WO2008081476A2

WO2008081476A2 - Process for preparing duloxetine hydrochloride

Info

Publication number: WO2008081476A2
Application number: PCT/IN2007/000632
Authority: WO
Inventors: Dhimant Jasubhai Patel; Shriprakash Dhar Dwivedi
Original assignee: Cadila Healthcare Ltd
Current assignee: Zydus Lifesciences Ltd
Priority date: 2006-12-29
Filing date: 2007-12-28
Publication date: 2008-07-10
Anticipated expiration: 2009-06-29
Also published as: WO2008081476A3

Abstract

Enantiomerically pure S-(+)-duloxetine hydrochloride with high purity as determined by area percentage of HPLC are disclosed. Also disclosed are improved process for preparing duloxetine hydrochloride of formula (I).

Description

PROCESS FOR PREPARING DULOXETINE HYDROCHLORIDE FIELD OF THE INVENTION

The present invention relates to improved process for preparing duloxetine hydrochloride of formula (I). More particularly, present invention relates to enantiomerically pure S-(+)-duloxetine hydrochloride with high purity as determined by area percentage of HPLC. The present invention also relates to the novel intermediates for the preparation of S-(+)-duloxetine hydrochloride. Duloxetine is useful for the treatment of depression.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Duloxetine HCl is a dual reuptake inhibitor of the neurotransmitter serotonin and norepinephrine. It is used for the treatment of stress urinary incontinence (SUI), depression, and pain management. It is commercially available as CYMBALTA . Duloxetine hydrochloride has the chemical name (S)-(+)-N-methyl-3-(l- naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride acid salt and represented by the structure of formula (I).

(I)

Duloxetine and related class of compounds like fluoxetine, tomoxetine etc. are important for treating psychiatric disorders. Fluoxetine is a selective inhibitor of serotonin in serotonergic neurons, tomoxetine and nisoxetine are selective inhibitors of norepinephrine in noradrenergic neurons while duloxetine is a dual inhibitor of serotonin and norepinephrine reuptake and thus have a better pharmacological profile as an antidepressant drug (EP 273658, 1988; Chem. Abstr., 1988, 109, 170224n; Life Sci. 1988, 43, 2049). Duloxetine having one chiral center can exist in two isomeric forms. In view of the different pharmacological activities displayed by individual enantiomers, differences in metabolic behavior and importance to provide enantiomerically pure forms as drugs, the preparation of this drug in enantiomerically pure form is highly desirable.

Duloxetine was disclosed in U.S. Pat. Nos. 5,023,269 and 4,956,388 by Robertson, et al. and the synthesis of it was discussed in more detail by Berglund, R. A., Org. Proc. Res. Devei, 1, 328, (1997) and Deeter, et al., in Tetrahedron Letters, 31 (40), 7101-04 (1990) and aspects patented in U.S. Patents No._. 5,362,886 and 5,491,243. US '269 describes the preparation of duloxetine base by reacting N.N-dimethyl-3-(2-thienyl)-3- hydroxypropanamide with fluoronaphthalene (stage a), followed by demethylation with phenyl chloroformate or trichloroethyl chloroformate (stage b) and basic hydrolysis (stage c) according to the following scheme-1.

DNT-base Duloxetine alkyl carbamate Base

Stage c R-OH

Scheme-1 The drawbacks of the process described in the above patents and publication are the use of the phenyl and trichlorinated chloroformates in stage b, which results in the formation of the very toxic substances, such as phenol and trichloroethanol in stage c. In addition, these processes require temperatures higher than 55⁰C.

Alternative process for the preparation of Duloxetine is reported in Liu, H.; Hoff, B. H.; Authonsen, T. Chirality, 12, 26 (2000) and Wheeler, W.J.; Kuo, F.S. Labelled compd. Radiopharm., 36, 213 (1995). Accordingly, both the reported processes have a common chloroalcohol intermediate, which is further arylated to give duloxetine. These processes, as reported in the above articles, are outlined in scheme 2

10

Scheme-2 and Scheme 3 below.

Chloroketone

Chira) Reduction

Duloxetine HCI

Scheme 3

I 5 The above process involves preparation of (S)-(-)-3-N-methylamino-l-(2- thienyl)-l-propanol, which involves toxic/ carcinogenic compound such as tin tetrachloride and benzene and the use of expensive compounds such as borohydride or borane and sodium iodide, the latter being in addition difficult to dispose.

WO 2003070720 Al discloses the preparation of N-methyl-3-hydroxy-3-(2- thienyl)propylamine via novel thiophene derivatives containing carbamate groups as intermediates. The below reaction scheme-4 discloses the process for preparation of thiophene derivative, an important intermediate for preparation of duloxetine hydrochloride.

Scheme 4

WO 2006/071868 A2 discloses the process for preparing pharmaceutically acceptable salts of duloxetine and intermediates thereof. The patent discloses the process for preparing DNT-base, duloxetine alkyl carbamate, duloxetine-base and duloxetine hydrochloride. Also provided, are processes for converting DNT-base, duloxetine carbamate and duloxetine-base into pharmaceutically acceptable salts of duloxetine.

WO 2006/099433 Al discloses chemically and/or enantiomerically pure duloxetine HCl and process for preparing chemically and/or enantiomerically pure duloxetine HCI. The present invention encompasses pharmaceutically acceptable salts of duloxetine, containing less than about 0.14 percent area by HPLC of the impurity (+)-jV-methyl-3-(l-napththalenyloxy)-3-(3-thienyl)propanamine (DLX-ISO3) and 0.04 percent area by HPLC of the duloxetine R-enantiomer.

WO 2006/081515 A2 discloses the polymorphs of duloxetine hydrochloride. Form A and Form B are the only known polymorphs for duloxetine hydrochloride characterized by XRD, IR and raman spectras. The patent application also encompasses that when duloxetine hydrochloride is prepared according to preparation 2 of U.S. Patent No. 5,362,886, an anhydrous crystalline form of duloxetine is obtained. As used herein, the term "Form A" referes to the anhydrous crystalline form of duloxetine HCl obtained using preparation 2 of U.S. Patent No. 5,362,886. Duloxetine HCl is available commercially as CYMBALT A^®, which contains Form A as the active ingredient.

WO 2007098923 Al claims the process for obtaining the enantiomers of duloxetine precursors of below general formula.

wherein, Ri, R₂ and R₃ are each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl containing 1 to 5 carbon atoms or substituted or unsubstituted aryl; X is -C(=O)-Z or -Y, wherein Y is selected from -CH₂-OR_-I-, -CH₂- halogen or -CH₂-NR^R₇ and Z is selected from - NR₆R₇ or OR₅, wherein R5 is selected from hydrogen, substituted or unsubstituted alkyl containing 1 to 5 carbon atoms or ester activating group; R₄ is selected from hydrogen, hydroxyl protecting group or hydroxyl activating group; R₆ and R₇ are each independently selected from hydrogen, amino protecting group, amido protecting group or substituted or unsubstituted alkyl contains about 1 to 5 carbon atoms, or pharmaceutically acceptable salt, complex or solvate thereof.

WO 2007096707 A2 discloses the process for the preparation of (S)-(+)- duloxetine HCl by condensation of (S)-3-(dimethyIamino)- 1 -(2-thienyl)- 1 -propanol and 1 -fluoronaphthalene and at least one alkaline metal hydroxide or alkoxide in DMSO or DMSO-cosolvent mixture, where said process doesn't require the use of phase transfer catalyst. Further reaction proceeds through oxalate salt of condense product characterized by XRD, DSC and IR. WO 2007/093439 A2 discloses the preparation of crystalline duloxetine HCl characterized by XRD and conversion of crystalline Form T to crystalline Form A. WO 2007/139984 A2 claims the crystalline duloxetine hydrochloride solvate of acetone designated as Form C. Also, claims the process for the preparation of crystalline duloxetine hydrochloride Form A characterized by XRD 20 values by drying crystalline solvated Form C. WO 2007/074060 Al discloses the process for the preparation of optically active (S)-3-chloro-l-(2-thienyl)-propane-l-ol by reducing 3-chloro-l-(2-thienyl)- propane-2-one by means of alcohol dehydrogenase from the genus therraoanaerobacter and the product thus formed is isolated in essentially enantiomerically pure form. Therefore, there is a further need to have simple process, that allow for preparation of highly pure duloxetine hydrochloride in a facile manner on an industrial scale which yields enantiomerically pure (S)-(+)-duloxetine hydrochloride with high chemical purity when measured by area percentage of HPLC. Objects of the Invention It is an important object of the present invention is to provide a process for the preparation of Duloxetine and its pharmaceutically acceptable salts.

Yet another object of the present invention is to provide novel intermediates for the preparation of Duloxetine and its pharmaceutically acceptable salts.

Still another object of the present invention is to provide a process for the preparation of substantially pure Duloxetine and its pharmaceutically acceptable salts

It is also the object of the present invention to provide novel intermediate for the preparation of enantiomerically pure (S)-(+)-Duloxetine hydrochloride and their process for preparation. Summary of the Invention In one embodiment, the invention provides a novel intermediate 2-(3-Hydroxy-

3-thiophen-2-yl-propyl)-isoindole-l,3-dione "compound IV" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.

In another embodiment, the invention provides a novel intermediate 2-(3- Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l ,3-dione "compound IV" which is isolated in a crystalline form and characterized by ¹H NMR, ¹³C NMR and X-ray powder diffraction pattern.

In another embodiment of the present invention, there is provided a process for the preparation of 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole- l ,3-dione ("Compound IV"), an intermediate for preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I)

which comprises of :

(a) reducing 3-chloro-l-thiophen-2-yl-propane-l-one of formula (II) to obtain 3- chIoro-l-thiophen-2-yl-propane-l-ol of formula (III); and

reacting 3-chloro-l-thiophen-2-yl-propane-l-ol of formula (III) with potassium phthalimide in a suitable organic solvent at a suitable temperature to give compound of formula IV

In another embodiment, the invention provides a novel intermediate 2-[3- (Naphthalen-l-yloxi)-3-thiophen-2-yl-propyl]-isoindole-l ,3-dione "compound V" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.

In another embodiment, the invention provides a novel intermediate 2-[3- (Naphthalen-l-yloxi)-3-thiophen-2-yl-propyl]-isoindole-l ,3-dione "compound V" which is isolated in a crystalline form and characterized by ¹H NMR, ¹³C NMR and X- ray powder diffraction pattern. In another embodiment of the present invention, there is provided a process for the preparation of 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-iso indole- 1, 3 -dione ("Compound V"), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I)

which comprises of :

(a) reducing 3-chloro-l-thiophen-2-yl-propane-l-one of formula (II) to obtain 3- chloro-l-thiophen-2-yl-propane-l-ol of formula (III);

O OH

(") <^m>

(b) reacting 3-chloro-l-thiophen-2-yl-propane-l-ol of formula (III) with potassium phthalimide in a suitable organic solvent at a suitable temperature to give

compound of formula IV; and

(c) reacting compound of formula (IV) with alpha naphthaol to give novel compound 2-[3-( l -naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole-l ,3(2//)-dione of formula

(V)

In another embodiment, the invention provides a novel intermediate 3-(Naphthlen- l -yloxy)-3-thiophen-2-yl-propylamine ("Compound VI") for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.

In another embodiment, the invention provides a novel intermediate a 3- (Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VI") which is isolated in a crystalline form and characterized by ¹H NMR, ¹³C NMR and X-ray powder diffraction pattern. In yet another embodiment, the isolated compound VI is racemic.

In another embodiment of the present invention, there is provided a process for the preparation of 3-(Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VI"), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I)

which comprises of :

(a) reducing 3-chIoro-l -thiophen-2-yl-propane-l-one of formula (II) to obtain 3- chloro-l-thiophen-2-yl-propane-l -ol of formula (III);

(b) reacting 3-chloro-l-thiophen-2-yl-propane-l-ol of formula (III) with potassium phthalimide in a suitable organic solvent at a suitable temperature to give compound of formula IV;

(c) reacting compound of formula (IV) with alpha naphthaol to give novel compound 2-[3-(l-naphthyloxy)-3-(2-thienyl)propyl]-l//-isoindole-l,3(2H)-dione of formula (V); and

(d) treating compound 2-[3-(l-naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole- l,3(2H)-dione of formula (V) with C₁-C₃ alkyl amine to provide 3-(l-naphthyloxy)- 3-(2-thienyl)propan- 1 -amine of formula (VI)

In another embodiment, the invention provides a novel intermediate (S)-(+)-3- (Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VII") for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.

In another embodiment, the novel intermediate crystalline (S)-(+)-3-(Naphthlen- l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VII") is characterized by X-ray powder diffraction pattern. In another embodiment of the present invention, there is provided a process for the preparation of (S)-(+)-3-(Naphthlen- 1 -yloxy)-3-thiophen-2-yl-propylamine

("Compound VII"), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I)

which comprises of :

(b) reacting S-chloro-l-thiophen^-yl-propane-l-ol of formula (HI) with potassium phthalimide in a suitable organic solvent at a suitable temperature to give

compound of formula IV; (c) reacting compound of formula (IV) with alpha naphthaol to give novel compound

2-[3-(l -naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole-l,3(2//)-dione of formula

(V); (d) treating compound 2-[3-( l-naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole- l,3(2H)-dione of formula (V) with Ci-C₃ alkyl amine to provide 3-(l-naphthyloxy)- 3-(2-thienyl)propan- 1 -amine of formula (VI); and

(e) resolving 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI) to obtain (S)-(+)-3-(l -naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII)

I l In yet another embodiment of the present invention, there is provided a process for the preparation of (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I):

comprises of:

(a) treating racemic 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI) with an optically active acid in suitable organic solvent;

(b) isolating the salt of (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII) with optically active acid; (c) treating said salt with a base to obtain (S)-(+)-3-(l-naphthyloxy)-3-(2- thienyl)propan-l -amine of formula (VII); and

(d) isolating crystalline (S)-(+)-3-(l-naphthyIoxy)-3-(2-thienyl)propan-l -amine of formula (VII).

In another embodiment of the present invention, there is provided a process for the preparation of (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I):

which comprises: (a) treating racemic 3-(l -naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI)

with an optically active Di-p-toluyl-L-tartaric acid in suitable organic solvent to form a salt of formula (Vila);

(Vila)

(b) isolating the salt of (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII) and optically active Di-p-toluyl-L-tartaric acid as formula (Vila);

(c) treating salt of formula (Vila) with a base to obtain (S)-(+)-3-(l-naphthyloxy)-3-(2- thienyl)propan-l -amine of formula (VII);

(d) isolating crystalline (S)-(+)-3-(I -naphthyloxy)-3-(2-thienyl)propan-l-amine of formula (VII);

(e) optionally converting compound of formula (VII) to duloxetine and its pharmaceutically acceptable salts thereof.

In another embodiment, invention provides a novel intermediate Di-p-toluyl-L- tartaric acid salt of (S)-(+)-3-(l -naphthyloxy)-3-(2-thienyl)propan-l -amine of formula Vila

(Vila ) In another embodiment, invention provides a novel intermediate Di-p-toluyl-L- tartaric acid salt of (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (Vila) in crystalline form characterized by X-ray powder diffraction pattern.

According to an important aspect of the present invention, there is provided a process for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I) substantially free from (R)-(-)-duloxetine hydrochloride and characterized by an X- ray powder diffraction with peaks at about 9.6°, 13.9°, 18.1°, 18.9°, 20.9° and 23.4° 2Θ ± 0.2° 2Θ comprising: (a) reducing 3-chloro-l-thiophen-2-yl-propane-l-one of formula (II) to obtain 3- chloro-l-thiophen-2-yl-propane-l-ol of formula (III);

reacting compound of formula (IV) with alpha naphthaol to give novel compound 2-[3- ( 1 -naphthyloxy)-3-(2-thienyl)propy I]- 1 H-isoindole- 1 ,3(2H)-dione of formula (V);

(c) treating compound 2-[3-(l -naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole- l,3(2H)-dione of formula (V) with Ci-Cj alkyl amine to provide 3-(l -naphthyloxy)- 3-(2-thienyl)propan-l -amine of formula (VI);

(d) resolving 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI) with an optically active acid to obtain (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l- amine of formula (VII); and

(e) treating (S)-(+)-3-(l -naphthyloxy)-3-(2-thienyI)propan-l -amine of formula (VII) with methylating agent to obtain Duloxetine base of formula (VIII), which is subsequently converted to Duloxetine hydrochloride of formula (I).

In one embodiment, the invention provides a novel intermediate 2-(3-oxo-3- thiophen-2-yl-propyl)-isoindole- ! ,3-dione "Compound of formula (Ha)" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.

In another embodiment, the invention provides a novel intermediate 2-(3-oxo-3- thiophen-2-yl-propyl)-isoindole- l ,3-dione "compound Ha" which is isolated in a crystalline form and characterized by ¹H NMR, ¹³C NMR and X-ray powder diffraction pattern. In one embodiment, the invention provides a novel intermediate 2-(3-oxo-3- thiophen-2-yl-propyl)-isoindole-l,3-dione "Compound of formula (Ha)" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.

In another embodiment, the invention provides a novel intermediate 2-(3-oxo-3- thiophen-2-yl-propyl)-isoindole-l ,3-dione "Compound of formula (Ha)" which is isolated in a crystalline form and characterized by ¹H NMR, ¹³C NMR and X-ray powder diffraction pattern.

In one of the aspect of the present invention, there is also provided a process for the preparation of 2-(3-oxo-3-thiophen-2-yl-propyl)-isoindole-l,3-dione ("Compound (Na)"), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I),

which comprises: (a) reacting thiophene with chloropropanone chloride under friedle-crafts condition in presence of anhydrous AlCl₃ to give chloroketone of formula II;

(b) treating chloroketone of formula II with potassium phthalimide in a suitable organic solvent at a suitable temperature to give compound of formula Ha;

(c) cooling the reaction mixture; and (d) isolating thiophene derivative of formula Ma. In one embodiment, the invention provides a novel intermediate Substituted sulfonic acid 3-(l ,3-dioxo-l ,3-dihydro-isoindol-2-yl)-l -thiophen-2-yl)-propyl ester "Compound IVa" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymoφhic Form A.

wherein R = mesyl or tosyl.

In another embodiment, the invention provides a novel intermediate methanesulfonic acid 3-( 1 ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl)- 1 -thiophen-2-yl)-propyl ester (Compound IVa')

which is isolated in a crystalline form and characterized by ¹H NMR, ¹³C NMR and X- ray powder diffraction pattern.

In one of the aspect of the present invention, there is also provided a process for the preparation of 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l,3-dione ("Compound V"), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I)

which comprises of :

(a) reacting thiophene with chloropropanone chloride under friedle-crafts condition in presence of anhydrous AlCl₃ to give chloroketone of formula II;

(c) reducing 2-[3-oxo-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (Ua) with a reducing agent in a suitable organic solvent or optionally in presence of water to obtain 2-[3-hydroxy-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of

formula (IV);

(d) reacting the compound of formula IV with RSO₂X to obtain novel compound of formula (IVa')

wherein in R represent Q-C₄ alkyl, or aryl and X represent halogen selected from Cl,

Br, I; (e) converting the compound of formula (IVa') to 2-[3-(Naphthalene-l-yloxy)-3- thiophen-2-yl-propyl]-isoindole-l, 3-dione ("Compound V"); and (f) using compound of formula V to prepare (S)-(+)-duloxetine hydrochloride of formula (I). BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

A preferred embodiment of the invention will now be described, by way of example only, with reference to the accompanying figures in which: FIG.l : X-ray diffraction of crystalline (S)-(+)-Duloxetine hydrochloride Form A FIG.2: IR Spectra of crystalline (S)-(+)-Duloxetine hydrochloride Form A FIG.3: DSC of crystalline (S)-(+)-Duloxetine hydrochloride Form A FIG.4: ¹H NMR spectrum of compound of formula IV FIG.5: ¹³C NMR spectrum of compound of formula IV

FIG.6: X-ray diffraction of crystalline compound of formula FV

FIG.7: ¹H NMR spectrum of compound of formula V

FIG.8: ¹³C NMR spectrum of compound of formula V FIG.9: X-ray diffraction of crystalline compound of formula V

FIG.10: ¹H NMR spectrum of compound of formula VI

FIG.ll: ¹³C NMR spectrum of compound of formula VI

FIG.12: X-ray diffraction of crystalline compound of formula VI

FIG.13: X-ray diffraction of crystalline compound of formula VII FIG.14: X-ray diffraction of crystalline Di-p-toluyl-L-tartaric acid salt of compound of formula VII.

FIG.15: H NMR spectrum of compound of formula Ha

FIG.16: ¹³C NMR spectrum of compound of formula Ha

FIG.17: X-ray diffraction of crystalline compound of formula Ha FIG.18: ¹H NMR spectrum of compound of formula IVa'

FIG.19: ¹³C NMR spectrum of compound of formula IVa'

FIG.20: X-ray diffraction of crystalline compound of formula IVa'

DETAILED DESCRIPTION

In one embodiment, the invention provides a novel intermediate 2-(3-Hydroxy- 3-thiophen-2-yl-propyl)-isoindole-l ,3-dione "compound IV" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.

In another embodiment, the invention provides a novel intermediate 2-(3- Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l ,3-dione "compound IV" which is isolated in a crystalline form and characterized by ¹H NMR (300 MHz, DMSO-D6) δ (ppm) :

7.81 (m, 4H), 7.36 (d, I H), 6.95 (m, J = 12 Hz, 2H), 5.71 (d, I H), 4.87 (m, I H), 3.70

(m, 2H), 2.01 (m, 2H); ¹³C NMR (75 MHz, DMSO-D6) : δ 167.87, 149.97, 134.24,

13 1.73, 126.47, 123.00, 122.90, 66.52, 37.57, 34.76 and X-ray powder diffraction pattern having peaks at 1 1.2°, 15.8°, 19.5°, 22.5°, 23.3° and 26.9° 2Θ ± 0.2° 2Θ. In another embodiment of the present invention, there is provided a process for the preparation of 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l,3-dione ("Compound IV"), an intermediate for preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I)

which comprises of :

(a) reducing 3-chloro-l -thiophen-2-yl-propand-l-one of formula (II) to obtain 3- chloro-l-thiophen-2-yl-propane-l-ol of formula (III);

(b) reacting 3-chloro-l-thiophen-2-yl-propane-l-ol of formula (III) with potassium phthalimide in a suitable organic solvent at a suitable temperature to give compound of formula IV; and

(c) isolating of 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindoIe-l ,3-dione ("compound IV") in crystalline form.

According to one of the aspect of the present invention, reduction of compound of formula (II) is carried by using reducing agent selected from the group comprising of sodium borohydride, lithium aluminum hydride, n-butyl lithium, lithium diisopropyl amide and the like. Most Preferably sodium borohydride can be used as reducing agent. The reaction is carried out in suitable organic solvent or optionally its presence of water. Preferred organic solvent is methylene dichloride.

According to further aspect of the embodiment, invention provides process for reacting reduced compound of formula (III) with potassium phthalimide in a suitable organic solvent selected form the group of alcohols like methanol, ethanol, propanol, isopropanol, butanol etc., esters like ethyl acetate, methyl acetate, n-butyl acetate etc., ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone, etc., chlorinated solvents like methylene dichloride, ethylene dichlorde, chloroform etc., amides like dimethyl formamide, dimethyl acetamide etc., sulphoxides like dimethyl sulfoxide., sulpholanes like dimethyl sulpholanes etc., preferably dimethyl sulfoxide. The reaction is carried out in presence of catalytic amount of reaction initiator like sodium iodide.

In another embodiment, the invention provides a novel intermediate 2-[3- (Naphthalen-l-yloxi)-3-thiophen-2-yl-propyl]-isoindole-l,3-dione "compound V".

In another embodiment, the invention provides a novel intermediate 2- [3- (Naphthalen-l-yloxi)-3-thiophen-2-yl-propyl]-isoindole-l ,3-dione "compound V" which is isolated in a crystalline form and characterized by ¹H NMR (300 MHz, DMSO-D6) δ (ppm) : 8.40 (s, IH), 8.13 (m, 2H), 7.78 (s, 4H), 7.35 (m, 3H), 7.23 (t, I H), 7.05 (d, IH), 6.88 (m, 2H), 5.05 (t, IH), 3.60 (t, 2H), 2.49 (m, 2H); ¹³C NMR (75 MHz, DMSO-D6) : δ 167.84, 152.16, 149.36, 134.22, 132.02, 131.68, 129.70, 126.51 , 124.94, 124.25, 124.18, 122.86, 122.62, 107.51, 38.94, 38.66, 36.35, 35.00 and X-ray powder diffraction pattern having peaks at 7.4°, 1 1.2°, 15.4°, 19.8° and 25.6° 2Θ ± 0.2° 29.

In another embodiment of the present invention, there is provided a process for the preparation of 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l,3-dione ("Compound V"), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I)

which comprises of :

(a) reducing 3-chloro- l -thiophen-2-yl-propane-l -one of formula (II) to obtain 3- chIoro-l-thiophen-2-yl-propane-l -ol of formula (III);

(b) reacting 3-chloro-l -thiophen-2-yl-propane-l -o) of formula (III) with potassium phthalimide in a suitable organic solvent at a suitable temperature to give compound of formula IV;

(c) reacting compound of formula (IV) with alpha naphthaol in presence of acid catalyst in suitable organic solvent to give novel compound 2-[3-(l-naphthyloxy)-3- (2-thienyl)propyl]-l//-isoindole-l ,3(2H)-dione of formula (V); and

isolating novel intermediate 2-[3-(l-naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole-

1 ,3(2//)-dione of formula (V) in crystalline form.

According to one of the aspect of the present invention, reduction of compound of formula (II) is carried by using metal hydride reducing agent selected from the group consisting of sodium borohydride, lithium aluminum hydride, n-butyl lithium, lithium diisopropyl amide and the like. Most Preferably sodium borohydride can be used as reducing agent. The reaction is carried out in suitable organic solvent or optionally its presence of water. Preferred organic solvent is methylene dichloride.

The compound of formula V is condensed with α-naphthol in presence of acid catalyst selected from organic acid like acetic acid, formic acid, triflouroacetic acid, perchloric acid and the like, inorganic acid like hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like, preferably triflouroacetic acid. The condensation is carried out in suitable organic solvent selected form the group of alcohols like methanol, ethanol, propanol, isopropanol, butanol and the like; esters like ethyl acetate, methyl acetate, n-butyl acetate and the like; ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone and the like; chlorinated solvents like methylene dichloride, ethylene dichlorde, chloroform and the like; aromatic hydrocarbons like toluene, xylene, ethyl benzene and the like; aliphatic hydrocarbons like n-hexane, n-heptane, cyclohexane and the like; amides like dimethyl formamide, dimethyl acetamide and the like; preferably aromatic hydrocarbons or aliphatic hydrocarbons like toluene or cyclohexane, respectively. The condensation is carried out at a temperature of about reflux temperature of solvent, particularly from about 6O⁰C to 7O⁰C for time sufficient to obtain compound V. The reaction mixture is concentrated under vacuum at 45⁰C to 55⁰C and cooled gradually to 10°C to 15⁰C to isolate crystalline compound V by filtration.

In another embodiment, the invention provides a novel intermediate 3- (Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VI") for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.

In another embodiment, the invention provides a novel intermediate a 3- (Naphthlen-l -yloxy)-3-thiophen-2-yl-propylamine ("Compound VI") which is isolated in a crystalline form and characterized by ¹H NMR (300 MHz, DMSO-D6) δ (ppm) :

8.16 (m, 2H), 7.41 (m, 2H), 7.22 (d, IH), 7.21 (d, I H), 6.96 (d, I H), 6.87 (m, 2H), 5.06

(t, I H), 4.45 (s, 2H). 2.48 (m, 2H), 2.20 (m, 2H); ¹³C NMR (75 MHz, DMSO-D6) : δ

152.24, 150.29, 132.17, 130.34, 126.42, 126.00, 125.05, 124.44, 123.96, 123.92, 123.96, 123.92, 123.48, 123.25, 122.64, 107.53, 39.49, 39.22, 38.66, 37.47 and X-ray powder diffraction pattern having peaks at about 1 1.7°, 14.4°, 19.1°, 21.6°, 22.5°, 24.7° and 28.5° 2θ ± 0.2° 2Θ. In yet another embodiment, the isolated compound VI is racemic. In another embodiment of the present invention, there is provided a process for the preparation of 3-(Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VI"), an intermediate for the preparation of crystalline (S)-(+)-duIoxetine hydrochloride of formula (I)

which comprises of :

(a) reducing S-chloro-l-thiophen^-yl-propane-l-one of formula (II) to obtain 3- chloro-l-thiophen-2-yl-propane-l-ol of formula (III);

(b) reacting S-chloro-l-thiophen-Z-yl-propane-l-ol of formula (III) with potassium phthalimide in a suitable organic solvent at a suitable temperature to give compound of formula IV;

(c) reacting compound of formula (IV) with alpha naphthaol in presence of acid catalyst in suitable organic solvent to give novel compound 2-[3-(l-naphthyloxy)-3-

(2-thienyl)propy I]- 1 //-isoindole- 1.3(2//)-dione of formula (V);

(d) treating compound 2-[3-( l-naphthyIoxy)-3-(2-thienyl)propyl]-l H-isoindole- l ,3(2//)-dione of formula (V) with C₁-C₃ alkyl amine to provide 3-(l-naphthyloxy)- 3-(2-thienyl)propan- 1 -amine of formula (VI);

and

(e) isolating 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI) in crystalline form.

2-[3-( 1 -naphthyloxy)-3-(2-thieny l)propyl]- 1 H-isoindole- 1 ,3(2H)-dione of formula (V) is treated with C1-C5 alkyl amine selected from mnonomethyl amine, ethyl amine, diethyl amine, triethyl amine, isopropyl amine and the like in suitable organic solvent selected form the alcohols like methanol, ethanol, propanol, isoproanol, butanol etc., esters like ethyl acetate, methyl acetate, n-butyl acetate etc., ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone, etc., water and mixture thereof, preferably in water at room temperature. The isolated compound of formula VI was purified to toluene followed by mixture of isopropanol and water and finally in ethyl acetate water mixture to obtain crystalline 3-(l-naphthyloxy)-3-(2-thienyl)propan- 1 -amine of formula in a racemic mixture.

In another embodiment, the invention provides a novel intermediate (S)-(+)-3- (Naphthlen-l -yloxy)-3-thiophen-2-yl-propylamine ("Compound VII") for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.

In another embodiment, the novel intermediate crystalline (S)-(+)-3-(Naphthlen- l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VII") is characterized by X-ray powder diffraction pattern having peaks at about 1 1.7°, 14.0°, 18.6°, 21.7°, 24.4° and 29.3° 2Θ ± 0.2° 20. In another embodiment of the present invention, there is provided a process for the preparation of (S)-(+)-3-(Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VII"), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I)

which comprises of :

(a) reducing 3-chloro-l -thiophen-2-yl-propane-l-one of formula (II) to obtain 3- chloro-l-thiophen-2-yl-propane-l-ol of formula (III);

(b) reacting 3-chloro- l -thiophen-2-yl-propane-l -ol of formula (III) with potassiumphthalimide in a suitable organic solvent at a suitable temperature to give compound of formula IV;

(c) reacting compound of formula (IV) with alpha naphthaol in presence of acid catalyst in suitable organic solvent to give novel compound 2-[3-( l -naphthyloxy)-3- (2-thienyl)propy I]- 1 //-isoindole- 1 ,3(2H)-dione of formula (V);

(d) treating compound 2-[3-(l -naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole- l,3(2H)-dione of formula (V) with Ci-C₃ alkyl amine to provide 3-( 1 -naphthyloxy)- 3-(2-thienyl)propan-l -amine of formula (VI);

(e) resolving 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI) with an optically active acid to obtain (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l- amine of formula (VII); and

(f) isolating (S)-(+)-3-( l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII) in crystalline form.

In yet another embodiment of the present invention, there is provided a process for the preparation of (S)-(+)-3-(l -naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII),

an intermediate for the preparation of crystalline (S)-(+)-duloxetihe hydrochloride of formula (I):

which comprises of:

(b) isolating the salt of (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII) and optically active acid;

(c) treating with a base to obtain (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l- amine of formula (VII); and

(d) isolating crystalline (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII). According to the most preferred embodiment of the present invention, optically active acid for resolving racemic 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI) can be selected from the group consisting of D-lactic acid, D-tartaric acid, D-malic acid, l S-10-camphor sulfonic acid, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenyl acetic acid, D-mandelic acid, Di- p-anisoyl-D-tartaric acid, D-tartaric acid monoparachloro anilide, Dibenzoyl-D-tartaric acid monodimethyl amide, (S)-(+)-l , l '-binaphthalene-2,2'-dihydrogen phosphate, Di- p-toluyl-D-tartaric acid, Di-p-toluyl-L-tartaric acid, preferably Di-p-toluyl-L-tartaric acid.

The resolution is performed in suitable organic solvent selected from the group consisting of an aliphatic C 1-C4 alcohol, an aliphatic C2-C6 ketone, an aliphatic CI -C4 chlorinated hydrocarbon, nitriles, and/or an aliphatic C2-C6 and mixtures thereof.

The isolated salt of formula Vila is treated with base selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such sodium carbonate, potassium carbonate, and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixture thereof. The bases can be used in the form of solids or in the form of aqueous solutions. In another embodiment of the present invention, there is provided a process for the preparation of (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I):

which comprises of:

(a) treating racemic 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI) with an optically active Di-p-toluyl-L-tartaric acid in suitable organic solvent to

form a salt;

(b) isolating the salt of (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII) and optically active Di-p-toluyl-L-tartaric acid as formula Vila;

(Vila)

(c) treating salt of formula (Vila) with a base to obtain (S)-(+)-3-(l-naphthyloxy)-3-

(2-thienyl)propan-l -amine of formula (VII);

(d) isolating crystalline (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VIl); and (e) converting compound of formula (VII) to duloxetine and its pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salt of duloxetine can be selected from maleate, succinate, benzenesulfonate, tartarate, hydrochloride and the like, preferably hydrochloride.

In another embodiment, invention provides a novel intermediate Di-p-toluyl-L- tartaric acid salt of (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (Vila):

(Vila)

In another embodiment, invention provides a novel intermediate Di-p-toIuyl-L- tartaric acid salt of (S)-(+)-3-( l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (Vila) in crystalline form characterized by X-ray powder diffraction pattern 6.1°, 9.5°, 11.8°, 17.2°, 18.4°, 20.8°, 23.0° and 23.7° 2Θ ± 0.2° 20.

According to an important aspect of the present invention, there is provided a process for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula

(I) substantially free from (R)-(-)-duloxetine hydrochloride and characterized by an X- ray powder diffraction with peaks at about 9.5°, 13.8°, 18.0°, 18.8°, 20.8° and 23.2° 2Θ ±

0.2° 2Θ comprising:

(a) reducing 3-chloro-l -thiophen-2-yl-propane-l-one of formula (II) to obtain 3- chloro-l-thiophen-2-yl-propane-l -ol of formula (III);

(b) reacting 3-chloro-l-thiophen-2-yl-propane-l -ol of formula (III) with potassium phthalimide in a suitable organic solvent at a suitable temperature to give compound of formula IV;

(c) reacting compound of formula (IV) with alpha naphthaol in presence of acid catalyst in suitable organic solvent to give novel compound 2-[3-(l-naphthyloxy)-3- (2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (V);

(d) treating compound 2-[3-(l-naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole- l ,3(2//)-dione of formula (V) with Ci-C₃ alkyl amine to provide 3-(l- naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI);

(e) resolving 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI) with an optically active acid to obtain (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l- amine of formula (VII);

and;

(f) treating (S)-(+)-3-( l -naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII) with methylating agent to obtain duloxetine base of formula (VIII), which is subsequently converted to (S)-(+)-duloxetine hydrochloride of formula (I).

In one embodiment, the invention provides a novel intermediate 2-(3-oxo-3- thiophen-2-yl-propyl)-isoindole-l,3-dione "compound Ha" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.

In another embodiment, the invention provides a novel intermediate 2-(3-oxo-3- thiophen-2-yl-propyl)-isoindole-l,3-dione "compound Ha" which is isolated in a crystalline form and characterized by ¹H NMR (300 MHz, CDCl₃) δ (ppm) : 7.85 (m, J=9.0 Hz, 2H), 7.72 (m, J = 8.4 Hz, 3H), 7.63 (t, J = 6.0 Hz, I H), 7.1 1 (t,l H), 4.13 (t, 2H), 3.35 (t, 2H); ¹³C NMR (75 MHz, CDCI₃) : δ 190.02, 168.06, 133.99, 132.07, 127.14, 123.29, 37.44, 33.54 and X-ray powder diffraction pattern 10.0°, 13.3°, 15.3°, 17.5°, 19.7°, 23.2°, 26.9° and 28.3° 2Θ ± 0.2° 20.

In one of the aspect of the present invention, there is also provided a process for the preparation of 2-(3-oxo-3-thiophen-2-yl-propyl)-isoindole-l ,3-dione ("Compound Ha"), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I),

which comprises of :

(a) reacting thiophene with chloropropanone chloride under friedle-crafts condition in presence of anhydrous AlCb to give chloroketone of formula II;

(c) cooling the reaction mixture; and

(d) isolating thiophene derivative of formula Ha.

According to an aspect of the invention, a reaction in step (b) can be carried out in a suitable organic solvent selected form the group of alcohols like methanol, ethanol, propanol, isopropanol, butanol etc., esters like ethyl acetate, methyl acetate, n-butyl acetate etc., ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone, etc., chlorinated solvents like methylene dichloride, ethylene dichloride, chloroform etc., amides like dimethyl formamide, dimethyl acetamide etc., sulphoxide like dimethyl sulphoxide, sulpholanes like dimethyl sulpholanes etc., preferably dimethyl foramide.

According to another embodiment of the present invention, the reaction in step (b) is performed at a suitable temperature from about 50⁰C to about reflux temperature of the solvent, preferably from about 85⁰C to about 15O⁰C, more preferably from about 100⁰C to about 105⁰C. The reaction mixture is further cooled at an ambient temperature below 4O⁰C, more particularly from about 25⁰C to about 35⁰C.

In one embodiment, the invention provides a novel intermediate Substituted sulfonic acid 3-( l ,3-dioxo- l ,3-dihydro-isoindol-2-yl)-l -thiophen-2-yl)-propyl ester "Compound IVa" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.

wherein R = mesyl or tosyl

In another embodiment, the invention provides a novel intermediate methanesulfonic acid 3-( 1 ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl)- 1 -thiophen-2-yl)-propyl ester (Compound IVa') which is isolated in a crystalline form and characterized by ¹H NMR (300 MHz, DMSO-D6) as disclosed in Fig. 18, ¹³C NMR (78 MHz, DMSO) as disclosed in Fig. 19 and X-ray powder diffraction pattern 7.6°, 15.2°, 17.6°, 20.2°, 26.1°, 27.4° and 32.1° 2Θ ± 0.2° 20.

In one of the aspect of the present invention, there is also provided a process for the preparation of 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole- l,3-dione ("Compound V"), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I)

which comprises of :

(a) reacting thiophene with chloropropanone chloride under friedle-crafts condition in presence of anhydrous AICl₃ to give chloroketone of formula II;

(c) reducing 2-[3-oxo-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (Ua) with a reducing agent in a suitable organic solvent or optionally in presence of water to obtain 2-[3-hydroxy-3-(2-thienyl.)propyl]-lH-isoindole-l,3(2//)-dione of formula (IV);

(d) reacting the compound of formula IV with RSO₂X to obtain novel compound of formula (IVa') wherein in R represent Ci-C₄ alkyl, or aryl and X represent halogen selected from Cl, Br, I;

(e) converting the compound of formula (IVa') to 2-[3-(Naphthalene-l-yloxy)-3- thiophen-2-yl-propyl]-isoindole-l , 3-dione ("Compound V"); and (f) using compound of formula V to prepare (S)-(+)-duloxetine hydrochloride of formula (I).

It is also an important aspect of the present invention to provide (S)-(+)- duloxetine hydrochloride wherein single individual impurity is less than 0.1% and total impurities is less than 0.5%. Thus, in its preferred form (S)-(+)-duloxetine hydrochloride is having purity of atleast 99.5% by area percentage of HPLC, preferably

99.9% by area percentage of HPLC. The term "substantially free from (R)-(-)-duloxetine hydrochloride" means (S)- (+)-duloxetine hydrochloride having chiral purity of atleast about 99.0%, preferably about 99.5%, preferably about 99.75% and more preferably about 99.9%.

It is also an important aspect of the present invention to provide S-(+)-Duloxetine Hydrochloride wherein S-(+)-Duloxetine hydrochloride is anhydrous crystalline Form A.

S-(+)-Duloxetine Hydrochloride is characterized by XRD as shown in Fig-1 , IR as shown in Fig-2 and DSC as shown in Fig-3.

According to the present invention, the process for the preparation of Duoxetine can be illustrated by below mentioned scheme, which should not be considered as

limiting the scope of the invention.

Scheme-5

Scheme-6

Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications.

The Impurity Profile Determination of Duloxetine hydrochloride comprised testing a sample using HPLC. Typically, the HPLC testing parameters included a column of C l 8 monomeric, 100 A, 4.6*250 mm (Grace Vydac or equivalent column) at a temperature of 25°C, Isocratic elution Buffer is 10 mL TEA in 1000 niL water and 5 mL of THF, adjusted to pH 4.0 with H₃PO₄. Mobile phase: Buffer: ACN :: 70:30. The system equilibrated further for 10 min and a flow rate of 1.0 ml/min. The detector was set for 230 nm. The sample volume was 5 μL and the diluent was mobile phase. As commonly known by the skilled artisan, the mobile phase composition and flow rate may be varied in order to achieve the required system suitability.

The sample was prepared by weighing accurately about 50 mg of Duloxetine hydrochloride sample in a 50ml amber volumetric flask. Dissolving the sample with 20 ml of diluent make up with diluent. Thereafter, the freshly prepared sample was injected. The sample solutions were injected into the chromatograph and the chromatogram of sample was continued up to the end of the gradient. Thereafter, the areas for each peak in each solution was determined using a suitable integrator. The calculations were obtained using the following formula: Impurity Profile Determination % Impurity = area impurity in sample X 100

Total area

EXAMPLE-1: Preparation of 3-Chloro-l-thiophen-2-yl-propane-l-one (II)

In 5 Lit. 4 neck RBF, 515.89 gm (3.869 mole) anhydrous aluminum chloride and 2 Lit. (8.0V/W) methylene dichloride at 25 to 35°C were taken. The reaction mixture was cooled to -10° to -2O⁰C. 15 mL (6% catalytic) H₃PO₄ was added into reaction mixture. 453.43 gm (3.571 mole) 3-chIoro propionyl chloride solution in 250 ml methylene dichloride was added. After the addition, the reaction mixture was maintained for 15 minutes. 250.0 gm (2.976 mole) thiophene solution in 250 ml methylene dichloride was added at -10 to -2O⁰C. Hydrochloric acid gas was evolved during addition. After addition, the reaction mixture was stirred for 3 hours. The reaction mixture was slowly dumped into 500 ml cone. HCI and 2 kg of ice. Aqueous layer was extracted with 1 Lit. of methylene dichloride. Combined MDC layer was washed with water and then with 15% NaHCO3 solution. The organic layer was distilled under vacuum at about 45° to 5O⁰C to yield 485 gm (93.40%) dark brown liquid residue of title compound.

EXAMPLE-2: Preparation of 3-Chloro-l-thiophen-2-yl-propane-l-ol (III)

497 gm (2.8481 mole) S-Chloro-l-thiophen^-yl-propane-l-one and 3976 ml

(8.0 v/w) methylene dichloride were taken into 4 neck 1OL RBF at 25 to 35⁰C. 107.74 gm (2.8481 mole) NaBH₄ solution in 3771.10 ml (35.0 V/W) SDS was added at 10- 2O⁰C and reaction mixture was stirred for 3 hours. The reaction mixture was treated with 100 mL acetic acid to adjust the pH. The reaction mixture was treated with 3 Liter of water at 25-35⁰C and stirred for 30 minutes to separate layer. Aqueous layer was extracted with 1 Liter of methylene dichloride. Combined organic layer was washed with 2 Liter fresh water and then 2 Liter 10% NaHCO3 solution. Organic layer was distilled out at 45-5O⁰C under vacuum to yield 475 gm (94.62%) dark brown liquid residue of title compound. EXAMPLE-3: Preparation of 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l, 3-dione (IV)

491 gm (2.7818 mole) 3-chloro-l-thiophen-2-yl-propane-l -ol, 515.28 gm (2.7818 mole) potassium phthalimide, 29.46 gm (6% catalytic) sodium iodide and 3437 ml (7.0 v/w) dimethyl sulfoxide were taken in to 5 liter 4 neck RBF at 25-35⁰C. The reaction mixture was heated to 70-80⁰C and maintained for 6 hours. The reaction mixture was cooled to room temperature and dumped in water. The precipitated solid was stirred for 30 minutes and filtered. The product was washed with 245 ml water. The product was dried and purified by n-Hexane to yield 530 gm (66.38%) creamish yellow solid of title compound. EXAMPLE-4: Preparation of 2-[3-(NaphthaIene-l-yloxy)-3-thiophen-2-yl-propyl]- isoindole-1, 3-dione (V)

537 gm (1.8701 mole) 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l,3- dione, 269.29 gm (1.8701 mole) α-Naphthol, 53.7 gm (10% catalytic) triflouroacetic acid and 5370 ml (10.0 v/w) toluene were taken in 1OL 4 neck RBF at 25 to 35⁰C. The reaction mixture was heated to 60° to 70⁰C for about 50 hours. 3 Liters of toluene was distilled under vacuum at 45 to 55⁰C and reaction mixture was cooled gradually to 10 to 15°C. The precipitated solid was stirred for 1 hour and filtered. The product was washed with toluene and suck dried to yield 350 gm (45.29%) greenish yellow solid of title compound.

EXAMPLE-5: Preparation of 2-[3-(Naphthalene-l-yloxy)-3-thiophen-2-yl-propyl]- isoindole-1, 3-dione (V)

425 gm (1.4800 mole) 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l ,3- dione, 213.12 gm (1.4800 mole) α-Naphthol, 21.25 gm (10% catalytic) triflouroacetic acid and 4250 mL ( 10.0 v/w) cyclohexane were taken in 5 L 4 neck RBF at 25 to 35°C. The reaction mixture was heated to 80° to 85⁰C for about 6 hours. Cyclohexane was azeotropicaJly distilled under vacuum at 50° to 55⁰C. Residue was crystallized in 2125 mL (5.0 v/w) toluene at 65 to 70⁰C. The reaction mixture was stirred for 15 minutes and cooled gradually to 0° to 10⁰C. The precipitated solid was stirred for 1 hour and filtered. The product was washed with 100 mL toluene and suck dried to yield 190.0 gm (31 %) greenish yellow solid of title compound. EXAMPLE-6: Preparation of 3-(Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine

(VI)

325 gm (0.7864 mole) 2-[3-(Naphthalen-l-yloxi)-3-thiophen-2-yl-propyl]- isoindole-l ,3-dione, 243.79 gm (3.1457 mole) monomethyl amine and 975.0 ml (3.0 v/w) water were taken in 4 neck 3L RBF at 25 to 35⁰C. The reaction mixture was stirred for about 24 hours. The product was filtered and washed with 150 ml water. The product was suck dried and purified by toluene, IP A/water and Ethyl acetate/water mixture to yield 170 gm (76.33%) creamish white solid of title compound.

EXAMPLE-7: Preparation of 3-(Naphthlen-l-yloxy)-3-thiophen-2-yl-propyIamine Di-p-toluyl-L-tartaric acid salt (Vila)

50.0 gm (0.1765 mole) 3-(Naphthlen-l-yIoxy)-3-thiophen-2-yl-propylamine and 250 mL (5.0 v/w) methanol were taken in 4 neck 1 L RBF at 25⁰C to 35°C. The reaction mixture was heated to reflux temperature. 39.27 gm (0.0971 mole) Di-p-toluyl- L-tartaric acid monohydrate solution in 250 mL (5.0 v/w) methanol was added to the reaction mixture at 64 to 67°C within 1 hour. The reaction mixture was maintained for 1 hour at same temperature and cooled down to room temperature. The reaction mass was stirred for 30 minutes and filtered. The solid thus isolated was washed with 25 mL of water and dried at 50⁰C to 55°C. The dry compound of formula Vila was purified in methanol water mixture to give compound of formula Vila. EXAMPLE-8: Preparation of (S)-(+)-3-(Naphthlen-l-yloxy)-3-thiophen-2-yl- propylamine (VII)

12.0 gm (0.01745 mole) of 3-(Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine Di-p-toluyl-L-tartaric acid salt, 60 mL (5.0 v/w) methylene dichloride and 60 mL water were taken in 4 neck 500 mL RBF at 25° to 35⁰C. The reaction mixture was cooled to 15° to 20⁰C. 1.74 gm sodium hydroxide (0.04363 mole) solution in 17.4 mL (10%) water was added to the reaction mixture within 30 minutes. The reaction mixture was stirred for 30 minutes and filtered. The solid thus obtained was washed with water and sucked dried to yield 4.5 gm (91.06%) (S)-(+)-3-(Naphthlen-l-yloxy)-3- EXAMPLE-9: Preparation of methanesulfonic acid 3-(l,3-dioxo-l,3-dihydro- isoindol-2-yl)-l-thiophene-2-yl-propyl ester (IVa')

503.0 gm (2.8825 mole) 3-chloro-l-thiophene-2yl-propan-l-one, 533.92 gm (2.8825 mole) potassium phthalimide, 25.15 gm (5% catalytic) sodium iodide and 3521 mL (7.0 v/w) acetonitrile were taken 4 neck 5 L RBF at 25°-35°C. The reaction mixture was heated to reflux and maintained for 3-4 hours. The reaction mixture was cooled gradually to room temperature and dumped into water. The precipitated solid was washed with25O mL water and dried at 50°-55°C under vacuum to yield 760.0 gm (92.63%) of title compound.

Similar procedure can be repeated by replacing acetonitrile with DMSO and DMF in the above experiment. EXAMPLE-9: Preparation of methanesulfonic acid 3-(l,3-dioxo-l,3-dihydro- isoindol-2-yl)-l-thiophene-2-yl-propyl ester (IVa')

2-(3-oxo-3-thiophene-2-yl-propyl)-isoindone-l,3-dione of formula (Ha) is reduced to 2-(3-hydroxy-3-thiophene-2-yl-propyl)-isoindone-l,3-dione with sodium borohydride by known process in the prior art. 25.46 gm (0.2516 mole) triethyl amine and 120 mL (5.0 v/w) methylene dichloride into 500 mL RBF at 25° to 35⁰C. The reaction mixture was cooled to 0° to 1O⁰C. 24.0 gm (0.08387 mole) 2-(3-hydroxy-3- thiophene-2-yl-propyl)-isoindone-l,3-dione solution in 120 mL (5.0 v/w) methylene dichloride was added to reaction mixture within 45 minutes. 1 1.52 gm (0.1006 mole) methane sulphonyl chloride was added within 1 hour and reaction mixture was maintained for 3 hours. The reaction mixture was treated with 240 mL (10.0 v/w) water and stirred for 30 minutes to separate the layer. Aqueous layer was extracted with 72.0 mL (3.0 v/w) methylene dichJoride. The combined organic layer was washed with 240 mL (10.0 v/w) water and distilled out at 5O⁰C under vacuum. The residue was crystallized in ethyl acetate to yield 10.5 gm (35%) methanesulfonic acid 3-(l ,3-dioxo- l,3-dihydro-isoindol-2-yl)-l-thiophene-2-yl-propyl ester (IVa') in crystalline form.

Claims

We claim::

1. 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l,3-dione ("Compound IV") having the formula:

2. The 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l,3-dione ("Compound IV") of claim 1, wherein the compound IV is isolated in a crystalline form. 3. A crystalline 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindoIe-l,3-dione

("Compound IV"), wherein the compound IV is isolated and is characterized by having atleast one of the following properties: (a) ¹H NMR (300 MHz, DMSO-D6) δ (ppm) : 7.81 (m, 4H), 7.36 (d, IH), 6.95 (m, J - 12 Hz, 2H), 5.71 (d, I H), 4.87 (m, IH), 3.70 (m, 2H), 2.01 (m, 2H); and/or

(b) ¹H NMR (300 MHz, DMSO-D6) δ(ppm) in accordance with Figure 4; and/or

(c) ¹³C NMR(75 MHz, DMSO-D6) : δ 167.87, 149.97, 134.24, 131.73, 126.47, 123.00, 122.90, 66.52, 37.57, 34.76; and/or (d) ¹³C NMR (75 MHz, DMSO-D6) in accordance with Figure 5; and/or

(e) A powder x-ray diffraction (PXRD) having characteristic peaks 1 1.2°, 15.8°, 19.5°, 22.5°, 23.

3° and 26.9° 2Θ ± 0.2° 20; and/or

(f) A powder x-ray diffraction (PXRD) pattern substantially in accordance with Figure 6.

4. A process for the preparation of crystalline 2-(3-Hydroxy-3-thiophen-2-yl-propyl)- isoindole-l ,3-dione ("Compound IV"),

which comprises of :

(a) reducing 3-chloro-l -thiophen-2-yl-propane-l-one of formula (II) to obtain 3- chloro-l -thiophen-2-yl-propane-l-ol of formula (III);

(b) reacting 3-chloro-l-thiophen-2-yl-propane-l-ol of formula (III) with potassium phthalimide in a suitable organic solvent at a suitable temperature to give compound of formula FV;

and

(c) isolating of 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l,3-dione ("compound IV") in crystalline form.

5. A process according to claim 4 (a), wherein reduction of compound of formula II is carried by using metal hydride reducing agent selected from the group consisting of sodium borohydride, lithium aluminum hydride, n-butyl lithium, lithium diisopropyl amide and the like, preferably sodium borohydride.

6. A process according to claim 4 (b), wherein suitable organic solvent is selected form the group of alcohols like methanol, ethanol, propanol, isopropanol, butanol and the like; esters like ethyl acetate, methyl acetate, n-butyl acetate and the like; ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone and the like; chlorinated solvents like methylene dichloride. ethylene dichloride, chloroform and the like; amides like dimethyl formamide, dimethyl acetamide and the like; sulfoxide like dimethyl sulfoxide, sulpholanes like dimethyl sulpholanes etc., preferably dimethyl sulfoxide.

7. A process according to claim 4 (b), wherein suitable temperature is from about

50°C to about reflux temperature of the solvent, preferably from about 85⁰C to about 150⁰C, more preferably from about 7O⁰C to about SO⁰C.

8. A process according to claim 4, wherein reaction is performed in presence of catalytic amount of sodium iodide.

9. 2-[3-(Naphthalen-l-yloxi)-3-thiophen-2-yl-propyl]-isoindole-l ,3-dione

("Compound V") having the formula:

10. The 2-[3-(Naphthalen- 1 -yloxi)-3-thiophen-2-yl-propyl]-isoindole- 1 ,3-dione ("Compound V") of claim 9, wherein the compound V is isolated in a crystalline form.

1 1. A crystalline 2-[3-(Naphthalen-l-yloxi)-3-thiophen-2-yl-propyl]-isoindole-l ,3- dione ("Compound V"), wherein the compound V is isolated and is characterized by having atleast one of the following properties:

(a) ¹H NMR (300 MHz, DMSO-D6) δ (ppm) : 8.40 (s, IH), 8.13 (m, 2H), 7.78 (s, 4H), 7.35 (m, 3H), 7.23 (t, I H), 7.05 (d, IH), 6.88 (m, 2H), 5.05 (t, I H), 3.60 (t, 2H), 2.49 (m, 2H); and/or (b) ¹H NMR (300 MHz, DMSO-D6) δ (ppm) in accordance with Figure 7; and/or

(c) ¹³C NMR (75 MHz, DMSO-D6) : δ 167.84, 152.16, 149.36, 134.22, 132.02, 131.68, 129.70, 126.51 , 124.94, 124.25, 124.18, 122.86, 122.62, 107.51 , 38.94, 38.66, 36.35, 35.00; and/or

(d) ¹³C NMR (75 MHz, DMSO-D6) in accordance with Figure 8; and/or (e) A powder x-ray diffraction (PXRD) having characteristic peaks 7.4°, 1 1.2°, 15.4°,

19.8° and 25.6° 2Θ ± 0.2° 20; and/or

(f) A powder x-ray diffraction (PXRD) pattern substantially in accordance with Figure 9.

12. A process for the preparation of crystalline 2-(3-Hydroxy-3-thiophen-2-yl-propyl)- isoindole- 1 ,3-dione ("Compound V)

which comprises of :

(a) reducing 3-chloro- l -thiophen-2-yl-propane- t -one of formula (II) to obtain 3- chloro-l -thiophen-2-yl-propane- l -ol of formula (III);

compound of formula IV;

(c) reacting compound of formula (FV) with alpha naphthaol in presence of acid catalyst in suitable organic solvent to give novel compound 2-[3-(l-naphthyloxy)-3- (2-thienyl)propyl]-l//-isoindole-l,3(2H)-dione of formula (V); and

(d) isolating novel intermediate 2-[3-(l-naphthyloxy)-3-(2-thienyl)propyl]-lH- isoindole-l ,3(2H)-dione of formula (V) in crystalline form.

13. A process according to claim 12 (c), wherein acid catalyst can be selected from organic acid like acetic acid, formic acid, triflouroacetic acid, perchloric acid and the like or inorganic acid like hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like, preferably triflouroacetic acid.

14. A process according to claim 12 (c), wherein suitable organic solvent can be selected form alcohols like methanol, ethanol, propanol, isopropanol, butanol and the like; esters like ethyl acetate, methyl acetate, n-butyl acetate and the like; ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone and the like; chlorinated solvents like methylene dichloride, ethylene dichlorde, chloroform and the like; aromatic hydrocarbons like toluene, xylene, ethyl benzene and the like; aliphatic hydrocarbons like n-hexane, n-heptane, cyclohexane and the like; amides like dimethyl formamide, dimethyl acetamide and the like; preferably aromatic hydrocarbons or aliphatic hydrocarbons like toluene or cyclohexane, respectively.

15. 3-(Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound Vl") having the formula:

16. The 3-(Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VI") of claim 15, wherein the compound VI is isolated in crystalline form. 17. A crystalline 3-(Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VI"), wherein the compound VI is isolated and is characterized by having atleast one of the following properties:

(a) ¹H NMR (300 MHz, DMSO-D6) δ (ppm): 8.16 (m, 2H), 7.41 (m, 2H), 7.22 (d, I H), 7.21 (d, IH), 6.96 (d, IH), 6.87 (m, 2H), 5.06 (t, I H), 4.45 (s, 2H). 2.48 (m, 2H), 2.20 (m, 2H); and/or

(b) ¹H NMR (300 MHz, DMSO-D6) δ (ppm) in accordance with Figure 10; and/or

(c) ¹³C NMR (75 MHz, DMSO-D6) : δ 152.24, 150.29, 132.

17, 130.34, 126.42, 126.00, 125.05, 124.44, 123.96, 123.92, 123.96, 123.92, 123.48, 123.25, 122.64, 107.53, 39.49, 39.22, 38.66, 37.47; and/or (d) ¹³C NMR (75 MHz, DMSO-D6) in accordance with Figure 1 1 ; and/or

(e) A powder x-ray diffraction (PXRD) having characteristic peaks 1 1.7°, 14.4°, 19.1°, 21.6°, 22.5°, 24.7° and 28.5° 2Θ ± 0.2° 2Θ; and/or

(f) A powder x-ray diffraction (PXRD) pattern substantially in accordance with Figure 12.

18. A process for the preparation of crystalline 3-(Naphthlen-l -yloxy)-3-thiophen-2-yl- propylamine ("Compound VI"),

which comprises of :

(a) reducing 3-chloro- l-thiophen-2-yl-propane- l-one of formula (II) to obtain 3- chloro-l -thiophen-2-yl-propane-l-ol of formula (III);

(d) treating compound 2-[3-(l -naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole- l ,3(2H)-dione of formula (V) with C₁-C₅ alkyl amine in suitable organic solvent to provide 3-(l -naphthyloxy)-3-(2-thienyl)propan- l -amine of formula (VI); and

(e) isolating 3-(l -naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI) in crystalline form.

19. A process according to claim 18 (d), wherein C 1 -C5 alkyl amine selected from mnonomethyl amine, ethyl amine, diethyl amine, triethyl amine, isopropyl amine and the like, preferably monomethyl amine.

20. A process according to claim 18 (d), wherein suitable organic solvent selected form the alcohols like methanol, ethanol, propanol, isoproanol, butanol and the like; esters like ethyl acetate, methyl acetate, n-butyl acetate and the like; ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone and the like; water and mixture thereof, preferably in water.

21. A process according to claim 18, wherein compound of formula VI is purified in toluene followed by mixture of isopropanol and water and finally in ethyl acetate water mixture to obtain crystalline 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula in form of a racemic mixture.

22. (S)-(+)-3-(Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VII") having the formula:

23. The (S)-(+)-3-(Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound

VII") of claim 22, wherein the compound VII is isolated in crystalline form.

24. A crystalline (S)-(+)-3-(Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VII") wherein the compound VII is isolated and is characterized by an X-ray powder diffraction with peaks at about 1 1.7°, 14.0°, 18.6°, 21.7°, 24.4° and 29.3° 2Θ ± 0.2° 2Θ.

25. A process for the preparation of crystalline (S)-(+)-3-(Naphthlen-l -yloxy)-3- thiophen-2-yi-propyIamine ("Compound VII"),

which comprises of :

(a) reducing 3-chloro- l -thiophen-2-yl-propane- l -one of formula (II) to obtain 3- chloro- l -thiophen-2-yl-propane- l -ol of formula (III);

compound of formula IV;

(c) reacting compound of formula (IV) with alpha naphthaol in presence of acid catalyst in suitable organic solvent to give novel compound 2-[3-(l-naphthyloxy)-3- (2-thienyl)propyI]-l//-isoindole-l,3(2H)-dione of formula (V);

(d) treating compound 2-[3-(l-naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole- l,3(2//)-dione of formula (V) with C₁-C₅ alkyl amine to provide 3-(l-naphthyloxy)- 3-(2-thienyl)propan-l -amine of formula (VI);

(e) resolving 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI) with an optically active acid to obtain (S)-(+)-3-(l -naphthyloxy)-3-(2-thienyl)propan-l -

amine of formula (VII); and

(f) isolating (S)-(+)-3-( l -naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII) in crystalline form.

26. A process for the preparation of crystalline (S)-(+)-3-(l-naphthyloxy)-3-(2- thienyl)propan- 1 -amine of formula (VII), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I):

comprises of: (a) treating racemic 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI) with an optically active acid in suitable organic solvent;

(d) isolating crystalline (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII).

27. A process according to claim 25 or 26, wherein said optically active acid can be selected from the group consisting of D_τlactic acid, D-tartaric acid, D-malic acid, I S-10-camphor sulfonic acid, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyI phenyl acetic acid, D-mandelic acid, Di-p- ani soy 1 -D-tartaric acid, D-tartaric acid monoparachloro anilide, Dibenzoyl-D- tartaric acid monodimethyl amide, (S)-(+)-l ,l '-binaphthalene-2,2'-dihydrogen phosphate, Di-p-toIuyl-D-tartaric acid, Di-p-toluyl-L-tartaric acid, preferably Di-p- toluyl-L-tartaric acid.

28. A process according to claim 25 or 26, wherein said suitable organic solvent is selected from the group consisting of an aliphatic C 1-C4 alcohol, an aliphatic C2- C6 ketone, an aliphatic C 1-C4 chlorinated hydrocarbon, nitriles, and/or an aliphatic C2-C6 and mixtures thereof, preferably aliphatic C 1 -C4 alcohol like methanol.

29. A process according to claim 26(c), wherein base can be selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such sodium carbonate, potassium carbonate, and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixture thereof, preferably sodium hydroxide.

30. A process according to claim 29, wherein bases can be used in the form of solids or in the form of aqueous solutions.

31. A process for the preparation of crystalline (S)-(+)-3-(l-naphthyloxy)-3-(2- thienyl)propan-l -amine of formula (VII), an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I): comprises of:

(a) treating racemic 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VI)

with an optically active Di-p-toluyl-L-tartaric acid in suitable organic solvent to form a salt; (b) isolating the salt of (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII) and optically active Di-p-toluyl-L-tartaric acid as formula Vila;

(Vila)

(2-thienyl)propan-l -amine of formula (VIl);

(d) isolating crystalline (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII); and (e) converting compound of formula (VII) to duloxetine and its pharmaceutically acceptable salts thereof.

32. A process according to claim 31, wherein suitable organic solvent to form a salt is selected from the group consisting of an aliphatic C1-C4 alcohol, an aliphatic C2- C6 ketone, an aliphatic C1-C4 chlorinated hydrocarbon, nitriles, and/or an aliphatic C2-C6 and mixtures thereof, preferably aliphatic C1-C4 alcohol like methanol.

33. A process according to claim 31 , wherein base can be selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such sodium carbonate, potassium carbonate, and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixture thereof, preferably sodium hydroxide.

34. A process according to claim 33, wherein bases can be used in the form of solids or in the form of aqueous solutions.

35. Di-p-toluyl-L-tartaric acid salt of (S)-(+)-3-( l-naphthyloxy)-3-(2-thienyl)propan-l- amine of formula (Vila):

(Vila)

36. Crystalline Di-p-toluyl-L-tartaric acid salt of (S)-(+)-3-(l-naphthyloxy)-3-(2- thienyl)propan-l -amine of formula (Vila) characterized by an X-ray powder diffraction pattern with peaks at about 6.1°, 9.5°, 1 1.8°, 17.2°, 18.4°, 20.8°, 23.0° and 23.7° 20 ± 0.2° 20.

37. A process for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I) substantially free from (R)-(-)-duloxetine hydrochloride and characterized by an X-ray powder diffraction with peaks at about 9.5°, 13.8°, 18.0°, 18.8°, 20.8° and 23.2° 20 ± 0.2° 20 comprising:

(a) reducing 3-chloro-l-thiophen-2-yl-propane-l-one of formula (II) to obtain 3-chloro- 1 -thiophen-2-yl-propane- 1 -ol of formula (III);

(b) reacting 3-chIoro-l -thiophen-2-yl-propane- l -ol of formula (III) with potassium phthalamide in a suitable organic solvent at a suitable temperature to give compound of formula IV;

(c) reacting compound of formula (IV) with alpha naphthaol in presence of acid catalyst in suitable organic solvent to give novel compound 2-[3-(l-naphthyloxy)-3- (2-thienyl)propyl]-l //-isoindole-l,3(2//)-dione of formula (V);

(d) treating compound 2-[3-(l-naphthyloxy)-3-(2-thienyl)propyl]-l//-isoindole- l,3(2H)-dione of formula (V) with C₁-C₃ alkyl amine to provide 3-(l-naphthyloxy)- 3-(2-thienyl)propan-l -amine of formula (VI);

(0 treating (S)-(+)-3-(l -naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII) with methylating agent to obtain duloxetine base of formula (VIII), which is

subsequently

(g) converted to Duloxetine hydrochloride of formula (I).

38. 2-(3-oxo-3-thiophen-2-yl-propyl)-isoindole-l,3-dione ("Compound Ha") having the formula:

39. The 2-(3-oxo-3-thiophen-2-yl-propyl)-isoindole-l,3-dione ("Compound Ha") of claim 29, wherein the compound Ha is isolated in crystalline form.

40. A crystalline 2-(3-oxo-3-thiophen-2-yl-propyl)-isoindole-l,3-dione ("Compound Ha"), wherein the compound Ha is isolated and is characterized by having atleast one of the following properties:

(a) ¹H NMR (300 MHz, CDCl₃) δ (ppm) : 7.85 (m, J=9.0 Hz, 2H), 7.72 (m, J = 8.4 Hz, 3H), 7.63 (t, J = 6.0 Hz₅IH), 7.1 1 (t,l H), 4.13 (t, 2H), 3.35 (t, 2H); and/or

(b) ¹H NMR (300 MHz, CDCl₃) δ (ppm) in accordance with Figure 15; and/or

(c) ¹³C NMR (75 MHz, CDCl₃) : δ 190.02, 168.06, 133.99, 132.07, 127.14, 123.29, 37.44, 33.54; and/or

(d) ¹³C NMR (75 MHz, CDCl₃) in accordance with Figure 16; and/or (e) A powder x-ray diffraction (PXRD) having characteristic peaks 10.0°, 13.3°, 15.3°,

17.5°, 19.7°, 23.2°, 26.9° and 28.3° 2Θ ± 0.2° 2Θ; and/or

(f) A powder x-ray diffraction (PXRD) pattern substantially in accordance with Figure 17.

41. A process for the preparation of 2-(3-oxo-3-thiophen-2-yl-propyl)-isoindole-l ,3- dione ("Compound Ha"), an intermediate for the preparation of crystalline (S)-(+)- duloxetine hydrochloride of formula (I),

comprises of :

(a) reacting thiophene with chloropropanone chloride under friedle-crafts condition in presence of anhydrous AlCI₃ to give chloroketone of formula II;

(c) cooling the reaction mixture; and

(d) isolating thiophene derivative of formula Ha.

42. A process according to claim 41 (b), wherein suitable organic solvent is selected form the group of alcohols like methanol, ethanol, propanol, isopropanol, butanol etc., esters like ethyl acetate, methyl acetate, n-butyl acetate etc., ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone, etc., chlorinated solvents like methylene dichloride, ethylene dichloride, chloroform etc., nitriles like acetonitrile, amides like dimethyl formamide, dimethyl acetamide etc., sulfoxide like dimethyl sulfoxide, sulpholanes like dimethyl sulpholanes etc., preferably acetonitrile, dimethyl sulfoxide or dimethyl formamide.

43. A process according to claim 41 (b), wherein suitable temperature is from about 50°C to about reflux temperature of the solvent, preferably from about 85⁰C to about 15O⁰C, more preferably from about 100⁰C to about 105⁰C.

44. A process according to claim 41 (c), wherein the reaction mixture is cooled at an ambient temperature below 4O⁰C, more particularly from about 25⁰C to about 35⁰C.

45. Substituted sulfuric acid 3-(l ,3-dioxo-l,3-dihydro-isoindoI-2-yl)-l-thiophen-2-yl)- propyl ester ("Compound IVa") having the formula

wherein R = Mesyl or Tosyl.

46. Methanesulfonic acid 3-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-l-thiophen-2-yl)- propyl ester (Compound IVa') having the formula

47. The methanesulfonic acid 3-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-l-thiophen-2- yl)-propyl ester (Compound IVa') of claim 37, wherein the compound FVa' is isolated in crystalline form.

48. A crystalline methanesulfonic acid 3-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-l- thiophen-2-yl)-propyl ester (Compound IVa'), wherein the compound FVa' is isolated and is characterized by having atleast one of the following properties: (a) ¹H NMR (300 MHz, DMSO d6) δ (ppm) in accordance with Figure 18; and/or

(b) ¹³C NMR (IOO MHz, DMSO) in accordance with Figure 19; and/or

(c) A powder x-ray diffraction (PXRD) having characteristic peaks 7.6°, 15.2°, 17.6°, 20.2°, 26.1°, 27.4° and 32.1° 2Θ ± 0.2° 20; and/or

(d) A powder x-ray diffraction (PXRD) pattern substantially in accordance with Figure 20.

49. A process for the preparation of 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-isoindole- 1 ,3-dione ("Compound V"), an intermediate for the preparation of crystalline (S)- (+)-duloxetine hydrochloride of formula (I)

comprises of :

(a) reacting thiophene with chloropropanone chloride under fried le-crafts condition in presence of anhydrous AlCl₃ to give chloroketone of formula II;

(b) treating chloroketone of formula II with potassium phthalimide in a suitable organic solvent at a suitable temperature to give compound of formula Ua;

5 (c) reducing 2-[3-oxo-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (Ha) with a reducing agent in a suitable organic solvent or optionally in presence of water to obtain 2-[3-hydroxy-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (IV);

IO

(d) reacting the compound of formula IV with RSO₂X to obtain novel compound of formula (IVa') wherein in R represent C₁-C₄ alkyl, or aryl and X represent halogen selected from Cl, Br, I;

!5 (e) converting the compound of formula (IVa') to 2-[3-(Naphthalene-l -yloxy)-3- thiophen-2-yl-propyl]-isoindole-l , 3-dione ("Compound V"); and (f) using compound of formula V to prepare (S)-(+)-duloxetine hydrochloride of formula (I).

50. A process according to claim 49, wherein reduction of compound of formula (Ha)0 is carried by using metal hydride reducing agent selected from the group consisting of sodium borohydride, lithium aluminum hydride, n-butyl lithium, lithium diisopropyl amide and the like, preferably sodium borohydride.

51. A process according to claim 49, wherein the reaction is carried out in suitable organic solvent or optionally its presence of water, preferably in methylene dichloride.

52. A process according to claim 49 (d), wherein R represent C₁-C₄ alkyl, or aryl and X represent halogen selected from Cl, Br, I.

53. A process according to claim 52, wherein RSO₂X represents methane sulfonyl chloride, ethane sulfonyl chloride, p-toluene sulfonyl chloride.

54. A process according to claim 49 (d), wherein the reaction is carried out in presence of base selected from inorganic or organic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium biarbonate, sodium or potassium alkoxide, amines such as ammonia, monomethyl amine, diethyl amine, triethyl amine, isopropyl amine and the like.

55. (S)-(+)-duloxetine hydrochloride crystalline Form A according to the process as claimed in claims 4, 12, 18, 25, 26, 31, 37, 41 and 49, wherein (S)-(+)-duloxetine hydrochloride is having purity atleast greater than 99.0% by area percentage of

HPLC

56. (S)-(+)-duloxetine hydrochloride crystalline Form A according to claim 55, wherein (S)-(+)-duloxetine hydrochloride is having purity atleast greater than 99.5% by area percentage of HPLC.

57. (S)-(+)-duloxetine hydrochloride crystalline Form A according to claim 56, wherein (S)-(+)-duloxetine hydrochloride is having purity atleast greater than 99.9% by area percentage of HPLC.

58. (S)-(+)-duloxetine hydrochloride crystalline Form A according to the process as claimed in claims 4, 12, 18, 25, 26, 31 , 37, 41 and 49, wherein (S)-(+)-duloxetine hydrochloride is having (R)-(-)-duloxetine hydrochloride less than 0.5% by area percentage of HPLC.

59. (S)-(+)-duloxetine hydrochloride crystalline Form A according to claim 58, wherein (S)-(+)-duloxetine hydrochloride is having (R)-(-)-duloxetine hydrochloride less than 0.25% by area percentage of HPLC.

60. (S)-(+)-duloxetine hydrochloride crystalline Form A according to claim 59, wherein (S)-(+)-duloxetine hydrochloride is having (R)-(-)-duloxetine hydrochloride less than 0.10% by area percentage of HPLC.

61. (S)-(+)-duloxetine hydrochloride crystalline Form A according to claim 60, wherein (S)-(+)-duloxetine hydrochloride is having (R)-(-)-duloxetine hydrochloride not in detectable amount by area percentage of HPLC.

62. (S)-(+)-duloxetine hydrochloride crystalline Form A substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompaying drawings and/or examples.