixture is heated to a temperature in the range of from 30 to 80 °C, more preferably to a temperature in the range of from 30 to 60 °C, more preferably to a temperature in the range of from 30 to 50 °C, more preferably to a temperature in the range of from 30 to 40 °C, prior to the addition of the tartaric acid. During the heating step, the temperature may be varied, constantly or stepwise, or held essentially constant. Preferably, the mixture is heated until a clear solution of the compound of formula (II) in the suitable solvent is obtained. Optionally, the mixture is afterwards cooled to room temperature.

The precipitation, preferably the crystallizing, in step (i) is preferably carried out at a temperature in the range of from 0 to 60 °C, wherein the temperature is preferably continuously or stepwise decreased during step (i). The chiral acid may thus e.g. be added to a solution of the compound of formula (II) in the suitable solvent which has been previously heated or which has been previously heated and afterwards cooled to a specific temperature or which has not been previously heated.

After the addition of the chiral acid, and optionally the further solvent, the mixture may again be heated or alternatively be cooled or the temperature may be held constant. Preferably, the mixture is cooled to a temperature in the range of from 0 to 50 °C, more preferably to a temperature in the range of from 0 to 40 °C, more preferably to a temperature in the range of from 10 to 30 °C.

Preferably, the mixture obtained in step (i) consists of the chiral acid salt (S), optionally the unreacted chiral acid, optionally the unreacted compound of formula (II), precipitated chiral acid salts (salt (S*) minus the amount of precipitated chiral acid salt (S)), the suitable solvent and optionally the further suitable solvent.

Step ( ii)

In the optional step (ii) of the process of the invention, the chiral acid salt (S) is separated from the mixture obtained in step (i).

The separation may be carried out by any suitable method known to those skilled in the art. Preferably, the separating in step (ii) is carried out by centrifugation or filtration, preferably filtration.

It is to be understood that the separated salt may be subjected to a further treatment such as an after-treatment such as a purification step and/or lyophilization.

Preferably, the obtained chiral acid salt (S) of the compound formula (II) contains at least 90 % by weight, more preferably at least 95 % by weight, more preferably at least 96 % by weight, more preferably at least 97 % by weight, more preferably at least 98 % by weight, more preferably at least 99 % by weight, of the tartaric salt of the compound of formula (II*), based on the total weight of chiral acid salt of the compound of formula (II), i.e. based on the sum of (II**) and (II*). More preferably, the chiral acid salt (S) of the compound of formula (II) is the isolated chiral acid salt of the compound of formula (II*).

The term "isolated chiral acid salt of the compound of formula (II*)" in this context is denoted to mean that the salt of the compound of formula (II*) comprises less than 1 % by weight of the salt of compound (II**), preferably less than 0.5 % by weight, more preferably less than 0.1 % by weight, more preferably less than 0.05 % by weight, more preferably less than 0.01 % by weight, more preferably essentially no, more preferably no compound of formula (II**) based on the total weight of the salts of (II*) and (II**).

Chiral resolution of the compound of formula (ΙΙα'*) or (Ha*) Alternatively, in case (II) differs from (IIa')/(IIa), also a chiral resolution of compound (IIa')/(IIa) may be carried out. As mentioned above, compound (II) may comprise a mixture of compounds Ila'*) and (IIa'**)/(IIa*) and (Ila**)

In this case, a chiral resolution of (IIa')/(IIa) may be carried out. More preferably, in case a chiral resolution is carried out at this stage, R ^2a is H, and R ^la is Boc and R ^lb is H. R ^E is preferably methyl.

Preferably, the compound (IIa')/(IIa), contains of from 20 to 75 % by weight % of the compound of formula (IIa'*)/(IIa*) based on the total weight of the sum of (Ila'*) and (IIa'**)/(IIa*) and (Ila**). This mixture is then resolved by chiral resolution to finally give, optionally after further steps, the compound (IF*).

Preferably, this is carried out by

(ia) adding a single stereoisomer of a chiral acid and precipitating, preferably crystallizing, a chiral acid salt (Sa) of compound (II'a)/(IIa), thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (Sa) and the solvent,

(iia) preferably separating the precipitated, preferably crystallized, chiral acid salt (Sa) of the compound of formula (Ila) from the mixture

obtained in (ia), wherein the chiral acid salt (S) contains at least 80 % by weight of the chiral acid salt of the compound of formula (IIa'*)/(IIaA) based on the total weight of the chiral acid salt of the compound of formula (II'a)/(IIa),

(iiia) converting the chiral acid salt (Sa) to the free base.

Preferably, in step (ia), upon addition of the chiral acid in a suitable solvent, a chiral acid salt (Sa'*) of at least part of the compound of formula (IIa')/(IIa) is formed, and at least part of this chiral acid salt (Sa'*) formed is precipitated, preferably crystallized, thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (S) and the solvent.

The chiral acid is preferably tartaric acid or a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, more preferably, the chiral acid is tartaric.

Step (ia)

The compound of formula (IIa')/(IIa) employed in (ia) contains of from 20 to 75 % by weight, more preferably of from 40 to 60 % by weight, of the compound of formula (Ila'*) based on the total weight of the sum of (Ila'*) and (IIa'**)/(IIa*) and (Ila**).

In step (ia), at least part of the compound of formula (IIa')/(IIa) is transformed into the corresponding chiral acid salt, preferably tartaric acid salt (Sa'*). The chiral acid salt (Sa'*) contains the chiral acid salt of the compound of formula (Ila'*), e.g. in an amount in the range of from 1 to 80 % by weight, such as in the range of from 10 to 70 % by weight, or in the range of from 30 to 60 % by weight, or in the range of from 45 to 55 % by weight, based on the total amount of the chiral acid salt (Sa'*).

Subsequently, at least part of (Sa'*) is precipitated, preferably crystallized. This is preferably achieved, by contacting (treating) the compound of formula (II) in a suitable solvent with the chiral acid. Thereby a mixture comprising the crystallized chiral acid salt (Sa') of the compound of formula (IIa'*)/(IIa*) and the solvent is formed. As mentioned above, the precipitated, preferably crystallized, tartaric acid salt (Sa') of the compound of formula (IIa')/(IIa) contains at least 80 % by weight of chiral acid salt of the compound of formula (IIa'*)/(IIa*) based on the total weight of the chiral acid salt of the compound of formula (IIa')/(IIa).

It is to be noted that the mixture obtained in step (ia) may comprise further compounds, in particular non-crystalline forms of the compound of formula (II) and salts thereof. Preferably, the mixture obtained in (ia) comprises non crystalline forms of the compound of formula (IIa**)/(IIa**)and chiral acid salts thereof.

The chiral acid salt (Sa*) of the compound of formula (Ila) is denoted to encompass all chiral acid salts of compound (Ila) formed in step (ia) including the chiral acid salt (Sa) which precipitates as well as all chiral acid salts formed which remain dissolved (Sa*-Sa). Thus, the chiral acid salt (Sa) may comprise a mixture of chiral acid salt of compounds of formula (Ila'*) and (IIa'**)/(IIa*) and (Ila**).

As to the solvent used in step (ia), any suitable organic solvent in which the compound of formula (Ila) is sufficiently soluble may be used. In particular, the solvent is selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH ₂ CI ₂ , ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, isopropyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketon, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof. More preferably, the suitable solvent comprises methylisobutylketon, preferably is methylisobutylketon.

It is to be understood that in step (ia) a further solvent may be added in order to precipitate, preferably crystallize, the chiral acid salt (Sa'). In this case, the mixture obtained in step (i) preferably additionally comprises the further solvent.

This further solvent may be added prior to, together with or after the addition of the chiral acid to the compound of formula (IIa')(IIa). According to a preferred embodiment, the compound of formula (IIa')/(IIa) is dissolved in the suitable solvent mentioned above and a mixture, preferably a solution of the chiral acid, in a further solvent is added to the solution, wherein the further solvent and the suitable solvent may be the same or may be different.

In particular, the further solvent is selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH ₂ CI ₂ , ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, isopropyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketone, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof. .More preferably, the further solvent comprises methylisobutylketone, preferably is methylisobutylketone.

More preferably, the suitable solvent and the further solvent are the same, in particular, they both comprise methylisobutylketone, preferably they are both methylisobutylketone.

Thus, the present invention also relates to a process for the preparation of a chiral acid salt (Sa') of a compound of formula (IIa')/(IIa), as described above, and a chiral acid salt (Sa') of a compound of formula (IIa')/(IIa), obtained or obtainable by said process, wherein step (ia) comprises dissolving the compound of formula (IIa')/(IIa) in the suitable solvent and adding a solution of the chiral acid dissolved in a further solvent to the solution, wherein the further solvent and the suitable solvent are preferably the same, more preferably methylisobutylketone .

Preferably, the compound of formula (IIa')/(IIa) is dissolved in the suitable solvent and the mixture is heated to a temperature in the range of from 30 to 80 °C, more preferably to a temperature in the range of from 30 to 60 °C, more preferably to a temperature in the range of from 30 to 50 °C, more preferably to a temperature in the range of from 30 to 40 °C, prior to the addition of the tartaric acid. During the heating step, the temperature may be varied, constantly or stepwise, or be held essentially constant. Preferably, the mixture is heated until a clear solution of the compound of formula (IIa')/(IIa) in the suitable solvent is obtained. Optionally, the mixture is afterwards cooled to room temperature. The precipitation, preferably the crystallizing, in (ia) is preferably carried out at a temperature in the range of from 0 to 60 °C, wherein the temperature is preferably continuously or stepwise decreased during step (ia). The chiral acid may thus e.g. be added to a solution of the compound of formula (IIa')/(IIa) in the suitable solvent, which has been previously heated or which has been previously heated and afterwards cooled to a specific temperature or which has not been previously heated.

After the addition of the chiral acid, and optionally the further solvent, the mixture may again be heated or alternatively be cooled or the temperature may be held constant. Preferably, the mixture is cooled to a temperature in the range of from 0 to 80°C, more preferably to a temperature in the range of from 10 to 50 C, more preferably to a temperature in the range of from 15 to 35 C.

Preferably, the mixture obtained in (ia) consists of the chiral acid salt (S), optionally unreacted chiral acid, optionally unreacted compound of formula (II), precipitated chiral acid salts (salt (Sa'*) minus the amount of precipitated chiral acid salt (Sa)), the suitable solvent and optionally the further suitable solvent.

Step (iia)

In the optional step (iia) of the process of the invention, the chiral acid salt (Sa) is separated from the mixture obtained in (ia).

The separation may be carried out by any suitable method known to those skilled in the art. Preferably, the separating in step (iia) is carried out by centrifugation or filtration, preferably filtration.

It is to be understood that the separated salt may be subjected to a further treatment such as an after-treatment like a purification step and/or lyophilization.

Preferably, the obtained chiral acid salt (Sa') of the compound of formula (IIa')/(IIa) contains at least 90 % by weight, more preferably at least 95 % by weight, more preferably at least 96 % by weight, more preferably at least 97 % by weight, more preferably at least 98 % by weight, more preferably at least 99 % by weight, of the tartaric salt of the compound of formula (IIa'*)/(IIa*) based on the total weight of chiral acid salt of the compound of formula (II), i.e. based on the sum of (Iia'*) and (IIa'**)/(IIa*) and (Iia**). More preferably, the chiral acid salt (S) of the compound of formula (IIa')/(IIa) is the isolated chiral acid salt of the compound of formula (IIa'*)/(IIa*).

The term "isolated chiral acid salt of the compound of formula (Iia'*)" in this context is denoted to mean that the salt of the compound of formula (Iia'*) comprises less than 1 % by weight of the salt of compound (Iia'**), preferably less than 0.5 % by weight, more preferably less than 0.1 % by weight, more preferably less than 0.05 % by weight, more preferably less than 0.01 % by weight, more preferably essentially no, more preferably no compound of formula (Ila'**) based on the total weight of the salts of (Ila'*) and (Ila'**).

Compounds (II) and (Ila) as discloses above are useful intermediates in a process for the preparation of compounds of formula (A) and (Aa) and compound (IX) as disclosed below. The provision of compound of formulae (II) or (Ila') or (Ila) according to the present invention as disclosed above it is indicated in the context of the present invention as "(a) provision of a compound of formula (II)" or providing a compound of formula (II) or similar expression.

As it is explained above, in some instances, compound (II) has the same structure of compound (Ila') or (Ila).

Processes for preparing compounds of formula (A)

The processes according to the present invention may further comprise

(b) reacting the compound of formulae (II) or (Ila') or (Ila) with a base obtaining a compound of formula A) or (Aa).

preferably

wherein R ¹ , R ² , R ^la and R ^2a are as defined above.

In an embodiment (b) comprises

(bl) reacting the compound of formula (II) or (Ila') or (Ila) with a base and obtaining composition com rising a compound of formula (A), preferably (A*) wherein n=l

(b2) optionally purifying the compound obtained in (bl), (b3) optionally reducing the compound of (bl) or (b2) and obtaining a compound of formula (A), preferably of formula (A*) wherein n=0.

It is preferred that the com ound (A*) is a compound of formula

It is further preferred that that the compounds (A) or (Aa) or (A*) or (Aa*) which have not formula (IX) are further reacted to a com ound of formula

The processes for preparing compounds of formula (A) are disclosed below in details.

The process for the preparation of a com ound of formula (A)

or a pharmaceutically acceptable salt or solvate thereof, wherein (A) is preferably (A*)

and wherein R ¹ is selected from the group consisting of H, PG ¹ and R ^A with R ^A being

and wherein R ² is selected from the group consisting of H, PG ² and R ^B with R ^B being

and wherein PG ¹ and PG ² are, independently of each other, suitable protecting groups, and wherein n is 0 or 1 , comprises

(a) providing a compound of formula II)

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

(b) reacting the compound of formula (II) with a base and optionally reducing the

compound

to give the compound of formula (A), preferably (A*).

The providing a compound of formula (II) according to (a) is preferably carried out according to the ethyldiamine process or homoalanine process of the invention.

The compound A

As described above, the compound of formula A) has the structure

wherein n is 1 or 0. Thus the com ound (A) has, e.g., the structure (la) or (lb)

Residue R :

R is as disclosed above. Thus, the compound of formula (A) has, e.g., a structure selected from the group consisting of

i.e. a structure selected from the roup consisting of

Most preferably R ¹ is H.

Residue R :

R ² is as described above. Thus, the compound of formula (A) has, e.g., a structure selected from the group consisting of

i.e. a structure selected from the roup consisting of

It is to be understood that in case R ¹ and R ² are both protecting groups, PG ¹ and PG ² preferably differ from each other. In this case, R ¹ and R ₂ are preferably orthogonal protecting groups.

The term "orthogonal protecting group" refers to a protecting group that is chemically resistant under one set of selected conditions, but is liable under another set of conditions, i.e. under certain conditions either PG ¹ is cleaved and PG ² is not, or vice versa. In such case, PG ¹ is preferably Boc and PG ² is preferably Cbz.

A bond shown as "·~ " in any one of the compounds shown above and below is denoted to represent a single bond, wherein the resulting structure including the bond encompasses the single (isolated) S isomer or the single (isolated) R isomer as well as mixtures of the S and R isomer.

Preferably, compound A e.g. has as structure selected from the structure shown in the table low:

Thus, the present invention also relates to a method for the preparation of a compound (A), as described above, and a compound obtained or obtainable by said process, wherein the compound has a structure selected from any one of the structures 1 to 24 shown above. In particular, the present compounds of formula (II) or (Ila) are useful in the preparation of a compound of formula (A), preferably (IX) shown above (which corresponds to structure 21 shown above), the compound being obtained or obtainable by the above described process, wherein said compound comprises less than 5 % by weight, more preferably less than 2 % by weight, more preferably less than 1 % by weight, more preferably less than 100 ppm, of the regio-isomeric side roduct (IX-S) as impurity

based on the total weight of the compound (IX), which includes the compound (IX-S). Preferably, the compound (IX) does not comprise the region-isomeric compound (IX-S) as impurity.

Step (b)

In step (b), the compound of formula II)

is reacted with a base, and optionally subsequently reduced, to give, optionally after further steps, the compound (A). Upon reaction with the base, the 7-membered ring of compound (A) is formed ("cyclization reaction").

The reaction may be carried out in any suitable solvent known to those skilled in the art. Preferably, the cyclization reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of R ^E -OH, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof, with R ^E being as described above and below, preferably wherein R ^E is selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl. Preferably the solvent has the structure R ^E -OH, with R ^E being as described above and below, preferably wherein R ^E is selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E alkyl, more preferably wherein R ^E methyl, ethyl or propyl, more preferably wherein R ^E methyl. Preferably, the cyclization is carried out at a temperature in the range of from -20 to 80°C, more preferably in the range of from 0 to 50, more preferably in the range of from 20 to 30 °C. During the reaction, the temperature may be varied or held essentially constant.

Preferably, as base, a base selected from the group consisting of NaOR ^E , Na-tert.butoxid, K-tert.butoxid, NaNH ₂ , DBU, Tetramethylguanidin, Na-CH ₂ S(0)CH ₃ and mixtures of two or more thereof is employed, with R ^E being selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E alkyl, more preferably wherein R ^E methyl, ethyl or propyl, more preferably wherein R ^E methyl. Most preferably, the base is sodium methanolate.

The weight ratio of base to compound of formula (II) is preferably in the range of from 0 to 8, more preferably in the range of from 1 to 5.

Generally, when providing the reaction mixture to be reacted in (b), the sequence of mixing the components of the reaction mixture is not subject to specific restrictions. Preferably, the compound of formula (II) is first admixed with at least a portion of a suitable solvent and, to the resulting mixture, the base is added which, for example, can be employed as mixture with at least a portion of the solvent or as such.

Compound (II) is preferably allowed to react with the base for a time in the range of from 0 to 24 h, more preferably in the range of from 0 to 5 h, more preferably in the range of from

0 to 3 h.

In case compound (A) has the structure (la) (which means that n in compound (A) is 1), in step (b) the compound of formula (II) is reacted with a base to give, optionally after further steps, the compound (A). In this case, no additionally reduction step is necessary. Directly upon reaction with the base, the 7-membered ring of compound (A) is formed ("cyclization reaction").

In case compound (A) has the structure (lb) (which means that n in compound (A) is 0), in step (b) the compound of formula (II) is reacted with a base to give, as intermediate product, the compound of formula (la), which is thereafter reduced to give, optionally after further steps, the compound (A). In this case, a reduction of the carbonyl group is thus carried out.

Thus, the present invention also relates to a process, as described above, as well as to a compound obtained or obtainable by said process, wherein the compound of formula (A) has the structure of formula (lb), and wherein in step (b), upon reaction with the base, a compound of formula (la) is formed

and wherein step (b) further comprises reducing the compound of formula (Ia). It is to be understood that in this case compound (la) may be isolated or may be directly reduced in situ to give the compound of formula (lb). If such isolation is carried out, this may be carried out by any method known to those skilled in the art. Such isolation may comprise one or more stages wherein preferably at least one stage comprises a purification, such as an extraction and/or a precipitation and/or filtration.

Preferably, step (b) comprises

(bl) reacting the compound of formula (II) with a base to give a composition comprising a compound of formula (la)

(b2) optionally purifying the composition obtained in (bl),

(b3) optionally reducing the compound of formula (Ia) to give a compound of

formula (lb)

As mentioned above with respect to step (b), also step (bl) is preferably carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof. Preferably the solvent has the structure R ^E -OH is employed, with R ^E being as described above and below, preferably wherein R ^E is selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl.

Preferably, step (bl) is carried out at a temperature in the range of from -20 to 80 °C, more preferably in the range of from 0 to 50, more preferably in the range of from 20 to 30 °C. During the reaction, the temperature may be varied or held essentially constant.

As to step (b3), step (b3) is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, nPrOH (n-propanol), i-PrOH (isopropanol), THF (tetrahydrofuran), 2-MeTHF (2-methyl- tetrahydrofuran), MTBE (Methyl-tert-butylether), DIPET (diisiopropylethylether) , toluene, acetonitrile, CH ₂ CI ₂ and mixtures of two or more thereof.

Preferably, step (b3) is carried out at a temperature in the range of from -20 °C to 110 °C. Preferably, in step (b3), the compound is reduced by reaction with a reducing agent selected from the group consisting of NaBH ₄ , NaCNBH ₃ , NaBH(OAc) ₃ , LiAlH ₄ , LiBH ₄ and H ₂ in the presence of transition metals, wherein the transition metal is preferably selected from the group consisting of IR, Pt, Fe, Rh, Pd, Re, Ru, Ni and Co. More preferably, the reducing agent is selected from the group consisting of NaBH ₄ , NaCNBH ₃ , NaBH(OAc) ₃ , LiAlH ₄ and LiBH ₄ , more preferably the reducing agent is NaBH ₄ , NaCNBH ₃ or NaBH(OAc) _3, more preferably NaBH ₄ .

Preferably, the compound (A) has the structure (la*) or (lb*)

Thus, in step (b), preferably compound (la*) or (lb*) is prepared. Thus, preferably, in step (b) of the process of the invention, the com ound of formula (II)

is reacted with a base and optionally subsequently reduced to give, optionally after further steps, the compound (A), with (A) being (la*) or (lb*). Upon reaction with the base, the 7-membered ring of compound (A) is formed ("cyclization reaction").

It is to be understood that since compound (II) comprises the single bond shown as "·~>~ ", i.e. that compound (II) has either the structure

or consists of a mixture of

R ^E 0 ^' (II*) and R ^fc O ^' (Π**)

as mentioned above.

In case compound (A) has the structure (A*), such as (la*) or (lb*), preferably in step (a) compound (II) is provided in the correct stereochemistry, i.e. as compound (II*)

This compound is then employed in step (b) instead of the racemic mixture consisting of (II*) and (II**) shown above.

According to an alternative preferred embodiment, in case compound (II) consists of a racemic mixture, in step (b), in the cyclization reaction of compound (II), a compound (A) consisting of a racemic mixture is obtained. Preferably, in this case, a chiral resolution of (A) us carried out. More preferabl , in this case, R ² is H, and compound (A) is (Al),

which consists of a racemic mixture of the com ounds (Al *) and (Al **) is obtained,

wherein the compound (Al) contains from 20 to 75 % by weight-% of the compound of formula (Al *) based on the total weight of the sum of (Al *) and (Al **), and wherein this mixture is then resolved by chiral resolution to finally give, optionally after further steps, the compound (A) in which R ² is H.

Preferably, this is carried out, after (b) by

(I) adding a single stereoisomer of a chiral acid and precipitating, preferably crystallizing, a chiral acid salt (T) of compound (Al), thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (T) and the solvent,

(II) preferably separating the precipitated, preferably crystallized, chiral acid salt (T) of the compound of formula (Al) from the mixture obtained in (I), wherein the chiral acid salt (T) contains at least 80 % by weight of the chiral acid salt of the compound of formula (Al *) based on the total weight of the chiral acid salt of the compound of formula (Al),

(III) converting the chiral acid salt (T) to the free base. Preferably, in step (I), upon addition of the chiral acid in a suitable solvent, a chiral acid salt (T*) of at least part of the compound of formula (II) is formed, and at least part of this chiral acid salt (T*) formed is precipitated, preferably crystallized, thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (T) and the solvent.

The chiral acid is preferably a single stereoisomer of a tartaric acid derivative, more preferably of a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof.

Preferably, the chiral acid is a di-benzoyl tartaric acid or a di-toluoyl tartaric acid.

For example, Al is (la),

and consists of a mixture of (la*) and (la**)

wherein R ² = H. In this case, the chiral acid is preferably or a di-toluoyl tartaric acid, more preferably L-di-toluoyl tartaric acid (LTTA). Most preferably R ² = H and R ¹ = H and the chiral acid is L-di-toluoyl tartaric acid. In this case, the suitable solvent is preferably methanol.

For example, Al is (lb , with R ² = H, and consists of a mixture of (lb*) and (lb**)

wherein R2 = H. In this case, the chiral acid is preferably a di-benzoyl tartaric acid, more preferably D-di-benzoyl tartaric acid (DBTA). Most preferably R ² = H and R ¹ = Cbz and the chiral acid is D-di-benzoyl tartaric acid. In this case, the suitable solvent is preferably acetone.

As mentioned above, the compound (A) is preferably being used for the preparation of the compound of formula (IX) (Suvorexant) with a process comprising

(A) preparing a compound of formula (A) as described hereinunder and above, wherein in case n = 0, at least one of R ^A or R ^B is H or a protecting group,

(B) transforming the compound (A) into the compound of formula (IX). Hence, the present invention relates to a process for the preparation of a compound of formula (IX) , wherein a compound of formula

or being a pharmaceutically acceptable salt or solvate thereof, wherein (la) is preferably (la*)

and wherein R ¹ is H and R ² is PG ² is used as intermediate, the process comprising

(a) providing a compound of formula (II),

preferably of formula (II*),

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

(b) reacting the compound of formula (II), preferably of formula (II*), with a base, to give the compound of formula (la), with R ¹ being H and with R ² being PG ² , preferably (la*) with R ¹ being H and with R ² being PG ² .

In step (a) compound (II) is provided according to the processes according to the present invention as disclosed above.

Preferably, compound (la), with R ¹ being H and with R ² being PG ² , thus compound

more preferably compound (la*) with R ¹ being H and with R ² being PG ² , thus compound

is used for the preparation of Suvorexant. Thus, the present invention also relates to the use ooff tthhee ccoommppoouunndd ooff ffoorrmmuullia (la), preferably (la*), in which R ¹ is H and R ² is PG ² , for the preparation of Suvorexant.

Further, the present invention relates to a process for the preparation of a compound of formula (IX) and a compound of formula (IX) obtained or obtainable by said process comprising

(A) providing a compound of formula (la) by a process comprising

(a) providing a compound of formula II)

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl, and wherein R ¹ is H and R ² is PG ² ,

(b) reacting the compound of formula (II) with a base,

to give the compound of formula (la), with R ¹ being H and with R ² being PG ² , preferably (la*) with R ¹ being H and with R ² being PG ² ,

(B) transforming the compound of step (A) into the compound of formula (IX), wherein preferably compound (II) I (a) is provided by processes according to the present invention as disclosed above

Preferably, step (B) comprises

(cl) removal of the protecting group PG ² ,

(dl) reacting the compound of formula (la) with R ¹ and R ² being H with a compound of formula (XI)

wherein E is -COOH or a reactive carboxy group, to give a compound of formula (Vila) in which R ¹ is H,

(Vila),

preferably

O (Vila*)

(el) reducing the compound, to ive a compound of formula (Vllb) in which R ¹ is H

(Vllb),

preferably

(Vllb*),

preferably with a reducing agent selected from the group consisting of NaBH , NaCNBH ₃ , NaBH(OAc) ₃ , L1AIH ₄ , L1BH ₄ and ¾ in the presence of transition metals, wherein the transition metal is preferably selected from the group consisting of Ir, Pt, Fe, Rh, Pd, Re, Ru, Ni and Co,

(fl) reacting the compound of formula (Vllb), preferably (Vllb*) with a compound of formula (XII)

wherein X* is a leaving group, preferably CI.

The present invention further relates to a compound obtained or obtainable by said process (this includes a salt thereof).

The present invention relates to a process for the preparation of a compound of formula (IX) , wherein a compound of formula

or being a pharmaceutically acceptable salt or solvate thereof, wherein (lb) is preferably (lb*)

and wherein R ¹ is H and R ² is PG ² , the process comprising

(a) providing a compound of formula (II),

preferably (II*), wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ¹ E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

(b) reacting the compound of formula (II) with a base, and reducing the resulting compound of formula (la),

to give the compound of formula (lb), with R ¹ being H and with R ² being PG ² , preferably (lb*) with R ¹ being H and with R ² being PG ² .

Preferably, compound (lb) with R ¹ bein H and with R ² being PG ² , thus compound

more preferably compound (lb*) with R ¹ being H and with R ² being PG ² , thus compound

is used for the preparation of Suvorexant. Thus, the present invention also relates to the use of the compound of formula (lb), preferably (lb*), in which R ¹ is H and R ² is PG ² , for the preparation of compound (IX Suvorexant)

Further, the present invention relates to a process for the preparation of a compound of formula (IX) comprising

(A) providing a compound of formula (lb) by a process comprising

(a) providing a compound of formula II),

preferably (II*), wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E methyl, wherein R ¹ is H and R ² is PG ² ,

(b) reacting the compound of formula (II) with a base,

to give the compound of formula (la),

with R ¹ being H and with R ² being PG ² , preferably (la*) with R ¹ being H and with R ² being PG ² , and reducing the resulting compound of formula (la), preferably (la*).

(B) transforming the compound of step (A) into the compound of formula (IX).

Preferably, step (B) comprises

(cl) removal of the protecting group PG ² , (dlb) reacting the compound of formula (lb) with R ¹ and R ² being H with a compound of formula

wherein E is -COOH or a reactive carboxy group, to give a compound of formula

(Vllb) in which R ¹ is H

preferably

(fl) reacting the compound of formula (Vllb), preferably (Vllb*) with a compound of formula (XII)

(XII)

wherein X* is a leaving group, preferably CI.

The present invention further relates to a compound obtained or obtainable by said process.

According to a further preferred embodiment, compound (A) has the structure (la), preferably (la*), with R ¹ being H and with R ² bein

i.e. the structure (Vila), preferably (Vila*), with R ¹ being H.

Thus, the present invention preferably relates to a process for the preparation of a compound, and a compound obtained or obtainable by said process, the compound having the structure (Vila), preferably (Vila*), with R ¹ being H,

the process comprising

(a) providing a compound of formula II),

preferably (II*), wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl, and wherein R ² is

(b) reacting the compound of formula (II), preferably (II*), with a base

to give the compound of formula (Vila), preferably (Vila*).

Preferably, compound (Vila), preferably (Vila*), with R ¹ = H, is used for the preparation of compound (IX) (Suvorexant).

Thus, the present invention also relates to the use of a compound (Vila), preferably

(Vila*), with R ¹ = H, for the reparation of compound (IX)

Further, the present invention relates to a process for the preparation of a compound of formula (IX) comprising

(A) providing a compound of formula (Vila) by a process comprising

(a) providing a compound of formula (II)

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E alkyl, more preferably wherein R ^E methyl, ethyl or propyl, more preferably wherein R ^E methyl, and wherein R ² is

(b) reacting the compound of formula (II) with a base,

to give the compound (Vila), preferably (Vila*), with R ¹ = H,

(B) transforming the compound of step (A) into the compound of formula (IX). Preferably, step (B) further comprises

reducing the compound to give a compound of formula (Vllb) in which R ¹ is H, preferably (Vllb*) in which R ¹ is H,

reacting the compound of formula (Vllb), preferably (Vllb*), with a compound of formula (XII)

wherein X* is a leaving group, preferably CI.

The present invention further relates to a compound obtained or obtainable by said process. Further, the present invention relates to a compound of formula (Vllb), preferably (Vllb*), as mentioned above. Further the present invention relates to the use of a compound (Vllb), preferably (Vllb*), as mentioned above.

According a further preferred embodiment, compound (A) has the structure (lb), preferably (lb*), with R ¹ being H and with R ² being

i.e. the structure (Vllb), preferably (Vllb*), with R ¹ being H.

Thus, the present invention preferably relates to a process for the preparation of a compound, and a compound obtained or obtainable by said process, the compound having the structure (Vila), preferably (Vila*), with R ¹ being H,

the process comprising

(a) providing a compound of formula (II),

preferably (II*) , wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is meth l, and wherein R ² is

(b) reacting the compound of formula (II), preferably (II*), with a base, and reducing the resulting compound to give a compound of formula (Vllb), preferably (Vllb*).

Preferably, compound (Vllb), preferably (Vllb*), with R ¹ = H, is used for the preparation of Suvorexant.

Thus, the present invention also relates to the use of compound (Vllb), preferably (Vllb*), with R ¹ = H, for the preparation of compound (IX)

Further, the present invention relates to a process for the preparation of a compound of formula (IX) comprising

(A) providing a compound of formula (Vllb) by a process comprising

(a) providing a compound of formula II), preferably (II*).

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl, and wherein R ² is

(b) reacting the compound of formula (II), preferably (II*), with a base to give the compound of formula (Vila), preferably (Vila*), and reducing the resulting compound to give a compound of formula (Vllb), preferably (Vllb*),

(B) transforming the compound of step (A) into the compound of formula (IX).

Preferably, step (B) comprises

(fl) reacting the compound of formula (Vllb), preferably (Vllb*), with a compound of formula (XII)

wherein X* is a leaving group, preferably CI.

The present invention further relates to a compound obtained or obtainable by said process. According a further preferred embodiment, compound (A) has the structure (la), preferably (la*), with R ¹ being R ^A and with R ² bein PG ² . Preferably, R ^A is

Thus, the present invention preferably relates to a process for the preparation of a compound, and a compound obtained or obtainable by said process, the compound having the structure

or being a pharmaceutically acceptable salt or solvate thereof, wherein (la) is preferably (la*)

and wherein R ¹ is R ^A with R ^A being

R ² is PG ² , the process comprising

providing a compound of formula II)

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

wherein R ¹ is R ^A with R ^A bein

and R ² is PG ² , preferably the compound of formula (la*), wherein R ¹ is R ^A with R ^A being

and R ² is PG ² ,

(b) reacting the compound of formula (II) with a base,

to give the compound of formula (la),

wherein R ¹ is R ^A with R ^A bein

and R ² is PG ² , preferably the compound of formula (la*), wherein R ¹ is R ^A with R ^A being

and R ² is PG ² .

The compound of formula (la) wherein R ¹ is R ^A with R ^A being

and wherein R ² is PG ² is hereinunder and above referred to as compound (Villa) (Villa),

the respective single isomer as (Villa*)

O (Villa*).

Preferably, compound (Villa), more preferably compound (Villa*), is used for the preparation of Suvorexant. Thus, the present invention also relates to the use of compound (Villa), more preferably of com ound (Villa*), for the preparation of Suvorexant

Further, the present invention relates to a process for the preparation of a compound of formula (IX) comprising

(A) providing a compound of formula (Villa) by a process comprising

(a) providing the compound of formula II),

preferably (II*),

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl, wherein R ¹ is R ^A with R ^A being

and R ² is PG ² , preferably the compound of formula (la*), wherein R ¹ is R^ with R ^A being

and R ² is PG ² ,

(b) reacting the compound of formula (II) with a base,

to give the compound of formula (Villa), preferably (Villa*),

(B) transforming the compound of step (A) into the compound of formula (IX).

Preferably, step (B) further comprises

(cl) removal of the protecting group PG ² ,

(dl) reacting the compound of formula (Villa), preferably the compound of formula

(Villa*), with a compound of formula

wherein E is -COOH or a reactive carboxy group, to give a compound

preferably a compound

(el) reducing the compound obtained in (fl ) .

The present invention further relates to a compound obtained or obtainable by said process. Further, the present invention relates to a compound of formula (Villa), preferably (Villa*), as mentioned above. Further the present invention relates to the use of a compound (Villa), preferably (Villa*), as mentioned above.

According to a further preferred embodiment, compound (A) has the structure (lb), preferably (lb*), with R ¹ being R ^A and with R ² bein PG ² . Preferably, R ^A is

Thus, the present invention preferably relates to a process for the preparation of a compound, and a compound obtained or obtainable by said process, the compound having the structure

or being a pharmaceutically acceptable salt or solvate thereof, wherein (lb) is preferably

(lb*)

and wherein R ¹ is R ^A with R ^A being

and R ² is PG ² , the process comprising providing a compound of formula II)

preferably (II*), wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

wherein R ¹ is R ^A with R ^A bein

and R ² is PG ² , preferably the compound of formula (la*), wherein R ¹ is R ^A with R ^A being

and R ² is PG ² ,

reacting the compound of formula (II) with a base, and reducing the compound to give the compound of formula (lb),

wherein R ¹ is R ^A with R ^A bein

and R ² is PG ² , preferably the compound of formula (lb*), wherein R ¹ is R ^A with R ^A being

and R ² is PG ² .

The compound of formula (lb) wherein Rl is RA with RA being

and wherein R ² is PG ² is hereinunder and above referred to as compound (Vlllb) (Vlllb),

the respective single isomer as Vlllb*) (Vlllb*).

Preferably, compound (Vlllb), more preferably compound (Vlllb*), is used for the preparation of compound (IX). Thus, the present invention also relates to the use of compound (Vlllb), more preferably of compound (Vlllb*), for the preparation of compound (IX).

Further, the present invention relates to a process for the preparation of the compound of formula (IX) comprising

(A) providing a compound of formula (Vlllb) by a process comprising

(a) providing a compound of formula II), preferably (II*),

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl, wherein R ¹ is R ^A with R ^A being

and R ² is PG ² , preferably the compound of formula (la*), wherein R ¹ is R^ with R ^A being

and R ² is PG ² , (b) reacting the compound of formula (II), preferably (II*), with a base, to give the compound of formula (Villa), preferably (Villa*), and reducing the compound compound of formula (Villa), preferably (Villa*),

to give the compound of formula (Vlllb), preferably (Vlllb*),

(B) transforming the compound of step (A) into the compound of formula (IX).

Preferably, step (B) further comprises

(cl) removal of the protecting group PG ² ,

(dlb) reacting the compound of formula (Vlllb), preferably the compound of formula (Vlllb*), with a compound of formula

wherein E is -COOH or a reactive carboxy group.

The present invention further relates to a compound obtained or obtainable by said process. Further, the present invention relates to a compound of formula (Vlllb), preferably (Vlllb*), as mentioned above. Further the present invention relates to the use of a compound (Vlllb), preferably (Vlllb*), as mentioned above.

According to a further preferred embodiment, compound (A) has the structure (la), preferably (la*), with R ¹ bein R ^A and with R ² being R ^B

Thus, the present invention preferably relates to a process for the preparation of a compound, and a compound obtained or obtainable by said process, the compound having the structure

or being a pharmaceutically acceptable salt or solvate thereof, wherein (la) is preferably

(la*)

and wherein R ¹ is R ^A and R ² is R ^B ,

comprising

(a) providing a compound of formula (II)

and wherein R ¹ is R ^A and R ² is R ^B ,

(b) reacting the compound of formula (II) with a base, to give the compound of formula la), and wherein R ¹ is R ^A and R ² is R ^B ,

The compound of formula (la) wherein R ¹ is R ^A and R ² is R ^B ,

is hereinunder and above referred to as com ound (Villa)

the respective single isomer as IXa*)

Preferably, compound (IXa), more preferably compound (IXa*), is used for the preparation of compound (IX). Thus, the present invention also relates to the use of compound (IXa), more preferably compound of IXa*), for the preparation of compound (IX)

(IX)

Further, the present invention relates to a process for the preparation of compound IX comprising

(A) providing a compound of formula (IXa*) by a process comprising

(a) providing a compound of formula (II), preferably (II*),

wherein R ¹ is R ^A and R ² is R ^B ,

(R ^B ), (b) reacting the compound of formula (II), preferably (II*), with a base, to give the compound of formula (IXa), preferably (IXa*),

(B) transforming the compound of step (A) into the compound of formula (IX).

Preferably, step (B) further comprises

(el) reducing the compound.

The present invention further relates to a compound obtained or obtainable by said process. Further, the present invention relates to a compound of formula (IXa), preferably (IXa*), as mentioned above. Further the present invention relates to the use of a compound (IXa), preferably (IXa*), as mentioned above.

Step ( cl ): Removal of the protecting group PG

In step (cl) mentioned above, the protecting group PG ² is removed. The way of removing the protecting group PG ² depends on the protecting group used. Suitable methods are known to those skilled in the art. Preferably, in case the protecting group R ² is a Cbz protecting group, the removal of PG ² is carried out under reductive conditions. More preferably, the removal is carried out with hydrogen and a metal catalyst, preferably a palladium catalyst, more preferably, the protecting group is removed with Pd/C. The removal of group PG ² may be carried out in any suitable solvent known to those skilled in the art. Preferably, the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, iPrOH, nPrOH, EtOAc, iPrOAc and mixtures of two or more thereof.

Preferably, the removal of group PG ² is carried out at a temperature in the range of from 0 °C to 100 °C, more preferably in the range of from 10 °C to 70 °C, more preferably at room temperature 20 °C to 50 °C. During the reaction, the temperature may be varied or held essentially constant.

In case hydrogen is used, the reaction is preferably carried out at a pressure in the range of from 1 to 4 bar, more preferably, 1.0 to 2.5 bar.

The compound is preferably allowed to react for a time in the range of from 10 min to 180 min, more preferably in the range of from 20 to 120 min, more preferably in the range of from 30 to 60 min.

Step (dl ):

In step (dl), the respective compound is reacted, i.e. coupled, with a compound of formula (XI), wherein E is -COOH or a reactive carboxy group, to give a compound of formula (Vila) in which R ¹ is H, preferably a compound of formula (Vila*) in which R ¹ is H.

The term "reactive carboxy group" as used in this context of the present invention is intended to mean an activated carboxy lie acid derivative that reacts readily with electrophilic groups, such as an NH group, optionally in the presence of a suitable base, in contrast to those groups that require a further catalyst, such as a coupling reagent, in order to react. The term "activated carboxylic acid derivative" as used herein preferably refers to acid halides, such as acid chlorides, and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides, such as isobutyloxycarbonylchloride and the like, isothiocyanates or isocyanates, anhydrides derived from reaction of the carboxylic acid with Ν,Ν'- carbonyldiimidazole and the like, and esters derived from activation of the corresponding carboxylic acid with a coupling reagent. Such coupling reagents include, but are not limited to, HATU (0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); HOAt, HBTU (0-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); TBTU (2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate); TFFH (Ν,Ν',Ν" ,N"-tetramethyluronium-2-fluoro- hexafluorophosphate); BOP (benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate); PyBOP (benzotriazol-l-yl-oxy-trispyrrolidino-phosphonium hexafluorophosphate; EEDQ (2-ethoxy-l-ethoxycarbonyl-l,2-dihydro-quinoline); DCC (dicyclohexylcarbodiimide); DIPCDI (diisopropylcarbodiimide); HOBt (1- hydroxybenzotriazole); NHS (N-hydroxysuccinimide); MSNT (l-(mesitylene-2-sulfonyl)- 3-nitro-lH-l,2,4-triazole); aryl sulfonyl halides, e.g. triisopropylbenzenesulfonyl chloride, EDC (l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, CDC (1-cyclohexyl- 3-(2-morpholinoethyl)carbodiimide), Pyclop, T3P, CDI, Mukayama's reagent, HODhbt, HAPyU, TAPipU, TPTU, TSTU, TNTU, TOTU, BroP, PyBroP, BOI, TOO, NEPIS, BBC, BDMP, BOMI, AOP, BDP, PyAOP, TDBTU, BOP-C1, CIP, DEPBT, Dpp-Cl, EEDQ, FDPP, HOTT, TOTT, PyCloP.

In case E is -COOH, the reaction is preferably carried out in the presence of a catalyst, such as a coupling reagent, or a reagent that forms in situ an acid chlorid with E, such as oxalyl chloride, and preferably further in the presence of a base. Preferably, in this case, the coupling reagent is selected from the group consisting of HATU (0-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); HOAt, HBTU (0-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); TBTU (2-(lH- benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate); TFFH (N,N',N",N"- tetramethyluronium-2-fluoro-hexafluorophosphate); BOP (benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate); PyBOP (benzotriazol-l-yl- oxy-trispyrrolidino-phosphonium hexafluorophosphate; EEDQ (2-ethoxy-l- ethoxycarbonyl-l,2-dihydro-quinoline); DCC (dicyclohexylcarbodiimide); DIPCDI (diisopropylcarbodiimide); HOBt (1-hydroxybenzotriazole); NHS (N- hydroxysuccinimide); MSNT (l-(mesitylene-2-sulfonyl)-3-nitro-lH-l,2,4-triazole); aryl sulfonyl halides, e.g. triisopropylbenzenesulfonyl chloride, EDC (l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride, CDC (l-cyclohexyl-3-(2- morpholinoethyl)carbodiimide), Pyclop, T3P, CDI, Mukayama's reagent, HODhbt, HAPyU, TAPipU, TPTU, TSTU, TNTU, TOTU, BroP, PyBroP, BOI, TOO, NEPIS, BBC, BDMP, BOMI, AOP, BDP, PyAOP, TDBTU, BOP-C1, CIP, DEPBT, Dpp-Cl, EEDQ, FDPP, HOTT, TOTT, PyCloP.

More preferably, E is a reactive carboxy group, in particular-C(=0)R ⁵ , wherein R ⁵ is selected from the group consisting of -O-Alkyl, -OH, -H and X with X being the leaving group of the activated ester group -C(=0)-X, preferably wherein X is selected from the group consistin of

According to an alternative embodiment, E is -COOH, as mentioned above, and the reaction includes the addition of a coupling reagent or a reagent that forms in situ an acid chlorid with E, such as oxalyl chloride.

The coupling with E being -COOH or a reactive carboxy group, is preferably carried out in the presence of a suitable base, preferably an organic base, most preferably an amino group comprising base, most preferably a base selected from the group consisting of diisopropylamine (DIEA), triethylamine (TEA), N-methylmorpholine, N-methylimidazole, l,4-diazabicyclo[2.2.2]octane (DABCO), N-methylpiperidine, N-methylpyrrolidine, 2,6- lutidine, collidine, pyridine, 4-dimethylaminopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). As regards the reaction conditions used in this coupling step, preferably, the reaction is carried out in an organic solvent, such as N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile, acetone, dimethyl acetamide (DMA), dimethyl formamide (DMF), formamide, tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, ter - butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, tetrachloromethane and mixtures of two or more thereof. More preferably, the reaction is carried out in dichloromethane.

The temperature of the coupling reaction is preferably in the range of from 0 to 100 °C, more preferably in the range of from 5 to 50 °C, and especially preferably in the range of from 15 to 30 °C. During the course of the reaction, the temperature may be varied, preferably in the above given ranges, or held essentially constant.

Step (dla): In step (dla), the respective compound is reacted, i.e. coupled, with a compound of formula (XI), wherein E is -COOH or a reactive carboxy group. With respect to details regarding group E and preferred reaction conditions, reference is made to the details presented above and below with respect to step (dl) which equally apply for step (dla). Step ( el ): Reducing the compound of formula (Vllb):

In step (el), the compound is reduced. In this case, a reduction of the carbonyl group is thus carried out. The reduction is preferably carried out as described with respect to step (b3) described hereinunder and above. Preferably, the reduction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, nPrOH, i-PrOH, THF, 2-MeTHF, MTBE, DIPET, toluene, acetonitrile, CH ₂ CI ₂ and mixtures of two or more thereof.

Preferably, step (b3) is carried out at a temperature in the range of from -20 °C to 110 °C.

Preferably, step (el) is carried out at a temperature in the range of from -20 °C to 110 °C.

Preferably, in step (el, the compound is reduced by reaction with a reducing agent selected from the group consisting of NaBH ⁴ , NaCNBH ₃ , NaBH(OAc) ₃ , LiAlH ₄ , LiBH ₄ and H ₂ in the presence of transition metals, wherein the transition metal is preferably selected from the group consisting of IR, Pt, Fe, Rh, Pd, Re, Ru, Ni and Co. More preferably, the reducing agent is selected from the group consisting of NaBH ₄ , NaCNBH ₃ , NaBH(OAc) ₃ , LiAlH ₄ and LiBH ₄ , more preferably the reducing agent is NaBH ₄ , NaCNBH ₃ or NaBH(OAc) ₃ , more preferably NaBH ₄ .

Step (fl ):

In step (fl), the respective compound is reacted with a compound of formula (XII)

wherein X* is a leaving group. The term leaving group is denoted to encompass any group that departs upon reaction of compound (XII) with an amine. Preferred leaving groups are - CI, -S, -SMe, -SEt or -Br, in particular -CI or -Br.

Preferably, the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluol, acetonitrile and mixtures of two or more thereof.

Preferably, the reaction is carried out at a temperature in the range of from 0 to 80 ⁰ C, more preferably in the range of from 10 to 50 °C, more preferably in the range of from 20 to 35 °C, more preferably at room temperature. During the reaction, the temperature may be varied or held essentially constant.

The compounds are preferably allowed to react for a time in the range of from 10 min to 72 h, more preferably in the range of from 30 min to 24 h, more preferably in the range of from 1 h to 12 h.

It is to be understood that after any one of the above-mentioned steps it is conceivable that the reaction mixture obtained is subjected to a suitable work-up, such as an isolation of the respective compound. Such working up may comprise one or more stages wherein preferably at least one stage comprises purification, such as an extraction and/or a precipitation and/or filtration and/or chromatography or the like. Alternatively, some reactions may be carried out with the crude intermediate products or even in situ.

Step (a)

Preferably, compound (II) is provided in step (a) according the process of the invention as disclosed above.

Use as antagonists oforexin receptor activity

The compound of formula (IX) obtained or obtainable by the above-described process or a pharmaceutical composition comprising this compound is useful in a method of antagonizing orexin receptor activity. Thus, the present invention also describes the compound of formula (IX) obtained or obtainable by the above-described process or a pharmaceutical composition comprising this compound for use as antagonists of orexin receptor activity, in particular for use in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with orexin receptors, in particular for enhancing the quality of sleep; augmenting sleep maintenance; increasing REM sleep; increasing stage 2 sleep; decreasing fragmentation of sleep patterns; treating insomnia; enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling depression; treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis; or treating, controlling, ameliorating or reducing the risk of schizophrenia, in a mammalian patient in need thereof.

In particular, the compound of formula (IX) obtained or obtainable by the above described process or a pharmaceutical composition comprising this compound is used for treating or preventing a sleep disorder, in particular for enhancing the quality of sleep or for treating insomnia in a mammalian patient, in particular, for treating or controlling obesity in a mammalian patient. As used herein, the terms "treatment" and "treating" refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such a disease or disorder.

By way of example, the following particularly preferred embodiments of the invention are mentioned:

1. A process for the preparation of a com ound of formula (A)

or a pharmaceutically acceptable salt or solvate thereof,

wherein A) is preferably

and wherein R ² is selected from the group consisting of H, PG ² and R ^B with R ¹ B being

and wherein PG ¹ and PG ² are, independently of each other, suitable protecting groups,

and wherein n is 0 or 1 ,

the process comprising (a) providing a compound of formula (II)

(II)

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

(b) reacting the compound of formula (II) with a base and optionally reducing the compound

to give the compound of formula (A).

The process according to embodiment 1, wherein the compound of formula (A) has the structure of formula (la)

The process according to embodiment 1 or 2, wherein the compound of formula (A) has the structure of formula la*)

The process according to embodiment 1 , wherein the compound of formula (A) has the structure of formula (lb

and wherein in step (b) upon reaction with the base a compound of formula (la) is formed,

and wherein step (b) further comprises reducing the compound of formula (la). The process according to embodiment 4, wherein the compound of formula (A) has the structure of formula (lb*

and wherein in step (b) upon reaction with the base a compound of formula (la*) is formed,

and wherein step (b) further comprises reducing the compound of formula (la*).

The process according to any one of embodiments 1 to 5, wherein PG ¹ is selected from the group consisting of Benzyl (Bn), t-butyloxycarbonyl (Boc), Cbz

(carboxybenzyl), PNZ (p-Nitrobenzylcarbamoyl)), allyloxycarbonyl (Alloc), Trifluoroacetate and Phthalimide.

The process according to any one of embodiments 1 to 6, wherein PG ² is selected from the group consisting of Benzyl, t-butyloxycarbonyl (Boc), Cbz

(carboxybenzyl), PNZ, allyloxycarbonyl (Alloc), Trifluoroacetate and Phthalimide.

The process according to any one of embodiments 1 to 7, wherein Rl is selected from the group consistin of H,

more preferably, wherein Rl is H.

The process according to any one of embodiments 1 to 8, wherein step (b) comprises

(bl) reacting the compound of formula (II) with a base to give a composition comprising a compound of formula (la)

preferably a compound of formula (la*)

optionally purifying the composition obtained in (bl),

optionally reducing the compound of formula (la), preferably of formula (la*), to give a compound of formula lb)

preferably (lb*)

The process according embodiment 9, wherein (bl) is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol,

tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof.

The process according embodiment 9 or 10, wherein step (bl) is carried out at a temperature in the range of from -20°C to 80°C, more preferably in the range of from 0 to 50, more preferably in the range of from 20 to 30 °C. During the reaction, the temperature may be varied or held essentially constant.

The process according any one of embodiments 9 to 11, wherein (b3) is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, nPrOH, i-PrOH, THF, 2-MeTHF, MTBE, DIPET, toluene, acetonitril, CH ₂ CI ₂ and mixtures of two or more thereof.

The process according any one of embodiments 9 to 12, wherein in step (b3), the compound is reduced by reaction with a reducing agent selected from the group consisting of NaBH4, NaCNBFB, NaBH(OAc)3, LiAlH4, LiBH4 and H2 in the presence of at least one transition metal.

The process of any one of embodiments 1 to 13, wherein compound (II) consists of a mixture of

The process of embodiment 14, wherein compound (II) contains of from 20 to 75 % by weight % of the compound of formula (II*) based on the total weight of the sum of (II*) and (II**) and wherein mixture is resolved by chiral resolution to give the compound (II*).

The process of embodiment 15, wherein the resolution is carried out by a process comprising

(i) adding a single stereoisomer of a chiral acid and precipitating, preferably crystallizing, a chiral acid salt (S) of compound (II), thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (S) and the solvent,

(ii) preferably separating the precipitated, preferably crystallized, chiral acid salt (S) of the compound of formula (II) from the mixture obtained in (i), wherein the chiral acid salt (S) contains at least 80 % by weight of the chiral acid salt of the compound of formula (II*) based on the total weight of the chiral acid salt of the compound of formula (II),

(iii) converting the chiral acid salt (S) to the free base.

A process of any one of embodiments 1 to 17, wherein the compound has the structure

or is a pharmaceutically acceptable salt or solvate thereof, wherein (la) is preferably (la*)

and wherein R ¹ is H and R ² is PG ² .

The process according to any one of embodiments 1 to 13, wherein step (a) comprises

(al) reacting a compound of formula (III)

with a compound of formula (IV)

to give a compound of formula (V)

(V)

wherein R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la

and wherein R ^2a is H, R ² , PG ² , R ^B or PG ^2a and wherein PG ^la and PG ^2a are, independently of each other, suitable protecting groups,

(a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V),

(a4) optionally replacing R ^2a and/or R ^la with R ¹ and/or R ² ,

to give the compound of formula (II).

The process of embodiment 18, wherein in step (a3), a compound having the structure

is obtained.

The process of embodiment 19, wherein compound (Ila) contains of from 20 to 75 % by weight % of the compound of formula (Ila*) based on the total weight of the sum of (Ila* and (Ila**)

and wherein the mixture is resolved by chiral resolution to give the compound (Ila*).

The process of embodiment 20, wherein the resolution is carried out by a process comprising

(ia) adding a single stereoisomer of a chiral acid and precipitating, preferably crystallizing, a chiral acid salt (Sa) of compound (Ila), thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (Sa) and the solvent,

(iia) preferably separating the precipitated, preferably crystallized, chiral acid salt (Sa) of the compound of formula (Iia) from the mixture obtained in (ia), wherein the chiral acid salt (S) contains at least 80 % by weight of the chiral acid salt of the compound of formula (Iia*) based on the total weight of the chiral acid salt of the compound of formula (Iia),

(iiia) converting the chiral acid salt (Sa) to the free base.

The process of any one of embodiments 1 to 21, wherein step (a) comprises

(al) reacting a compound of formula (III)

R ^1a HN^ _{NHR2a (m)} with a compound of formula (IV)

O O X OR ^E (IV)

to give a compound of formula (V)

(V)

wherein R ^la is PG ¹ and wherein R ^2a is H, and PG ^la is a suitable protecting group, preferably a Boc group,

(a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V) to give a compound of formula (Iia), wherein R ^la is PG ¹ and wherein R ^2a is H

(a4) replacing R ^2a with

by reacting a compound of formula (Iia) with a compound of formula (XI)

wherein E is -COOH or a reactive carboxy group, and replacing R ^la with H by removing the protecting group PG ¹ .

to give the compound of formula (II) in which R ¹ is H and R ² is

The process according any one of embodiments 18 to 22, wherein step (al) is carried out at a temperature in the range of 0 to 80 °C, more preferably in the range of from 10 to 50 °C, more preferably in the range of from 20 to 35 °C.

The process according to any one of embodiments 18 to 23, wherein (al) is carried out in an organic solvent, more preferably in a solvent trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof. .

The process according any one of embodiments 18 to 24, wherein (al) is carried in the presence of a catalysing agent, such as a dehydrating reagent or an acidic catalyst, preferably in the presence of Si0 ₂ or a molecular sieve or a mixture thereof.

The process according any one of embodiments 28 to 25, wherein (a3) is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof.

Preferably, the solvent is methanol or TFE.

The process according any one of embodiments 18 to 26, wherein (a3) is carried out at a temperature in the range of from 10 to 100 °C, more preferably in the range of from 20 to 60 °C, more preferably at 25 to 40 C.

The process according any one of embodiments 18 to 27, wherein in step (a3), the compound is reduced with Pd/C.

The process according any one of embodiments 18 to 28, wherein in step (a3), the compound is stereoselectivel reduced to give a compound of formula (Ila*)

The process according to embodiment 29, wherein the metal catalyst is selected from the group consisting of a catalyst comprising Pd, Fe, Ir, Rh or a mixture of two or more thereof.

The process according to any one of embodiments 1 to 25, wherein the base in step (b) is selected from the group consisting of NaOR ^E , Na-tert.butoxid, K-tert.butoxid, NaNH2, DBU, Tetramethylguanidin, Na-CH ₂ S(0)CH ₃ and mixtures of two or more thereof, with R ^E being selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E methyl, ethyl or propyl, more preferably wherein R ^E is methyl, most preferably wherein the base is sodium methanolate.

The process of any one of embodiments 1 to 31, wherein compound (A) has the structure (la)

or is a pharmaceutically acceptable salt or solvate thereof, wherein (la) is preferably (la*)

and wherein R ¹ is H and R ² is PG ² , the process comprising

(a) providing a compound of formula II)

preferably of formula (II*),

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl, reacting the compound of formula (II), preferably of formula (II*), with a base, to give the compound of formula (la), with R ¹ being H and with R ² being PG ² , preferably (la*) with R ¹ being H and with R ² being PG ² .

The process of any one of embodiments 1 to 31, wherein compound (A) has the structure (lb)

or is a pharmaceutically acceptable salt or solvate thereof, wherein (lb) is preferably (lb*),

and wherein R ¹ is H and R ² is PG ² , the process comprising

(a) providing a compound of formula (II),

preferably (II*), wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

(b) reacting the compound of formula (II) with a base, and reducing the resulting compound of formula (la), to give the compound of formula (lb), with R ¹ being H and with R ² being PG ² preferably (lb*) with R ¹ being H and with R ² being PG ² .

The process of any of embodiments 1 to 33, wherein compound (A) has the structure (Vila) with R ¹ being H

(Vila),

preferably (Vila*)

(Vila*),

the process comprising

(a) providing a compound of formula (II),

preferably (II*)

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl, and wherein R ² is

(b) reacting the compound of formula (II), preferably (II*), with a base to give the compound of formula (Vila), preferably (Vila*).

The process of any one of embodiments 1 to 33, wherein compound (A) has the structure (Vllb) with R ¹ being H

(Vllb),

preferably (Vllb*)

(Vllb*),

the process comprising

(a) providing a compound of formula (II),

preferably (II*), wherein R is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl, and wherein R ² is

(b) reacting the compound of formula (II), preferably (II*), with a base, and reducing the resulting compound to give a compound of formula (Vllb), preferably (Vllb*).

The process of any one of embodiments 1 to 33, wherein

compound (A) has the structure

or is a pharmaceutically acceptable salt or solvate thereof, wherein (la) preferably (la*)

and wherein R ¹ is R ^A with R ^A being

R ² is PG ² , the process comprising

providing a compound of formula (II)

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

wherein R ¹ is R ^A with R ^A bein and R ² is PG ² , preferably the compound of formula (la*), wherein R ¹ is R ^A with R ^A being

and R ² is PG ² ,

(b) reacting the compound of formula (II) with a base,

to give the compound of formula (la),

wherein R ¹ is R ^A with R ^A being

and R ² is PG ² , preferably the compound of formula (la*), wherein R ¹ is R ^A with

R ^A being

and R ² is PG ² , or

— compound (A) has the structure

or is a pharmaceutically acceptable salt or solvate thereof, wherein (la) is preferably (la*)

and wherein R ¹ is R ^A with R ^A bein

and R ² is PG ² , the process comprising

(a) providing a compound of formula (II)

(II) wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

wherein R ¹ is R ^A with R ^A bein

and R ² is PG ² , preferably the compound of formula (la*), wherein R ¹ is R ^A with R ^A being

and R ² is PG ² ,

(b) reacting the compound of formula (II) with a base, and reducing resulting compound

to give the compound of formula (lb),

wherein R ¹ is R ^A with R ^A being

and R ² is PG ² , preferably the compound of formula (la*), wherein R ¹ is R ^A with R ^A being

and R ² is PG ² .

The process according to any one of embodiments 1 to 33, wherein the compound of formula (A) has the structure of formula IX)

The process according to any one of embodiments 1 to 3377,, \ wherein R ² in the compound of formula (A) is H, and wherein in (b) a compound of formula (Al) consisting of an enantiomeric mixture of the compounds (Al *) and (Al **) is obtained

wherein the compound of formula (Al) contains of from 20 to 75 % by weight, of the compound of formula (Al *) based on the total weight of the sum of (Al *) and (Al **), step (b) further comprising

(I) forming a chiral acid salt, preferably a tartaric acid salt, (T*) of at least part of the compound of formula (Al) by treating the compound of formula (Al) with a single stereoisomer of a chiral acid salt, preferably of a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, in a suitable solvent, and precipitating, preferably crystallizing, at least part of the tartaric acid salt (T*) formed, thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (T) and the solvent;

(II) preferably separating the precipitated, preferably crystallized, chiral acid salt (T) of the compound of formula (Al) from the mixture obtained in (I), wherein the chiral acid salt (T) of the compound of formula (Al) contains at least 80 % by weight of the chiral acid salt of the compound of formula (Al *) based on the total weight of the chiral acid salt of the compound of formula (Al),

(III) converting the chiral acid salt (T) of (Al) to the free base (Al *),

wherein (A) is preferably (Al *) or wherein (Al *) is converted in further steps to give (A).

The process according to embodiment 38, wherein the chiral acid salt (T) of the compound formula (Al) contains at least 90% by weight, more preferably at least 95 % by weight, more preferably at least 96 % by weight, more preferably at least 97 % by weight, more preferably at least 98 % by weight, more preferably at least 99 % by weight, more preferably at least 99,5 % by weight, more preferably at least 99,9 % by weight, of the tartaric salt of the compound of formula (Al *), based on the total weight of chiral acid salt of the compound of formula (Al). The process according to embodiment 38 or 39, wherein the compound of formula (Al) employed in step (I) contains of from 40 to 60 % by weight of the compound of formula (Al *) based on the total weight of the sum of (Al *) and (Al **).

The process of any one of embodiments 38 to 40, wherein

n is 1 and the chiral acid is di-toluoyl-L-tartaric acid (LTTA), or

n is 0, and the chiral acid is di-benzoyl-D-tartaric acid (DBTA).

The process of embodiment 35 to 39, wherein the suitable solvent in step (I) is selected from the group consisting of selected from the group consisting of consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH2C12, ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, isopropyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketon, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof.

Process for the preparation of a compound of formula (IX), comprising

(A) preparing a compound of formula (A) according to the method of any one of embodiments 1 to 42, wherein in case n = 0, at least one of R ^A or Pv ^B is H or a protecting group,

(B) transforming the compound of step (A) into the compound of formula (IX).

The process of embodiment 43 wherein (A) comprises

providing a compound of formula (la) by a process comprising

(a) providing a compound of formula (II)

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl, wherein R ¹ is H and R ² is PG ² ,

(b) reacting the compound of formula (II) with a base,

to give the compound of formula (la), with R ¹ being H and with R ² being PG ² , preferably (la*) with R ¹ being H and with R ² being PG ² .

The process of embodiment 44, wherein step (B) comprises (cl) removal of the protecting group PG ² ,

(dl) reacting the compound of formula (la) with R ¹ and R ² being H with a

compound of formula

wherein E is -COOH or a reactive carboxy group, to give a compound of formula (Vila), in which R ¹ is H,

(Vila),

preferably

(Vila*),

(el) reducing the compound, to give a compound of formula (Vllb), in which R ¹ is

H

(Vllb),

preferably

(Vllb*),

(fl)reacting the compound of formula (Vllb), preferably (Vllb*), with a compound of formula (XII)

wherein X* is a leaving group, preferably CI, S, SMe, SEt, Br, more preferably -Br or -CI, more preferably -CI. .

The process of embodiment 43 comprising

(A) providing a compound of formula (lb) by a process comprising

(a) providing a compound of formula II), preferably (II*),

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl, wherein R ¹ is H and R ² is PG ² .

(b) reacting the compound of formula (II) with a base, to give the compound of formula la)

with R ¹ being H and with R ² being PG ² , preferably (la*) with R ¹ being H and with R ² being PG ² , and reducing the resulting compound of formula (la), preferably (la*), (B) transforming the compound of step (A) into the compound of formula (IX).

The process of embodiment 46, wherein step (B) comprises

(cl) removal of the protecting group PG ² ,

(dlb) reacting the compound of formula (lb) with R ¹ and R ² being H with a

compound of formula

wherein E is -COOH or a reactive carboxy group, to give a compound of formula (Vllb), in which R ¹ is H,

(Vllb),

preferably

(Vllb*),

(fl) reacting the with a compound of formula (Vllb), preferably (Vllb*), with a compound of formula (XII)

wherein X* is a leaving group, preferably Cl.

The process of embodiment 43 comprising

(A) providing a compound of formula (Vllb) by a process comprising (a)providing a compound of formula (II), preferably (II*),

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl, and wherein R ² is

(b) reacting the compound of formula (II), preferably (II*), with a base to give the compound of formula (Vila), preferably (Vila*), and reducing the resulting compound to give a compound of formula (Vllb), preferably (Vllb*),

(B) transforming the compound of step (A) into the compound of formula (IX).

The process of embodiment 48, wherein step (B) comprises

(fl) reacting the compound of formula (Vllb), preferably (Vllb*), with a

compound of formula (XII)

(XII)

wherein X* is a leaving group, preferably CI.

The process of embodiment 43 comprising

(A) providing a compound of formula (Vila) by a process comprising

(a) providing a compound of formula (II)

wherein R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl, and wherein R ² is

(b) reacting the compound of formula (II) with a base,

to give the compound (Vila), preferably (Vila*), with Rl = H,

(B) transforming the compound of step (A) into the compound of formula (IX). The process of embodiment 50, wherein step (B) further comprises

(el) reducing the compound, to give a compound of formula (Vllb), in which R ¹ is H, preferably (Vllb*) in which R ¹ is H,

(fl) reacting the compound of formula (Vllb), preferably (Vllb*), with a compound of formula (XII)

wherein X* is a leaving group, preferably CI.

A process for preparing a com ound of formula (Ha')

the process comprising

(al) reacting a compound of formula (ΠΓ) _R 1 b

N /\ 2a

R1 a" ^N/ ^ NHR ^: with a compound of formula (IV)

O O

to give a compound of formula V)

(a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V), to give a compound of formula (Ila')

wherein at each occurrence

R ^E is selected from the group consisting of H, alkyl, aryl, preferably Ci-C ₆ alkyl alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, preferably Ci-C ₆ alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la and R ^lb is H, or

R ^la is H and R ^lb is H, R ¹ , PG ¹ , R ^A or PG ^la ,

or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido roup of formula (p)

and succinimido group of formula (s)

R ^2a is H, R ² , PG ² , R ^B or PG ^2a ,

PG ^la and PG ^2a are, independently of each other, suitable protecting groups,

R ¹ is selected from the group consisting of H, PG ¹ and R ^A ,

R ² is selected from the group consisting of H, PG ² and R ^B ,

PG ¹ and PG ² are, independently of each other, suitable protecting groups,

R ^A is

R is

The process of embodiment 52, wherein R is H,

the compound of formula (Ha') is a compound of formula (Ila)

the compound of formula (ΠΓ) is a compound of formula (III),

R ^1a HN ^ _{N HR2a (m)} the compound of formula (V) is a com ound of formula (V)

(V). The process according to embodiment 52 or 53, wherein the process further comprises

(a4) replacing R ^2a with R ² and/or R ^la with R ¹ , preferably being R ^lb =H, or

replacing R ^2a with R ² and/or R ^lb with R ¹ , preferably being R ^la =H, or replacing R ^2a with R ² and/or when R ^la and R ^lb are taken together to form a cyclic imide group optionally replacing the cyclic imide group with R ¹ and H.

A process for the preparation of a com ound of formula (Ila)

comprising

(al) reacting a compound of formula (III)

R ^{1 a} HN^ _NHR2a with a compound of formula (IV)

O O A A OR ^E (IV)

to give a compound of formula V)

wherein R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la and wherein R ^2a is H, PG ² , R ^B or PG ^2a and wherein PG ^la and PG ^2a are, independently of each other, suitable protecting groups,

(a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V),

to give the compound of formula (Ila).

The process of embodiment 52 to 55, wherein R ^2a is H and R ^la is Boc.

A process for the preparation of a compound of formula (II), comprising the steps

(al) to (a3) according to embodiment 52 to 56, the process further comprising (a4) replacing R ^2a and/or R ^la with R ¹ and/or R ² ,

to give the compound of formula (II).

The process of any of embodiments 55 to 57, wherein the process further comprises (a4) replacing R ^2a with R ² and/or R ^la with R ¹

to give the compound of formula (II)

The process of any of embodiments 52 to 58, wherein when R ^2a is H then R ^la is not H or wherein when R ^la is H then R ^2a is not H.

The process of any of embodiments 52 to 59, wherein R ^2a is H and R ^la is Boc. The process of any of embodiments 52 to 60, wherein

R ^la is PG ¹ , R ^A or PG ^la with R ^A bein

The process of any of embodiments 52 to 61, wherein R ^2a is H and R ^la is Boc. The process of any of embodiments 52 to 62, wherein

in (al) R ^la is PG ^la and R ^2a is H, and PG ^la is a suitable protecting group, preferably a Boc group, R ^lb is H;

in (a3) R ^la is PG ^la and R ^2a is H and PG ^la is a suitable protecting group, preferably a Boc group, R ^lb is H; and

in (a4) R ^lb is H and R ^2a is replaced with

by reacting a compound of formula (Ha') with a compound of formula (XI)

wherein E is -COOH or a reactive carboxy group, and replacing R ^la with H by removing the protecting group PG ¹ .

to give the compound of formula II) in which R ¹ is H and R ² is

The process of embodiment 61, wherein in (a4) a compound of formula (II) wherein R ^E is methyl, R ² is

and wherein R ¹ is H or Boc, preferably Boc is obtained.

The process of any of embodiments 52 to 64, wherein in compound (Ha') R ^la is PG ¹ , preferably Boc and R ^lb is H,

or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido roup of formula (p)

and succinimido group of formula (s)

R ^a is H, wherein the process comprises

(a4) replacing R ^2a =H with

by reacting a compound of formula Ha') with a compound of formula (XI)

wherein E is -COOH or a reactive carboxy group, and replacing R ^la with H by removing the protecting group PG ¹ or by replacing R ^la and R ^lb , taken together to form a cyclic imide, with hydrogens, and obtaining the compound of formula (II) which R ¹ is H and R ² is

The process of any of embodiments 52 to 65,

wherein in (a3) in compound (Ha') R ^la is PG ^la , preferably Boc and R ^lb is H, or R ¹⁽ and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group and succinimido group and R ^2a is H, wherein the process comprises

(a4) replacing R ^2a =H with PG ² , wherein PG ² is preferably Boc or Cbz and replacing R ^la , or R ^la taken together with R ^lb with hydrogens, and obtaining the compound of formula (II) in which R ¹ is H and R ² is PG ² wherein PG ² is preferably Boc or Cbz, wherein PG ^la and PG ² are orthogonal protecting groups, or

wherein in (a3) in compound (Ila) R ^la is PG ^la , preferably Boc or Cbz, and R ^2a is H, wherein the process comprises

(a4') replacing R ^2a =H with PG ² , wherein PG ² is preferably Boc or Cbz and

replacing R ^la with H, and obtaining the compound of formula (II) in which R ¹ is H and R ² is PG ² wherein PG ² is preferably Boc or Cbz, wherein PG ^la and PG ² are orthogonal protecting groups.

The process of embodiment 66 wherein (a4) or (a4') comprises

(a4-l) replacing R ^2a =H with PG ² wherein PG ² is preferably Boc or Cbz and

obtaining an intermediate compound and wherein PG ^la or the cyclic imide group and PG ² are orthogonal protecting groups and

(a4-2) replacing R ^la or R ^la and R ^lb of the intermediate compound obtained in (a4-l) with hydrogens and obtaining the compound of formula (II) in which R ¹ is H and R ² is PG ² wherein PG ² is preferably Boc or Cbz.

The process of embodiments 66 or 67, wherein in the intermediate compound R ^la is Boc or R ^la and R ^lb taken together with the N atom to which they are attached form phthalimido group or a succinimido group and R ² is PG ² wherein PG ² is selected from the group consisting of Cbz, Bn, and Fmoc, more preferably PG ² is Cbz.

The process of any of embodiments 52 to 68, wherein R ^E is methyl.

The process of any of embodiment 52 to 69, wherein compound (Ila') contains of from 20 to 75 % by weight % of the compound of formula (Ila*) based on the total weight of the sum of (Ila'* and (Ila'**)

and wherein the mixture is resolved by chiral resolution to give the compound (Ila'*).

The process of embodiment 70, wherein the resolution is carried out by a process comprising (ia) adding a single stereoisomer of a chiral acid and precipitating, preferably crystallizing, a chiral acid salt (Sa) of compound (Ha'), thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (Sa) and the solvent,

(iia) preferably separating the precipitated, preferably crystallized, chiral acid salt (Sa) of the compound of formula (Iia'), from the mixture obtained in (ia), wherein the chiral acid salt (S) contains at least 80 % by weight of the chiral acid salt of the compound of formula (Iia'*) based on the total weight of the chiral acid salt of the compound of formula (Iia'),

(iiia) converting the chiral acid salt (Sa) to the free base.

The process of any of embodiment 52 to 69, wherein compound (Iia) contains of from 20 to 75 % by weight % of the compound of formula (Iia*) based on the total weight of the sum of Iia*) and (Iia**)

and wherein the mixture is resolved by chiral resolution to give the compound (Iia*)

The process of embodiment 72, wherein the resolution is carried out by a process comprising

(ia) adding a single stereoisomer of a chiral acid and precipitating, preferably crystallizing, a chiral acid salt (Sa) of compound (Iia), thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (Sa) and the solvent,

(iia) preferably separating the precipitated, preferably crystallized, chiral acid salt (Sa) of the compound of formula (Iia), from the mixture obtained in (ia), wherein the chiral acid salt (S) contains at least 80 % by weight of the chiral acid salt of the compound of formula (Iia*) based on the total weight of the chiral acid salt of the compound of formula (Iia),

(iiia) converting the chiral acid salt (Sa) to the free base.

The process of any of embodiments 52 to 71, wherein compound (II) contains of from 20 to 75 % by weight % of the compound of formula (II*) based on the total weight of the sum of (II*) and (II**)

and wherein the mixture is resolved by chiral resolution to give the compound (II*).

75. The process of embodiment 74, wherein the resolution is carried out by a process comprising

(ia')adding a single stereoisomer of a chiral acid and precipitating, preferably crystallizing, a chiral acid salt (Sa) of compound (II), thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (Sa) and the solvent,

(iia') preferably separating the precipitated, preferably crystallized, chiral acid salt (Sa) of the compound of formula (II) from the mixture obtained in (ia'), wherein the chiral acid salt (S) contains at least 80 % by weight of the chiral acid salt of the compound of formula (II*) based on the total weight of the chiral acid salt of the compound of formula (II),

(iiia') converting the chiral acid salt (Sa) to the free base.

76. The process of any of embodiments 52 to 75, wherein step (al) is carried out at a temperature in the range of 0 to 80 °C, more preferably in the range of from 10 to 50 °C, more preferably in the range of from 20 to 35 °C.

77. The process of any of embodiments 52 to 76, wherein (al) is carried out in an organic solvent, more preferably in a solvent trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof.

78. The process of any of embodiments 52 to 77, wherein (al) is carried in the presence of a catalysing agent, such as a dehydrating reagent or an acidic catalyst, preferably in the presence of Si0 ₂ or a molecular sieve or a mixture thereof.

79. The process of any of embodiments 52 to 78, wherein (a3) is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof, preferably, the solvent is methanol or TFE.

The process of any of embodiments 52 to 79, wherein (a3) is carried out at a temperature in the range of from 10 to 100 °C, more preferably in the range of from 20 to 60 °C, more preferably at 25 to 40 °C.

The process of any of embodiments 52 to 80, wherein in step (a3), the compound of formula (V) or of formula (V) is stereoselective ly reduced to give a compound of formula Ila'*) or of formula (Ila*)

(Ila'*) preferably (H _a *)

The process of any of embodiment 81, wherein the reduction is carried out in the presence of a metal catalyst wherein the metal catalyst is selected from the group consisting of a catalyst comprising Pd, Fe, Ir, Rh or a mixture of two or more thereof.

The process of any of embodiments 52 to 82 wherein in step (a3), the compound is reduced with Pd/C.

The process of any of embodiments 52 to 83 further comprising

(b) reacting the compound of formulae (II) or (Ila') or (Ila) with a base,

preferably selected from the group consisting of NaOR ^E , Na-tert.butoxid, K- tert.butoxid, NaNH ₂ , DBU, Tetramethylguanidin, Na-CH ₂ S(0)CH ₃ and mixtures of two or more thereof is employed, with R ^E being selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E methyl, ethyl or propyl, more preferably wherein R ^E methyl and obtainin a compound of formula (A) or Aa)

preferably

85. The process of any of embodiments 84, wherein (b) is according to any of

embodiments 1 to 51.

86. The process of embodiment 85, wherein (b) comprises

(bl) reacting the compound of formula (II) or (Ha') or (Ila) with a base and obtaining a composition comprising a compound of formula (A), preferably (A*) wherein n=l

(A) preferably (A*)

(b2) optionally purifying the compound obtained in (b 1 ),

(b3) optionally reducing the compound of (bl) or (b2) and obtaining a compound of formula (A), preferably of formula (A*) wherein n=0.

87. The process of any of embodiments 84 to 86, wherein compound (A*) is a

compound of formula

88. The process of any of embodiments 84 to 86, wherein the compound (A) or (Aa) or (A*) or (Aa*) are further reacted to a com ound of formula

The process of embodiment 57, wherein step (a4) comprises

(a4) replacing R ^a with

by reacting a compound of formula Ila) with a compound of formula (XI)

wherein E is -COOH or a reactive carboxy group, and replacing R ^la with H by removing the protecting group PG ¹ ,

to give the compound of formula (II).

A process for the preparation of a com ound of formula (Ila')

comprising

(a-i) reacting a compound of formula (1)

with a compound of formula (2)

R ^1b O

and obtaining a compound of formula (Ila') and

(a-ii) optionally purifying the compound of formula (Ila'),

wherein at each occurrence

R ^E is selected from the group consisting of H, alkyl, aryl, preferably Ci-C ₆ alkyl alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, preferably Ci-C ₆ alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la ' and R ^lb is H, or

R ^la is H, and R ^lb is H, R ¹ , PG ¹ , R ^A or PG ^la

preferably,

R ^la is R ¹ , PG ¹ , R ^A or PG ^la ' and R ^lb is H, in this case preferably R ¹ not being H, or

R ^la is H, and R ^lb is R ¹ , PG ¹ , R ^A or PG ^la in this case preferably R ¹ not being H, or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido roup of formula (p)

and succinimido group of formula s)

R ^2a is H, PG ² , R ^B or PG ^2a '

PG ^la and PG ^2a are, independently of each other, suitable protecting groups,

R ¹ is selected from the group consisting of H, PG ¹ and R ^A

R ² is selected from the group consisting of H, PG ² and R ^B

PG ¹ and PG ² are, independently of each other, suitable protecting groups,

R ^A is

R is

91. The process of embodiment 90, further comprising

(a4) replacing R ^2a with R ² and/or R ^la with R ¹ , preferably being R ^lb =H, or replacing R ^2a with R ² and/or R ^lb with R ¹ , preferably being R ^la =H, or replacing R ^2a with R ² and/or when R ^la and R ^lb are taken together to form a cyclic imide group optionally replacing the cyclic imide group with R ¹ and H

92. The process of embodiment 90 or 91 , wherein R ^la and R ^lb taken together form a phthalimido group (p) or a succinimido group (s).

93. The process of any of embodiments 90 to 92, wherein

either R ^la or R ^lb is PG ¹ , R ^A or PG ^la with R ^A being

or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido roup of formula (p)

and succinimido group of formula s)

The process of any of embodiments 90 to 93, wherein

in (a-i) R ^la or R ^lb is PG ^la and R ^2a is H, wherein PG ^la is a suitable protecting group, preferably a Boc group or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consistin of phthalimido group of formula (p)

and succinimido group of formula s)

The process of any of embodiments 90 to 94, wherein in compound (Ha') R ^la is PG ¹ or PG ^la , preferably Boc and R ^lb is H or wherein R ^lb is PG ¹ or PG ^la , preferably Boc and R ^la is H or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consistin of phthalimido group of formula (p)

and succinimido group of formula s)

R ^a is H, wherein the process comprises

(a4) replacing R ^2a =H with

by reacting a compound of formula Ha') with a compound of formula (XI)

wherein E is -COOH or a reactive carboxy group, and replacing either R ^la or R ^la being PG ¹ or PG ^la with H by removing the protecting group PG ¹ or PG ^la or by replacing R ^la and R ^lb , taken together to form a cyclic imide, with hydrogens, and obtaining the compound of formula II) in which R ¹ is H and R ² is

The process of any of embodiments 90 to 95, wherein in compound (Ha') R ^la is PG ^la or PG ¹ , preferably Boc and R ^lb is H, or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group and succinimido group and R ^2a is H, wherein the process comprises

(a4) replacing R ^2a =H with PG ² , wherein PG ² is preferably Boc or Cbz and

replacing R ^la , or R ^la or R ^la taken together with R ^lb with hydrogens, and obtaining the compound of formula (II) in which R ¹ is H and R ² is PG ² wherein PG ² is preferably Boc or Cbz, wherein PG ^la or PG ¹ and, PG ² are orthogonal protecting groups.

The process of embodiment 95, wherein (a4) comprises

(a4-l) replacing R ^2a =H with PG ² wherein PG ² is preferably Boc or Cbz and

obtaining an intermediate compound and wherein PG ^la or the cyclic imide group and PG ² are orthogonal protecting groups and (a4-2) replacing R ^la or R ^la and R ^lb of the intermediate compound obtained in (a4-l) with hydrogens and obtaining the compound of formula (II) in which R ¹ is H and R ² is PG ² wherein PG ² is preferably Boc or Cbz.

98. The process of embodiment 97, wherein in (a4-l) a compound is formed wherein PG ^la or PG ¹ is Boc or R ^la and R ^lb taken together with the N atom to which they are attached form phthalimido group or a succinimido group and PG ² is selected from the group consisting of Cbz.

99. The process of any of embodiments 90 to 98, wherein compound (Ila') contains of from 20 to 75 % by weight % of the compound of formula (Ila'*) based on the total weight of the sum of Ila*) and (Ila**)

and wherein the mixture is resolved by chiral resolution to give the compound (H'a*).

100. The process of embodiment 99, wherein the resolution is carried out by a process comprising

(ia) adding a single stereoisomer of a chiral acid and precipitating, preferably crystallizing, a chiral acid salt (Sa) of compound (Ila'), thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (Sa) and the solvent,

(iia) preferably separating the precipitated, preferably crystallized, chiral acid salt (Sa) of the compound of formula (Ila') from the mixture obtained in (ia), wherein the chiral acid salt (S) contains at least 80 % by weight of the chiral acid salt of the compound of formula (Ila'*) based on the total weight of the chiral acid salt of the compound of formula (Ila'),

(iiia) converting the chiral acid salt (Sa) to the free base.

101. The process of any of embodiments 90 to 100, wherein compound (II) contains of from 20 to 75 % by weight % of the compound of formula (II*) based on the total weight of the sum of II*) and (II**)

(Π*) (II**),

and wherein the mixture is resolved by chiral resolution to give the compound (II*).

102. The process of embodiment 101, wherein the resolution is carried out by a process comprising

(ia) adding a single stereoisomer of a chiral acid and precipitating, preferably crystallizing, a chiral acid salt (Sa) of compound (II), thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (Sa) and the solvent,

(iia) preferably separating the precipitated, preferably crystallized, chiral acid salt (Sa) of the compound of formula (II) from the mixture obtained in (ia), wherein the chiral acid salt (S) contains at least 80 % by weight of the chiral acid salt of the compound of formula (II*) based on the total weight of the chiral acid salt of the compound of formula (II),

(iiia) converting the chiral acid salt (Sa) to the free base.

103. The process of any of embodiments 90 to 102, wherein the reacting of (a-i) is a reduction, preferably the reacting of (a-i) is selected from a reductive amination and hydrogenation, preferably reductive amination.

104. The process of embodiment 103 wherein the reductive amination is carried out using a reagent selected form the group consisting of NaBH ₄ , NaBH ₃ CN, NaBH(OAc) ₃ , LiAlH ₄ .

105. The process of embodiment 103 or 104, wherein the reductive amination of step (a- i) is carried out at a temperature in the range of -30 to 70 °C, more preferably in the range of from -10 to 50 °C, even more preferably in the range of from 10 to 30°C.

106. The process of any of embodiments 103 to 105, wherein the reductive amination of (a-i) is carried out in an organic solvent, more preferably in an organic solvent is selected from the group consisting of tetrahydrofuran (THF), trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof, even more preferably in a solvent selected from the group consisting of tetrahydrofuran (THF), methyltetrahydrofuran, methyltertbutylether, dichlormethane...

107. The process of embodiment 103, wherein the hydrogenation is carried out. 108. The process of embodiment 103 or 107, wherein the hydrogenation of (a-i) is carried out at a temperature in the range of -10 to 100 °C, more preferably in the range of from 10 to 70°C, even more preferably in the range of from 20 to 50°C.

109. The process of any of embodiments 103 or 106 to 108 wherein hydrogenation of (a- i) is carried out in an organic solvent, more preferably the organic solvent is selected from the group consisting tetrahydrofuran (THF), trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile , ethyl acetate, isopropyl acetate and mixtures of two or more thereof, more preferably in tetrahydrofuran, ethyl acetate, methanol, ethanol, acetic acid and mixtures of two or more thereof, even more preferably in a solvent selected from the group consisting of tetrahydrofuran (THF), methyltetrahydrofuran, methyltertbutyleter, dichlormethan.

110. The process of any of embodiments 90 to 109, further comprising

(b) reacting the compound of formulae (II) or (Ha') with a base, preferably selected from the group consisting of NaOR ^E , Na-tert.butoxid, K- tert.butoxid, NaNH ₂ , DBU, Tetramethylguanidin, Na-CH ₂ S(0)CH ₃ and mixtures of two or more thereof is employed, with R ^E being selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E methyl, ethyl or propyl, more preferably wherein R ^E methyl and obtainin a compound of formula (A) or (Aa)

preferabl

111. The process of embodiment 110, wherein (b) is according to embodiments 1 to 51.

112. The process of embodiment 111, wherein (b) comprises (bl) reacting the compound of formula (II) or (IF a) with a base and obtaining a composition com rising a compound of formula (A), preferably (A*) wherein n=l

(b2) optionally purifying the compound obtained in (b 1 ),

(b3) optionally reducing the compound of (bl) or (b2) and obtaining a compound of formula (A), preferably of formula (A*) wherein is n=0.

The process of any of embodiments 110 to 111, wherein compound (A*) is a compound of formula

114. The process of any of embodiments 110 to 112, wherein the compound (A) or (Aa) or (A*) are further reacted to a com ound of formula

115. A process for preparing a compound of formula (II) or (Ila) or (Ila'), according to any of embodiments 52 to 83.

116. A process for preparing a compound of formula (II) or (Ila'), according to any of embodiments 90 to 109.

117. A compound of formula (IX) wherein the compound contains less than 5 % by weight, more preferably less than 2 % by weight, more preferably less than 1 % by weight, more preferably less than 100 ppm, of the regio-isomeric side product (IX- S) as impurity

based on the total weight of the compound (IX), which includes the compound (IX-

S).

118. A compound of formula (Ila) or (Ha') or (Ila) obtained or obtainable by

the process of any of embodiments 52 to 83.

119. A compound of formula (Ila) or (Ila') obtained or obtainable by the process of any of embodiments 90 to 109.

120. A compound of formula (II) obtained or obtainable by the process of any of embodiments 52 to 83, 90 tol09.

121. A compound of formula (A

or a pharmaceutically acceptable salt or solvate thereof,

wherein A) is preferably

and wherein R ² is selected from the group consisting of H, PG ² and R ^B with R ¹ B being

and wherein PG ¹ and PG ² are, independently of each other, suitable protecting groups,

and wherein n is 0 or 1 , and wherein in case n = 0 and R ¹ is R ^A , R ² is not R ^B .

122. The compound according to embodiment 121 having the structure of formula (VI)

wherein PG ¹ is a suitable protecting group, preferably Boc.

123. The compound according to embodiment 121 having the structure

preferably

wherein R ¹ is H or PG ¹ and PG ¹ is a suitable protecting group, preferably wherein PG ¹ is Boc, more preferably wherein R ¹ is H.

124. The compound of embodiment 121 , wherein n is 1 and R ¹ is H.

125. The compound of embodiment 121 in crystalline form, wherein n is 0 and R ¹ is H, wherein the compound has the structure

wherein the crystalline form has an X-ray powder diffraction pattern comprising a peak at 2-theta angle of approximately 12.4 ° ± 0.2 °, more preferably has an X-ray powder diffraction pattern comprising peaks at 2-theta angles of approximately 4.8 ± 0.2 °, 12.4 ° ± 0.2 °, 14.2 ° ± 0.2 °, 19.9 ° ± 0.2 ° and 20.8 ° ± 0.2 ° or at approximately 7.7 ± 0.2 °, 11.4 ° ± 0.2 °, 12.4 ° ± 0.2 °, 16.2 ° ± 0.2 ° and 18.1 ° ± 0.2 °, more preferably, at approximately 4.8 ± 0.2 °, 12.4 ° ± 0.2 °, 14.2 ° ± 0.2 °, 19.9 ° ± 0.2 ° and 20.8 ° ± 0.2 ° the X-ray is when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm.

The compound according to embodiment 121 having the structure of formula (VI)

The compound accordin to embodiment 121 having the structure of formula (VIII)

with R ² being H or PG ² and PG ² being a suitable protecting group.

A compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof,

preferably of formula (II*)

wherein R ^E is selected from the group consisting of H, alkyl, preferably Ci-C ₆ alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, even more preferably, Ci-C ₆ alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl,

wherein R ¹ is selected from the roup consisting of H, PG ¹ and R ^A with R ^A being

and wherein R ² is selected from the group consisting of H, PG ² and R ^B with R ¹ being

and wherein PG ¹ and PG ² are, independently of each other, suitable protecting groups.

The compound of embodiment 128, wherein

when R ¹ is H R ² is not H and wherein when R ² is H R ¹ is not H or

wherein PG ¹ is selected from the group consisting of Boc (t-butyloxycarbonyl, Cbz

(carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates, trityl, benzyl, benzylidene, tosyl, PNZ, trifluoroacetate, formyl, and benzoyl t-butyldimethylsilyl and triisopropylsilyl. The compound of embodiment 129, wherein PG ¹ is selected from the group consisting of Boc and Cbz.

The compound of embodiment 128, wherein R ^E is methyl, R ² is

and wherein R ¹ is H or Boc, preferably Boc.

132. The compound of embodiment 128, wherein R ^E is methyl, R ¹ is H and R ² is Cbz.

133. The compound of embodiment 128, wherein R ^E is methyl, R ¹ is Boc and R ² is Cbz.

134. The compound of embodiment 128, wherein R ^E is methyl, R ¹ is Boc and R ² is H.

135. The compound of formula Ila')

(Ila') preferably of formula

(Ila*)

wherein

R ^E is selected from the group consisting of H, Ci-C ₆ , alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably R ^E is alkyl, more preferably R ^E is methyl, ethyl or propyl, more preferably R ^E is methyl,

R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of phthalimido group of formula

and succinimido group of formula s)

R ^2a is H, PG ² , R ^B or PG ^2a '

PG ² or PG ^2a are suitable protecting groups, preferably selected from the group consisting of Boc and Cbz

R is

136. The compound of embodiment 135, wherein R ^la and R ^lb taken together form a phthalimido group (p) or a succinimido group (s).

137 Use of a compound of formula (A)

preferably of formula (A*

or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is selected from the group consisting of H, PG ¹ and R ^A with R ^A being

and wherein R ² is selected from the group consisting of H, PG ² and R ^B with R ¹ being

and wherein PG ¹ and PG ² are, independently of each other, suitable protecting groups,

and wherein n in case n = 0, at least one of R ^A or R ^B is H or a protecting group, for the preparation of a compound having the structure of formula (IX)

Use of a compound of formula (II)

preferably of formula (II*)

(IP),

wherein R ¹ is selected from the group consistin of H, PG ¹ and R ^A with R ^A being

and wherein R ² is selected from the group consisting of H, PG ² and R ^B with R ¹ being

and wherein PG ¹ and PG ² are, independently of each other, suitable protecting groups

for the preparation of a com ound having the structure of formula (IX).

(IX). Use of the compound according to embodiments 137 and 138, for the preparation of a compound havin the structure of formula (IX).

A process for the preparation of a compound of formula (IV)

wherein R4 is H or a protecting group PG2

and R3' is H or a protecting group PG1

the process comprising:

(i) providing a compound of formula (I)

wherein R is H or alkyl

(ii) reacting the compound of formula (I) with a compound of formula (III)

in the presence of an activating agent, wherein

and R4' is H or alkyl

(iii) removing either PG1 or PG2

(iv) subjecting the compound obtained in step (iii) to basic reaction conditions to give the compound of formula (IV)

with the proviso that at least one of R3 or R4' is H, and wherein either R4 or R3'

H.

The process of embodiment 140, wherein - R3 is H and R4' is alkyl, or

- R3 is alkyl and R4' is H.

142 The process of embodiment 140 or 141, wherein step (i) comprises

ia) providing a compound of formula (II)

and

ib) providing a compound of formula (IF)

ic) reacting compound (II) and compound (IF) to give a compound of formula

(I ) wherein R3" is a protecting group PG3, preferably Benzyl, id) subjecting compound (F) to reductive conditions, obtaining a mixture comprising the compound of formula (I-H)

if) protecting the amine group of (I-H) with a protecting group PG1

to give the compound of formula (I).

143. The process of any of embodiments 140 to 142, wherein R4' is H and PG2 is a protecting with a negative mesomeric effect.

144 The process of embodiment 143, wherein PG2 is selected from the group consisting of trifluoroacetate, trichloroacetate, Fmoc, Pthalimide and Boc, preferably wherein PG2 is Boc.

145. The process of embodiment 143 or 144, wherein PG1 is a protecting group with a positive inductive effect, preferably benzyl or phenylethyl. The process of any of embodiments 140 to 145, wherein the compound (IV) has the structure (IVa),

wherein PG1 is a protecting group preferably a protecting group with positive inductive effect, more preferably benzyl or ethylphenyl, more preferably benzyl, and wherein process comprises

(i) providing a compound of formula (la)

O NH-PG ¹

R ³ 0- — ^ (la)

wherein R3 is alkyl, preferably methyl

reacting the compound of formula (la) with a compound of formula (Ilia)

PG ² -HN^ ^0H

O (Ilia)

in the presence of an activating agent to give a compound having the structure (Ia-IIIa)

removing PG2 to give a compound

(iv) subjecting the compound obtained in step (iii) to basic reaction conditions to give the compound of formula (Via).

The process of embodiment 146 wherein R3" is benzyl and wherein in step ib) the compound (IF) is provided by reacting a compound of formula (II")

with Phenyl-CHO under reductive conditions.

148. The process of any of embodiments 140 to 142, wherein R3 is H and PGl is a protecting with a negative mesomeric effect.

149. The process of embodiment 148, wherein PGl is selected from the group consisting of rifluoroacetate, trichloroacetate, Fmoc, Pthalimide and Boc, preferably wherein PGl is Boc.

150. The process of embodiments 148 or 149, wherein PG2 is a protecting group with a positive inductive effect, preferably benzyl or phenylethyl.

151. The process of any one of embodiments 140 to 142 or 148 to 150, wherein the compound (IV) has the structure (IVb)

wherein PG2 is a protecting group preferably a protecting group with positive inductive effect, more preferably benzyl or ethylphenyl, more preferably benzyl, and wherein process comprises

(i) providing a compound of formula (lb)

reacting the compound of formula (lb) with a compound of formula (Illb)

(nib)

wherein R4' is alkyl, preferably methyl, in the presence of an activating agent to give a compound having the structure (Ib-IIIb)

(iii) removing PG1 to give a compound

(iv) subjecting the compound obtained in step (iii) to basic reaction conditions to give the compound of formula (VIb).

152. The process of any of embodiments 140 to 151, wherein the activating agent in (ii) is selected from the group consisting of HATU (0-(7-azabenzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate); HOAt, HBTU (O- benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); TBTU (2- (lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate); TFFH (N,N',N",N"-tetramethyluronium-2-fluoro-hexafluorophosphate) ; BOP (benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate); PyBOP (benzotriazol- 1 -yl-oxy-trispyrrolidino-phosphonium hexafluorophosphate; EEDQ (2-ethoxy-l-ethoxycarbonyl-l,2-dihydro-quinoline); DCC

(dicyclohexylcarbodiimide); DIPCDI (diisopropylcarbodiimide); HOBt (1- hydroxybenzotriazole); NHS (N-hydroxysuccinimide); MSNT (l-(mesitylene-2- sulfonyl)-3-nitro-lH-l,2,4-triazole); aryl sulfonyl halides, e.g. triisopropylbenzenesulfonyl chloride, EDC (l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, CDC (l-cyclohexyl-3-(2- morpholinoethyl)carbodiimide), Pyclop, T3P, CDI, Mukayama's reagent, HODhbt, HAPyU, TAPipU, TPTU, TSTU, TNTU, TOTU, BroP, PyBroP, BOI, TOO, NEPIS, BBC, BDMP, BOMI, AOP, BDP, PyAOP, TDBTU, BOP-Cl, CIP, DEPBT, Dpp-Cl, EEDQ, FDPP, HOTT, TOTT and PyCloP.

153. A process for the preparation of a compound of formula (A)

wherein R is selected from the group consisting H, PG2, PG4 and

wherein PG4 is a suitable protecting group

and wherein R ² is selected from the roup consisting of H, PGl, PG5, and

wherein PG5 is a suitable protecting group

the process comprising

(I) providing a compound (IV)

wherein R4 is H or a protecting group PG2

and R3' is H or a protecting group PGl

preferably according to the method of any one of embodiments 1 to 12,

(II) reducing the compound of formula (IV)

(III) optionally replacing R4 with Rl in case Rl differs from R4, and

optionally replacing R3 ' with R2 in case R2 differs from R3 '

to give the compound of formula (A).

The process of embodiment 153, R4 is H and Rl is

and wherein step (III) comprises

reacting the compound with a compound of formula (XII)

wherein X* is a leaving group, preferably CI.

The process of any of embodiments 153 or 154 wherein R3' is H and wherein R ² is

and wherein step (III) comprises

reacting the compound with a com ound of formula (XI)

E is selected from the group consisting of halogen, -CN and -C(=0)R ⁵ , wherein R ⁵ is selected from the group consisting of -O-Alkyl, -OH, -H and X with X being the leaving group of the activated ester group -C(=0)-X, preferably wherein E is - COOH.

The process of any one of embodiments 153 to 155, wherein (A) has the structure

The process of embodiment 156, wherein the process comprises

(I) providing a compound (IV)

wherein R ⁴ is H

and R ³ is a protecting group PGl, and wherein PGl is preferably a protecting group with + I effect, more preferably benzyl

wherein compound (IV) is preferably provided by a method as described above,

(II) reducing the compound of formula (IV) to give a compound (IV-H)

(III) replacing R ⁴ with R ¹ and replacing R ³ with R ² wherein step (III) comprises:

(Ilia) protecting R4 with a suitable protecting group PG ^IIIA , which is preferably a protecting group being orthogonal to the protecting group PGl, more preferably which is Boc,

(Illb) removing PGl to give a compound of formula (IV-PGIIIa-H) (IV-PGIIIa-H)

coupling (IV-PGIIIa-H with with a compound of formula (XI)

wherein E is selected from the group consisting of halogen, -CN and - C(=0)R ⁵ , wherein R ⁵ is selected from the group consisting of -O-Alkyl, -OH, -H and X with X being the leaving group of the activated ester group -C(=0)-X

(Hid) removing PGIIIa

(Hie) reacting the compound with a compound of formula (XII)

wherein X* is a leaving group

to give the compound of formula (A).

The process of embodiment 156, wherein the process comprises

(I) providing a compound (IV)

wherein R ⁴ is PG2, wherein PG2 is preferably a protecting group with -M effect, more preferably benzyl

and R ^3' H wherein compound (IV) is preferably provided by a method as described above,

(II) reducing the compound of formula IV) to give a compound (IV-H)

(III) replacing R ⁴ with R ¹ and replacing R ³ with R ²

wherein step (III) comprises:

(Ilia) protecting R3' with a suitable protecting group PG ^{IIIA b} , which is preferably a protecting group being orthogonal to the protecting group PG1, more preferably which is Boc,

(Illb) removing PG2 to give a compound of formula (IV-PGIIIa/b-H)

N-PG ^{llla b}

(IV-PGIIIa/b-H)

reacting the compound with a compound of formula (XII)

wherein X* is a leaving group, preferably CI

(Hid) removing PGIIIa-b

(Hie) coupling (IV-PGIIIa/b-H with with a compound of formula (XI)

wherein E is selected from the group consisting of halogen, -CN and - C(=0)R ⁵ , wherein R ⁵ is selected from the group consisting of -O-Alkyl, -OH, -H and X with X being the leaving group of the activated ester group -C(=0)-X

to give the compound of formula (A).

Process for the preparation of a compound of formula (I)

wherein R ³ is H or alkyl, wherein alkyl is preferably Ci-C ₆ alkyl,

the process comprising

ia) providing a compound of formula (II)

and

ib) providing a compound of formula (IF)

ic) reacting compound (II) and compound (IF) to give a compound of formula

(I )

wherein R3" is a protecting group PG3, preferably Benzyl,

id) subjecting compound (F) to reductive conditions, obtaining a mixture comprising the compound of formula (I-H)

if) protecting the amine group of (I-H) with a protecting group PG1

to give the compound of formula (I).

The process of embodiment 159 wherein R3" is benzyl and wherein in step ib) the compound (IF) is provided by

reacting a compound of formula (II")

with Phenyl-CHO in the presence of a reducing agent. 161. The process of embodiment 159 or 160, wherein PG1 is a benzyl group and wherein the protecting condition of step if) comprises reacting the compound (I-H) with Phenyl-CHO in the presence of a reducing agent.

162. A compound formula (IV)

obtained or obtainable by a method of any one of embodiments 1 to 12.

163. A compound of formula (A)

obtained or obtainable by a method of any one of embodiments 13 to 18.

164. A compound of formula (I)

obtained or obtainable by a method of any one of embodiments 19 to 20

165. A compound formula (IV)

wherein R4 is H or a protecting group PG2

and R3 ' is H or a protecting group PG1.

166. The compound of embodiment 165, wherein R4 is H and R3' is benzyl.

167. The compound of embodiment 166, wherein R4 is benzyl and R3' is H.

168. A compound of formula (I-H) wherein R3 is alkyl, preferably methyl.

169. A compound of formula (Γ)

wherein R3" is a protecting group PG3, preferably Benzyl, Use of a compound of formula (I)

O NH-PG ¹

R3 ₀ ^\^\ (I) wherein R3 is H or alkyl, preferably alkyl, more preferably methyl, and wherein PG1 is a protecting group

for preparing a compound of formula (IV) or a compound of formula (A).

Use of a compound of formula (I)

O NH-PG ¹

R3 ₀ ^\^\ (I) for the preparation of a compound of formula (A), wherein the compound of formula (A) has a structure accordin to formula (IX)

FIGURES:

Fig. 1 and 2 show preferred synthesis schemes according to the invention.

Fig. 3 and Fig. 4 show alternative schemes of suvorexant synthesis based on homoalanine

Fig. 5 show a schemes of the synthesis of compound (II) and (A) based on homoalanine process.

EXAMPLES:

Preparation of (Z)-Methyl 3-((2-((fert.-Butoxycarbonyl)amino)ethyl)amino)but-2- enoate ,ΝΗΒοο X X . J!¾_^ _, ΑΑ _,

MED

C ₇ H ₁₆ N ₂ 0 ₂ C ₅ H ₈ 0 ₃ r.t. C ₁₂ H22N ₂ 04

MW: 160,21 MW: 1 16,12 MW: 258,31

Boc-ethylenediamine (84.3 g, 500 mmol) was dissolved in CH ₂ CI ₂ (110 mL), transferred into a 500 mL Schmizo and cooled to 10 °C. Silica gel (120 g) was added in portions and the slurry was diluted with CH ₂ CI ₂ (50 mL). Methyl acetoacetate (54 mL, 500 mmol) was added, the reaction mixture was stirred at 20 °C and the reaction progress was monitored by GC. The reaction was judged complete after one hour. The silica gel was filtered off and the filter cake was washed with CH ₂ CI ₂ (250 mL). The slightly yellow solution was concentrated under reduced pressure to give the enamine as slightly yellow oil (127.9 g).

1H NMR (300 MHz, CDC1 ₃ ): δ:= 8.57 (br s, 1H), 4.84 (br s, 1H), 4.47 (s, 1H), 3.61 (s, 3H), 3.33 (m, 2H), 3.23 (m, 2H), 1.91 (s, 3H), 1.43 (s, 9H). ¹³ C NMR (75 MHz, CDC1 ₃ ): δ= 170.9, 162.0, 155.9, 82.7, 79.6, 50.0, 42.8, 41.3, 28.3, 19.3. All data are in agreement with the data reported in literature (see J. Org. Chem. 2010, 75, 6023).

Preparation of Methyl 3-((2-((tert.-butoxycarbonyl)amino)ethyl)amino)butanoate via Hydrogenation

^12^22^2^4 C-I2H24N2O4

MW: 258,31 MW: 260,33

A solution of the enamine (58.7 g, 227 mmol) in MeOH (650 mL) was hydrogenated in the /presence of 73 g Pd/C at 55 °C at a pressure of 3 bar. The reaction was monitored by GC. After complete conversion (approximately 7 hours) the suspension was filtered over a K150 filter and the solid was washed with MeOH. The solution was concentrated under give the β-aminoester (51.6 g, 87%) as oil.

1H NMR (300 MHz, CDC1 ₃ ): δ= 5.28 (br s, 1H, NH), 3.99 (br s, 1H, NH) 3.66 (s, 3H, OCH ₃ ), 3.13 - 3.25 (overlapping m, 3H, CH ₂ + CH), 2.78 (m, 2H, CH ₂ ), 2.48 (m, 2H, CH ₂ ), 1.41 (s, 9H, C(CH ₃ ), 1.15 (d, J = 6.3 Hz, 3H, CH ₃ ). ¹³ C NMR (75 MHz, CDCI3): δ = 172.2, 156.1, 79.2, 51.6, 50.1, 45.9, 40.6, 39.8, 28.3, 19.7.

Preparation of Methyl 3-((2-((tert.-butoxycarbonyl)amino)ethyl)amino)butanoate with an Enantiomeric Excess of ee = 93% via Asymmetric Hydrogenation

46.2mg (0.085 mmol) ferrocenyl ligand and 29.0 mg (0.077 mmol) [Rh(nbd)2]BF4 were placed in a lOmL Schlenk flask that was previously set under an atmosphere of argon. Then 6mL degassed 2,2,2-trifluoroethanol (TFE) was added and the resulting red solution stirred for 30 min. at 50°C. In a second Schlenk flask, 0.5g (1.94mmol) of enamine ((Z)- methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)but-2-enoate) was placed, followed by 14mL degassed TFE. The clear solution was stirred for 10 min. Then, both the substrate and the catalyst solution were transferred via syringe into a 50mL stainless steel reactor that was previously set under an atmosphere of argon. The reactor was sealed, purged with argon in three cycles (lbar/20bar) and finally, the argon replaced by hydrogen (4 cycles lbar/20bar). The reactor pressure was set to lObar hydrogen, heating to 50°C and stirring started. After 21 firs, reaction time, the autoclave was cooled to ambient temperature and the pressure released.

The crude product was analyzed by GC with respect to conversion and chemoselectivity and upon derivatization with 4-chlorobenzoylchloride by chiral HPLC method. The conversion after 21 hrs. was >99.5%, and product 2 (methyl 3-((2-((tert- butoxycarbonyl)amino)ethyl)amino)butanoate) was formed with approx. 60% chemoselectivity and 93%ee (first-eluting enantiomer).

Preparation of Methyl 3-((2-((tert.-butoxycarbonyl)amino)ethyl)amino)butanoate via Reduction

C-12H22N2O4 C-12H24 2O4

MW: 258,31 MW: 260,33

NaBH ₄ (33.0 g, 872 mmol) was added in small portions over a period of 90 minutes into vigorously stirred acetic acid (500 mL) and the internal temperature was kept between 15 - 20 °C. Vigorous gas formation was observed as well as the formation of a thick suspension halfway through the addition. MeCN (250 mL) was added, the suspension was stirred for 30 minutes and the internal temperature was adjusted to 0 - 5 °C. A solution of the enamine (113.0 g, 437 mmol) in MeCN (150 mL) was added over a period of 45 minutes at 0 - 5 °C followed by a MeCN-rinse (100 mL). The reaction mixture was stirred for 2.5 hours at 5 °C before being cautiously quenched with H ₂ 0 (100 mL, gas formation). (At that stage the pH was adjusted to pH = 7.0 with NaOH (50%) and CH ₂ C1 ₂ (100 mL) was added which resulted in the formation of two phases. The two phases were stirred over night: holding point). The pH-value was adjusted to pH = 11.5 with NaOH (50%). In order to avoid the formation of solids in the aqueous layer H ₂ 0 (-800 mL) was added. The organic phase was separated and washed with H ₂ 0. The combined aqueous phases were extracted twice with ethyl acetate (250 mL each). The combined organic phases were dried over Na ₂ S0 ₄ , filtered and concentrated to give the β-aminoester (112. Og) as colorless oil.

The analytical data were in full agreement with the data obtained by hydrogenation.

Preparation of Methyl 3-((2-((tert.-butoxycarbonyl)amino)ethyl)amino)butanoate with an Enantiomeric Excess of ee = 33% via Chiral Resolution

Racemic β -aminoester was resolved with tartaric acid to give enantiomerically enriched b- aminoester.

Preparation of 7-Methyl-l,4-diazepan-5-one:

MW: 260,33 MW: 128,17 Procedure "Cbz-protection":

H ₂ 0 (500 mL) was added to a solution of the b-aminoester (78.0 g, 300 mmol) in EtOAc (1000 mL) at room temperature. Benyzl chloro formate (Cbz-CI, 51.4 mL, 360 mmol) was added slowly and the pH-value was kept between pH = 8 - 9 by the addition of NaOH (10 M). The reaction was slightly exotherm and GC indicated complete conversion of the starting material after 30 minutes. The two phases were separated and the organic phase was washed with a saturated NaHC0 ₃ solution (300 mL). The solution was concentrated under reduced pressure to give the Cbz-protected amine quantitatively (128.4 g) as oil. The crude product was used in the next step without any further purification. 1H NMR (300 MHz, CDC1 ₃ ): = 7.33 - 7.39 (m, 6H, H _arom + NH), 5.13 (s, 2H, OCH ₂ ), 4.32 (br s, 1H, CH), 3.61 (s, 3H, OCH ₃ ), 3.21 - 3.35 (br m, 4H, CH ₂ , CH ₂ ), 2.42 - 2.80 (series of br m, 2H, CH ₂ ), 1.43 (s, 9H, C(CH ₃ ) ₃ ), 1.26 (br s, 3H, CH ₃ ).

Procedure "Boc-deprotection": HC1 (37w%, 45 mL, 540 mmol) was added to a stirred solution of the Boc-protected amine (128.4 g, calcd. as 270 mmol) in MeOH (1200 mL) and the reaction mixture was stirred at 50 °C for two hours and at 80 °C for one hour. The reaction progress was monitored by HPLC and the reaction was judged complete after 4 hours. The reaction mixture was concentrated to a volume of approximately 250 mL. A solid precipitated during the MeOH-destillation. Acetone (1000 mL) was added dropwise and the solvent was removed completely. CH2CI2 (300 mL) was added and then removed by distillation. The product (amine in form of HC1 salt, 1 16.7 g) was obtained as foam and used in the next step without any further purification.

Procedure "Cyclization":

NaOMe (51.2 g, 972 mmol) was added to a stirred solution of the amine. HC1 salt (1 16.2 g, calculated as 243 mmol) im MeOH (1000 mL) at room temperature. An exotherm reaction was observed. The reaction mixture was stirred over night at room temperature. The solids were filtered off over a K150 filter and washed with MeOH (100 mL). The solution of the crude product was used directly in the next step without further purification.

A small aliquot was used for characterization. 1H NMR (300 MHz, CDC1 ₃ ): δ = 7.36 (m, 5H, H _arom .), 5.15 (s, 2H, OCH ₂ ), 4.74 (br m, 2H, NH, CH), 4.25 (br s, 1H, CH _A ), 3.34 (m, 1H, CHx), 3.15 (m, 2H, CH _B , CH _Y ), 2.81 (d, / = 14.5 Hz, 1H, CH _P ), 2.50 (dd, / = 14.5, 5.9 Hz, 1H, CH _Q ), 1.26 (d, / = 7.0 Hz, 3H, CH ₃ ).

Procedure "Cbz-deprotection":

The abovementioned solution of the Cbz-protected amine (calcd. as 219 mmol) in MeOH (1 100 mL) was concentrated to a volume of approximately 700 mL. This solution was hydrogenated in the presence of Pd/C (46 g, 10%Pd) at room temperature at a H ₂ -pressure of 2 bar. The hydrogenation was monitored by HPLC and judged complete after two hours. The suspension was filtered over a K150 filter and the filter cake was washed with MeOH. The solution of the crude product was concentrated under reduced pressure and the residue (71.4 g) was taken up in CH ₂ C1 ₂ (200 mL). The solution was stirred for 30 minutes and the remaining solids were filtered off. The solution was concentrated and the residue (30 g) started crystallizing upon standing at room temperature. MTBE (200 mL) was added and the suspension was stirred for one hour. The solid was filtered off, washed with MTBE and dried over night at 40 °C/2 mbar to give 7-methyl-l ,4-diazepan-5-one (17.4 g, 62%) as colorless crystals.

1H NMR (300 MHz, CDC1 ₃ ): δ = 7.31 (br s, 1H, C(O)NH), 3.28 (m, 1H, CH _A ), 2.90 - 3.14 (series of overlapping m, 3H, CH, CH _B , CH _X ), 2.77 (m, 1H, CH _Y ), 2.51 (dd, J = 14.1 , 9.6 Hz, 1H, CHp), 2.35 (apparent d, / = 14.3 Hz, 1H, CH _Q ), 2.03 (br s, 1H, NH), 1.09 (d, / = 6.5 Hz, 3H, CH ₃ ). ¹³ C NMR (75 MHz, CDC1 ₃ ): δ = 177.3, 49.4, 47.2, 44.4, 23.6.

Chiral Resolution of 7-Methyl-l,4-diazepan-5-one:

Chiral resolutions were achieved with several chiral acids with varying degree of induction by performing a systematic screening. Here, the best hit will be described as a representative example. DTTA corresponds to (-)-Di-0,0'-toluyl-D-tartaric acid and LTTA corresponds to the enantiomer (+)-Di-0,0'-toluyl-L-tartaric acid. A solution of the chiral acid (62.8 mg, 0.16 mmol) in MeOH (0.5 mL) and a solution of racemic 7-methyl- l,4-diazepan-5-one (41.4 mg, 0.32 mmol) in MeOH (0.8 mL) were combined and allowed to crystallize over night. The solid was filtered and the enantiomeric excess was determined by HPLC. The enantiomeric ratio was > 40 : 1 in both cases, the absolute stereochemistry is determined according to literature proceedings.

Reaction of Methyl 3-((2-((tert.-butoxycarbonyl)amino)ethyl)amino)butanoate and 5- Methyl-2-(2H-l,2,3-triazol-2-yl)benzoic Acid:

Oxalyl chloride (14.26 g, 118.1 mmol) was added over a period of 14 minutes to a stirred suspension of 5-Methyl-2-(2H-l,2,3-triazol-2-yl)benzoic Acid (20.0 g, 98.4 mmol) in CH ₂ CI ₂ (132 mL) and DMF (2.0 mL) at 1 °C. After complete addition the reaction mixture was stirred for 30 minutes at 5 °C. An addition funnel was charged with a solution of 3- ((2-((iert.-butoxycarbonyl)amino)ethyl)amino)butanoate (24.4 g, 93.7 mmol) in CH ₂ CI ₂ (340 mL) and NEt ₃ (19.0 g, 187.4 mmol). The amine solution was added over a period of 40 minutes to the stirred acid chloride solution at a rate to keep the internal temperature < 10 °C. The reaction progress was monitored by HPLC and the reaction was judged complete after two hours. The reaction was quenched with ¾0 (250 mL) and the pH- value was adjusted to pH = 10.0 by the addition of NaOH (2.0 M). The organic layer was separated and washed with H ₂ 0 (250 mL) at a pH = 2.0 adjusted with HC1 (2.0 M). The organic phase was concentrated under reduced pressure. The residue was taken up in toluene (100 mL) and concentrated under reduced pressure to give 49.6 g residue. The residue was taken up in cyclohexane (~ 250 mL) and stirred for two hours at room temperature. The solid was filtered, washed twice with cyclohexane (2 x 20 mL) and dried (40 °C, < 5 mbar) to give the product (35.4 g, 84% yield) as a crystalline solid. 1H NMR (300 MHz, DMSO-D ₆ ):5= 6.77 - 8.07 (series of overlapping m, 6H), 3.88 - 4.37 (series of overlapping m, 1H), 3.42 - 3.66 (three s, 3H), 2.56 - 3.35 (series of overlapping m, 6H), 2.39 (three s, 3H), 0.82 - 1.40 (series of overlapping m, 12H).

Preparation of Methyl 3-(N-(2-aminoethyl)-5-methyl-2-(2H-l,2,3-triazol-2- yl)benzamido)butanoate Hydrochloride by Boc-Cleavage:

C22H31 N5O5 C ₁₇ H ₂₄ CIN ₆ 0 ₃

MW: 445,51 MW: 381 ,86

HC1 (1.25 M in MeOH, 136.3 mmol) was added to a solution of the Boc-protected amine (30.4 g, 68.2 mmol) in MeOH (304 mL) and the reaction mixture was refluxed. The reaction progress was monitored by HPLC and judged complete after 5.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in toluene (100 mL) and concentrated under reduced pressure to give 30.5 g foam. Crystallization from toluene and cyclohexane gave Methyl 3-(N-(2- aminoethyl)-5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)benzamido)butanoate Hydrochloride (25.1 g, 97%) as a crystalline solid.

1H NMR (300 MHz, D ₂ 0): δ = 7.14 - 7.93 (series of overlapping m, 5H), 2.88 - 4.41 (series of overlapping m, 8H), 2.05 - 2.77 (series of overlapping m, 5H), 1.10 - 1.33 (series of d, 3H).

Preparation of 7-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoyl)-l,4-d iazepan- 5-one via Cyclization of Methyl 3-(N-(2-aminoethyl)-5-methyl-2-(2H-l,2,3-triazol-2- yl)benzamido)butanoate Hydrochloride:

C ₁₇ H ₂₄ CIN ₆ 0 ₃ C ₁₆ H ₁₉ N ₅ 0 ₂

MW: 381 ,86 MW: 313,35

NaOMe (6.0 g, 115.3 mmol) was added to a solution of Methyl 3-(N-(2-aminoethyl)-5- methyl-2-(2H-l,2,3-triazol-2-yl)benzamido)butanoate Hydrochloride (29.34 g, 76.8 mmol) in MeOH (380 mL) at room temperature and the reaction progress was monitored by HPLC. The reaction was judged complete after 1.5 hours. The suspension was diluted with CH ₂ C1 ₂ (380 mL) and H ₂ 0 (380 mL) and the organic layer was separated. The aqueous layer was extracted twice with CH ₂ CI ₂ (2 x 200 mL) and the combined organic phases were concentrated under reduced pressure to give a residue that was taken up in cyclohexane (100 mL), filtered and dried to give 7-Methyl-l-(5-methyl-2-(2H-l ,2,3- triazol-2-yl)benzoyl)-l ,4-diazepan-5-one (17.6 g, 85% yield) as a crystalline solid. A second crystallization from the mother liquor gave additional 7-Methyl-l-(5-methyl-2-(2H- l ,2,3-triazol-2-yl)benzoyl)-l ,4-diazepan-5-one (1.7 g).

1H NMR (300 MHz, CDC1 ₃ , suspension): δ = 7.76 - 7.90 (m, 3H), 6.94 - 7.36 (series of m, 3H), 5.35 (m, -0.5H), 4.89 (m, -0.5H), 3.95 - 4.09 (series of m, -0.5H), 3.21 - 3.64 (series of overlapping m, 2H), 2.72 - 3.15 (series of overlapping m, -2.5H), 2.16 - 2.64 (series of m + s, 4H), 0.92 - 1.36 (series of d, 3H).

Preparation of 7-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoyl)-l,4-d iazepan- 5-one via Reaction of 7-Methyl-l,4-diazepan-5-one and 5-Methyl-2-(2H-l,2,3-triazol- 2-yl)benzoic Acid:

MW: 128,17 C ₁₀ H ₉ N ₃ O ₂ C16H19N5O2

MW: 203,20 MW: 313,35 A solution of oxalyl chloride (1.08 mL, 12.6 mmol) in CH ₂ CI ₂ (2 mL) was added over a period of 15 minutes to a suspension of 5-Methyl-2-(2H-l ,2,3-triazol-2-yl)benzoic Acid (2.13 g, 10.5 mmol) in CH ₂ C1 ₂ (14 mL) and DMF (0.22 mL) at 0 - 2 °C. The resulting clear solution was stirred for 30 minutes at 5 °C. An addition funnel was charged with a solution of 7-Methyl-l ,4-diazepan-5-one (1.34 g, 10.0 mmol) in CH ₂ C1 ₂ (1 1 mL) and NEt ₃ (2.9 mL, 21 mmol) and the solution was added over a period of 20 minutes. The reaction mixture was stirred for one hour at 5 °C and the reaction progress was monitored by HPLC. The reaction was quenched by the slow addition of ¾0 (27 mL) and the two phases were stirred for 15 minutes. The phases were separated and the organic layer was dried over MgS0 ₄ , filtered and concentrated under reduced pressure to give 3.3 g of a foam. The crude product was taken up in MeOH (7.5 mL) and the product was allowed to crystallize over night. The solid was filtered off, washed with MeOH and dried over night (40 °C, 2 mbar) to give 2.5 g (80% yield) 7-Methyl-l-(5-methyl-2-(2H-l ,2,3-triazol-2- yl)benzoyl)-l ,4-diazepan-5-one as a crystalline solid.

1H NMR (300 MHz, CDC1 ₃ ): δ = 7.77 - 7.91 (m, 3H), 6.85 - 7.37 (series of m, 3H), 5.36 (m, -0.5H), 4.90 (m, -0.5H), 3.93 - 4.13 (series of m, -0.5H), 3.21 - 3.64 (series of overlapping m, 2H, 2.16 - 3.16 (series of overlapping m, -6.5H), 0.92 - 1.37 (series of d, 3H). The analytical data are in full agreement with the data obtained via the other variant 1. Preparation of (7-Methyl-l,4-diazepan-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)methanone via Reduction of 7-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl)-l,4-diazepan-5-one:

C ₁₆ H ₁₉ N ₅ 0 ₂ C ₁₆ H ₂₁ N ₅ 0

MW: 313,35 MW: 299,37 7-Methyl-l-(5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoyl)-l,4-d iazepan-5-one (5.0 g, 15.9 mmol) was added to a suspension of NaBH ₄ (6.03 g, 159.9 mmol) in 2-MeTHF (100 mL) and the suspension was warmed to 45 °C. TFA (24.6 mL, 318 mmol) was added via syringe pump over a period of 16 hours at 55°C. (In this case the reaction did not go to completion. Additional NaBH ₄ and TFA had to be added). The reaction progress was monitored by HPLC and after complete conversion the reaction mixture was cooled to room temperature. The reaction was quenched by the addition of brine (500 mL). The organic phase was separated, washed with H ₂ 0 (200 mL) and dried over MgS0 ₄ . The drying agent was filtered and the solution was concentrated to give (7-M ethyl- 1,4- diazepan-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)meth anone (5.59 g) as a white solid.

The crude product was taken up in a mixture (25 mL) of heptane/ethyl acetate/NEt ₃ (1/1.5/0.1) and the solid was filtered to give (7-M ethyl- 1,4-diazepan-l -yl)(5 -methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone (3.30 g, 69%) as a crystalline solid.

Preparation of Suvorexant from (7-Methyl-l,4-diazepan-l-yl)(5-methyl-2-(2H-l,2,3- triazol-2-yl)phenyl)methanone and 2,5-Dichlorobenzoxazol

^c Xx SruvoreOxant¾

C ₇ H ₃ CI ₂ NO C ₁₆ H ₂₁ N ₅ 0 C ₂₃ H ₂₃ CIN ₆ 0 ₂

MW: 188,01 MW: 299,37 MW: 450,92

Oxalyl chloride (1.20 g, 9.4 mmol) was added dropwise to a stirred suspension of 2- mercapto-5-chlorobenzoxazol (1.28 g, 6.9 mmol) in CH ₂ C1 ₂ (37 mL) at < 20°C. DMF (4.59 g, 62.8 mmol) was added dropwise. A vigorous gas formation was observed and the suspension turned into a solution halfway throughout the addition. The reaction mixture was stirred for 20 minutes. Two additional aliquots oxalyl chloride (#1 : 0.20g, 1.35 mmol; #2: 0.40 g, 2.70 mmol) were added and the reaction mixture was stirred for 1.5 hours. HPLC indicated complete conversion of 2-mercapto-5-chlorobenzoxazol into 2,5- Dichlorobenzoxazol.

The solution of 2,5-Dichlorobenzoxazol was added to a solution of (7-Methyl-l,4- diazepan-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)meth anone (1.88 g, 6.3 mmol) and NEt ₃ (3.18 g, 6.3 mmol) in DMF (24 mL) at room temperature. The reaction mixture was then stirred at 70 °C for 19 hours and at 90 °C for 20 hours. The reaction mixture was then cooled to room temperature and quenched with a saturated solution of NaHC0 ₃ (50 mL). The organic phase was separated and washed with H ₂ 0 (50 mL) followed by brine (50 mL). The organic phase was dried over MgSC^, filtered and concentrated to give crude Suvorexant (3.58 g).

Chiral Resolution of a diazepam

(a) Formation of (R)-benzyl 5-methyl-l,4-diazepane-l-carboxylate.DBTA (compound 12).

OBz

Cbz- _N NH : Cbz- _N NH.DBTA

a ^cetone kA, ΗΟ ₂ 0

C ₁₄ H ₂₀ N ₂ O _{2 2} H ₃₄ N ₂ O ₁₀ - OBz

MW: 248,32 _{MW: 606 62} DBTA ^¾Η small scale

A solution of DBTA (1.48 g, 4.13 mmol) in acetone (6.5 mL) was added to a solution of racemic benzyl 5 -methyl- 1,4-diazepane-l-carboxylate (1.02 g, 4.11 mmol) and stirred at room temperature. A seeding crystal was added and the crystallization was stirred for 4 hours at room temperature and for 1 hour at 0 °C. The solid was filtered, washed with acetone (2.5 mL) and dried in vacuo to give 0.44 g (R)-benzyl 5 -methyl- 1,4-diazepane-l- carboxylate .DBTA (18% yield) with an enantiomeric ration of e.r. = 96.7 : 3.3.

large scale

A solution of DBTA (5.24 g, 14.62 mmol) in acetone (25 mL) was added to a stirred solution of racemic benzyl 5 -methyl- 1,4-diazepane-l-carboxylate (7.26 g, 29.24 mmol) in acetone (30 mL) at 40 °C. The onset of the crystallization occurred after 10 minutes. The crystallization was stirred at 40 °C for 4 hours and at room temperature over night. The solid was filtered, washed twice with acetone (2 x 8 mL) and dried under reduced pressure (<50 mbar, 45 °C) to give 5.50 g (R)-benzyl 5-methyl-l,4-diazepane-l-carboxylate.DBTA (31% yield) with an enantiomeric ratio of e.r. = 88.3 : 11.7.

(b) Recrystallization of (R)-benzyl 5-methyl-l,4-diazepane-l-carboxylate.DBTA

2Ο _{10 2} Ο ₁₀

MW: 606,62 MW: 606,62

(R)-benzyl 5-methyl-l,4-diazepane-l-carboxylate.DBTA (450 mg, 0.74 mmol) with an enantiomeric ration of e.r. = 88.3 : 11.7 was re-crystallized from EtOH (5 mL) by forming a solution at 60 °C and crystallizing at room temperature. The solid was filtered, washed twice with EtOH (2 x 2 mL) and dried to give (R)-benzyl 5 -methyl- 1,4-diazepane-l- carboxylate.DBTA (290 mg, 64% yield) with an enantiomeric ration of e.r. = 97.7 : 2.3.

(c) Isolation of (R)-benzyl 5 -methyl- 1,4-diazepane-l-carboxylate (compound (enantio)- 4) from (R)-benzyl 5-methyl- 1,4-diazepane-l -carboxylate.DBTA.

Cbz~ _N Cbz~ _{N H}

—

MW: 606,62 MW: 248,32 A solution of (R)-benzyl 5-methyl-l,4-diazepane-l-carboxylate.DBTA (2.04 g, 3.36 mmol) in CH ₂ C1 ₂ (40 mL) was extracted with H ₂ 0 at pH = 12.0 (adjusted with NaOH, 1.0 M). The organic layer was washed twice with H ₂ 0 (2 x 20 mL), concentrated under reduced pressure and dried in vacuo to give (R)-benzyl 5 -methyl- 1,4-diazepane-l- carboxylate (1.02 g, quant, yield).

1H NMR (CDC1 ₃ , 300 MHz, hindered rotation is observed): d = 7.28 - 7.36 (m, 5H), 5.13 (m, 2H), 3.54 - 3.78 (m, 2H), 3.32 - 3.49 (m, 2H), 3.11 (m ~ tt, / = 13.1, 3.5 Hz, 1H), 2.70 - 2.87 (m, 2H), 2.08 (br. s, 1H), 1.89 (m, 1H), 1.47 (m, 1H), 1.13 (d, / = 5.9 Hz, 1.5H. The analytical data are in full agreement with the analytical data obtained from from LKL8-57.

The chirality in (R)-benzyl 5 -methyl- 1,4-diazepane-l-carboxylate was determined to be R according to the CIP system. The Chirality was determined by protecting the second amine group with Boc ₂ 0, by measuring the specific rotation of the product and comparing it to literature values.

Preparation of Suvorexant according to Org. Process Res. Dev. 2011, 15, 367, WO2012/148553

MW: 265,74 MW: 203,20 C ₂₃ H ₂₃ CIN ₅ 0 ₂

MW: 450,92

suvo

C ₂₃ H ₂₃ CIN ₆ 0 ₂

MW: 450,92

Suvorexant (left) and its regioisomeric impurity (right):

C ₂ 3H ₂ 3CIN _e 0 ₂

MW: 450,92

Procedure:

To a solution of the amine.0.5DBTA salt (4.25 g, 10.0 mmol) in CH ₂ CI ₂ (31 mL) was added a solution of NaOH (10 M solution, 24.6 mL, 246 mmol) in H ₂ 0 (40 mL) at room temperature. The heterogeneous mixture was stirred at room temperature for one hour. The two phases were separated. A solution of NaCl (11 g) in H ₂ 0 (22 mL) was added to the aqueous phase followed by the addition of CH ₂ CI ₂ (5.5 mL). The heterogeneous mixture was stirred for 10 minutes and the phases were separated. The organic layers were combined and concentrated under reduced pressure to a total volume of approximately 11 mL to give a concentrated solution of the free amine in CH ₂ CI ₂ .

Oxalyl chloride (1.08 mL, 10.0 mmol) was added dropwise to a stirred suspension of 5- methyl-2-triazolylbenzoic acid (2.13 g, 10.5 mmol) in CH ₂ C1 ₂ (14 mL) and DMF (0.22 mL) at 0 °C - 2 °C and the resulting acid chloride solution was stirred for 30 minutes.

NEt ₃ (2.9 mL, 21 mmol) was added to the solution of the free amine in CH ₂ CI ₂ (total volume approximately 11 mL). The amine solution was then added over a period of 30 minutes to a stirred solution of the acid chloride (total volume approximately 14 mL) at a rate to keep the internal temperature at 5 °C - 10 °C. The reaction mixture was stirred for one hour before being quenched by the addition of H ₂ 0 (27 mL) at a rate to keep the internal temperature < 15 °C. The two layers were separated and the organic phase was concentrated under reduced pressure to a total volume of approximately 15 mL. Acetonitrile (90 mL) was added followed by the addition of activated charcoal (0.4 g) and the suspension was stirred for 80 minutes at room temperature. The suspension was filtered, the solid was washed with acetonitrile and the solution was concentrated under reduced pressure to a total volume of approximately 18 mL. H ₂ 0 was added to the solution over a period of 40 minutes at 25 °C. The solution was stirred over night. A white precipitate formed during that period. The solid was filtered, washed twice with acetonitrile/H ₂ 0 (1 :5, 5 mL each), washed with H ₂ 0, and dried over night in vacuo at 45 °C to give Suvorexant (3.1 g, 68%) with an assay of 89.3 area% according to HPLC. The assay of the "regioisomer" of Suvorexant was 5.2 area%.

Purification of Suvorexant by extraction and crystallization.

Procedure:

To a solution of Suvorexant (32.6 g) in MeOH (326 mL), CH ₂ C1 ₂ (163 mL), and H ₂ 0 (114 mL) at 45 °C was added NaHC0 ₃ in order to adjust the pH-value to pH = 10.0 and the solution was stirred at 45 °C for two hours. CH ₂ C1 ₂ (640 mL) and H ₂ 0 (320 mL) was added, the organic layer was separated, and concentrated to a total volume of approximately 120 mL. Acetonitril (720 mL) was added and the solution was concentrated to a total weight of approximately 160 g. H ₂ 0 (360 mL) was added at room temperature. The solid was filtered, washed with H ₂ 0 and dried at 45 °C over night to give Suvorexant (29.3 g, 90%) with an assay of 96.7 area%> according to HPLC. The assay of the "regioisomer" of Suvorexant was 0.9 area%.

Claims

1. A process for preparing a compound of formula (Ha')

the process comprising

(al) reacting a compound of formula (ΠΓ)

_R 1 b

^' NHR 2a

(ΙΙΓ)

with a compound of formula (IV)

O o

Λ OR ^E (IV)

to give a compound of formula V)

(a2) optionally purifying the compound of formula (V),

(a3) reducing the compound of formula (V), to give a compound of formula (Ila')

wherein at each occurrence

R ^E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R ^E is alkyl, more preferably wherein R ^E is methyl, ethyl or propyl, more preferably wherein R ^E is methyl

R ^la is H, R ¹ , PG ¹ , R ^A or PG ^la and R ^lb is H, or

R ^la is H and R ^lb is H, R ¹ , PG ¹ , R ^A or PG ^la ,

or R ^la and R ^lb taken together with the N atom to which they are attached form a cyclic imide group, wherein the cyclic imide group is preferably selected from the group consisting of a phthalimido group of formula (p)