PREPARATION OF DULOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS BY THE USE OF ASYMMETRIC TRANSFER HYDROGENATION PROCESS

Technical Field

The invention belongs to the field of chemical synthesis and relates to a process for the preparation of duloxetine and its pharmaceutically acceptable salts. In the narrow sense, the invention relates to the preparation of duloxetine and its pharmaceutically acceptable salts with high enantiomeric and chemical purity via beta-keto amines wherein the amino group is optionally protected and the subsequent asymmetric transfer hydrogenation using chiral Ru- or Rh-catalysts to the corresponding alcohol.

Prior Art

Duloxetine with the chemical name (S)-JV-methyl-3-(l-naphthoxy)-3-(2-thienyl)propanamine is a double serotonin and norepinephrine inhibitor. Duloxetine in the form of its hydrochloride salt is used in medical therapy particularly as an antidepressant and for alleviation of urinary incontinence problems. It can also be prepared in the form of other pharmaceutically acceptable salts such as oxalic acid salt, maleic acid salt, and similar. Duloxetine and its pharmaceutically acceptable salts were for the first time described in EP 0 273 658 Bl.

Several processes for the preparation of duloxetine or its pharmaceutically acceptable salts are disclosed in the literature i.e.: US 5,023,269 and US 4,956,388, Tetrahedron Letters (1990) 31(49), 7101, Drugs of the Future (2000) 25(9), 907 _; Journal of Labeled Compounds and Radiopharmaceuticals (1995) 36(3), 213.

Duloxetine hydrochloride can exist in different polymorphic forms as disclosed for example in WO 2006081515, RD 498011 and in WO2007093439. WO 2005/019199 describes the preparation of amorphous duloxetine hydrochloride. In addition to the above-mentioned processes, the pharmaceutical industry has still a need for the preparation of duloxetine and/or its pharmaceutically acceptable salts with high enantiomeric and chemical purity in a technologically simple and economical way.

Therefore, the purpose of the present invention is to prepare duloxetine and its pharmaceutically acceptable salts with high enantiomeric purity of at least 99% and high chemical purity of at least 99%. This objective is accomplished by a process via beta-keto amines wherein the amino group is optionally protected, by asymmetric transfer hydrogenation using chiral Ru- or Rh-catalysts to the corresponding alcohol, which is then converted into duloxetine or its pharmaceutically acceptable salts. Surprisingly, it has been found by the present inventors that such asymmetric transfer hydrogenation on N-methyl- beta-keto amines with a protected amino group gives the corresponding alcohol with high enantiomeric purity and in a high yield, wherefrom duioxetine with high enantiomeric and chemical purity can be prepared, which can be further converted into its pharmaceutically acceptable salts if necessary.

Figures

Figure 1 : ¹ H NMR (D ₂ O) spectrum of prepared compound of formula I ₅ Figure 2: ¹ H NMR (CDCIj) spectrum of prepared compound of formula 2a, Figure 3: ¹ H NMR (CDCl ₃ ) spectrum of prepared compound of formula 2b, Figure 4: ¹ H NMR (DMSO-£4) spectrum of prepared compound of formula 3a, Figure 5: ¹ H NMR (CDCl ₃ ) spectrum of prepared compound of formula 3b, Figure 6: ¹ H NMR (CDCl ₃ ) spectrum of prepared compound of formula 4, Figure 7: ¹ H NMR (CDCl ₃ ) spectrum of duloxetine.

Summary of the Invention

One aspect of the present invention is a step of asymmetric transfer hydrogenation of N- protected N-methyl-beta-keto amines or unprotected N-methyl -beta-keto amines or their acid salts, to yield the corresponding alcohol by using chiral Ru- or Rh-catalysts which are prepared from the corresponding metal source and a chiral ligand. Another aspect of the present invention is the process for preparing duloxetine or its pharmaceutically acceptable salts comprising as a process step asymmetric transfer hydrogenation of N-protected N-methyl-beta-keto amines or unprotected N-methyl-beta-keto amines or their acid salts, to yield the corresponding alcohol by using chiral Ru- or Rh- catalysts which are prepared from the corresponding metal source and a chiral ligand.

Still another aspect of the present invention is the process for the synthesis of duloxetine or its pharmaceutically acceptable salts with high enantiomeric purity of at least 99% and high chemical purity of at least 99% comprising the following reaction steps:

- synthesis of N-methyl-beta-keto amine hydrochloride from 2-acelyl-thiophene,

- synthesis of N-prolected N-methyl-beta-keto amine following the reduction of the keto group by asymmetric transfer hydrogenation and subsequent removal of the N -protecting group or,

- alternatively asymmetric transfer hydrogenation of N-methyl-beta-keto amine hydrochloride,

- preparation of duloxetine and, if necessary, further conversion into its pharmaceutically acceptable salts.

Still another aspect of the present invention are the following compounds that are used in the preparation of duloxetine or its pharmaceutically acceptable salts with high enantiomeric purity and high chemical purity, wherein enantiomeric purity for each compound is most preferably at least 99%, and wherein chemical purity for each compound is most preferably at least 99%:

(5)-3-(7V ^: "ethoxycarbonyl-iV-methyl)amino-l-t2-thienyl)propan-l -ol with enantiomeric purity of at least 90%, preferably at least 95%, and more preferably at least 97%; (5)-3-(jV-trifluoroacetyl-jV-methyl)amino-l-(2-thienyl)propa n-l-ol with enantiomeric purity of at least 95%, preferably at least 97%, and more preferably at least 99%; (S)-3-methylaniino-l -(2-thienyl)propan-l-ol with enantiomeric purity of at least 80%, preferably at least 89%, more preferably at least 97%, and even more preferably at least 99%;

Still another aspect of the present invention is duloxetine or its pharmaceutically acceptable salts, obtained by any process according to the present invention having an enantiomeric purity of at least 99% and chemical purity of at least 99%. Still another aspect of the present invention is the pharmaceutical composition comprising duloxetine or its pharmaceutically acceptable salts with high enantiomeric purity of at least 99% and high chemical purity of at least 99% and prepared by the processes according to the present invention.

Detailed description of the invention

One of the aims of the present invention is to prepare duloxetine or its pharmaceutically acceptable salts with high enantiomeric purity. Preferably, enantiomeric purity is at least 98%, more preferably at least 99%. It is also desired that the chemical purity is high. Preferably, chemical purity is at least 98%, more preferably at least 99%. According to a particularly preferred aspect of the invention, enantiomeric purity is at least 99% and chemical purity of at least 99%. A further objective is to provide duloxetine in the desired degree of enantiomeric and/or chemical purity in a technologically simple and economical way.

Therefore, the first subject of the present invention is the process for the preparation of duloxetine or its pharmaceutically acceptable salts with high enantiomeric and chemical purity.

The essential step of this process is the step of asymmetric transfer hydrogenation of N- protected N -methyl -beta-keto amines or unprotected N-methyl-beta-keto amines or their acid salts (formula I) to yield the corresponding alcohol (formula II):

II In the above general formulae I and II, the variable PG group represents either a hydrogen atom (in this case, compound I can be as the amine or the amine salt, such as hydrochloride salt) or a protecting group selected from the group consisting of, but not limited to, formyl, alkylcarbonyl, preferably C _MO alky lcar bony 1, cycloalkylcarbonyl, preferably C _4- io cycloalkylcarbonyl, arylcarbonyl, preferably C ₆ - _J o arylcarbonyl, alkoxycarbonyl, preferably C _{1 -} I _O alkoxycarbonyl, cycloalkoxycarbonyl, preferably C _{4-J 0} cycloalkoxycarbonyl, aryloxycarbonyl, preferably C _6- Io aryloxycarbonyl. Preferably the PG group represents a hydrogen atom wherein the amino group can be free or as an amine salt such as for example HCl salt, or the PG group represents alkylcarbonyl or alkoxycarbonyl.

Compound II can be subjected to further chemical reactions to eventually yield duloxetine or its pharmaceutically acceptable salts. Such further chemical reactions include deprotection of the amino group (if appropriate), introduction of the naphlhyl group and salt formation (if desired). The order of these reactions is not further limited. It is, however, preferred that the deprotection step is carried out before the introduction of the naphthyl group, whereas the duloxetine salt formation step is carried out from duloxetine.

A particularly preferred embodiment of this subject of the invention is a process for the preparation of duloxetine or its pharmaceutically acceptable salts in a high enantiomeric purity of preferably at least 99% and high chemical purity of preferably at least 99% as depicted in Scheme 1. Scheme 1 :

duloxetine in the form of its pharmaceutically acceptable salts wherein R stands for:

- a hydrogen; or

- a Ci-io alkyl or a C _4- ]Q cycloalkyl such as for example methyl (Me), ethyl (Et), propyl (Pr), iso-propyl, n-butyl (Bu), iso-butyl, sec-butyl, tert-butyl, pentyl, iso- pentyl, 2-methylbutyl, sec-pentyl, tert-pentyl, cyclopentyl, hexyl, sec-hexyl, cyclohexyl, heptyl, wherein the alkyl is optionally substituted by F, Cl or by optionally substituted aryl; preferably R represents Me, Et, CF ₃ , CH ₂ Cl, CCl ₃ , 3- phenylpropionyl and more preferably R is CF ₃ ; or

- Ci-Io alkoxy, such as for example methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, sec-bυtoxy, tert-butoxy, pentoxy, iso-pentoxy, 2-methylbutoxy, sec- pentoxy, 3-pentoxy, tert-pentoxy, cyclopentoxy, hexyloxy, sec-hexyloxy, cyclohexyloxy, heptyloxy, optionally substituted by F, Cl or by optionally substituted aryl; preferably R represents ethoxy, 2-chloroethoxy, 2,2,2- trichloroethoxy, 2-phenylethoxy, butoxy, sec-butoxy, iso-butoxy, tert-butoxy, benzyloxy, methoxybenzyloxy, and more preferably R represents ethoxy, tert- butoxy, benzyloxy; or

- aryl, preferably Cs-io aryl, or aryloxy, preferably C _6- io aryloxy, which can both be optionally substituted such as for example phenyl, phenoxy.

According to preferred embodiments of the present invention, the conversion of compound I into compound II is carried out as described below in the context of steps cl and c2. These steps cl or c2 can be further combined with one or more of the remaining steps a, b (optionally), d (if appropriate), e and/or f. For instance, it is possible in accordance with the present invention to obtain an optionally protected ketone of formula I by other means, to subject this to the asymmetric transfer hydrogenation to yield the corresponding alcohol of formula II, and subsequently to effect deprotection (if appropriate), followed by conversion e and optionally salt formation f. It is preferred that the steps are carried out in the specified/indicated order. More particularly, the process according to a particularly preferred embodiment of the present invention comprises all of the following reaction steps in the specified order: step a): synthesis of N-methyl-beta-keto amine hydrochloride of formula 1 from 2-acetyl- thiophene,

step b): synthesis of N-protected N-methyl-beta-keto amine of formula 2, wherein R is as defined above,

- step c2): asymmetric transfer hydrogenation of the ketone of formula 2 to obtain the compound of formula 3, wherein R is as defined above, by using chiral Ru- or Rh-catalysts prepared from the corresponding metal source and a chiral ligand, wherein,

- the metal source can be [RuX ₂ (^ ⁶ -arene)] ₂ or [RliX ₂ (?7 ⁵ -arene)]2 wherein ^ ⁶ -arene represents for example benzene, p-cymene, mesitylene, 1 ,3,5-triethylbenzene, hexamethylbenzene or anisole, and ?7 ⁵ -arene represents for example cyclopentadienyl (Cp) or pentamethyl cyclopentadienyl (Cp*), and X is an anion preferably a halide such as chloride, bromide, iodide; preferably the metal source is [RuCl ₂ (mesitylene)] ₂ or [RuCl ₂ (p-cymene)]2; and

- the chiral ligand is preferably represented by the general formula 5 with enantiomeric purity of at least 95%, preferably of at least 97% and more preferably of at least 99%:

R ² -. I ^NHSO ₂ R ¹ C*

C ^{* 5}

R ² ^NH ₂

wherein:

C* represents an asymmetric carbon atom of S or R-configuration; R ¹ represents aryl, preferably C ₆ -io aryl, optionally substituted by halogen and/or by linear or branched C _1-1 O alkyl such as Me, Et, iPr, and/or by groups such as NO ₂ , CN, or R ¹ represents C ₁ -Io perfluoroalkyl, or R ¹ represents R ³ R ⁴ N wherein R ³ and R ⁴ independently represent a linear or branched C ₁ - ₅₅ alkyl optionally substituted by aryl, such as C _{6-J O} aryl, or R ³ and R ⁴ represent a cycloalkyl and especially C _4-6 cycloalkyl group, or are joined together to form a C ₄ . ₆ ring optionally substituted by an alkyl and especially Ci. so alkyl group;

R ² independently represents Cg.io aryl (such as phenyl) or cycioalkyl and especially Cβ-io (di)cycioalkyl group, or both R' are linked together to form a cyclohexane ring; preferably the chiral ligand is N-(R ^! Sθ ₂ )dpen wherein dpen represents 1,2-diphenylethylenediamine, such as for example (S,S)-Me ₂ NS0 ₂ dpen or (S ₅ S)- (CH ₂ ) ₅ NS0 ₂ dpen,

step d): removal of the N-protecting group of the compound of formula 3, wherein R is as defined above, to obtain the compound of formula 4,

- or alternatively step cl): asymmetric transfer hydrogenation of the compound of formula 1 to obtain the compound of formula 4 by using chiral Ru- or Rh-catalysts which are prepared from the corresponding metal source and a chiral ligand, wherein,

- the metal source can be [RuX2(?/-arene)]2 or [RhX2(7 ⁵ -arene)J2 wherein 77 ⁶ -arene represents for example benzene, p-cymene, mesitylene, 1 ,3,5-triethylbenzene, hexamethylbenzene or anisole, and ?7 ⁵ -arene represents for example cyclopentadienyl (Cp) or pentamethylcyciopentadienyl (Cp*), and X is an anion preferably a halide such as chloride, bromide, iodide; preferably the metal source is [RuCl2(mesitylene)] ₂ or [RuCl2(p-cymene)] ₂ ; and

- the chiral ligand is represented by the general formula 5 with enantiomeric purity of at least 95%, preferably of at least 97% and more preferably of at least 99%: R ² S. I .NHSO ₂ R

C ^{* 5}

H wherein:

C* represents an asymmetric carbon atom of S or R-confϊguration;

R ¹ represents aryl, preferably C ₆ -Io aryl, optionally substituted by halogen and/or by linear or branched C _J . _JO alky! such as Me, Et, iPr, and/or by groups such as NO ₂ , CN, or R ¹ represents Ci-I ₀ perfluoroalkyl, or R ¹ represents R ³ R ⁴ N wherein R ³ and R ⁴ independently represent a linear or branched C] _{-I 5} alkyl optionally substituted by aryl, such as C ₆ -Io aryl, or R ³ and R ⁴ represent a cycloalkyl and especially C _4-6 cycloalkyl group, or are joined together to form a C _4-6 ring optionally substituted by an alkyl and especially C _MO alkyl group;

R ² independently represents C ₆ -Io aryl (such as phenyl) or cycloalkyl and especially

Cg-io (di) cycloalkyl group, or both R ² are linked together to form a cyclohexane ring; preferably the chiral ligand is N-(R ^] Sθ ₂ )dpen wherein dpen represents

1 ,2-diρhenylethylenediamine, such as for example (S, S)-Me ₂ N S O ₂ dpen or (S, S)-

(CH ₂ ) ₅ NS0 ₂ dpen ₅

step e) and step f): preparation of duloxetine form the compound of formula 4, and, if necessary, further conversion into its pharmaceutically acceptable salts

n duloxetine in the form of ** its pharmaceutically acceptable salts dutoxetine The synthesis of the starting material 2-acetyllhiophene is known from the literature and is described for e.g. in P. G. Stevens, J. Am. Chem. Soc. (1934) 58, 450; J. R. Johnson, Org. Synthesis (1938) 18, 1 ; H. Hartough, A. J. Kosak, J. Am. Chem. Soe. (1946) 68, 2639.

The synthesis of the compound of formula 1 is known from the prior art such as for example from EP 1 539 673 Bl . It can be prepared via Mannich reaction, for instance from 2- acetylthiophene, paraformaldehyde and methylamine hydrochloride. The reaction typically takes place at a temperature above 100°C, preferably above 1 10 ⁰ C, more preferably between 110 and 120 ⁰ C, in a polar solvent, which can be selected from a group consisting of, but not limited to MeOH, EtOH, /PrOH, 1.2-propyleneglycol, pentanol, glycerol, THF, dioxane, DMF or AcOH. The isolated product of formula 1 typically has chemical purity of at least 90%, preferably at least 93% (determined by ¹ H NMR).

The protection of amino group of the compound of formula 1, i.e., the protective group represented by PG in formulae I and II, is performed by any known method in the art wherein any known protecting groups can be used. For example groups disclosed in Protective Groups in Organic Synthesis, by P.G.M. Wuts and T.W. Greene, J. Wiley and Sons, 3 ^rd Ed. 1999, chapter 7 or 4 ^lh Ed. 2007, as the protecting group on N-monomethyl-beta-keto amine can be used. Preferably the ethoxycarbonyl, isobutoxycarbonyl, butoxycarbonyl or trifluoroacetyl protecting groups can be used. For example, the ethoxycarbonyl protecting group can be introduced with ethyl chloroformate in CH ₂ Cl ₂ using Et ₃ N as a base, and the trifluoroacetyl group can be introduced with trifluoroacetic anhydride in CH ₂ Cl ₂ using Iϊt ₃ N as a base.

Asymmetric transfer hydrogenation on the ketone of formula I gives the product of formula II with high enantiomeric purity, typically an enantiomeric purity of at least 85%, preferably at least 90%, more preferably at least 95%, and even more preferably at least 99%. In a specific aspect of this subject of the invention, asymmetric transfer hydrogenation on the ketone of formula 2 gives the product of formula 3 with enantiomeric purity of typically at least 90%, preferably at least 95%, more preferably at least 97%, and even more preferably at least 99%. Preferably, asymmetric transfer hydrogenation on the ketone of formula 2a, wherein in formula 2 R stands for OCH ₂ CH ₃ , gives the product with the chemical name (S)-3-(N~ ethoxycarbonyl-Λ ^/' -methyl)amino-l-(2-thienyl)propan-l-ol (compound of formula 3a) with enantiomeric purity of at least 90%, preferably at least 95%, and more preferably at least 97%. Even more preferably, asymmetric transfer hydrogenation on the ketone of formula 2b, wherein in formula 2 R stands for CF ₃ , gives the product with the chemical name (S)-3-(N- trifluoroacetyl-Λ ^r -methyl)amino-l-(2-thienyI)propan-l-ol (compound 3b) with enantiomeric purity of at least 95%, preferably at least 97%, and more preferably at least 99%,

N-Deprotection of the compound of formula 3 can be carried out in any solvent such as for example in alcohol. For example, N-deprotection of compound of formula 3b, wherein in formula 3 R stands for CF ₃ can be carried out with Na ₂ CO ₃ in methanol. The compound of formula 4 with the chemical name (S)-3-methylamino-l-(2-thienyl)propan-l-oI is obtained after extraction and crystallization typically having enantiomeric purity of at least 90%, preferably at least 95%, more preferably at least 97%, and even more preferably at least 99%.

Alternatively the compound of formula 4 with the chemical name (5)-3-methylamino-l-(2- thienyl)propan-l-ol and with enantiomeric purity of typically at least 80%, preferably at least 85%, and more preferably at least 89% can be obtained by asymmetric transfer hydrogenation on the compound of formula 1.

Asymmetric transfer hydrogenation according to the present invention on the compound of formula I, specifically the N-protected compound of formula 2 or unprotected compound of formula 1 , is performed by using chiral Ru- or Rh-catalyst, prepared from the corresponding metal source and a chiral ligand, wherein, the metal source can be [RuX ₂ (?7 ⁶ -arene)]2 or [RhX ₂ (/| ⁵ -arene)]2 wherein //-arene represents for example benzene, p-cymene, mesitylene, 1,3,5-triethylbenzene, hexamethylbenzene or anisole, and 7 ⁵ -arene represents for example cyclopentadienyl (Cp) or pentamethylcyclopentadienyl (Cp*), and X is an anion preferably a halide such as chloride, bromide, iodide; preferably the metal source is [RuCl2(mesitylene)]2 or [RuCl2(p-cymene)]2; and the chiral ligand is represented by the general formula 5_with enantiomeric purity of at least 95%, preferably of at least 97% and more preferably of at least 99%: wherein:

- C* represents an asymmetric carbon atom of S or R-configuration;

- R ¹ represents aryl, preferably C ₆ -Io aiyl, optionally substituted by halogen and/or by linear or branched C _M O alkyl such as Me, Et, iPr, and/or by groups such as NO ₂ , CN, or R ¹ represents C _MO perfluoroalkyl, or R represents R R ⁴ N wherein R ³ and R ⁴ independently represent a linear or branched CM _S alkyl optionally substituted by aryl, such as C ₆ - _I o aryl, or R and R represent a cycloalkyl and especially C ₄ . ₆ cycloalkyl group, or are joined together to form a C _4-6 ring optionally substituted by an alkyl and especially C _{M O} alkyl group;

- R ² independently represents C ₆ -Io aryl (such as phenyl) or cycloalkyl and especially C _6-I0 (di)cycloalkyl group, or both R ² are linked together to form a cyclohexane ring; preferably the chiral ligand is N-(R ^l SO ₂ )dpen wherein dpen represents 1,2-diphenylethyIenediamine, such as for example (S,S)-Me ₂ NSO ₂ dpen or (S ₅ S)- (CH ₂ ) ₅ NSO ₂ dpen.

The molar ratio of the metal catalyst to the ketone compound of formula I, for example of N- protected compound of formula 2 or unprotected compound of formula 1 , is typically between about 1 :20 and about 1 :10000, preferably between about 1 :50 and about 1 : 1000 or even between about 1 : 100 and about 1 : 1000, more preferably between about 1:200 and about 1 :500.

The asymmetric transfer hydrogenation reaction according to the present invention takes place in a solvent or mixture of solvents such as, but not limited to, dimethylformamide (DMF), acetonitrile (MeCN), methylene chloride, 1 ,2-dichloroethane, preferably MeCN or methylene chloride, in the presence of at least one hydrogen donor such as for example 2- propanol, formic acid and its salts such as for example Li, Na, K- salt, formic acid-amine mixtures such as for example HCO ₂ H-Et ₃ N, HCO ₂ H-Pr ₃ N ₅ HCO ₂ H-Bu ₃ N, HCO ₂ H-JPrNEt ₂ , preferably HCO ₂ H-Et ₃ N is used; typically at a reaction temperature between around O ⁰ C up to 7O ⁰ C, preferably between 15 ⁰ C and 70 ⁰ C and more preferably between around 20 ⁰ C up to 60 ⁰ C.

It is known from the literature (J. Am. Chem. Soc. (1996) 118, 2521) that the reaction rate of asymmetric transfer hydrogenation increases with temperature, whereas the enantiomeric purity somewhat decreases (for 1 to 5%). Also in the process according to the present invention, using the ketone of formula 2b, wherein in formula 2 R is CF ₃ , and carrying out the reaction at 6O ⁰ C instead of 35°C led to increase in the reaction rate, whereas the enantiomeric purity of the compound with formula 3b surprisingly remained unchanged. It is therefore preferred to carry the asymmetric transfer hydrogenation out at a temperature between around 20 to 60 ⁰ C.

More preferably, in the step of asymmetric transfer hydrogenation by the use of 0.5 mol% Ru-catalyst prepared from [RuCi ₂ (p-cymene)] ₂ and (S, S) -Me ₂ NS C^dpen, at reflux in CH ₂ Cl ₂ within 14 hours, alcohol of formula 3 or 4 is obtained with enantiomeric purity of at least 80%, preferably of at least 90%, more preferably at least 97%, and even more preferably at least 99% and with chemical purity of at least 95%, preferably of at least 98% and more preferably of at least 99%.

The preparation of duloxetine and its pharmaceutically acceptable salts from compound of formula 4 (= formula II with PG representing hydrogen) is known in the literature. Thus, e.g. Tetrahedron: Asymmetry (2005) 16, 1873 states that duloxetine with 88% yield and 96.5% enantiomeric purity (calculated from the given enantiomeric rotation: [α]D ²⁰⁼ +113 (c 0.9, MeOH): Tetrahedron Lett. (1990) 31, 7101) was prepared with 1 -fluoronaphthalene in the presence of NaH in DMSO at 5O ⁰ C within 1 hour; Tetrahedron Lett. (2003) 44, 4783 states that the reaction takes place within 8 hours with 81% yield and 97.5% ee (calculated from the given optical rotation: [CC] _D ²⁰ = +1 14 (c 1, MeOH)).

The formation of pharmaceutically acceptable salts of duloxetine can be accomplished by means of any known method in the art wherein any known protecting groups can be used. For example, addition of hydrogen chloride in an organic solvent such as diethylether to duloxetine in an organic solvent such as ethyl acetate, leads to the formation of duloxetine hydrochloride salt.

A further object of the present invention is the use of chiral Ru- or Rh-catalyst according to the present invention for asymmetric transfer hydrogenation on the compound I ₅ i.e., specifically the N-protected compound of formula 2 or unprotected compound of formula 1, for the synthesis of a chiral substance, which can be further employed in the preparation of duloxetine or its pharmaceutically acceptable salts with high enantiomeric purity of at least 99% and high chemical purity of at least 99%.

A further subject of the invention is the provision of the following compounds that are beneficially used in the preparation of duloxetine or its pharmaceutically acceptable salts according to the present invention:

- the compound of formula 3a with chemical name (£)-3-(iV-ethoxycarbonyl-jV- methy!)amino-l-(2-thienyl)propan-l-ol and with enantiomeric purity of at least 90%, preferably at least 95%, and more preferably at least 97%;

- the compound of formula 3b with chemical name (5)-3-(jV-trifluoroacetyl-iV-methyl)amino- l-(2-thienyl)propan-l-ol and with enantiomeric purity of at least 95%, preferably at least 97%, and more preferably at least 99%;

- the compound of formula 4 with chemical name (5)-3-methyIamino-l-(2-thienyI)propan-l- ol and with enantiomeric purity of at least 80%, preferably at least 89%, more preferably at least 97%, and even more preferably at least 99%.

Still another aspect of the present invention is the pharmaceutical composition comprising duloxetine or its pharmaceutically acceptable salts with high enantiomeric purity of typically at least 99% and high chemical purity of typically at least 99% and prepared by the processes according to the present invention. Enantiomeric purity can be determined by means of HPLC using a chiral column, such as Chiralcel OJ or OD-H, and detection of UV absorption at e.g. 205 nm, 236 nm or 280 nm. Chemical purity can also be determined by means of HPLC and detection of UV absorption, for instance as area percentages.

Further specific aspects of the present invention are described with respect to the following specific numbered embodiments:

1. A process for the preparation of optically pure duloxetine and its pharmacetucally acceptable salts according to a process as shown in the following scheme:

^ duloxetine in the form of pharmaceutically acceptable salt wherein R stands for:

- C] to Cio alkyl, which can be substituted by F, Cl, Br, I;

- Ci to Cio alkyloxy, which can be substituted by F, Cl, Br, I;

- aryl, aryloxy, which can be substituted or unsubstituted.

2. A process for the preparation of optically pure duloxetine and its pharmacetucally acceptable salts according to a process comprising the following steps: step a): synthesis of N-methyl beta-keto amine hydrochloride of formula 1. from 2- acetyl-thiophene,

step b): synthesis of N-protected N-methyl beta-keto amine of formula 2, wherein R is selected from a group comprising C] to Cio alkyl, which can be substituted by F, Cl, Br, I; Ci to Cio alkyloxy, which can be substituted by F ₅ Cl, Br, I; aryl, aryloxy, which can be substituted or unsubstituted; preferably, R is selected from a group comprising OCH ₂ CH ₃ or CF ₃ ,

step c): asymmetric transfer hydrogenation of the obtained ketones of formula 2, whereat R is selected from the above group, with chiral Ru- all Rh-catalysts, selected from a group comprising [Ru(^ ⁶ -aren)(R'Sθ ₂ dpen)]) and [Rh(T/ ⁵ - arenXR'SC^dpen)]) (dpen= 1 ,2-diphenyl ethylenediamine), preferably there can be used [Ru(mesitylene)((S,S)-Me ₂ NS0 ₂ dpen)], [Ru(p-cymene)((S,S)-

(CH ₂ )sNS0 ₂ dρen)] _s

step d): deprotection of protecting groups of the compound of formula 3, whereat R is selected from the above group,

step e): synthesis of duloxetine and, if necessary, further conversion into its pharmaceutically acceptable salts.

3. A process for the preparation of optically pure duloxetine and its pharmaceutically acceptable salts according to any of the preceding embodiments, characterized in that in step b) ethyloxycarbonyl protecting group or trifluoroacetyl protecting group are used as the protecting group on N-monomethyl beta-keto amine.

4. A process for the preparation of optically pure duloxetine and its pharmacetucally acceptable salts according to any of the preceding embodiments, characterized in that asymmetric transfer hydrogenation in step c) on a protected ketone of formula 2 gives a product of formula 3 with enantiomeric purity of more than approximately 95%, preferably more than approximately 96%.

5. A process for the preparation of optically pure duloxetine and its pharmacetucally acceptable salts according to any of the preceding embodiments, characterized in that asymmetric transfer hydrogenation in step c) on a protected ketone of formula 2, wherein R stands for trifluoro acetyl protecting group, gives a product of formula 3, wherein R stands for trifluoroacetyl protecting group, with enantiomeric purity of more than approximately 99%.

6. A process for the preparation of optically pure duloxetine and its pharmacetucally acceptable salts according to any of the preceding embodiments, characterized in that asymmetric transfer hydrogenation in step c) takes place in HCO ₂ H-Et ₃ N, preferably in a ratio of 5:2.

7. A process for the preparation of optically pure duloxetine and its pharmacetucally acceptable salts according to any of the preceding embodiments, characterized in that compound 4 with enantiomeric purity of more than approximately 95%, preferably more than approximately 98.5% is obtained.

8. A process for the preparation of optically pure duloxetine and its pharmacetucally acceptable salts according to a process comprising the following steps:

- step a): synthesis of N-methyl beta-keto amine hydrochloride of formula 1 from 2- acetyl-thiophene,

step b): asymmetric transfer hydrogenation of a compound of formula 1. with chiral Ru- ali Rh-catalysts, selected from a group comprising [Ru(^ ⁶ -aren)(R ¹ Sθ ₂ dpen)]), [Rh^-arenXR'SOzdpen)]), preferably there can be used [Ru(mesitylene)((S,S)- Me ₂ NS0 ₂ dpen)], [Ru(p-cymene)((S,S)-(CH ₂ )sNS0 ₂ dpen)] _s

step c): synthesis of duloxetine and. if necessary, further conversion into its pharmaceutically acceptable salts. 9. The use of chiral Ru- or Rh-catalyst in the step of asymmetric transfer hydrogenation in the synthesis of duloxetine and its pharmaceutically acceptable salts, which is prepared in situ from N-(R Sθ2)-l ,2-diamine type of ligands with enantiomeric purity of more than approximately 99% and represented by the general formula 5:

wherein:

* represents an asymmetric carbon atom,

R ¹ represents aryl, unsubstituted or substituted by halogens and/or groups such as Me, Et, iPr, NO ₂ and CN, Ci-C _1O alkyl, linear or branched, C ₁ -C _fO perfluoroalkyl, or R represents R R N, wherein R ³ and R ⁴ independently represent hydrogen atom, Ci-i ₅ alkyl, linear or branched, optionally substituted with aryl; cycloalkyl group; or R ³ and R ⁴ are joined togehter to form, with a nitrogen atom, a C _4-O ring, which can be substituted with alkyl group,

R ² represents phenyl or cycloaikyl group or both R ² together form a cyclohexane ring; and from ruthenium or rodhium dimer represented by general formula 6 or 7

[RuX ₂ (η ⁶ -aren)] ₂ (6) [RhX ₂ (η ⁵ -aren)] ₂ (7) whereat:

- X represents halogenide anion, e.g. choride or iodide;

- η ⁶ -aren represents benzene, p-cymene, mesitylene, 1,3,5-triethylbenzene, hexamethylbenzene or anisole,

- η ⁵ -aren represents Cp or Cp*, in an organic solvent and with HCO ₂ H-Et ₃ N 5:2 as a hydrogen donor.

10. The use of chiral Ru-catalyst in the step of asymmetric transfer hydrogenation in the synthesis of duloxetine and its pharmaceutically acceptable salts according to embodiment 9, wherein the molar ratio between ruthenium catalyst and the starting compound is between about 1 :50 and about 1 : 1000, preferably between about 1 :200 and about 1 :500.

11. A compound selected from the group (5}-3-(jV-ethoxycarbonyl-Λ ^r -methyl)arnino-l-(2-thienyl)propan-l-ol with enantiomeric purity of more than approximately 95%, preferably more than approximately 96%; (5)-3-(jV-trifluoroacetyl-Λ ^f -methyl)amino-l-(2-thienyl)propan-l-ol with enantiomeric purity of more than approximately 95%, preferably more than approximately 99%; (5)-3-methylamino-l-(2-thienyl)propan-l-ol with enantiomeric purity of more than approximately 85%, preferably more than 99%.

12. A compound according to embodiment 11 used in the synthesis of duloxetine and/or its pharmaceutically acceptable salts.

The present invention is described in more detail by the following Examples which are not to be construed as ! imitative:

General

¹ H (300 MHz, internal standard Me ₄ Si) ₅ ¹³ C (75 MHz ₅ internal standard CDCl ₃ ) and ¹⁹ F NMR (282 MHz, internal standard CFCl ₃ ) spectra were recorded in CDCl ₃ if not otherwise stated.

Example ϊ

Synthesis of 3-methyIamino-l-(2-thienyl)-propan-l-one hydrochloride (compound of formula 1)

2-Acetylthiophene (12.60 g, 0.10 mole), methylamine hydrochloride (7.44 g, 0.11 mole), paraformaldehyde (4.20 g, 0.14 mole), ethanol (50 ml, 96%) and 36% HCl (0.5 ml) were heated at 110 ⁰ C under stirring for 9 h. When the reaction was complete, the reaction mixture was cooled to room temperature, concentrated approximately to half its volume under vacuum and EtOAc (50 ml) was added. Under vigorous stirring the mixture was cooled on an ice bath and stirred for another 3 h. The white-yellow precipitate was filtered and rinsed with EtOAc (2x10 ml). 15.33 g (69%) of the product with 93% chemical purity were obtained.

Example 2 Synthesis of 3-(7V-ethoxyearbonyl-iV-methyI)ammo-l-(2-thienyS)propan-l-oi ic (compound of formula 2a)

A mixture of 1 (4.10 g, 18.5 mmole; prepared as in Example 1) and Et ₃ N (7.5 mi, 54 mmole) in CH ₂ Cl ₂ (60 ml) was stirred at room temperature under inert atmosphere (N ₂ ) for 15 min then cooled to 0-5 ⁰ C and ethyl chloroformate (2.25 ml, 23.5 mmole) was added. After stirring at room temperature overnight, water (60 ml) was added, the phases were separated and the organic layer was washed with 1 mM HCl followed by a saturated aqueous NaIICO ₃ , dried (Na ₂ SO ₄ ) and concentrated affording an oil (4.06 g, 91%).

Example 3

Synthesis of 3~(N-trifluoroacetyl-iV-methyl)amino-l-(2-thienyl)propan-l-o ne (compound of formula 2b)

A mixture of 1 (4.10 g, 18.5 mmole; prepared as in Example 1), and Et ₃ N (7.5 ml, 54 mmole) in CH ₂ Cl ₂ (60 ml) was stirred at room temperature under inert atmosphere (N ₂ ) for 15 min then cooled to 0-5 ⁰ C and trifluoroacetic anhydride (3.3 ml, 23.5 mmole) was added. After stirring at room temperature overnight, water (60 ml) was added, the phases were separated and the organic layer was washed with H ₂ O (30 ml) and with 5% NaHCO ₃ (30 ml), dried (Na ₂ SO ₄ ) and concentrated affording an oil. This was crystallized from hexane yielding crystalline product (4.35 g, 89%).

Mp= 45^6°C (hexane)

¹ H NMR (CDCl ₃ ): (£=3.07 (s, 0.7H; CH ₃ ), 3.23 (q, J=I.5 Hz, 2.3H; CH ₃ ), 3.28 (t, J=6.6 Hz,

2H; CH ₂ ), 3.82 (t, J=6,6 Hz ₃ 1.6H; NCH ₂ ), 3.90 (tq, 7=6.6 Hz ₅ J=LO Hz, 0.4H; NCH ₂ ), 7.13-

7.18 (m, IH; Ar-H), 7.67-7.77 (m, 2H; Ar-H);

¹³ C NMR (CDCl ₃ ): £=34.9 (CH ₃ ), 36.3 (q, J=3 Hz; CH ₂ ), 36.5 (q, J=3 Hz; COCH ₂ ), 38.0

(COCH ₂ ), 44.8 (q, J=3 Hz; NCH ₂ ), 44.7 (q, J=3 Hz; NCH ₂ ), 46.0 (NCH ₂ ), 1 16.3 (q, J=283

Hz; CF ₃ ), 1 16.5 (q, J-283 Hz; CF ₃ ), 128.42 and 128.45 (2s, CHCHCH), 132.5, 132.7, 134.4,

134.6, 143.3 and 143.6 (2s, CC(O)), 156.9 and 157.2 (2q, J=35 Hz; COCF ₃ ), 189.7 and 190.7

(COCH ₂ );

¹⁹ F NMR (CDCl ₃ ): δ=-\ 12.5, -1 13.5.

HRMS: (M ⁺ +H) m/z calculated for Ci ₀ Hi ,NO ₂ F ₃ S 266.0463, found 266.0472. Example 4

Synthesis of (^-S-^-ethoxycarbonyl-jV-methy^araino-ϊ-tl-thieny^propan-l- ol (compound of formula 3a)

Preparation of the catalyst: A mixture of [RuCl ₂ (p-cym)] ₂ (3.0 mg, 5 μmole, 1 mole %) and (.SyS)-Me ₂ NSO ₂ DPEN (3.8 mg, 12 μmole) in 1 ,2-dichloroethane (0.5 ml) was progressively heated to 80 ⁰ C and stirred at this temperature for 30 min. The red-orange solution was cooled to room temperature and HCO ₂ H-Et ₃ N 5:2 (10 μl) was added, and the solution colour immediately turned into light yellow-orange.

Reduction: To a mixture of 3-(Λ ^r -ethoxycarbonyl-Λ ^r -raethyl)amino-l-(2-thienyl)propan-l-one

(compound 2a) (124 rag, 0.5 mmole) in MeCN (1 ml) was added HCO ₂ H-Et ₃ N 5:2 (216 mg, 0.5 mmole) and then the above-prepared catalyst solution . The reaction mixture was heated at 35 ⁰ C under stirring. After 2, 8, 24, 28 and 32 h, 5M HCO ₂ H in CH ₂ Cl ₂ was added so that the pH of the vapours above the reaction mixture was ~7 (use of a damp pH paper). After 48 h the reaction mixture was concentrated and the product was purified on silicagel eluting with CH ₂ CVEtOAc 3 : 1. The product 3a (63 mg, 52%) was obtained as a colourless oil.

Ee=97% (HPLC: column Chiralcel OJ, mobile phase hexane/2-propanol 98:2, UV detection at 237 ran)

Example S

Synthesis of (5)-3-{N-trifluoroacetyI-iV-methyl)amino-l-(2-thienyI)propan -l-oI (compound of formula 3b)

Preparation of the catalyst: A mixture of [RuCl ₂ (p-cym)] ₂ (30.6 mg, 50 μmole, 0.5 mole %) and (SVS)-Me ₂ N SO ₂ DPEN (38.5 mg, 120 μmole) in 1 ,2-dichloroethane (5 ml) was progressively heated to 80 ⁰ C and stirred for 30 min. The red-orange solution was cooled to room temperature and HCO ₂ H-Et ₃ N 5:2 (100 μl) was added, and the solution colour immediately turned into light yellow-orange. Reduction: To a mixture of 3-(A ^/ -trifluoroacetyl-N-methyl)amino-l-(2-thienyl)propan-l- one (compound 2b) (5.30 g, 20 mmole) in CH ₂ Cl ₂ (40 ml) was added HCO ₂ H-Et ₃ N 5:2 (8.65 g, 20 mmole) and then the above -prepared catalyst solution. The reaction mixture was refluxed under stirring and a 5M HCO ₂ H in CH ₂ Cl ₂ (0.4 ml, 2 mmole) was added after 2 hours. After the addition, the pH of the vapours above the reaction mixture was ~7 (use of a damp pH paper). The pH was kept ~7 by periodic addition of 5M HCO ₂ H in CH ₂ Cl ₂ . This was repeated within 2, 4, 6, 8 and 14 h. After this, the reaction mixture was cooled to room temperature and washed with water (150 ml). The aqueous phase was extracted with CH ₂ Cl ₂ (4x50 ml), and the combined organic phases were dried (Na ₂ SO^ and concentrated affording an oil (5.18 g, 97%).

[α] _D ²⁰ = -U (C 1.5, CHCl ₃ )

[α W°= +20.5 (c 1.5, CHCI ₃ )

Ee>99% (HPLC: column Chiralcel OD, mobile phase hexane/2-propanol 98:2, UV detection at 205 nm)

¹ H NMR (DMSO-J ₆ , 25fC): 5=1.92-2.03 (m, 2H; CH(OH)CZZ ₂ ), 2.96 (s, 1.2H; CH ₃ ), 2.96

(s, 1.2H; CH ₃ ), 3.09 (q, J=I.5 Hz, 1.8H; CH ₃ ), 3.42-3.59 (m, 2H; NCH ₂ ), 4.83-4.88 (m, IH,

CZZOH), 5.73 (dd, J=A. % Hz, J=I .5 Hz, 0.6H; OH), 5.80 (dd, J-4.8 Hz, 1.5 Hz, 0.4H; OH),

6.94-6.98 (m, 2H, Ar-H), 7.37-7.14 (m, IH; Ar-H);

¹ H NMR (DMSO-J ₆ , 130°C): ^=2.03-2.10 (m, 2H; CH(OH)CZZ ₃ ), 3.07 (s, 3H; CH ₃ ), 3.42-

3.59 (m, 2H, NCH ₂ ), 4.90 (dd, ./=4.8 Hz, 4,8 Hz ₅ IH; CiZOH), 5.25, (br s, IH, OH), 6.96-

7.00 (m, 2H, Ar-H), 7.32-7.34 (m, IH; Ar-H);

¹³ C NMR (DMSO-J ₆ ): ^34.2 (s) and 34.7 (q, J=4 Hz; CH ₃ ), 35.7 and 37.6 (CH(OH)CH ₂ ),

46.1 (q, J=3 Hz) and 46.4 (s, NCH ₂ ), 66.1 and 66.3 (CHOH), 116.4 and 1 16.4 (2q, J=284 Hz;

CF ₃ ), 122.9, 122.9, 124.1, 124.2, 126.5, 126.5, 149.7 and 150.0 (SCCH), 155.4 and 155.5 (q,

J=34 Hz; COCF ₃ );

¹⁹ F NMR(DMSO-J ₆ ): £=-106.9, -107.7.

MS (ES): m/z 290 (64%,M+Na ⁺ ), 250 (75), 172 (100), 123 (44).

HRMS: (M+Na ⁺ ) m/z calculated for C ₁₀ Hi ₂ NO ₂ F ₃ ²³ NaS 290.0439, found 290.0430.

Example 6 Synthesis of (^-S-røeihylamino-l-^-ihienyiJpropan-l-oI (compound of formula 4)

To a solution of (jS)-3-(jV-trifluoroacetyl-jV-methyl)amino-l-(2-thienyl)prop an-l-ol (compound 3b) (2.14 g, 8 mmole) in MeOH (20 ml), H ₂ O (10 ml) and Na ₂ CO ₃ (5.09 g, 48 mmole) were added and the mixture was stirred at room temperature for 4 h. H ₂ O (40 ml) was added and the product was extracted with CH ₂ Cl ₂ (4x10 ml). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated affording an oil. To this oil, warm hexane (20 ml) was added and stirred on ice-bath for 30 min. The precipitate was filtered, rinsed with hexane and dried in vacuum. A light brownish powder (1.29 g, 94%) was obtained.

Ee>99% (HPLC: column OD-H, mobile phase hexane/2-propanol/Et ₂ NH 98:1 :1, UV detection at 236 nm)

Example 7

Synthesis of duloxetine and duloxetine hydrochloride

To (S)-3-methylamino-l-(2-thienyl)propan-l-ol (compound 4) (171 mg, 1.0 mmole, ee>99%) in dry DMSO (2 ml) was added at room temperature and under stirring NaH (60% suspension in a mineral oil, 44 mg, 1.1 mmole) in two portions. After 30 min, 1- fluoronaphthalene (195 μl, 1.5 mmole) was added, and the mixture heated to 5O ⁰ C and stirred at this temperature for 8 h. The cooled reaction mixture was poured onto ice-cold H ₂ O (80 ml), the pH of the solution was adjusted to 3 and the aqueous phase was washed with hexane (2x10 ml). The pH of the aqueous solution was adjusted to pH 11 with IM NaOH and the product was extracted with diethylether (3x20 ml). The combined ether phases were washed with water (4x10 ml) and with a saturated aqueous NaCl (10 ml), and dried (Na ₂ SO ₄ ). After concentration, duloxetine as a light yellow oil (205 mg, 69%) was obtained.

Ee=98.2% (HPLC: column Chiralcel OD-H, mobile phase hexane/2-propano 1/Et ₂ NH 90: 10:0.1, UV detection at 280 nm)

¹ H NMR (CDCl ₃ ): £=2.16-2.42 (m, IH), 2.41-2.52 (m, IH), 2.42 (s, 3H) ₁ 2.80-2.86 (m, 2H), 5.79 (dd ₃ J=7.8 Hz, J=5.1 Hz, IH), 6.86 (m, IH), 6.93 (m, IH), 7.05 (m, IH), 7.20 (m, IH) ₃ 7.26 (m, IH), 7.39 (m, IH), 7.44-7.51 (m, 2H), 7.75-7.79 (m, IH), 8.33-8.37 (m, IH). Preparation of duloxetine hydrochloride

Duloxetine (1 19 mg, 0.4 mmole, ee==98.2%) was dissolved in EtOAc (2 ml) and IM HCl in Et ₂ O (0.36 ml) was added under stirring at 0 ⁰ C. The suspension was stirred at around 0 ⁰ C for 4 h and the precipitate was filtered, rinsed with hexane and dried. The solid was recry stall ized from a mixture of 2-propanol/acetone affording the pure title compound. £6=99.1% (determined using the product free of its HCl) Chemical purity: 99%.

Preparation of duloxetine with >99% enantiomeric purity and >99% chemical purity

Duloxetine hydrochloride (240 mg, 0.8 mmole, ee=99, l%, prepared as above) was suspended in water and the pH adjusted to 11 with IM NaOH and the product was extracted with diethylether (3x30 ml). The combined ether phases were washed with water, a saturated aqueous NaCl, and dried (Na ₂ SO ₄ ). After concentration, pure duloxetine was obtained. Ee=99.1% (HPLC: column Chiralcel OD-H, mobile phase hexane/2-ρroρanol/Et ₂ NH 90:10:0.1, UV detection at 280 nm). Chemical purity: ≥99%.