Background

Obesity strongly affects millions of people worldwide and the number of obese people is largely increasing. Despite changes in a lifestyle, on the other hand pharmacotherapy is needed for a successful treatment. As a response to this challenge, much development is focused on 5-HT _2c receptor agonists for the treatment of this life-threatening disorder. Lorcaserin is one of the most challenging and used compounds.

So far only the preparation of racemic lorcaserin followed by chiral resolution of the enantiomers was presented and resulting in only low yields of the desired compound . Therefore, there is a growing interest to develop a simple and industrially acceptable process for the preparation of racemic 8- chloro-l-methyl-benzo[c/]azepine or related compounds and preferably a stereoselective process for the preparation of essentially enantiopure or enantiopure 8-chloro-l-methyl-benzo[c/]azepine or related compounds, especially lorcaserin ((fl)-8-chlor-l-methyl-2,3,4,5-tetrahydro-lH-benzo[d] azepine). Special focus is also oriented in the final synthetic step where efficient methodologies for ring closing of final intermediates lead to 8- chloro-l-methyl-benzo[c/]azepine or related compounds, especially lorcaserin.

Description of the prior art

The first synthesis of lorcaserin was reported by Smith & Smith in the patent application WO03086306 (Scheme 1). The synthetic process has been done with the reaction of 2-(4-chlorophenyl)ethanamine 19 with trifluoroacetic anhydride where trifluoroacetamide intermediate 20 was isolated. In the next step the aromatic ring was iodinated using expensive iodine chloride in the presence of carbonate as a basic activator. Amide 21 was then activated with allyl bromide in biphasic conditions followed by intramolecular Heck cyclization in the presence of palladium catalyst to form the exo-methylene derivative 23. The exocyclic double bond was then hydrogenated using Pd/C and after the deprotection reaction the racemic lorcaserin 9 was obtained .

9 24 23

Scheme 1. First synthetic process to the racemic lorcaserin molecule.

Later the patent application by Burbaum et al. (WO05019179) has been filed, where three novel synthetic pathways were described (Scheme 2) . All these synthetic pathways start from para-chlorobenzene derivatives.

The first route starts from the same 2-(4-chlorophenyl)ethanamine 19 as used in WO03086306 but further transformations enabled a more simple and efficient process. The amino intermediate is then acylated with chloropropionyl chloride to form the amide precursor 25 which is cyclized in presence of aluminum chloride as Lewis acid activator. Finally the amide 26 is reduced to racemic lorcaserin 9. The optically active lorcaserin 18 has been obtained by using classical optical resolution of the racemic mixture with tartaric acid .

The second route is using the amide precursor 25 which is reduced directly to the secondary amine 27 and then cyclized using aluminum chloride in 1,2-dichlorobenzene, which is known to be toxic, to yield racemic lorcaserin 9.

The third route starts from 2-(4-chlorophenyl)ethanol 28 which is first brominated using phosphorous tribromide, which is known to be expensive. The bromide 29 is transformed to the alcohol precursor 30 with an excess of l-amino-2-propanol . Afterwards, the alcohol is substituted with thionyl chloride in the presence of a catalytic amount of DMA to give the same solid hydrochloride precursor 27 as obtained also in the second route. Finally the chloride precursor is closed via Friedel-Crafts alkylation in the presence of AICI ₃ to the desired lorcaserin.

Scheme 2. Synthesis of chiral lorcaserin via classical chemical optical resolution.

In the next patent application WO07120517 by Weigl et al. , a similar (identical) process like in WO05019179 is described. It could be seen that some improvements addressing the isolation procedure of the Friedel-Crafts cyclization reaction are described using a Si0 ₂ -H ₂ 0 mixture to quench the reaction.

The process covered in the patent application WO08070111 by Gharbaoui et al. (Scheme 3) starts with the coupling reaction between 2-(4- chlorophenyl)acetic acid 31 and l-amino-2-propanol in the presence of various coupling reagents (trifluorophenylboric acid, phenylboric acid, EDC or toluenesulfonic acid / dimethoxypropane). The resulting amide 32 or its mixture with the minor dihydrooxazole compound 33 are then reduced using various reducing agents (borane in THF or DMS, sodium borohydride in the presence of iodine) to afford the similar alcohol precursor 30 which has already been presented in the previously cited patent applications (WO05019179 and WO07120517). The final steps are similar as described in the previously cited patent applications.

Scheme 3. Synthesis via 2-acetamido and dihydrooxazole precu

The patent application WO09111004 by Carlos et al. discloses a similar (identical) process as WO05019179 and WO07120517 (Scheme 4). A new bromination methodology is described using HBr gas instead of the expensive PBr ₃ . On the other hand, the impurity 34 resulting from di- alkylation of l-amino-2-propanol with bromide is also described and claimed (present in less than 10 % in the final product).

Scheme 4. Improvement of the synthetic process via bromo intermediates.

The patent application WO10148207 (Scheme 5) by Demattel et al. discloses a similar (identical) process like in the previously cited patent applications (WO05019179, WO07120517 and WO09111004). A new chlorination methodology is described based on thionyl chloride instead of the hazardous and dangerous HBr gas or the expensive PBr ₃ .

28 35 30 27

Scheme 5. Improvement of the synthetic process via chloro intermediates. Objects of the present invention

This invention has the object to provide a new, simple and economical process for the preparation of 8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-benzo[c/]azepine or related compound, especially lorcaserin, via novel intermediates. The invention has the further object to provide novel intermediates to be useful in the preparation of 8-chloro-l-methyl- 2,3,4,5-tetrahydro-lH-benzo[c/]azepine or related compound, especially lorcaserin. The invention has the further object to provide a process for producing these novel intermediates.

It is a particular object of this invention to provide a highly selective asymmetric synthesis leading to essentially enantiopure or enantiopure (R)- 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[c/]azepine, especially lorcaserin, or its (S)-enantiomer, in order to avoid or overcome the low efficient chemical optical resolution used in all prior art processes.

Summary of the invention

In order to solve one or more of the above objects, the present invention provides a novel racemic synthetic route for synthesizing 8-chloro-l- methyl-2,3,4,5-tetrahydro-lH-benzo[c/]azepine (compound A), or its salt, as illustrated in Scheme 6. The present invention further provides for the first time a highly selective asymmetric synthetic route for synthesizing (R)- 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[c/]azepine ((R)-A), or its salt, or (S)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[c/]azepine ((S)-A), or its salt, as illustrated in Scheme 7.

Scheme 6. The synthetic route to racemic 8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-benzo[c/]azepine, wherein * in the formulae denotes an asymmetric C atom.

The synthetic route is simple, industrial friendly and enables transformations with no racemization of chiral intermediates. Further, the synthesic route requires only simple and commercially available reagents and catalysts.

Scheme 7. The asymmetric route to the optically active (fl)-8-chloro-l- methyl-2,3,4,5-tetrahydro-lH-benzo[c/]azepine (or its corresponding (S)- enantiomer if starting from (S)-I).

Besides the racemic synthetic strategy, the present invention provides the possibility of an efficient and highly selective asymmetric approach. This is more advantageous in comparison with a low efficiency of chemical optical resolution of the racemic mixture of the final lorcaserin used in the prior art. The highly selective asymmetric synthesis uses optically active starting material which is simple, reliable and suitably cost-beneficial. Thus, the chirality is already present in the molecule in early steps (first synthetic step). There is no need for using special asymmetric methodologies based on expensive and hazardous transition metal chiral catalysts or specific enzymes in order to induce enantioselectivity.

By means of the synthetic routes as being illustrated in Schemes 6 and 7, the present invention performs the final ring closing in the para-position relative to the CI substituent so that the chirality of the methyl substituent in the present invention is not prone to racemization compared to the prior art final ring closing performed in the mefa-position relative to the CI substituent as illustrated by the above Schemes 1 to 3.

The following items summarize in more details the aspects and preferred features or embodiments which contribute to solve the objects of the present invention alone or in combination.

1. Method for preparing 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[c/] azepine being illustrated b the following formula A, or a salt thereof:

wherein * in the formulae denotes an asymmetric C atom, the method comprising the steps of:

(a) converting the compound according to the following formula I : (I)

to a cyclic sulfamidate compound according to the following formula II :

wherein R in the formula II is an amino protecting group which is preferably selected from -Boc (terf-butyloxycarbonyl), -Cbz (carbo- benzyloxy), -Bz (benzoyl), -Bn (benzyl), -Ac (acetyl), or -CH ₂ CH(OR ² ) ₂ (wherein R ² is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R ² may bond together to constitute a C2- or C3- alkylene chain for forming a 5- or 6-membered ring);

(b) converting the compound according to the formula II to a compound according to the following formula III:

wherein R in the formula III is the same as defined for the formula II above; and

(c) converting the compound according to the formula III to

(c-1) a compound according to the following formula Ilia :

(Ilia)

wherein X in the formula Ilia is a leaving group suitable for a cyclizing intramolecular Friedel-Crafts alkylation reaction or a group which can suitably be converted to a such a leaving group, and wherein X is preferably -OH, tosylate, mesylate, triflate, or a halogen selected from CI, Br, I, and wherein X is most preferably CI or Br; or

(c-2) a compound according to the following formula Illb:

(Illb)

wherein X in the formula Illb is the same as defined for the compound according to the above formula Ilia;

or

(c-3) a compound according to the following formula IIIc or Hie:

wherein R ² is the same as defined for the formula II above, wherein R* is an amino protecting group,

wherein the formation of the compound according to the formula IIIc may be omitted for the event that R in the compound according to the above formulae II and III is already represented by the above defined -CH ₂ CH(OR ² ) ₂ ;

and;

(d) converting the compound according to the formula Ilia or the formula Illb or the formula IIIc or the formula Hie into the compound according to the above formula A by:

(d-1) performing a cyclizing intramolecular reaction, which is preferably a cyclizing intramolecular Friedel-Crafts or a

photochemically induced ring closing reaction;

(d-2) optionally and where appropriate, a reduction reaction; and (d-3) optionally and where appropriate, a deprotection reaction.

The present invention comprises new methods for the synthesis of hereinafter defined novel key intermediates II" (wherein the compound according to the formula II" corresponds to the above defined formula II in which R= R" being represented by the above defined -CH ₂ CH(OR ² ) ₂ ), III' (wherein the compound according to the formula III' corresponds to a compound according to one of the formulae III, Ilia, Illb, IIIc, and Hid, Hie, IVa, IVc, IVd, and IVe, which are particularly valuable and useful for the preparation of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[c/]azepine (compound A), or its salt, or one of the corresponding enantiomers from simple starting materials. By the process according to the present invention a high yield synthesis of the key intermediates and the final compound A, or its salt, or one of the corresponding enantiomers is achieved starting from l-amino-2-propanol (formula I). By using cheap and simple materials, the present invention facilitates a short and economically reasonable process for the preparation of the aforementioned key intermediates and the final compound A, or its salt, or one of the corresponding enantiomers.

Further, in the embodiments proceeding via the intermediate compound II, wherein R is represented by the above -CH ₂ CH(OR ² ) ₂ , an elegant synthetic pathway to the final compound A, or its salt, or one of the corresponding enantiomers is provided without the need for a deprotection of the group R prior to the cyclization of the intermediate compounds IIIc.

2. The method according to item 1 wherein the step (a) comprises the steps of:

(a-1) converting the compound according to the formula I to a

compound according to the following formula V: (V) wherein R in the formula V is the same as defined for the formula II above;

and

(a-2) converting the compound according to the formula V to a

compound according to the above formula II,

wherein the step (a-2) optionally includes

(a-2-1) converting the compound according to the formula V to a compound according to the following formula VI :

wherein R in the formula VI is the same as defined for the formula V above; and (a-2-2) subsequently oxidizing the compound according to the formula VI to obtain the compound according to the formula II, preferably without isolating the intermediate compound VI.

3. The method according to item 2 wherein the compound according to the formula I in the step (a-1) is reacted with a reagent selected from

(i) benzyl chloroformate, (PhCH ₂ OCO) ₂ 0 or Na-(benzyloxycarbonyloxy) succinimide for introducing -Cbz;

(ii) di-tert- butyl dicarbonate for introducing -Boc;

(iii) benzoyl chloride for introducing -Bz;

(iv) benzyl chloride or benzyl bromide for introducing -Bn;

(v) acetanhydride or acetyl chloride for introducing -Ac;

(vi) X ³ CH ₂ CH(OR ² ) ₂ or OHC-CH(OR ² ) ₂ wherein X ³ is tosylate, mesylate, triflate or a halogen, preferably CI or Br, and R ² is the same as defined above, for introducing the above defined -CH ₂ CH(OR ² ) ₂ (wherein R ² is the same as defined above).

4. The method according to items 2 or 3 wherein the step (a-2-2) comprises the oxidation of the compound according to the formula VI by using an oxidizing agent selected from Ru0 ₂ , NaI0 ₄ , H ₂ 0 ₂ , urea-H ₂ 0 ₂ , cumene H ₂ 0 ₂ , m-CPBA (mefa-chloroperoxybenzoic acid), NaB0 ₃ -xH ₂ 0, Mn0 ₂ , and Oxone, preferably NaI0 ₄ and Ru0 ₂ .

5. The method according to any one of items 1 to 4 wherein the compound according to the formula II in the step (b) is reacted with a compound according to the following formula VII :

wherein M in the formula VII is selected from Li, MgBr and MgCI, preferably MgCI; and wherein the reaction is preferably catalyzed by CuX (X= CI, Br, I), ZnCI ₂ , FeCI ₃ , more preferably by Cul or CuCI, and wherein M = MgCI catalyzed by Cul is specifically preferred . 6. The method according to any one of items 1 to 5, wherein the step (c) further comprises:

for the step (c-1) :

(c-1-1) removing the group R from the compound according to the formula III if R is a group other than the above defined

-CH ₂ CH(OR ² ) ₂ , to obtain the compound according to the following formula Hid :

and

(c-1-2) reacting the compound according to the formula Hid with a compound represented by the following formula VIII :

wherein X ¹ is selected from OH, F, CI, and Br, preferably CI, and X ² is selected from OH, CI, and Br, and is preferably CI or Br,

to obtain the compound according to the formula Ilia, wherein - if X ² = OH - this hydroxyl group may further be converted to one of tosylate, mesylate, triflate, CI, Br or I, preferably to CI or Br, and/or provided that - if X ¹ = OH - this hydroxyl group is activated for forming an amide bond; for the step (c-2) :

(c-2-1) - following the analogous reaction steps (c-1-1) and (c-1-2) - subsequently reducing the amide bond of the compound according to formula Ilia by a suitable reducing agent, preferably selected from LiAIH ₄ , RED-AI, DIBAL-H, diborane, BH ₃ -THF complex or hydrides, to obtain the compound according to the formula Illb;

or (c-2-2) - following the analogous removal step (c-1-1) - subsequently reacting the compound according to the formula Hid with a compound represented by the following formula IX:

wherein X ² is the same as defined for formula VIII above,

to obtain in a one-pot reductive amination reaction using a suitable reducing agent, preferably selected from H2/Pd/C/HCI, sodium borohydride, sodium cyanoborohydride and sodium triacetoxyboro- hydride, the compound according to the formula Illb, provided that if X ² = OH, this hydroxyl group may further be converted to one of tosylate, mesylate, triflate, CI, Br or I, preferably to CI or Br; he step (c-3) :

(c-3-1) - if R in the compound according to the above formula III is not already represented by the above defined -CH ₂ CH(OR ² ) ₂ , following the analogous removal step (c-1-1) - subsequently reacting the compound according to the formula Hid with a compound represented by the above defined formula X ³ CH ₂ CH(OR ² ) ₂ (wherein X ³ is preferably CI or Br, and R ² is preferably methyl or ethyl) or OHC- CH(OR ² ) ₂ (wherein R ² is preferably methyl or ethyl) to obtain the compound according to the formula IIIc, or

(c-3-2) - if R in the compound according to the above formula III is not already represented by the above defined -CH ₂ CH(OR ² ) ₂ , reacting the compound according to the formula III with a compound represented by the above defined formula X ³ CH ₂ CH(OR ² ) ₂ (wherein X ³ is preferably CI or Br, and R ² is preferably methyl or ethyl) or OHC- CH(OR ² ) ₂ (wherein R ² is preferably methyl or ethyl) to obtain the compound according to the formula Hie, wherein R* is the same as R.

(c-3-3) - if R in the compound according to the above formula III is already represented by the above defined -CH ₂ CH(OR ² ) ₂ , protecting the amino group with a protecting group, preferably selected from unsubstituted benzyl (Bn) or substituted, preferably a-methyl, p- nitro, p-methyl or p-methoxy substituted benzyl (PMB), polyphenyl substituted methyl preferably trityl (Tr), unsubstituted or fluorinated Ci-C ₄ -alkanesulfonyl, preferably methanesulfonyl (mesyl, Ms) or trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl, unsubstituted or substituted Ci-C ₆ -alkanoyl, preferably acetyl (Ac) or arylcarbonyl, preferably benzoyl (Bz), to obtain the compound according to the formula Hie, wherein R* is represented by said group, preferably by -Bn, -PMB, -Tr, -Ms, -Tf, - Ts, -Ac, or -Bz, respectively.

7. The method according to any one of items 1 to 6, wherein the cyclizing intramolecular reaction in step (d/d-1) is accomplished

(i) in the presence of a Lewis acids selected from AICI ₃ , FeCI ₃ , InCI ₃ , InBr ₃ , Bi(OTf) ₃ , BiCI ₃ , Sc(OTf) ₃ , TeCI ₄ , BF ₃ xOEt ₂ , preferably anhydrous AICI ₃ , or a Br0nsted acid selected from HOTf, pTsOH, TFA, CH ₃ S0 ₃ H, H ₃ P0 ₄ / P ₂ 0 ₅ , H ₂ S0 ₄ / AcOH mixture, cone. H ₂ S0 ₄ or polyphosphoric acid (PPA), and preferably H ₂ S0 ₄ or PPA, or

(ii) - for the compounds according to the formulae Ilia and Illb - optionally by a photochemically induced ring closing reaction, to obtain :

(d-1-1) - if cyclizing the compound according to the formula Ilia - a compound according to the following formula IVa :

(IVa)

(d-1-2) - if cyclizing the compound according to the formula Illb - a compound according to the formula A; (d-1-3)- if cyclizing the compound according to the formula IIIc or Hie a compound according to the following formula IVc, IVd or IVe, or a mixture thereof:

wherein R ³ is H, methyl or ethyl, and R* is the same as defined in c-3-2 or c-3-3 of item 6 and and wherein the reduction in the step (d-2), required only for the

compounds according to the formulae IVa, IVc, IVd, and IVe, is conducted by use of a suitable reducing agent which is preferably selected from BH ₃ complexes, H^metal cat. (preferably Rh, Ru, Pd), NaBH ₄ / H ₂ S0 ₄ , LiAIH ₄ , Et ₃ N / HCOOH, RED-AI, DIBAL-H, Hz/Pd/C/HCI or Zn/HCI, and most preferably BH ₃ -THF complex or hydrides for the reduction of the compound according to the formulae IVa, and H^Pd/C/HCI, H^PtO, or Zn/HCI for the reduction of the compound according to the formula IVc, and H^PtO for the reduction of the compound according to the formula IVd or IVe,

respectively, to obtain, and optionally after deprotection if the compound according to the formula IVe is formed, the compound according to the formula A.

8. The method according to any one of the above items 1 to 7 wherein the methods proceed by:

(a-1) converting the compound according to the formula I to the compound according to the formula V (with R preferably being -Boc);

(a-2-1) reacting the compound according to the formula V with thionylchloride and (a-2-2) subsequently oxidizing (preferably by using NaI0 ₄ and Ru0 ₂ ) the intermediate compound according to the formula VI to obtain the compound according to the formula II;

(b) performing a ring opening reaction analogous to item 5, wherein preferably M = MgCI being catalyzed by Cul, to obtain the compound according to the formula III;

(c-1) converting the compound according to the formula III to the compound according to the formula Ilia (with X = CI, Br) by

(c-1-1) removing R and

(c-1-2) reacting with bromo acetyl chloride or chloro acetyl chloride to obtain the compound according to the formula Ilia with X = Br or CI;

(d-1-1) cyclizing the compound according to the formula Ilia by a Friedel-Crafts reaction using preferably anhydrous AICI ₃ or by a photo- chemically induced ring closing reaction to obtain the compound according to the formula IVa;

(d-2) reducing the compound according to the formula IVa preferably by BH3-THF complex or hydrides to obtain the compound according to the formula A.

9. The method according to any one of the above items 1 to 7 wherein the methods proceed by:

(a-1) converting the compound according to the formula I to the compound according to the formula V (with R preferably being -Boc);

(a-2-1) reacting the compound according to the formula V with thionylchloride and

(a-2-2) subsequently oxidizing (preferably by using NaI0 ₄ and Ru0 ₂ ) the intermediate compound according to the formula VI to obtain the compound according to the formula II;

(b) performing a ring opening reaction analogous to item 5, wherein preferably M = MgCI being catalyzed by Cul, to obtain the compound according to the formula III; (c-2) converting the compound according to the formula III to the compound according to the formula Illb (with X = CI, Br) by

(c-2-1) removing R and reacting with bromoacetyl chloride or chloroacetyl chloride to obtain the compound according to the formula Ilia with X = Br or CI and

(c-2-2) subsequently reducing the amide bond of the compound according to formula Ilia by a suitable reducing agent, preferably selected from LiAIH ₄ , RED-AI, DIBAL-H, diborane, BH ₃ -THF complex or hydrides, most preferably BH ₃ -THF complex;

(d-1-2) cyclizing the compound according to the formula Illb by a Friedel-Crafts reaction using preferably anhydrous AICI ₃ or by a

photochemically induced ring closing reaction to obtain the compound according to the formula A.

10. The method according to any one of items 1 to 7 wherein

the methods proceed by:

(a-1) converting the compound according to the formula I to the compound according to the formula V, wherein R is the above defined -CH ₂ CH(OR ² ) ₂ , preferably by reacting the compound according to the formula I with one compound selected from 2-bromo-l,l-dimethoxyethane, 2-bromo-l,l-diethoxyethane, 2,2-dimethoxyacetaldehyde and 2,2- diethoxyacetaldehyde;

(a-2-1) reacting the compound according to the formula V with thionyl chloride and

(a-2-2) subsequently oxidizing (preferably by using NaI0 ₄ and Ru0 ₂ ) the intermediate compound according to the formula VI to obtain the compound according to the formula II;

(b) performing a ring opening reaction analogous to item 5, wherein preferably M = MgCI being catalyzed by Cul, to obtain the compound according to the formula IIIc, wherein OR ² is defined as above;

(d-1-3) cyclizing the compound according to the formula IIIc by a Friedel-Crafts reaction preferably using anhydrous AICI ₃ , cone. H ₂ S0 ₄ or PPA to obtain the compound according to the formula IVc; (d-2) reducing the compound according to the formula IVc preferably by H2/Pd/C/HCI or Zn/HCI to obtain the compound according to the formula A.

11. The method according to any one of the above items 1 to 7, wherein the methods proceed by:

(a-1) converting the compound according to the formula I to the compound according to the formula V (with R preferably being -Boc);

(a-2-1) reacting the compound according to the formula V with thionylchloride and

(a-2-2) subsequently oxidizing (preferably by using NaI0 ₄ and Ru0 ₂ ) the intermediate compound according to the formula VI to obtain the compound according to the formula II;

(b) performing a ring opening reaction analogous to item 5, wherein preferably M = MgCI being catalyzed by Cul, to obtain the compound according to the formula III;

(c-3) converting the compound according to the formula III to the compound according to the formula IIIc by

(c-3-1) removing R and reacting with the compound according to the above formula X ³ CH ₂ CH(OR ² ) ₂ (wherein X ³ is preferably CI or

Br, and R ² is preferably methyl or ethyl) or OHC-CH(OR ² ) ₂ (wherein

R ² is preferably methyl or ethyl);

(d-1-3) cyclizing the compound according to the formula IIIc by a Friedel-Crafts reaction preferably using anhydrous AICI ₃ , cone. H ₂ S0 ₄ or PPA to obtain the compound according to the formula IVc or IVd;

(d-2) reducing the compound according to the formula IVc preferably by H^Pd/C/HCI or Zn/HCI and reducing the compound according to the formula IVd preferably by H^PtO to obtain the compound according to the formula A.

12. The method according to any one of items 1 to 11, wherein the method is a stereoselective synthesis which leads to the essentially enantiopure or enantiopure R enantiomer of the compound according to the formula A, or its salt, represented by the following formula (R)-A, or its salt:

((R)-A) wherein the stereoselective synthesis starts from the essentially enantiopure or enantiopure R-enantiomer of the compound according to the formula I represented by the following formula (R)-I :

and wherein the synthesis proceeds stereoselectively via the essentially enantiopure or enantiopure R-enantiomer of the compound according to the formula II represented by the following formula (R)-II :

((R)-ii)

wherein the compound according to the formula (R)-II is converted in step (b) to the essentially enantiopure or enantiopure R-enantiomer of the compound according to the formula III represented by the following formula (R)-III :

((R)-III) and wherein the chirality is subsequently retained in the course of the syntheses leading to the essentially enantiopure or enantiopure chiral compound according to following formula (R)-A, or its salt.

13. The method according to any one of items 1 to 11 wherein the method is a stereoselective synthesis which leads to the essentially enantiopure or enantiopure S-enantiomer of the compound according to the formula A, or its salt, represented by the following formula (S)-A, or its salt:

wherein the stereoselective synthesis starts from the essentially

enantiopure or enantiopure S-enantiomer of the compound according to the formula I represented by the following formula (S)-I :

((S)-I)

and wherein the synthesis proceeds stereoselectively via the essentially enantiopure or enantiopure S-enantiomer of the compound according to the formula II represented by the following formula (S)-II : (S)-II

wherein the compound according to the formula (S)-II is converted in the step (b) to the essentially enantiopure or enantiopure S-enantiomer of the compound according to the formula III represented by the following formula (S)-III:

and wherein the chirality is subsequently retained in the course of the syntheses leading to the essentially enantiopure or enantiopure chiral compound according to following formula (S)-A, or its salt.

14. The method according to any one of items 1 to 9 and 11, which leads to the essentially enantiopure or enantiopure R-enantiomer of the compound according to the formula A, or its salt, represented by the following formula (R)-A, or its salt:

wherein the racemic compound according to the formula Hid in the step (c) is transformed to the essentially enantiopure or enantiopure R- enantiomer of the compound according to the formula ( ?)-IIId

((R)-nid) by removing the opposite enantiomer by additional steps of one or more crystallizations of the salt of ( ? -IIId with a chiral organic acid,

and wherein the chirality is subsequently retained in the course of the syntheses leading to the essentially enantiopure or enantiopure chiral compound according to following formula (R)-A, or its salt.

15. The method according to any one of items 1 to 9 and 11, which leads to the essentially enantiopure or enantiopure S-enantiomer of the compound according to the formula A, or its salt, represented by the following formula (S)-A, or its salt:

wherein the racemic compound according to the formula Hid in the step (c) is transformed to the essentially enantiopure or enantiopure S- enantiomer of the compound according to the formula (S)-IIId ((S)-IIId) by removing the opposite enantiomer by additional steps of one

crystallizations of the salt of (S -IIId with a chiral organic acid, and wherein the chirality is subsequently retained in the course of the syntheses leading to the essentially enantiopure or enantiopure chiral compound according to following formula (S)-A, or its salt.

16. The method according to item 14, wherein the chiral organic acid is selected from (7R (-)-2-phenylpropionic acid .

17. The method according to item 14, wherein the chiral organic acid is selected from L-(-)-3-phenyllactic acid .

18. A compound according to formula III', or its salt:

wherein R' in formula III' is represented (i) by the above defined R, which is an amino protection group, which is preferably selected from -Boc (tert- butyloxycarbonyl), -Cbz (carbobenzyloxy), -Bz (benzoyl), -Bn (benzyl), -Ac (acetyl), or -CH ₂ CH(OR ² ) ₂ (wherein R ² is alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R ² may bond together to constitute a C2- or C3-alkylene chain for forming a 5- or 6-membered ring) or is represented by (ii) -H, -COCH ₂ X or -CH ₂ CH ₂ -X (wherein X is defined as above and is preferably -OH, tosylate, mesylate, triflate or a halogen, preferably CI, Br or I, and wherein X is most preferably CI or Br).

The compound according to the formula III', or its salt, is a useful novel intermediate for the synthesis of the compound A or related 8-chloro- l-methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.

19. The compound according to item 18 which is represented by the compound according to the above defined formula Hid (R = H in the above defined formula III).

20. The compound according to item 18 which is represented by the compound according to the above defined formula Ilia (preferably with X being represented by CI, Br or I, more preferably CI or Br) or Illb

(preferably with X being represented by CI, Br or I, more preferably CI or Br).

21. The compound according to item 18 which is represented by the compound according to the above formula IIIc (preferably with R ² being methyl or ethyl).

22. A compound according to any one of items 18 to 21 which is the essentially enantiopure or enantiopure R-enantiomer of the compound according to the formula III' represented by the following formula (R)- III', or its salt:

((R)-III')

wherein R' in the compound (R)-III' is the same as defined in any one of items 14 to 17.

The compound according to the formula (R)-III', or its salt, is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro-l-methyl- benzo[c/]azepine derivatives, or its salts.

23. A compound according to any one of items 18 to 21 which is the essentially enantiopure or enantiopure S-enantiomer of the compound according to the formula III', represented by the following formula (S)- III', or its salt:

wherein R' in compound (S)-III' is the same as defined in any one items 18 to 21 The compound according to the formula (S)-III', or its salt, is a useful novel intermediate for the synthesis of (S)-lorcaserin (compound (S)-A) or related (S)-8-chloro-l-methyl-benzo[c/]azepine derivatives, or its salts.

24. A compound according to item 22 which is represented by the

compound according to the above formula (R)-IIId in a form of a salt with a chiral organic aci A* is a chiral anion

25. A compound of formula (7R 2-(3-chlorophenyl)propan-l-ammonium (R)-(-)-2-phenylpropanoate

26. A compound of formula (7R 2-(3-chlorophenyl)propan-l-ammonium (L)-(-)-phenyllactate

27. A compound according to item 23 which is represented by the

compound according to the above formula (S)-IIId in a form of a salt with a chiral organic acid. A* is a chiral anion

28. The use of a compound according to any one of items 22 to 27 for manufacturing an anti-obesity agent having a 8-chloro-l-methyl- benzo[c/]azepine skeleton, which is preferably lorcaserin, or its salt.

29. A method for producing a compound according to any one of items 22 to 27 wherein the method comprises the reaction step (b) as defined by any one of items 1, 5, 8, 9, 12 or 13, the method optionally further comprising one or more of the reaction steps (c), (c-1), (c-2), (c-3), (c-1-1), (c-1-2), (c-2-1), (c-2-2), and (c-3-1) as defined by any of items 1, 6, 8, 9, 11, 12 or

13. 30. A compound represented by the formula IVa:

which may be racemic, essentially enantiopure or enantiopure in the R- or S- form .

The compound according to the formula IVa is a useful novel intermediate for the synthesis of the compound A or related 8-chloro- l- methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.

31. The compound according to item 30 which is essentially enantiopure or preferably enantiopure in the R-form (formula (R)-IVa).

The compound according to the formula (R)-IVa is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro-l-methyl-benzo[c/]azepine derivatives, or its salts.

32. The method for producing a compound according to items 30 or 31 wherein the method comprises the reaction step (d- 1) and/or (d- 1- 1) as defined by any one of items 1 , 7, 8, 12 or 13, the method preferably using anhydrous AICI ₃ or hv.

33. A compound represented by the formula IVc, or its salt:

(IVc)

which may be racemic, essentially enantiopure or enantiopure in the R- or S- form, wherein R ² is defined as above and is preferably methyl or ethyl . The compound according to the formula IVc is a useful novel intermediate for the synthesis of the compound A or related 8-chloro- l- methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.

34. The compound according to item 33 which is essentially enantiopure or preferably enantiopure in the R-form (formula (R)-IVc).

The compound according to the formula (R)-IVc is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro- l-methyl-benzo[c/]azepine derivatives, or its salts.

35. A compound represented by the formula IVd, or its salt: (IVd)

which may be racemic, essentially enantiopure or enantiopure in the R- or S- form .

The compound according to the formula IVd is a useful novel intermediate for the synthesis of the compound A or related 8-chloro- l- methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.

36. The compound according to item 35, which is essentially enantiopure or enantiopure in the R-form (formula (R)-IVd).

The compound according to the formula (R)-IVd is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro-l-methyl-benzo[c/]azepine derivatives, or its salts.

37. A compound represented by the formula IVe, or its salt:

(IVe) which may be racemic, essentially enantiopure or enantiopure in the R- or S- form, wherein R* is the same as defined in c-3-2 or c-3-3 of item 7, preferably p-toluenesulfonyl.

The compound according to the formula IVe is a useful novel intermediate for the synthesis of the compound A or related 8-chloro-l- methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.

38. The compound according to item 37, which is essentially enantiopure or enantiopure in the R-form (formula (R)-IVe).

The compound according to the formula (R)-IVe is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro-l-methyl-benzo[c/]azepine derivatives, or its salts.

39. A compound represented by the formula X, or its salt:

which may be racemic, essentially enantiopure or enantiopure in the R- or S- form, wherein R ^* is defined as above and is preferably p-toluenesulfonyl.

The compound according to the formula X is a useful novel intermediate for the synthesis of the compound A or related 8-chloro-l- methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.

40. The compound according to item 41, which is essentially enantiopure or enantiopure in the R-form (formula (R)-X).

The compound according to the formula (R)-X is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro-l-methyl-benzo[c/]azepine derivatives, or its salts.

41. The method for producing a compound according to any one of items 33 to 40 wherein the method comprises the reaction steps (d-1) and/or (d-1-3) as defined by any one of items 1, 7, 10, 11, 12 or 13, the method

preferably using anhydrous AICI ₃ , cone. H ₂ S0 ₄ or PPA.

42. A compound represented by the formula II": (II") wherein R" in the formula II" is represented by the above defined

-CH ₂ CH(OR ² ) ₂ (wherein R ² is methyl or ethyl or both R ² may bond together to constitute a C2- or C3-alkylene chain for forming a 5- or 6-membered ring) which may be racemic, essentially enantiopure or enantiopure in the R- or S- form.

The compound according to the formula II" is a useful novel intermediate for the synthesis of the compound A or related 8-chloro-l- methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts.

43. The compound according to item 42 which is essentially enantiopure or preferably enantiopure in the R-form (formula (R)-II") .

The compound according to the formula (R)-II' is an especially useful novel intermediate for the stereoselective synthesis of lorcaserin (compound (R)-A) or related (fl)-8-chloro-l-methyl-benzo[c/]azepine derivatives, or its salts.

44. The method for producing a compound according to items 42 or 43, wherein the method comprises the reaction steps (a) and/or (a-1) and/or (a-2) and/or (a-2-1) and/or (a-2-2) as defined by any one of items 1, 2, 3 (vi), 4, 10, 12 or 13.

45. The use of a compound according to any one of items 30 to 43 for manufacturing an anti obesity agent having a 8-chloro-l-methyl- benzo[c/]azepine skeleton which is preferably lorcaserin, or its salt. Detailed description of the invention

Hereinafter, the present invention is described in more detail by referring to further preferred and further advantageous embodiments and examples which shall not be understood as being limiting.

The present invention provides an industrially applicable, economical and simple asymmetric process for the preparation of serotonin antagonizing 8-chloro-l-methyl-benzo[c/]azepine or related compounds, or its salts, particularly lorcaserin, as well as key intermediates for the synthesis thereof. Lorcaserin is a selective 5-HT _2c receptor agonist, and in vitro testing of the drug showed reasonable selectivity for 5-HT _2c over other related targets. The activation of 5-HT _2c receptors in the hypothalamus is supposed to activate proopiomelanocortin (POMC) production and consequently promote weight loss through satiety. For 8-chloro-l-methyl- benzo[c/]azepine and related compounds, or its salts, particularly lorcaserin, the synthetic route described herein benefits from simple reactions, mild reaction conditions and readily available and cheap chemicals. The starting material for the overall synthesis is readily available and it is represented by racemic, essentially enantiopure or enantiopure l-aminopropan-2-ol (I, (R)-I or (S)-I). If the method starts from essentially enantiopure or enantiopure (2fl)-l-aminopropan-2-ol ((R)-I), the synthesis leads in a highly selective asymmetric manner to the essentially enantiopure or enantiopure lorcaserin (formula (R)-A).

The term "essentially enantiopure" as used herein means an enantiomeric excess (ee) of 70 % ee or more, preferably 80 % ee or more, more preferably 90 % ee or more, most preferably 97 % ee or more.

The term "salt" as used herein refers to any suitable salt form of the respective compound. Preferably, the salt is pharmaceutically acceptable.

A detailed overview of the synthetic route will be given hereinafter.

In a first step, racemic, essentially enantiopure or enantiopure l-aminopropan-2-ol (I, (R)-I or (S)-I) may be converted in step (a-1) to a compound according to the formula V, wherein R in the formula V is an amino protecting group, or -CH ₂ CH(OR ² ) ₂ (wherein R ² is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R ² may bond together to constitute a C2- or C3-alkylene chain for forming a 5- or 6-membered ring).

The term "amino protecting group" as used herein means a group that protects an amine in particular transformations of the process of the invention and can be selected from known "amino protecting groups" as recited in "Greene's Protective Groups in Organic Synthesis", 4th Edition (Peter G. M . Wuts, Theodora W. Greene; ISBN : 978-0-471-69754-1). Preferably, the "amino protecting group" in the present invention is selected from -Boc (tert-butyloxycarbonyl), -Cbz (carbobenzyloxy), -Bz (benzoyl), - Bn (benzyl), -Ac (acetyl). Particularly preferred is the use of the -Boc group. Specific conditions for protecting the amino group by means of these groups can be found in the above referenced "Greene's Protective Groups in Organic Synthesis". Preferably, the invention uses

(i) benzyl chloroformate, (PhCH ₂ OCO) ₂ 0 or Na-(benzyloxycarbonyloxy) succinimide for introducing -Cbz;

(ii) di-tert- butyl dicarbonate for introducing -Boc;

(iii) benzoyl chloride for introducing -Bz;

(iv) benzyl chloride or benzyl bromide for introducing -Bn;

(v) acetanhydride or acetyl chloride for introducing -Ac.

The protocol for -Boc protection as described by Hebeisen et al. (Tetrahedron Lett. 2011, 52, 5229) is specifically preferred.

In another embodiment the protecting group is selected for use in cyclisation of the compound according to the formula III to the compound of formula IV, wherein besides the groups as disclosed above some others which are less suitable for formation of the cyclic sulfonamide according to the formula II can be used. Such preferable additional "amino protecting groups" are introduced by conditions using

(vi) trityl chloride for introducing -Tr

(vii) p-toluenesulfonyl chloride for introducing -Ts. If the above group -CH ₂ CH(OR ² ) ₂ is used as the group R in the alternative embodiment, the synthetic route benefits in that the amino deprotection, i.e. the removal of the group R, is not required in the subsequent synthetic route as described above. Preferably, the invention uses (vi) a compound represented by the above defined X ³ CH ₂ CH(OR ² ) ₂ (wherein X ³ is tosylate, mesylate, triflate or a halogen, preferably CI or Br, and R ² is the same as defined above, preferably methyl or ethyl) or the above defined OHC-CH(OR ² ) ₂ , wherein X ³ is tosylate, mesylate, triflate or a halogen, preferably CI or Br, and R ² is the same as defined above, for introducing the above defined -CH ₂ CH(OR ² ) ₂ (wherein R ² is the same as defined above).

Due to the easy accessibility, low costs and suitable reactivity in the subsequent synthesis, one of 2-bromo-l,l-dimethoxyethane, 2-bromo-l,l- diethoxyethane, 2,2-dimethoxyacetaldehyde and 2,2-diethoxyacetaldehyde is preferred for introducing the group -CH ₂ CH(OR ² ) ₂ . If one of 2,2- dimethoxyacetaldehyde and 2,2-diethoxyacetaldehyde is used in the reductive amination reaction, the present invention takes advantage of a one-pot reaction using a suitable reducing agent, preferably H^Pd/C/HCI, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy- borohydride, most preferably H^Pd/C/HCI .

After the step (a-1) is accomplished to give the compound according to the above formula V, the synthesis route may proceed with the step (a- 2). This step (a-2) may be accomplished in a one-step procedure or in a two-step procedure.

In the one-step procedure, the compound according to the formula II may directly be formed from the compound according to the formula V by protocols as reviewed by Melendez et al. (Tetrahedron, Volume 59, Issue 15, pages 2581-2616) by making use of sulfuryl chloride or preferably 1,1'- sulfonyl diimidazole.

In the two-step procedure, the compound according to the formula II may be formed from the compound according to the formula V via the step (a-2-1) of forming of an intermediate compound according to the formula VI which is subsequently oxidized in the step (a-2-2) to yield the compound according to the formula II. Notably, the intermediate compound according to the formula VI needs not to be isolated, but may be oxidized immediately following a simple liquid extraction protocol, such as washing the organic reaction phase with an aqueous phase for removing salts, etc. The formation of the intermediate compound according to the formula VI in the step (a-2-1) is preferably accomplished by the use of thionyl chloride under the conditions, such as reviewed by Melendez et al. (Tetrahedron, Volume 59, Issue 15, pages 2581-2616) or described by Hebeisen et al. (Tetrahedron Lett. 2011, 52, 5229). The subsequent oxidation of the intermediate compound according to the formula VI in the step (a-2-2) may be accomplished by known methodologies, such as those reviewed by Melendez et al. (Tetrahedron, Volume 59, Issue 15, pages 2581-2616) or described by Hebeisen et al. (Tetrahedron Lett. 2011, 52, 5229). Suitable oxidizing agents may be selected from Ru0 ₂ , NaI0 ₄ , H ₂ 0 ₂ , urea-H ₂ 0 ₂ , cumene H ₂ 0 ₂ , m-CPBA (meta-chloroperoxybenzoic acid), NaB0 ₃ -xH ₂ 0, Mn0 ₂ , and Oxone (Potassium peroxysulfate), which may be used in combination with a catalyst. Most preferably, the invention uses NaI0 ₄ catalyzed with a Ruthenium catalyst (such as Ru0 ₂ or RuCI ₃ ).

Notably, the compound represented by the formula II":

wherein R" in the formula II" is the above defined -CH ₂ CH(OR ² ) ₂ represents a novel and suitable intermediate for the synthesis of compound A or related 8-chloro-l-methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts. This compound may be racemic or essentially enantiopure or even enantiopure in the R- or S-form, preferably in the R- form. This novel intermediate is suitably produced according to the above described reaction steps (a) and/or (a-1) and/or (a-2) and/or (a-2-1) and/or (a-2-2) as defined by any one of the above items 1, 2, 3 (vi), 4, 10, 12 or 13. After the step (a-2) is accomplished to give the compound according to the formula II, the synthesis route may proceed with the step (b) in order to yield the compound according to the formula III. The compound according to the formula II may be ring opened in the step (b) with an organometallic compound accordin to the formula VII :

wherein M in the formula VII is a suitable metal for said ring opening, which is preferably selected from Li, MgBr and MgCI, most preferably MgCI. The reaction is preferably catalyzed with CuX (X= CI, Br, I), ZnCI ₂ , FeCI ₃ , more preferably with Cul or CuCI. M = MgCI catalyzed with Cul is particularly preferred. Suitable reaction conditions are reviewed by Melendez et al. (Tetrahedron, Volume 59, Issue 15, pages 2581-2616) or described by Hebeisen et al. (Tetrahedron Lett. 2011, 52, 5229). Most preferably, the present invention takes advantage of a Knochel type halogen metal exchange of l-chloro-3-iodo-benzene with isopropyl- magnesium chloride, preferably upon the addition of a catalytic copper(I) salt such as Cul.

Remarkably, the ring opening reaction in the step (b) proceeds with an inversion of configuration (see Scheme 7 above). Therefore, the synthesis may be performed in a highly selective asymmetric manner by suitably selecting an essentially enantiopure or even enantiopure starting material I which, as being illustrated in the above items 12 and 13, subsequently leads to the essentially enantiopure or even enantiopure final product according to the formula (R)-A or (S)-A, or its salt, respectively. It is preferred in the present invention that the synthesis leads to the essentially enantiopure or even enantiopure compound according to the formula (R)-A by using the essentially enantiopure or even enantiopure compound according to the formula (R)-I as a starting material.

Notably, the compound represented by the formula III', or its salt:

wherein R' in formula III' represented

(i) by the above defined R which is an amino protection group which is preferably selected from -Boc (terf-butyloxycarbonyl), -Cbz (carbobenzyloxy), -Bz (benzoyl), -Bn (benzyl), -Ac (acetyl) or -CH ₂ CH(OR ² ) ₂ (wherein R ² is an alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl, or both R ² may bond together to constitute a C2- or C3-alkylene chain for forming a 5- or 6-membered ring) or is represented by

(ii) -H, -COCH ₂ X or -CH ₂ CH ₂ -X (wherein X is defined as above and is preferably -OH, tosylate, mesylate, triflate or a halogen, preferably CI, Br or I, and wherein X is most preferably CI or Br), represents a novel and suitable intermediate for the synthesis of compound A or related 8-chloro- l-methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts. This compound may be racemic or essentially enantiopure or even enantiopure in the R- or S-form, preferably in the R- form . This novel intermediate is preferably represented by compounds as defined by one of the above items 15 to 19.

If the compound according to the formula III' is represented by the above defined formula Ilia, the residue X is most preferably represented by CI or Br.

If the compound according to the formula III' is represented by the above defined formula Illb, the residue X is most preferably represented by CI or Br.

If the compound according to the formula III' is represented by the above defined formula IIIc, the residue R ² is most preferably represented by methyl or ethyl .

Further, this intermediate compound is suitably produced according to the above described reaction step (b) as defined by any one of the above items 1, 5, 8, 9, 12 or 13. The method optionally further comprises one or more of the reaction steps (c), (c- 1 ), (c-2), (c-3), (c- 1- 1 ), (c- 1-2), (c-2- 1), (c-2-2), and (c-3- 1) as defined by any of the above items 1, 6, 8, 9, 11, 12 or 13.

After the step (b) is accomplished to give the compound according to the formula III, the synthesis route may proceed with the step (c) . This step (c) may split into three alternatives given by the above described steps (c- 1), (c-2) and (c-3), respectively.

First alternative (c-1 )

In the step (c- 1) according to the first alternative, the compound according to the formula III is converted to a compound according to the formula Ilia:

wherein X in the formula Ilia is a leaving group suitable for an cyclizing intramolecular Friedel-Crafts alkylation reaction or a group which can suitably be converted to a such a leaving group wherein X is preferably -OH, tosylate, mesylate, triflate or a halogen, preferably selected from CI, Br, I, more preferably CI or Br. Most preferably, X is represented by CI or Br.

The term "leaving group suitable for a cyclizing intramolecular Friedel-Crafts alkylation reaction" and "a group which can suitably be converted to such a leaving group" used in this invention mean a group which forms an electrophilic species suitably reacting with aromatics in a Friedel-Crafts reaction upon the presence of a Lewis acid or Br0nsted acid or by a photochemical reaction . A "group which can suitably be converted to such a leaving group" has the capability of being conventionally converted to a desired leaving group which preferably takes place in situ. The respective leaving group of a precursor group thereof can be protected by usual and known protecting groups. The respective meanings of these terms become further apparent from the more specific definitions provided herein in the disclosure of preferred embodiments.

The step (c-1) may further comprise the step (c-1-1) of removing the group R from the compound according to the formula III, if R is a group other than the above defined -CH ₂ CH(OR ² ) ₂ , to obtain the compound according to the formula Hid :

Notably, if R in the compound according to the formula III is represented by the above defined -CH ₂ CH(OR ² ) ₂ , such a compound is already represented by the compound according to the above formula IIIc (which corresponds to the above formula III in which R = -CH ₂ CH(OR ² ) ₂ ) and the subsequent synthesis would then proceed via the alternative (c-3), so that no deprotection is required.

Specific conditions for the deprotection of group R are not specifically limited. It is within the disposal of a skilled person to choose certain and suitable conditions for removing the respective amino protecting group based e.g. on the reviewed conditions of the above referenced "Greene's Protective Groups in Organic Synthesis".

After the step (c-1-1) is accomplished, the step (c-1) may further comprise the step (c-1-2) of reacting the compound according to the formula Hid with a compound represented by the above formula VIII :

wherein X ¹ is selected from OH, F, CI, and Br, preferably CI, and X ² is selected from OH, CI, and Br, and is preferably CI or Br, to obtain the compound according to the above formula Ilia wherein - if X ² = OH - this hydroxyl group may further be converted to one of tosylate, mesylate, triflate, CI, Br or I, preferably CI or Br, and/or provided that - if X ¹ = OH - this hydroxyl group is activated for forming an amide bond . A conversion of the alcoholic hydroxyl group (i.e. X ² = OH) to a halogen selected from CI or Br or to one of tosylate, mesylate, triflate can be accomplished by conventional procedure which may be represented by a procedure as described in the above referenced prior art literature. This conversion is preferably from the viewpoint of increasing the yield of the subsequent Friedel-Crafts reaction. However it is also possible to react the alcoholic hydroxyl group in the Friedel-Crafts reaction with e.g . the use of excess Lewis acid or Br0nsted acid. If required, the activation of the free acid (X ¹ = OH) for forming the amide bond follows a straightforward amide synthesis.

Due to the accessibility, low costs and facile subsequent reactivity for the Friedel-Crafts reactions, it is preferred that the compound represented by the formula VIII is one selected from chloroacetyl chloride or bromoacetyl chloride.

After the step (c-1) is accomplished, the compound according to the formula Ilia of the first alternative is converted in the step (d) according to above item 1 to give a compound according to the formula A, or its salt, or its R- or S-enantiomer if following the above described asymmetric protocol .

The step (d) may be divided in the above defined first step (d-1) and (d-1-1), respectively, and the above defined second step (d-2).

In the first steps (d-1) and (d-1-1), respectively, the compound according to the formula Ilia is converted in a Friedel-Crafts alkylation reaction or photochemically induced ring closing reaction to give the compound according to the formula IVa. Such a Friedel-Crafts alkylation reaction may be accomplished in the presence of a Lewis acids selected from AICIs, FeCIs, InCI ₃ , InBr ₃ , Bi(OTf) ₃ , BiCI ₃ , Sc(OTf) ₃ , TeCI ₄ , BF ₃ xOEt ₂ , preferably anhydrous AICI ₃ , or a Br0nsted acid selected from HOTf, pTsOH, TFA, CH ₃ S0 ₃ H, H ₃ P0 ₄ / P ₂ 0 ₅ , H ₂ S0 ₄ / AcOH mixture, cone. H ₂ S0 ₄ or polyphosphoric acid (PPA), preferably H ₂ S0 ₄ or PPA. Most preferably, the Friedel-Crafts alkylation takes advantage of the anhydrous AICI ₃ . Reaction conditions for the conversion of alcohols (i.e. X = OH) may usually take advantage of excessive amount of Lewis or Br0nsted acid while reaction conditions without excess of Lewis acid or Br0nsted acid are reviewed by Magnus Rueping et al. (Beilstein Journal of Organic Chemistry 2010, 6, No. 6). Alternatively, the ring closing may be accomplished by a photochemical reaction. Such a photochemical ring closing reaction may be performed in a photochemical reactor by using solar-light or UV irradiation. The photochemical ring closing reaction may use for instance a 100 W lamp to irradiate the compound according to the formula Ilia dissolved in a suitable solvent such as aqueous MeCN or aqueous EtOH . Photochemical reactions can preferably be conducted in an immersion-type reactor consisting of a reactor body made from borosilicate glass with inserted double-walled borosilicate immersion well. Preferably, a medium pressure Hg-lamp (P= 100-150 W, A=predominantly >300 nm) can be used . This Hg-lamp can be inserted into a vertically arranged double-walled, water cooled immersion well. The reacting time is not specifically limited and the efficiency and selectivity of the reaction may be monitored by e.g. mass spectroscopy. Usually, the reaction time for the Friedel-Crafts reaction of 2 to 36 hours is sufficient while irradiation time of 0.25 to 4 hours may be sufficient. Common reaction conditions may be applied while the conditions according to one of the examples 15 to 18 are particularly preferred.

Subsequently, in the step (d-2), the compound according to the formula IVa is reduced by a suitable reducing agent to yield the compound according to the formula A, or its salt, or its R- or S- enantiomer if following the above described asymmetric protocol. The reducing agent is not specifically limited but it is preferably selected from BH ₃ complexes, Hz/metal cat. (preferably Rh, Ru, Pd), NaBH ₄ / H ₂ S0 ₄ , LiAIH ₄ , Et ₃ N / HCOOH, RED-AI, DIBAL-H, and most preferably BH ₃ -THF complex or hydrides. Common reaction conditions may be applied while the conditions according to example 14 are particularly preferred.

Notably, the compound represented by the formula IVa :

represents a novel and suitable intermediate for the synthesis of compound A or related 8-chloro-l-methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts. This compound may be racemic or essentially enantiopure or even enantiopure in the R- or S-form, preferably in the R- form.

This compound is suitably produced according to the above described reaction steps (d-1) and/or (d-1-1) as defined by any one of items 1, 7, 8, 13 or 14, the method preferably using anhydrous AICI ₃ or hv.

Second alternative (c-2)

In the step (c-2) according to the second alternative, the compound according to the formula III is converted to a compound according to the formula Illb:

wherein X in the formula Illb is the same as defined for the compound according to the above formula Ilia.

The step (c-2) may be accomplished by means of the above step (c-2-1) or alternatively by means of the above step (c-2-2).

If following the procedure of the step (c-2-1), the group R from the compound according to the formula III is removed according to the above described deprotection step (c-1-1), if R is a group other than the above defined -CH ₂ CH(OR ² ) ₂ , to obtain the compound according to the following formula Hid :

Notably, if R in the compound according to the formula III is represented by the above defined -CH ₂ CH(OR ² ) ₂ , such a compound is already represented by the compound according to formula IIIc and the subsequent synthesis would then proceed via the alternative (c-3) so that no deprotection is required . Following the deprotection step (c-1-1), the compound according to the formula Hid may first be converted to the compound according to the formula Ilia following the above reaction step (c-1-2). Thereafter, the compound according to the formula Ilia is subsequently reduced according to step (c-2-1) to give the compound according to formula Illb by use of a suitable reducing agent, preferably selected from LiAIH ₄ , RED-AI, DIBAL-H, diborane, BH ₃ -THF complex or hydrides, most preferably BH ₃ -THF complex.

Alternatively, if following the procedure of the step (c-2-2), the compound according to the formula Hid may be converted to the compound according to the formula Illb according to the step (c-2-2) by means of a reductive amination reaction with use of a compound represented by the above formula IX:

wherein X ² is the same as defined for formula VIII above, to obtain in a one-pot reductive amination reaction using a suitable reducing agent, preferably selected from H2/Pd/C/HCI, sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride, most preferably H2/Pd/C/HCI , the compound according to the formula Illb, provided that if X ² = OH, this hydroxyl group may further be converted to one of tosylate, mesylate, triflate, CI, Br or I, most preferably CI or Br. The compound according to the formula IX may be bromoacetaldehyde (The Journal of Organic Chemistry, 48, p. 2111, 1983) and more preferably readily available chloroacetaldehyde. Common reaction conditions may be applied during the reductive amination reaction.

After the step (c-2) is accomplished by means of the above step (c-2- 1) or alternatively by means of the above step (c-2-2), the compound according to the formula Illb of the second alternative is converted in the step (d) of item 1 to give a compound according to the formula A, or its salt, or its R- or S- enantiomer if following the above described asymmetric protocol. This step (d) corresponds to the above defined first step (d-1) and (d-1-2), respectively.

In the step (d-1) and (d-1-2), respectively, the compound according to the formula Illb is converted in a Friedel-Crafts alkylation reaction or photochemically induced ring closing reaction to give the compound according to the formula A, or its salt, or its R- or S-enantiomer if following the above described asymmetric protocol. The Friedel-Crafts alkylation reaction or the photochemically induced ring closing reaction may be accomplished in the same way as described for the step (d-1-1) with respect to first alternative described for the compound according to the formula Ilia above.

Third alternative (c-3)

In the step (c-3) according to the third alternative, the compound according to the formula III is converted to a compound according to the formula IIIc:

wherein R ² is as defined above. The formation of the compound according to the formulas IIIc may be omitted for the event that R in the compound according to the above formulae II and III is already represented by the above defined -CH ₂ CH(OR ² ) ₂ .

If R in the compound according to the formula III is not already represented by the above defined -CH ₂ CH(OR ² ) ₂ , the step (c-3) may be represented by the above step (c-3-1) according to the above item 6 which comprises the above deprotection step (c-1-1) for removing the group R from the compound according to the formula III, if R is a group other than the above defined -CH ₂ CH(OR ² ) ₂ , to obtain the compound according to the formula Hid :

Further, in the reaction step (c-3-1), the compound according to the formula Hid is reacted with the compound represented by the above defined formula X ³ CH ₂ CH(OR ² ) ₂ (wherein X ³ is preferably CI or Br, and R ² is preferably methyl or ethyl), most preferably bromoacetaldehyde dimethyl acetal or bromoacetaldehyde diethyl acetal, or with the compound represented by the above defined formula OHC-CH(OR ² ) ₂ (wherein R ² is preferably methyl or ethyl), to obtain the compound according to the formula IIIc.

After the step (c-3-1), the compound according to the formula IIIc in the third alternative is converted in the step (d) of item 1 to give a compound according to the formula A, or its salt, or its R- or S-enantiomer if following the above described asymmetric protocol .

This step (d) may be divided into the above defined first step (d-1) and (d-1-3), respectively, and the above defined second step (d-2.

In the first step (d-1) and (d-1-3), respectively, the compound according to the formula IIIc is converted in a Friedel-Crafts reaction under essentially the same conditions as described for the step (d-1-1) with respect to the compound according to the formula Ilia above. That is to say, the acetal (which represents a group that can be suitably converted to a Friedel-Crafts leaving group in situ) in the compound according to the formula IIIc is activated by a Lewis acid, preferably anhydrous AICI ₃ or BF ₃ xOEt ₂ , or a Br0nsted acid, preferably cone. H ₂ S0 ₄ , PPA or MeS0 ₃ H, to react with the aromatic ring upon the formation of a compound according to the formula IVc ^' wherein R ² derives from the acetal group being not limited to methyl or ethyl.

IVC'

But in the step (d-1) and (d-1-3), respectively, the compound according to the above defined formula IIIc (where R ² is preferably selected but not limited to methyl or ethyl) is intramoleculary cyclized under Friedel-Crafts reaction conditions to give products depending on the reaction conditions. If the Friedel-Crafts reaction is performed without solvents in molten phase (neat conditions), the reaction yields the compound according to the below formula IVd, which can be isolated in the form of hydrochloride by partitioning between brine and dichloromethane. If the reaction is performed in a solvent, such as dichloromethane, the intermediate compounds according to the below formulae IVc' and/or its hydrolytic derivative IVc", wherein R ² is defined as above, preferably represented by methyl or ethyl, can also be isolated, under some conditions as predominate products. In some cases all three compounds are detected in the mixture.

IVc' IVc" IVd

In order to guarantee a more univocal process, the reaction should be forced to yield the final product with a double bond according to the formula IVd.

Such a Friedel-Crafts alkylation reaction applied in the present invention are preferably accomplished in the presence of a Lewis acids, preferably selected from AICI ₃ , FeCI ₃ , InCI ₃ , InBr ₃ , Bi(OTf) ₃ , BiCI ₃ , Sc(OTf) ₃ , TeCI ₄ , most preferably from anhydrous AICI ₃ . The Friedel-Crafts reaction is carried out without solvent (neat conditions) or in a solvent, selected from nitromethane, aromatic hydrocarbons, preferably nitrobenzene, chlorinated hydrocarbons, preferably dichloromethane for 10 min to 36 hours. The Friedel-Crafts reaction is preferably carried out without solvent (neat conditions) for cyclizing the compound according to the formula IVd, where the secondary amine is unprotected.

It was surprisingly found by the inventors, that if the secondary amino group of the compound according to the formula IIIc is protected by an amino protection group (R*), as represented by the structure according to the formula Hie,

Ille

the Friedel-Crafts reaction leads univocally to a product with the double bond as represented by the structure according to the formula IVe

IVe

wherein * defines a chiral C-atom and R* being represented by a protecting group. The amino protecting group R* as used herein means a group that protects the secondary amine of the compound according to the formula IIIc such that this group is applicable to the Friedel-Crafts reaction conditions applied in step (d-1), and (d-1-3), respectively. Such an amino protecting group R* is thus limited only by its suitability to perform under the reaction conditions of said reactions step (d) and can be selected from known "amino protecting groups" as recited in "Greene's Protective Groups in Organic Synthesis", 4th Edition (Peter G. M . Wuts, Theodora W. Greene; ISBN : 978-0-471-69754-1). Preferably, the amino protecting group R* used in the present invention is selected from unsubstituted benzyl (Bn) or substituted, preferably a-methyl, p-nitro, p-methyl or p-methoxy substituted benzyl (PMB), polyphenyl substituted methyl, preferably trityl (Tr), unsubstituted or fluorinated Ci-C ₄ -alkanesulfonyl, preferably methanesulfonyl (mesyl, Ms) or trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl, unsubstituted or substituted Ci-C ₆ -alkanoyl, preferably acetyl (Ac) or arylcarbonyl, preferably benzoyl (Bz), to obtain the compound according to the formula Hie, wherein R* is represented by said group, preferably by -Bn, -PMB, -Tr, -Ms, -Tf, -Ts, -Ac, or -Bz, respectively.

The media of the protection reactions are preferably selected from aprotic solvents, preferably dichloromethane.

Methods of preparation of the starting compound according to the formula Hie may be divided into two options (c-3-2) and (c-3-3). In the step (c-3-2), the compound according to the formula III, wherein R is a group other than the above defined -CH ₂ CH(OR ² ) ₂ , is reacted with the compound represented by the above defined formula X ³ CH ₂ CH(OR ² ) ₂ (wherein X ³ is preferably CI or Br, and R ² is preferably methyl or ethyl), most preferably bromoacetaldehyde dimethyl acetal or bromoacetaldehyde diethyl acetal, or with the compound represented by the above defined formula OHC-CH(OR ² ) ₂ (wherein R ² is preferably methyl or ethyl), not applying previous removing to obtain the compound according to the formula Hie, wherein R* is limited to the substituents R.

In the step (c-3-3), the compound according to the formula Hie is prepared from the compound according to the formula IIIc by a reaction of introduction of a protecting group by methods such as:

- unsubstituted benzyl or substituted, preferably a-methyl, p-nitro, p- methyl or p-methoxy substituted benzyl, or polyphenyl substituted methyl by a reaction with the corresponding halogenide, selected from chloride, bromide or iodide in basic conditions; - unsubstituted or fluorinated Ci-C ₄ -alkanesulfonyl, preferably trifluoromethanesulfonyl (triflyl, Tf), or unsubstituted or para substituted, preferably p-methyl (tosyl, Ts) substituted benzenesulfonyl by a reaction with the corresponding sulfonyl halogenide, preferably chloride, such as tosyl chloride (TsCI), or sulfonyl anhydrides, such as triflic anhydride (Tf ₂ 0) in basic conditions; or

- or unsubstituted or substituted Ci-C ₆ -alkanoyl, preferably acetyl or arylcarbonyl, preferably benzoyl by a reaction with corresponding acyl halogenide, preferably chloride, or acyl anhydride, such as acetic anhydride (Ac ₂ 0) or benzoyl chloride in basic conditions.

In the step (c-3-3) some protected groups, which are not possible in the method according to the step (c-3-2), can be introduced. Such type of groups is represented by sulfonyl protecting groups, which are preferable in the Fridel-Crafts transformation in view of yields and purity. The media of the protection reactions are preferably selected from aprotic solvents, most preferably from dichloromethane.

The compound of formula IIIc, used in the step (c-3-3) can be prepared from the compound according to the formula II in the step (b) if R is -CH ₂ -CH(OR ² ) ₂ , or from the compound according to the formula III in the step (c-3-1) if R is not a group other than the above defined - CH ₂ CH(OR ² ) ₂ .

After Friedel-Crafts transformation the compounds according to the formula IVc', IVc", IVd, and IVe are usually isolated by quenching the reaction mixture with water, neutralizing the mixture with a base, such as sodium hydroxide, and extracting the product with a water immiscible solvent, followed by removal of the solvent.

Subsequently, in the step (d-2), the compounds according to the formulae IVc', IVc", IVd or mixtures thereof are reduced with a suitable reducing agent to yield the compound according to the formula A, or its salt, or its R- or S-enantiomer if following the above described asymmetric protocol. The reducing agent is not specifically limited but it is preferably selected from Hz/Pd/C/HCI or Zn/HCI . Alternatively in the step (d-2), the compound according to the formula IVe is reduced to a compound according to the formula X:

x

using reducing agents preferably selected from boron hydrides, such as alkali metal borohydrides, preferably NaBH ₄ or borane complexes, preferably BH ₃ -THF, aluminum hydrides, preferably LiAIH ₄ , DIBALH, RedAI, by NEt ₃ /HC0 ₂ H, Zn in acidic conditions, or by catalytic hydrogenation using metal transition catalysts preferably selected from palladium, platinum, nickel, ruthenium, most preferable by catalytic hydrogenation using metal transition catalysts. The preferred method for reduction of the compounds of the formulae IVd or IVe is the catalytic hydrogenation on platinum oxide.

In the step (d3), the amino protection group R* of the compound according to the formula X is deprotected using standard protocols, known to a skilled person, which may be selected from acid or alkali hydrolysis or hydrogenation, to give the final product according to the formula A, or a salt thereof, preferably lorcaserin, or a salt thereof.

Alternatively, it is possible to convert the compound according to the formula IVe to the final product according to the formula A by first removing the protecting group followed by final reduction. However, due to the possibility of enamine-imine tautomery on unprotected intermediates, this synthetic route is inferior in view of yields and purity. For the same reason, it is preferred to introduce an amino protection group R* by means of the step (c-3-3) prior to the Friedel-Crafts alkylation applied in the step (d).

Notably, the compound represented the formula IVe', or its salt:

(IVC)

represents a novel and suitable intermediate for the synthesis of the compound A or related 8-chloro-l-methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts. This compound may be racemic or essentially enantiopure or even enantiopure in the R- or S-form, preferably in the R-form.

This compound is suitably produced according to the above described reaction step (d-1) and/or (d-1-3) as defined by any one of items 1, 7, 10, 11, 12 or 13, the method preferably using anhydrous AICI ₃ , cone. H ₂ S0 ₄ or PPA.

By virtue of the above described synthesis, the present invention for the first time provides the possibility for an asymmetric synthesis of 8-chloro-l-methyl-benzo[c/]azepine derivatives, preferably lorcaserin, or its salts, by using essentially enantiopure or enantiopure starting material. In this way, the present invention provides a facile, economically and selective synthesis. Moreover, the invention provides an insight about new key intermediates for the synthesis of such compounds and their respective production way.

Alternatively, it is possible to perform the whole procedure according to the invention from steps (a) to (d) of item 1 with racemic starting materials and intermediates and finally to separate enantiomers of the compound A by crystallization of a diastereoisomeric salt with tartaric acid to obtain the pharmaceutically applicable (R)- ^' \somer of lorcaserin, as it is described in WO05019179. But by eliminating more than half of material by removal of unusable opposite enantiomer in the last step the competitiveness of the process may be considerably challenged. Yet another alternative is to separate enantiomer in a step of earlier intermediates. For example, optical resolution of the non-chlorinated analogue 2-phenyl-l-propaneamine with L-malic acid in EtOH at 70 °C is disclosed in the following patent applications: WO008073789, WO01090057, WO01089530. It was surprisingly found, that optical resolution of the chlorinated derivative Hid with L-malic acid is completely useless due to precipitation of malate with racemic Hid .

It was found out that the compound according to the formula Hid can be successfully isolated in an essentially enantiopure or enantiopure form by crystallization of a diastereoisomeric salt with some less commonly used chiral organic acids.

Thus, the racemic compound according to the formula Hid (Hid)

is separated to enantiomers by treating with a chiral organic acid, preferably selected from phenyl substituted alkanoic acids in an organic solvent, from which one enantiomer precipitates in a highly enriched or essentially enantiopure form. The most preferred chiral acids are 2- phenylpropanoic acid and 3-phenyl lactic acid . For example, by treating the compound Hid with (R)-(-)-2-phenylpropanoic acid (RPP) in ethanol, the compound (7? IIId is isolated in a highly enriched form in one step, while by further recrystallization of the isolated salt essentially enantiopure isomer with over 98 % e.e. is obtained.

(RJ-llld x RPP

Similar results are obtained by crystallization of the racemic compound according to the formula Hid with L-(-)-3-phenyllactic acid (LPL) in toluene.

CH ₃

(RJ-llld x LPL

Enantiomeric purity can be further improved by one or more crystallisations to obtain enantiopure material.

The crystallization is performed by mixing both components with the solvent, heating above 50 degrees to dissolve all or most of solid material, optionally filtering impurities and cooling down the solution to crystallise the salt. The precipitated material is isolated by filtration or centrifugation and dried .

The obtained compound according to the formula (7? IIId is recovered in a form a base by alkalizing, for example by aqueous NaOH followed by extraction with a water unmixable solvent and evaporation. Such compound can be further used in the steps (c) and (d) to obtain the compound of formula A in essentially enantiopure or enantiopure form, preferably lorcaserin in the (R) form, or its salts.

An analogous transformation can be performed for the (S)- enantiomers using (7RX+)-2-phenylpropanoic acid (SPP) or D-( + )-3- phenyllactic acid (DPL).

The racemic compound of formula Hid may be synthesised by a newly disclosed alternative way from 2-(3-chlorophenyl)acetonitrile via 2- (3-chlorophenyl)propanenitrile followed by reduction to 2-(3- chlorophenyl)propan-l-amine, which was reported in J. Med. Chem. 2013, 56, 4786-4797) and in J. Am. Chem. Soc. 2013, 135, 2100-2103 (Scheme 8).

Mid x HCI

Scheme 8 A skilled person may choose which enantioselective method is more favorable in view of yields and price. A choice between using chiral aminopropanol of the formula I following the steps (a) to (d) according to the present invention or preparing the racemic compound of the formula Hid according to the steps (a), (b), and (c) or according to Scheme 8, followed by optical resolution via diastereoisomeric salts and the further step (d) may offer an opportunity not to make optical resolution in the final step of preparation of pharmaceutical compound, such as lorcaserin. The resolution in the final step is an inevitable option if prior art processes from para-chloro substituted starting materials are used .

Detailed description of the ways of carrying out the invention (examples) in a way that examples can be reproduced.

Example 1: Synthesis of i ^" eri ^" -butyl-2-(hydroxypropyl)-carbamate (V-Boc) from l-aminopropan-2-ol (I) :

Into a flask equipped with a magnetic stir bar the starting material l-amino-2-propanol (I; 3.0 g, 60 mmol) was placed and it was dissolved in dry methanol (MeOH) (110 ml_). The alkaline activator Et ₃ N (16 mL) was added followed by slow addition of bis-tert-butyldicarbonate (60 mmol, 13.1 g) and the obtained reaction mixture was stirred under nitrogen for 30 minutes at 60°C. After completion of the reaction, methanol was evaporated under reduced pressure, the residue was diluted with water and then extracted with ethyl acetate (30 mL). The organic phase was washed with brine, dried over anhydrous Na ₂ S0 ₄ and the organic solvent was evaporated under reduced pressure. A colorless oily product (V-Boc, 6.8 g, 97% yield) was obtained and characterized with *Η, ¹³ C NMR and IR analysis. *H NMR (500 MHz, CDCI ₃ , ppm) δ 5.20 (bs, NH), 3.85 (m, 1H), 3.25 (m, 1H), 3.05 (bs, OH), 2.90 (m, 1H), 1.43 (s, 9H), 1.10 (d, J= 8 Hz, 3H);

1 ³ C NMR (125 MHz, CDCI ₃ , ppm) δ 157.0, 79.7, 67.6, 48.1, 28.5, 20.8;

IR (neat) : v = 3351 (broad, OH), 2975, 2931, 1684 (CO), 1514, 1365, 1248, 1167 cm ^"1 .

Example 2: Synthesis of optically active teri ^" -butyl-2-(hydroxypropyl)- carbamate ((R)-V-Boc or (S)-V-Boc from chiral l-aminopropan-2-ol ((R)- I or (S)-I) :

HO NH ₂ Boc O HO NHBoc

υ I ^ VRiy

/ Et ₃ N/MeOH

H3C H3C

or enantiomer or enantiomer

Into a flask equipped with a magnetic stir bar the starting material 1- amino-2-propanol ((R)-I or (S)-I; 13 mmol, 0.98 g) was placed and it was dissolved in dry MeOH (40 ml_). The alkaline activator Et ₃ N (4 ml_) was added followed by slow addition of bis-tert-butyldicarbonate (1 equiv. calculated to the starting material) and the obtained reaction mixture was stirred under nitrogen for 30 minutes at 60°C. After the completion of the reaction, methanol was evaporated under reduced pressure, the residue was diluted with water and then extracted with ethyl acetate (2 x 20 ml_). The combined organic phases were washed with brine, dried over anhydrous Na ₂ S0 ₄ and the organic solvent was evaporated under reduced pressure. A colorless oily product ((R)-V-Boc or (S)-V-Boc, 2.21 g, 95% yield) was obtained and analyzed with HPLC and confirmed with ¹³ C NMR spectroscopy.

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 157.0, 79.8, 67.6, 48.2, 28.6, 20.8. Example 3: Synthesis of tert-butyl-5-methyl-l,2,3-oxathiazolidine-3- carboxylate-oxide (VI-Boc) from tert-butyl-2-(hydroxypropyl)-carbamate (V-Boc)

Into a flask equipped with a magnetic stir bar imidazole (4.10 g, 60 mmol) which was dissolved in CH ₂ CI ₂ (40 ml_) was placed and the solution was cooled down to 0°C. Afterwards the solution of SOCI ₂ (1.3 ml_, 18 mmol) in CH ₂ CI ₂ was slowly added and the reaction mixture was stirred for an hour at 20°C and cooled to -5°C. The solution of teri ^" -butyl-2-(hydroxypropyl)- carbamate (V-Boc, 1.75 g, 10 mmol) in CH ₂ CI ₂ was then slowly dropped into the reaction mixture and vigorously stirred for 2-3 hours at 20°C. The reaction mixture was first diluted with deionized water. The organic phase was separated, washed with aqueous solution of citric acid (50 ml_) and brine (50 ml_) and the solvent was than evaporated under reduced pressure. A solid material (mixture of isomers) was obtained (VI-Boc, 1.99g, 90% yield) and characterized with ¹³ C NMR spectroscopy.

1 ³ C NMR (125 MHz, CDCI ₃ , ppm) δ 156.1, 83.8, 79.8, 71.7, 67.8, 50.6, 46.1, 28.6, 28.3, 20.1 17.1.

Example 4: Direct synthesis of tert-butyl-5-methyl-l,2,3-oxathiazolidine-3- carboxylate-2,2-dioxide (II-Boc) from teri ^" -butyl-2-(hydroxypropyl)- carbamate (V-Boc)

Into a flask equipped with a magnetic stir bar was placed imidazole (60 mmol) which was dissolved in CH ₂ CI ₂ (40 mL) was placed and the solution was cooled down to 0°C. Afterwards the solution of SOCI ₂ (18 mmol) in CH ₂ CI ₂ was slowly added and the reaction mixture was stirred for an hour at 20°C and cooled to -5°C. The solution of teri ^" -butyl-2-(hydroxypropyl)- carbamate (V-Boc, 10 mmol) in CH ₂ CI ₂ was slowly dropped into the reaction system and vigorously stirred for 2 hours at 20°C. The reaction mixture was first diluted with deionized water, the organic phase was separated, washed with aqueous solution of citric acid (50 mL) and brine (50 mL). The organic phase was then used for further oxidation process where the aqueous solution of NaI0 ₄ (5.8 g in 50 mL of water) was slowly added into the system at 0°C followed by the addition of Ru0 ₂ -H ₂ 0 catalyst (90 mg). The reaction system was then vigorously stirred for an hour at 0°C and then 2-3 hours at room temperature. The reaction mixture was first diluted with aqueous solution of ascorbic acid, the organic phase was separated, washed with brine (50 mL) and solvent was evaporated under reduced pressure. The crude material (yellowish oil) was dried under vacuum to afford the final crystalline product (II-Boc, 1.91 g, 80% yield) which was characterized with ¹ H and ¹³ C NMR spectroscopy.

*H NMR (500 MHz, CDCI ₃ , ppm) δ 4.95 (m, 1H), 4.06 (m, 1H), 3.62 (m, 1H), 1.60 (d, J= 7.5 Hz, 3H), 1.51 (s, 9H);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 148.8, 85.5, 76.4, 51.9, 28.1, 18.2;

IR (neat): v = 1716, 1332, 1198, 1144, 763 cm ^"1 .

Example 5: Direct synthesis of optical active teri ^" -butyl-5-methyl-l,2,3- oxathiazolidine-3-carboxylate-2,2-dioxide ((R)-II-Boc or (S)-II-Boc)

or enantiomer or enantiomer Into a flask equipped with a magnetic stir bar imidazole (66 mmol) which was dissolved in CH ₂ CI ₂ (45 mL) was placed and the solution was cooled down to 0°C. Afterwards the solution of SOCI ₂ (19.8 mmol) in CH ₂ CI ₂ was slowly added and such reaction mixture was stirred for an hour at 20°C and cooled to -5°C. The solution of i ^" eri ^" -butyl-2-(hydroxypropyl)-carbamate ((R)-V-Boc or (S)-V-Boc, 11 mmol) in CH ₂ CI ₂ was slowly dropped into the reaction system and intensively stirred for 2 hours at 20°C. The reaction mixture was first diluted with deionized water. The organic phase was separated, washed with aqueous solution of citric acid (50 mL) and brine (50 mL). The organic phase was then used for the oxidation process where aqueous solution of NaI0 ₄ (6.0 g in 50 mL of water) was first slowly added into the system at 0°C followed by Ru0 ₂ - H ₂ 0 catalyst (110 mg). The reaction system was than vigorously stirred for an hour at 0°C and then 3 hours at room temperature. The reaction mixture was first diluted with aqueous solution of citric acid, the organic phase was separated, washed with brine (50 mL) and solvent was than evaporated under reduced pressure. The crude material (yellowish oil) was dried under vacuum to afford a crystalline yellow product ((R)-II-Boc or (S)-II-Boc, 2.32 g, 86% yield). Analytical data were in accordance to previous example 4 (HPLC analysis (single enantiomer) and ¹ H, ¹³ C NMR spectroscopy).

Example 6: Synthesis of tert-butyl-(2-(3-chlorophenyl)propyl)carbamate (III-Boc) from tert-butyl-5-methyl-l,2,3-oxathiazolidine-3-carboxylate- 2,2-dioxide (II-

Into a two necked flask equipped with a magnetic stir bar and rubber septum l-chloro-3-iodo-benzene (1.42g, 6 mmol) dissolved in Et ₂ 0 was placed and cooled down to -14°C. Afterwards / ^' PrMgCI (3 ml, 2M ethereal solution, 6 mmol) was slowly dropped into reaction system (1 hour dropping) and the reaction mixture was stirred at 0°C for 2.5 hours. Cul (11 mg) was then added and the reaction system was stirred for additional 30 minutes. Finally, the suspension of 5-methyl-l,2,3-oxathiazolidine-3- carboxylate-2,2-dioxide (II-Boc, 1.18 g, 5 mmol) in Et ₂ 0 was then slowly added at -10°C and such reaction system was vigorously stirred for 2 hours at 0°C. The reaction mixture was first diluted with aqueous solution of citric acid at room temperature and stirred there for an hour to allow good separation of phases. Organic phase was then washed with brine, dried over Na ₂ S0 ₄ and the solvent was evaporated . The crude oily material was dried under vacuum to afford colorless oil (III-Boc, 1.33 g, 99 % yield) which was characterized with H and ¹³ C NMR and IR spectroscopy.

*H NMR (500 MHz, CDCI ₃ , ppm) δ 7.16-7.05 (m, 3H), 4.45 (bs, NH), 3.32 (m, 1 H), 3.15 (m, 1 H), 2.87 (m, 1H), 1.30 (s, 9H), 1.22 (d, J= 8 Hz, 3H); ¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 156.1, 146.6, 134.6, 130.1, 127.6, 126.9, 125.7, 79.5, 47.4, 40.1, 20.6, 19.1 ;

IR (neat) : v = 3352 (br, NH), 2974, 2930, 1692, 1506, 1247, 1163 cm ^"1 .

Example 7: Synthesis of optical active teri ^" -butyl-(2-(3- chlorophenyl)propyl)carbamate ((R)-III-Boc or (S)-III-Boc) from chiral i ^" eri ^" -butyl-5-methyl-l,2,3-oxathiazolidine-3-carboxylate-2, 2-dioxide ((R)- II-Boc or (S)-II-Boc)

or enantiomer or enantiomer

Into a two necked flask equipped with a magnetic stir bar and rubber septum l-chloro-3-iodo-benzene (0.24g, 1 mmol) dissolved in Et ₂ 0 was placed and cooled down to -14°C. Afterwards / ^' PrMgCI as 2M ethereal solution (1 mmol) was slowly dropped into the reaction system (1 hour dropping) and the reaction mixture was stirred at 0 °C for 2.5 hours so that Grignard exchange reaction occurred efficiently. Cul (5 mg) was then added and the reaction system was stirred for additional 30 minutes. Finally, the suspension of 5-methyl-l,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide ((R)-II-Boc or (S)-II-Boc, 0.85 mmol) in Et ₂ 0 was then slowly added at -10°C and such reaction system was vigorously stirred overnight at 0°C. The reaction mixture was first diluted with aqueous solution of citric acid at room temperature and stirred for an hour to allow good separation of phases. The organic phase was then washed with brine, dried over Na ₂ S0 ₄ and the solvent was evaporated . The crude oily material was dried under vacuum to afford colorless oil ((R)-III-Boc or (S)-III-Boc, 86 % yield) Analytical data were in accordance to previous example 6 (HPLC analysis (single enantiomer) and H, ¹³ C NMR spectroscopy).

Example 8: Deprotection of teri ^" -butyl-(2-(3- chlorophenyl)propyl)carbamate (III-Boc) to 2-(3-chlorophenyl)propan-l- amine (Hid)

Into a solution of tert-butyl-(2-(3-chlorophenyl)propyl)carbamate (III-Boc, 0.8 g, 3 mmol) in THF (6 ml_) hydrochloric acid (10 ml_, 6 M) was added and the reaction system was stirred for a few hours at 40-45°C. The solvent was evaporated, the organic residue was diluted with water, pH was adjusted to 9 using NaOH aqueous solution and then extracted with two portions of ethyl acetate (40 ml_). The organic phase was dried over Na ₂ S0 ₄ and the solvent was evaporated to obtain an oily product (Hid, 0.4 g, 78% yield) which was confirmed with H and ¹³ C NMR analysis.

*H NMR (500 MHz, CDCI ₃ , ppm) δ 8.25 (bs, NH ₂ ), 7.25-7.10 (m, 4ArH), 3.15 (m, 1H), 2.92 (m, 2H), 1.15 (d, J= 9 Hz, 3H);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 147.4, 134.5, 130.0, 127.6, 126.9, 125.7, 49.4, 43.5, 19.4. Example 9: Preparation of hydrochloride salt of (S) or (R)-2-(3- chlorophenyl)propan- l-amine ((R)-IIId or (S)-IIId)

or enantiomer or enantiomer or enantiomer

Into a cold solution of tert-butyl-(2-(3-chlorophenyl)propyl)carbamate ((R)- III-Boc or (S)-III-Boc, 2.65 g, 9.8 mmol) in TH F (20 mL) hydrochloric acid (32 mL, 6 M) was added and the reaction system was stirred for 3 hours at 45°C. The solvent was evaporated, the organic residue was diluted with water, pH was adjusted to 9 using NaOH aqueous solution and then extracted with two portions of ethyl acetate (50 mL). The organic phase was dried over Na ₂ S0 ₄ and the solvent was evaporated to obtain crude material which was then diluted in diethyl ether. Hydrochloric acid ( 1 M, 12 mL) was then dropping for 1 hour into the reaction system at room temperature. Afterwards the reaction system was slowly cooled down where the salt started to precipitate. The resulting solid was filtered off, dried in vacuum ((R)-IIId or (S)-IIId, 1.42g, 71% yield) and characterized with NM R spectroscopy and HPLC analysis.

*H NM R (500 M Hz, DMSO, ppm) δ 8.30 (bs, 3H), 7.30-7.15 (m, 4ArH), 3.18 (m, 1 H), 2.96 (m, 2H), 1.24 (d, J = 9 Hz, 3H).

¹³ C NM R ( 125 M Hz, DMSO, ppm) δ 145.4, 133.2, 130.5, 127.2, 126.9, 126.1, 44.5, 37.1, 19.2.

IR (tablet) : v = 3000-2721 (br), 1597, 1572, 1505, 1466, 1393, 785, 674 cm ^"1 .

Example 10: Synthesis of 2-chloro-N-(2-(3-chlorophenyl)propyl)acetamide (Illa-CI)

Into a cold solution of 2-(3-chlorophenyl)propan-l-amine (Hid; 250 mg, 1.5 mmol) in CH ₂ CI ₂ (4 ml_) Na ₂ C0 ₃ (1.6 mmol) was added and the reaction mixture was stirred for 15 min at 5-10°C. Afterwards chloroacetyl chloride (1.6 mmol) was slowly dropped into the reaction system and stirred for a few hours at 25 °C. The reaction mixture was diluted with water, phases were separated, the organic phase was washed with brine (20 ml_) and dried over Mg ₂ S0 ₄ . The solvent was evaporated under reduced pressure to afford an oily product (Illa-CI, 350 mg, 95% yield).

*H NMR (500 MHz, CDCI ₃ , ppm) δ 7.30-7.18 (m, 3ArH), 7.10 (m, lArH), 4.00 (s, 2H), 3.65 (m, 1H), 3.34 (m, 1H), 2.97 (m, 1H), 1.32 (d, J = 8.7 Hz, 3H).

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 166.2, 145.8, 134.8, 130.2, 127.5,

127.3, 125.6, 46.4, 42.8, 39.6, 19.0.

IR (neat) : v = 3291 (br), 1656, 1537, 1381 cm ^"1 .

The same experimental procedure has been successfully performed also with the optical active analogous compound.

Example 11: Synthesis of 2-bromo-N-(2-(3-chlorophenyl)propyl)acetamide (IIIa-Br)

Into a cold solution of 2-(3-chlorophenyl)propan-l-amine (Hid; 1.5 mmol) in CH ₂ CI ₂ (2 ml_) / ^' Pr ₂ EtN (3.05 mmol) was added and the reaction mixture was stirred for 15 min at 20°C. Afterwards bromoacetyl chloride (1.6 mmol) was slowly dropped into the reaction system and stirred overnight at 25 °C. The reaction mixture was diluted with water, phases were separated, the organic phase was washed with brine (20 ml_) and dried over Mg ₂ S0 ₄ . The solvent was evaporated under reduced pressure to afford an oily product (IIIa-Br, 351 mg, 81 % yield).

*H NMR (500 MHz, CDCI ₃ , ppm) δ 7.28-7.19 (m, 3ArH), 7.12 (m, lArH), 6.50 (bs, NH), 3.76 (s, 2H), 3.45 (m, 1H), 3.22 (m, 1H), 2.89 (m, 1H), 1.21 (d, J = 8.7 Hz, 3H).

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 165.7, 145.8, 134.8, 130.2, 127.6,

127.4, 46.8, 42.6, 39.6, 29.3, 19.0.

IR (neat) : v = 3283, 1652, 1538, 1380, 783, 695 cm ^"1 .

The same experimental procedure has been successfully performed also with the optical active analogous compound.

Example 12: Synthesis of 2-(3-chlorophenyl)-/V-(2,2-diethoxyethyl) propan-l- -Et)

Into a solution of 2-(3-chlorophenyl)propan-l-amine (Hid; 480 mg, 2.3 mmol) in DMF (10 ml_), potassium carbonate (643 mg, 2 equiv.) and bromoacetaldehyde diethyl acetal (0.4 ml_, 1.1 equiv.) were added successively. Reaction was heated to 80°C and was stirred overnight. Reaction was cooled down to room temperature and was diluted with water (40 ml_) and MTBE (40 ml_). Phases were separated and water phase was re-extracted with MTBE (40 ml_). Combined organic phase was washed with water (20 ml_), was dried over sodium sulfate, filtered and concentrated . Pure sample was obtained by purification on reverse phase column purification (Systag 25-M, C18, 10 to 90% MeCN in water) to yield 2-(3- chlorophenyl)-/V-(2,2-diethoxyethyl)propan-l-amine (IIIc-Et, 227 mg, 35%).

*H NMR (500 MHz, CDCI ₃ , ppm) δ 7.24-7.13 (m, 3H), 7.10 (d, J =7.4 Hz, 1H), 4.54 (t, J = 5.6 Hz, 1H), 3.63 (m, 2H), 3.47 (m, 2H), 2.90 (hex, J = 7.1 Hz, 1H), 2.77 (d, J = 7.2 Hz, 2H), 2.72 (dd, J = 5.5 Hz, J = 12.1 Hz, 1 H), 2.66 (dd, J = 5.8 Hz, J = 12. 1 Hz, 1 H), 1.24 (d, J = 6.9 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H).

¹³ C N MR (125 M Hz, CDCI ₃ ppm) δ 147.4, 134.3, 129.8, 127.3, 126.5, 125.5, 101.9, 62.4, 56.8, 52.0, 39.9, 19.7, 16.3.

The same experimental procedure has been successfully performed also with the optical active analogous compound .

Example 13: Synthesis of 2-(3-chlorophenyl)-/V-(2,2-dimethoxyethyl) propan- l-amine (IIIc-Me)

Compound 2-(3-chlorophenyl)propan- l-amine (III; 1 g, 4.8 mmol) in methanol (2 mL) was treated with dimethoxyacetaldehyde (60% in H ₂ 0, 1.46 mL, 2 equiv.) and solution was stirred at room temperature for 48 hours. 10% Pd/C ( 100 mg, 10 wt%) was added and reaction atmosphere was flushed several times with nitrogen and hydrogen alternatively. Hydrogen pressure was set at 5 atmospheres and the reaction was stirred for 4 hours. Reaction was filtrated on Celite® and concentrated . The residue was dissolved in DCM (20 mL) and solution was washed with 2/1 solution of brine and HCI 1 M (20 / 10 mL) . The DCM phase was dried over sodium sulfate, filtered and concentrated . Compound was dissolved in toluene (40 mL) and solution was extracted three times with water (3 x 30 mL) . Combined water phase was saturated with NaCI and solution was extracted twice with DCM (2 x 30 mL) . The combined DCM phase was dried over sodium sulfate, filtered and concentrated to give clean product IIIc-Me characterized by H NM R.

*H NM R (500 MHz, CDCI ₃ , ppm) δ 7.33-7.22 (m, 3H), 7.18 (d, J =7.2 Hz, 1 H), 4.89 (t, J = 5.0 Hz, 1 H), 3.49 (m, 1 H), 3.44 (s, 3H), 3.42 (s, 3H), 3.31 (m, 1H), 3.19 (m, 1H), 3.08 (m, 1H), 3.00 (m, 1H), 1.44 (d, J = 6.9 Hz, 3H).

Example 14: Synthesis of hydrochloride salt of A/-(2-chloroethyl)-2-(3- chlorophenyl)propan-l-amine (Illb-CI)

A round bottom flask was charged with 2-chloro-N-(2-(3- chlorophenyl)propyl)acetamide (Illa-CI, 2 mmol) and then reducing agent BH3-THF complex (1M solution in THF; 2.5 equiv.) was slowly added . The reaction mixture was vigorously stirred for 15 hours at 25°C. Afterwards the mixture was cooled to 5°C, quenched with methanol and the solvent was evaporated under reduced pressure. The organic residue was then diluted in diethyl ether and hydrochloric acid was added dropwise. The reaction mixture was stirred at room temperature for 1 h and then slowly cooled down to precipitate white solid material. The obtained white solid (Illb-CI, 353 mg, 76% yield; mp = 160°C) was dried in vacuum and then characterized with H and ¹³ C NMR analysis.

*H NMR (500 MHz, CDCI ₃ + d ₆ -Acetone, ppm) δ 7.24-7.16 (m, 4ArH), 3.91

(m, 2H), 3.44 (m, 1 H), 3.21 (m, 4H), 1.38 (d, J = 8.7 Hz, 3H).

¹³ C NMR (125 MHz, CDCI ₃ + d ₆ -Acetone ppm) δ 144, 134.9, 130.6, 127.9,

127.4, 125.7, 54.3, 49.3, 38.4, 36.7, 19.9.

IR (tablet) : v = 2931, 2743, 1594, 1444, 1029 cm ^"1 .

The same experimental procedure has been successfully performed also with the optical active analogous compound. Example 15: Transformation of A/-(2-chloroethyl)-2-(3- chlorophenyl)propan-l-amine (IHb) to 8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-benzo[c/]azepine (A)

Into a test tube equipped with a magnetic stir bar liquid substrate (Illb); 0.5 mmol) was placed. Afterwards fresh anhydrous AICI ₃ (1.75 equiv according to starting material) was added and efficiently mixed with liquid substrate to obtain a paste. The reaction system was slowly heated (10 °C/min) to 150 °C and stirred there overnight. A saturated solution of sodium chloride was added and the reaction system was cooled down slowly. The pH was adjusted to 9.5-10 using 1M NaOH and then efficiently extracted with EtOAC. Combined organic phases were washed with brine, dried over Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained crude mixture was analyzed using H NMR spectroscopy. The NMR data were in agreement with known literature or patent data.

*H NMR (500 MHz, CDCI ₃ ) δ 7.18 (m, ArH), 7.11 (m, ArH), 7.00-6.94 (m, ArH), 3.20-2.78 (m, 5H), 2.75 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H).

The same experimental procedure has been successfully performed also with the optical active analogous compound in order to obtain (S) or (R)- 8- chloro-l-methyl-2,3,4,5-tetrahydro-lH-benzo[c/]azepine.

Example 16: Synthesis of 7-chloro-5-methyl-4,5-dihydro-lH- benzo[c/]azepine-2-(3H)-one (IVa)

Into a test tube equipped with a magnetic stir bar liquid substrate (Illa-CI, 0.25 mmol) was placed . Afterwards fresh anhydrous AICI ₃ (0.9 mmol) was added and efficiently mixed with liquid substrate to obtain a paste. The open reaction system was slowly heated to 80°C where a molten phase was obtained and it was stirred at 80°C for 15 minutes. The reaction mixture was then slowly (5°C/min) heated to 160°C and stirred overnight. A saturated solution of sodium chloride was added and the reaction system was cooled down slowly. The reaction mixture was then efficiently extracted with CH ₂ CI ₂ , combined organic phases were washed with brine, dried over Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained crude mixture was analyzed and the compound IVa was characterized / detected with GC-MS analysis (m/z : 210 (M + l); CI) where 20% with m/z : 210 (M + l) was detected .

Example 17: Photochemical synthesis of 7-chloro-5-methyl-4,5-dihydro- lH-benzo[c/]azepine-2-(3H)-one (IVa)

X= CI, Br

A solution of starting material (Illa-CI or IIIa-Br, 0.25 mmol) in 50% aqueous MeCN or aqueous EtOH was charged into a photochemical reactor and irradiated with a 100 W lamp (medium pressure Hg-lamp (P= 100-150 W, A=predominantly >300 nm) for 1 hour under intensive stirring . After evaporation of the solvent the residue was extracted into ethyl acetate, dried over Na ₂ S0 ₄ and the solvent was evaporated under reduced pressure. The obtained crude mixture was analyzed and the compound was characterized / detected with GC-MS analysis (m/z : 210 (M + l); CI), where 20% of the desired compound with m/z : 210 (M + l) was detected . Example 18: Synthesis of 7-chloro-l-ethoxy-5-methyl-2,3,4,5-tetrahydro- l -benzo[d]azepine (IVc)

Compound IIIc-Et (113 mg, 0.35 mmol) was dissolved in DCM (3.5 mL) and solution was treated with aluminum chloride (82 mg, 1.75 equiv.). Solution was stirred overnight at room temperature. Solution was diluted with DCM (20 mL) and brine (20 mL). The phases were separated and water phase was re-extracted with DCM (10 mL). Combined DCM was dried over sodium sulfate, filtered and concentrated. The obtained crude mixture was analyzed and the compound IVc was characterized / detected with GC-MS analysis (m/z : 240 (M + 1); CI) as a major product and7-chloro-l- hydroxy-5-methyl-2,3,4,5-tetrahydro-lH-benzo[d]azepine as a minor product.

The same experimental procedure has been successfully performed also with the optical active analogous compound in order to obtain (S)- or (R)-7- chloro-l-ethoxy-5-methyl-2,3,4,5-tetrahydro-lH-benzo[d]azepi ne and (S)- or (R)-7-chloro-l-hydroxy-5-methyl-2,3,4,5-tetrahydro-lH-benzo[ d]azepi- ne, respectively.

Example 19: Preparation of 2-(3-chlorophenyl)propanenitrile from 2-(3- chlorophenyl) acetonitrile

VII VIII

To a solution of 2-(3-chlorophenyl)acetonitrile VII (66.0 mmol; 10.0 g) in dry THF (250 mL) under nitrogen atmosphere at -78 °C was added LiHMDS (66.0 mmol; 66.0 mL; 1M in THF). The mixture was stirred for 1 hour at - 78 °C followed by addition of Mel (66.0 mmol; 4.2 mL). After stirring at -78 °C for 1 hour, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with water (200 ml_) and extracted with EtOAc (3x150 ml_). The combined organic phases were dried over MgS0 ₄ , filtered and evaporated to the dryness. After purification by flash chromatography (silca gel; mobile phase: n-heptane/EtOAc, EtOAc gradient 2-20%), oily product VIII was obtained (7.6 g; 72 %)

*H NMR (500 MHz, CDCI ₃ , ppm) δ 7.34 (m, 3H), 7.26 (m, 1 H), 3.89 (q, 1H, J = 7.2 Hz), 1.65 (d, 3H, J = 7.4 Hz);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 138.9, 135.0, 130.5, 128.4, 127.0, 125.0, 121.0, 31.0, 21.3.

Example 20: Preparation of 2-(3-chlorophenyl)propan-l-amine from 2-(3- chlorophenyl)propanenitrile

To a solution of 2-(3-chlorophenyl)propanenitrile VIII (45.3 mmol; 7.5 g) in toluene (150 ml_) under nitrogen atmosphere at 0 °C was added BH ₃ .THF (135.8 mmol; 135.8 ml_, 1 M). The reaction mixture was stirred under reflux for 4 hours. After cooling to room temperature, the reaction mixture was quenched with water (150 ml_) followed by extraction with EtOAc (1x300 ml_). The organic phase was dried over MgS0 ₄ , filtered and solvent was removed by evaporation. The pure product was isolated as a hydrochloride salt by treatment of residue with HCI (Et ₂ 0 solution) in 70 % yield (6.6 g). *H NMR (500 MHz, CDCI ₃ , ppm) δ 7.22 (m, 3H), 7.08 (d, 1 H), 2.83 (m, 2H), 2.72 (m, 1H), 1.23 (d, 1H), 1.08 (bs, NH);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 145.4, 133.2, 130.5, 127.2, 126.9, 126.1, 44.5, 37.1, 19.2. Example 21: Optical resolution of 2-(3-chlorophenyl)propan (R)-(-)-2-phenylpropionic acid

To a solution of 2-(3-chlorophenyl)propan-l-amine III (3.0 mmol; 0.5 g) in EtOH (3 mL) at 70 °C was added a solution of (R)-(-)-2-phenylpropionic acid (1.5 mmol; 0.2 g) in EtOH (1 mL). The reaction mixture was stirred at 70 °C for 30 min and then cooled to room temperature in several hours. After stirring for 16 hours, obtained precipitate was filtered, washed with EtOH and dried under reduced pressure to give 0.29 g of salt III-PP (Chiral HPLC: 74.1 % ee, R-enantiomer).

Recrystallization :

0.28 g of obtained salts was dissolved in EtOH (3 mL) at 70 °C. The solution was stirred at 70 °C for 30 min and then cooled to room temperature in several hours. After stirring for 16 hours, obtained precipitate was filtered, washed with EtOH and dried under reduced pressure to give 0.19 g of salt (KJ-III-PP (Chiral HPLC: 98.1 % ee, R-enantiomer).

Example 22: Optical resolution of 2-(3-chlorophenyl)propan-l-amine with L-(-)-3-phenyllactic acid

III (RJ-lll-lact To a solution of 2-(3-chlorophenyl)propan-l-amine III (4.1 mmol; 0.7 g) in toluene (5 ml_) at 70 °C was added L-(-)-3-phenyllactic acid (2.1 mmol; 0.3 g). The reaction mixture was stirred at 70 °C for 30 min and then cooled to room temperature in several hours. After stirring for 16 hours, obtained precipitate was filtered, washed with toluene and dried under reduced pressure to give 0.44 g of salt III-lact (Chiral HPLC: 80.5 % ee, R- enantiomer).

Recrystallization:

0.43 g of obtained salts was dissolved in i-PrOH (2 ml_) at 70 °C. The solution was stirred at 70 °C for 30 min and then cooled to room temperature in several hours. After stirring for 16 hours, obtained precipitate was filtered, washed with i-PrOH and dried under reduced pressure to give 0.23 g of salt (7RJ-III-lact (Chiral HPLC: 96.7 % ee, R- enantiomer).

The lactic salt was optionally transformed to the base by washing ethyl acetate solution with aqueous Na ₂ C0 ₃ followed by removal of the solvent by evaporation.

Example 23: Preparation of (7RJ-2-(3-chlorophenyl)-/V-(2,2- dimethoxyethyl) propan-l-amine hydrochloride

(Rj-lllc-Me.HCI

(7R 2-(3-chlorophenyl)propan-l-amine (R)-III (1 g, 4.8 mmol) in methanol (2 ml_) was treated with dimethoxyacetaldehyde (60% in H ₂ 0, 1.46 ml_, 2 equiv.) and the solution was stirred at room temperature for 48 hours. 10% Pd/C (100 mg, 10 wt%) was added and the reaction atmosphere was flushed several times with nitrogen and hydrogen alternatively. The hydrogen pressure was set at 1 atmospheres and the reaction was stirred for 4 hours. The reaction was filtrated on Celite® and concentrated . The residue was dissolved in CH ₂ CI ₂ (20 ml_) and the solution was washed with 2 : 1 solution of brine and HCI 1 M (20 / 10 ml_) . The CH ₂ CI ₂ phase was dried over sodium sulfate, filtered and concentrated . The residue was dissolved in toluene (40 ml_) and the solution was extracted three times with water (3 x 30 ml_) . The combined water phase was saturated with NaCI and the solution was extracted twice with CH ₂ CI ₂ (2 x 30 ml_) . The combined CH ₂ CI ₂ phases were dried over sodium sulfate, filtered and concentrated to give clean product (fl IIIc-Me.HCI characterized by H NM R.

*H NM R (500 MHz, CDCI ₃ , ppm) δ 7.33-7.22 (m, 3H), 7.18 (d, J =7.2 Hz, 1 H), 4.89 (t, J = 5.0 Hz, 1 H), 3.49 (m, 1 H), 3.44 (s, 3H), 3.42 (s, 3H), 3.31 (m, 1 H), 3.19 (m, 1 H), 3.08 (m, 1 H), 3.00 (m, 1 H), 1.44 (d, J = 6.9 Hz, 3H) .

Example 24: Synthesis of (K N-(2-(3-chlorophenyl)propyl)-N-(2,2- dimethoxyethyl)-4-methylbenzenesulfonamide from 2-(3-chlorophenyl)-N- (2,2-dimethoxyethyl)propan- l-amine

A solution of 2-(3-chlorophenyl)propan- l-amine (7R IIIc-Me (2.95 mmol; 0.76 g) in CH^I^pyridine (8/1, 4.2 ml_) was cooled to 0 °C and afterwards a solution of TsCI (5.31 mmol ; 1.0 g) in CH ₂ CI ₂ ( 1.8 ml_) was added . The reaction mixture was allowed to warm at room temperature and stirred for 2.5 hours. The reaction mixture was washed with 2M HCI (2 x 4.3 ml_) and saturated aqueous solution of NaHC0 ₃ (4.3 ml_) . The organic layer was dried over MgS0 ₄ , filtered and evaporated under reduced pressure to remove solvent. The residue was purified by flash chromatography (eluent: EtOAc/n- heptane, EtOAc gradient 7 - 60 %) . Colorless oily product (R)- IIIc'-Me-Ts (0.85 g; 71 % yield) was obtained and characterized with H and ¹³ C NMR.

*H NMR (500 MHz, CDCI ₃ , ppm) δ 7.64 (d, 2H), 7.28 (d, 2H), 7.19 (m, 2H), 7.08 (m, 2H), 4.43 (t, IH), 3.45 (m, I H), 3.36 (d, 6H), 3.13 (m, 4H), 2.42 (s, 3H), 1.25 (d, 3H);

¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 146.2, 143.4, 136.6, 134.2, 129.8, 129.7, 127.6, 127.2, 126.7, 125.5, 104.6, 56.5, 55.3, 55.1, 50.8, 38.2, 21.5, 18.6.

Example 25: Synthesis of 8-chloro-l-methyl-3-tosyl-2,3-dihydro-lH- benzo[d]azepine from N-(2-(3-chlorophenyl)propyl)-N-(2,2- dimethoxyethyl)-4-methyl benzene sulfonamide

A solution of N-(2-(3-chlorophenyl)propyl)-N-(2,2-dimethoxyethyl)-4- methylbenzene sulfonamide IIIc'-Me-Ts (2.1 mmol; 0.85 g) in CH ₂ CI ₂ (10 mL) was added to a suspension of AICI ₃ (8.3 mmol; 1.1 g) in CH ₂ CI ₂ (15 mL) under nitrogen atmosphere. The reaction mixture was stirred for 10 min at room temperature and then was cooled to 0 °C. After quenching with 1 M NaOH (11 mL) and H ₂ 0 (11 mL), the phases was separated. The aqueous phase was extracted with CH ₂ CI ₂ (3 x 15 mL). The combined organic phases were dried over MgS0 ₄ , filtered and solvent was removed by evaporation. Yellow solid product IV'-Ts (0.6 g; 85 % yield) was obtained and characterized with *H and ¹³ C NMR.

*H NMR (500 MHz, CDCI ₃ , ppm) δ 7.72 (d, 2H), 7.32 (d, 2H), 7.10 (m, IH), 7.05 (m, 2H), 6.89 (dd, IH), 5.55 (d, IH), 4.06 (m, IH), 3.14 (m, 2H), 2.42 (s, 3H), 1.17 (d, 3H); ¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 145.3, 144.2, 135.8, 132.2, 131.8, 131.5, 130.0, 129.4, 128.1, 127.0, 126.6, 126.1, 107.4, 50.3, 40.1, 21.6, 18.0.

Example 26: Synthesis of 8-chloro-l-methyl-3-tosyl-2,3,4,5-tetrahydro- lH-benzo[d]azepine from 8-chloro-l-methyl-3-tosyl-2,3-dihydro-lH- benzo[d]azepine

(R)-W-Ts (R)-A--Ts

To a solution of 8-chloro-l-methyl-3-tosyl-2,3-dihydro-lH-benzo[d]azepine IV'-Ts (0.54 mmol; 0.19 g) in methanol (3 mL) was added Pt0 ₂ (20 mg) and several drops of HCI . The reaction mixture was stirred at 25 °C under 5 bar of hydrogen for 48 hours. After filtration through Celite® pad, the solvent was removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (6 mL), washed with water (6 mL), dried over MgS0 ₄ , filtered and evaporated to the dryness. After purification by flash chromatography (eluent: n-heptane/EtOAc, EtOAc gradient 7 - 60 %), the product was characterized with H and ¹³ C NMR.

*H NMR (500 MHz, CDCI ₃ , ppm) δ 7.62 (d, 2H), 7.27 (d, 2H), 7.07 (m, 2H), 7.05 (m, 2H), 6.97 (d, 1H), 3.28-2.92 (m, 6H), 2.40 (s, 3H), 1.40 (d, 3H); ¹³ C NMR (125 MHz, CDCI ₃ , ppm) δ 146.0, 143.3, 137.8, 135.2, 132.4, 131.3, 129.7, 127.5, 127.1, 126.3, 53.5, 48.1, 40.0, 35.9, 21.5, 17.5.

Example 27: Synthesis of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[d]azepine from 8-chloro-l-methyl-3-tosyl-2,3,4,5-tetrahydro-lH- benzo[d]azepine

A reaction mixture of 8-chloro-l-methyl-3-tosyl-2,3,4,5-tetrahydro-lH- benzo[d]azepine A'-Ts (0.17 mmol, 59 mg), phenol (0.55 mmol, 53 mg), 48% HBr (0.45 mL) and propionic acid (0.09 mL) was stirred under reflux for 6 hours. After cooling to room temperature, the reaction mixture was quenched with water (2 mL) followed by extraction with Et ₂ 0 (2x5 mL). The aqueous phase was basified with 8M NaOH (pH > 9) and product was extracted with CH ₂ CI ₂ (3x5 mL). The combined organic phases were dried over MgS0 ₄ , filtered and evaporated to the dryness. Obtained product was detected by GC-MS (m/z = 195).