FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"NOVEL PROCESS FOR PREPARATION OF DULOXETINE HYDROCHLORIDE AND ITS INTERMEDIATES THEREOF"

We, CADILA HEALTHCARE LIMITED, of Zydus Research Centre, "Zydus Tower", Satellite Cross Roads, Sarkhej- Gandhinagar Highway, Ahmedabad - 380015, Gujarat, India.

The following specification describes the invention:
1

FIELD OF THE INVENTION:
The present invention relates to improved process for preparing duloxetine
hydrochloride of formula (I). More particularly, present invention relates to enantionmerically 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 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 HC1 is a dual reuptake inhibitor of the neurotransmitters 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)"

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
2

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
behaviour 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. Devel., 1, 328, (1997) and Deeter, et al., in Tetrahedron Letters, 31 (40), 7101-04 (1990) and aspects patented in U.S. Patents No.s 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

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 55°C.
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
3

4
chloroalcohol intermediate, which is further arylated to give duloxetine. These processes, as reported in the above articles, are outlined in scheme 2 and 3 below.



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 present invention relates to provide 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 HC1 and process for preparing chemically and/or enantiomerically pure duloxetine HC1. 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-IS03) 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 characeterized by XRD, IR and raman spectras. The patent application also emcompasses that when duloxetine hydrochloride is prepared according to preparation 2 of U.S. Patent No. 5,362,886, an anhydrous cyrstalline form of duloxetine is obtained. As used herein, the term "Form A"
5

refers to the anhydrous crystalline form of duloxetine HC1 obtained using preparation 2 of U.S. Patent No. 5,362,886. Duloxetine HC1 is available commerically as CYMBALTA®, which contains Form A as the active ingredient.
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.
Object of Invention
The main object of the present invention is to provide a process for the preparation of Dloxetine and its pharmaceutically acceptable salts.
Yet another object of the present invention is to provide novel intermediates for the preparation of Dloxetine 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 enatiomerically pure (S)-(+)-Duloxetine hydrochloride and their process for preparation. BRIEF DESCRIPTION OF FIGURES:-
A preferred embodiment of the invention will now be described, by way of example only, with reference to the accompaying figures in which:
FIG.l: X-ray diffraction of crystalline (S)-(+)-Duloxetine hydrochloride
FIG.2: IR Spectra of crystalline (S)-(+)-Duloxetine hydrochloride
DETAILED DESCRIPTION:
The present invention relates to the process for the preparation of Duloxetine
hydrochloride of formula (I), which comprises
(a) reducing 2-[3-oxo-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (III) to
obtain 243-hydroxy-3-(2-thienyl)propyl]-lH-isoindole-l,3(H)-dione of formula (IIIa)

(b) reacting 2-[3-hydroxy-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (IIIa) with RS02X to obtain novel compound of formula (IV)
6


wherein in R represent C1-C4 alkyl, or aryl and X represent halogene selected from C1, Br, I. (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(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 C1-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) to obtain (S)-resolving 3-(l-naphthyloxy)-3-(2-thienyl)propan-l-amine of formula (VII)
(f) treating (S)- resolving 3-(l-naphthyloxy)-3-(2-thienyl)propan-l-amine of formula (VII) with methylating agent to obtain Duloxetine, which is subsequently converted to Duloxetine hydrochloride.
7

According to the present invention, there is provided a process for the preparation of novel compound of formula (IV)

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

b) reacting the compound of formula IIIa with with RS02X to obtain novel compound of
formula (IV)

wherein in R represent C1-C4 alkyl, or aryl and X represent halogene selected from C1, Br, I. c) isolating the compound of formula IV
According to the preferred embodiment of the present invention, reduction of compound of formula (III) 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 2-[3-hydroxy-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (IIIa) is further treated with RS02X, wherein in R represent C1-C4 alkyl, or aryl and X represent halogene selected from C1, Br, I in presence o
8

base in suitable solvent Preferably RS02X represents methane sulfonyl chloride, ethane sulfonyl chloride, p-toluene sulfonyl chloride.
The reaction is carried out in presence of base, wherein base is 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.
The present invention further provides novel compound of 2-[3-(l-naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindoIe-l,3(2H)-dione of formula (V)

According to preferred embodiment for the preparation of-[3-(l-naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (V), which comprises:
a) reduction of 2-[3-oxo-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (III) 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 (IIIa)

b) reacting the compound of formula Ilia with with RS02X to obtain novel compound of
formula (lV)

wherein in R represent C1-C4 alkyl, or aryl and X represent halogene selected from C1, Br, I.
9

c) reacting compound of formula (IV) with alpha naphthaol to give novel compound 2-[3-(l-naphthyloxy)-3-(2-thienyl)propyl]- 1H-isoindole-1,3(2H)-dione of formula (V)
According to the preferred embodiment of the present invention, reduction of compound of formula (III) 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 2-[3-hydroxy-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (IIIa) is further treated with RS02X, wherein in R represent C1-C4 alkyl, or aryl and X represent halogene selected from C1, Br, I in presence o base in suitable solvent. Preferably RS02X represents methane sulfonyl chloride, ethane sulfonyl chloride, p-toluene sulfonyl chloride.
The reaction is carried out in presence of base, wherein base is 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.
Thus obtained compound of formua (V) is further treated with alpha-napthol in suitable solvent in presence of base to give -[3-(l-naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (V).
The suitable organic solvent can be 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., chlorinated solvents like methylene dichloride, ethylene dichlorde, chloroform etc., amides like dimethyl formamide, dimethyl acetamide etc., sulphoxide like dimethyl sulphoxides., sulpholanes like dimethyl sulpholanes etc., preferably dimethyl foramide.
The reaction is carried out in presence of base, wherein base is 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.
The present invention further provides a process for the preparation of Duloxetine hydrochloride of formula (I), which comprises
10

(a) treating compound 2-[3-(l-naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole-l,3(2H)-dione of formula (V) with C1-C5 alkyl amine to provide 3-(l-naphthyloxy)-3-(2-thienyl)propan-l-amine of formula (VI)
(b) resolving 3-(l-naphthyloxy)-3-(2-thienyl)propan-l-amine of formula (VI) with a chiral resoluting agent in a an organic solvent to obtain (S)-3-(l-naphthyloxy)-3-(2-thienyl)propan-1-amine of formula (VII)
(c) treating (S)- resolving 3-(l-naphthyloxy)-3-(2-thienyl)propan-l-amine of formula (VII) with methylating agent to obtain Duloxetine, which is subsequently converted to Duloxetine hydrochloride.
2-[3-(l-naphthyloxy)-3-(2-thienyl)propyl]-lH-isoindole-l,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., chlorinated solvents like methylene dichloride, ethylene dichlorde, chloroform etc., amides like dimethyl formamide, dimethyl acetamide etc., sulphoxide like dimethyl sulphoxides., sulpholanes like dimethyl sulpholanes etc., preferably dimethyl foramide.
The resolution can be performed by using suitable resolving agent selected from the p-Ditolyl tartric aicd or Dibenzoyl tartaric acid, more preferably p-DTTA.
The methylation is performed by using methyl iodide to give S-(+)-Duloxetine base which is then converted to pharmaceutically acceptable salt is S-(+)-Duloxetine hydrochloride.
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%.
It is also an important aspect of the present invention to provide S-(+)-Duloxetine Hydrochloride wherein S-(+)-Duloxetine hydrochloride is anhydrous cyrstalline Form A.
S-(+)-Duloxetine Hydrochloride is characeterized by XRD as shown in Fig-1 and IR as shown in Fig-2.
The present invention further provides an improved process for preparation of compound
of formula III

11

comprises of:
a) reacting thiophene with chloropropanone chloride under friedle-crafts condition in presence of anhydrous AICI3 to give chloroketone of formula II;

b) treating chloroketone of formula II with potassium phthalamide in a suitable organic solvent at a suitable temperature to give compound of formula III;
c) isolating thiophene derivative of formula III
The reaction step (b) is carried out in suitable organic solvent selected form the group of 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., chlorinated solvents like methylene dichloride, ethylene dichlorde, chloroform etc., amides like dimethyl formamide, dimethyl acetamide etc., sulphoxide like dimethyl sulphoxides., sulpholanes like dimethyl sulpholanes etc., preferably dimethyl foramide
The process of the present invention can be performed with suitable temperature from about 50°C to about reflux temperature of the solvent, preferably from about 85°C to about 150°C, more preferably from about 100°C to about 105°C.
The reaction mixture is cooled at an ambient temperature below 40°C, more particularly from about 25°C to about 35°C.
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.
12


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 C18 momomeric, 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 mL 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 run. The sample volume
13

was 5 mL 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

Example-1:
Preparation of compound of formula III
Chloroketone (0.01 mole) and potassium phthalamide (0.012 mole) were taken in 500 mL three necked round bottom flask. DMF (250 mL) was added to the RBF. The reaction mixture was heated upto 100°C to 105°C and mainatined for 4 to 6 hours. The reaction mixture was cooled and dumped into the 2.5 L chilled water at 0°C to 20°C. The isolated product was filtered and washed with chilled water.
Example-2:
Preparation of compound of formula IV
The compound of formula III (0.01 mole) and MDC (250 mL) were taken in 500 mL three necked round bottom flask. Sodium borohydride (0.005 mole) and dilute sodium
hydroxide solution were added at 10°C to 15°C. The reaction mixture was stirred for 1 hour. The reaction mixture was washed with dilute acetic acid. MDC was distilled under vacuum
and product was isolated. The compound was treated with CH3SO2CI (0.05 mole) in
methylene dichloride (250 mL) in presence of Triethyl amine. The reaction mixture was
stirred for 2 hours at an ambient temperature. The reaction mixture was washed with water.
MDC was distilled to get compond formula IV.
Example-3:
Preparation of compound of formula V
The compound of formula IV (0.05 mole) and a-naphthol (0.025 mole) were taken in 500 mL three necked round bottom flask. The reaction mixture was taken in DMSO as a solvent. The reaction mixture was heated to reflux in presence of potassium hydroxide
14

(0.0015 mole). The reaction mixture was extractrd with MDC. The organic layer was separated and washed with water. The separted organic layer was subjected to distiallation under vacuum to obtain compound of formula V.
ExampIe-4:
Preparation of compound of formula VI
The compound of formula V (0.01 mole) was taken in 250 mL three necked round bottom flask. Water (150 mL) was added to the RBF. The reaction mixture was stirred at 40°C. 40% solution of monomethyl amine was added to the reaction mixture and was further stirred for 2 hours. The obtained solid was filtered and washed with water to obtain the compound of formula VI,
Example-5:
Preparation of compound of formula VII
6.5 g of di-p-toluoyl-L-tartaric acid was added to the solution of 5 g of compound of formula VII dissolved in 50 ml of ethyl acetate, and the resulting mixture was stirred for about 1 hour. The resulting solid was filtered and washed with 10 ml of the appropriate solvent, and dried in a vacuum oven at 50°C for 16 hours. The product obtained is di-p-toluoyl-L-tartarte salt of compound of formula VII.
A 2 litre reactor equipped with a mechanical stirred is charged with a mixture of 107 g of Di-p-toluoyl-L-tartarte salt of compound of formula VII, 600 mL of water, 96 mL of a 22 % solution of Sodium hydroxide and 1 litre of toluene. The mixture is stirred at 25°C for 20-30 minutes, and the organic phase is seperated and washed with water (3x300 mL). The toluene solution is distilled to obtain the compound of formula VII.
Example-7:
Preparation of S-(+)-Duloxetine Free Base

A 1 litre reactor equipped with a mechanical stirred is charge with 0.01 mole of compound of formula VII (0.01 mole), methylene dichloride 250 mL and methyl iodide 0.01 mole in presence of triethyl amine. The reaction mixture was stirred for 3-4 hours. The product fraction was evaporated under vacuum to obtain desired product as an amber oil. The product thus obtained can be transferred to is pharmaceutically acceptable salts, preferably
hydrochloride.

Dated this the 21st day of December 2006
15