WO2009109992A1

WO2009109992A1 - Novel process for preparation of duloxetine and intermediates for use therein

Info

Publication number: WO2009109992A1
Application number: PCT/IN2009/000058
Authority: WO
Inventors: Nishikant Digambar Ghadge; Bapu Atmaram Chaudhari; Ganesh Gurpur Pai
Original assignee: Arch Pharmalabs Limited
Priority date: 2008-01-23
Filing date: 2009-01-22
Publication date: 2009-09-11

Abstract

A novel process for the preparation of substantially (S)-(+)-N-methyl-3-(l-naphthalenyloxy)- 3-(2-thiophenyl) propanamine hydrochloride comprising formation of lewis acid salt of (S)- (+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and (S)-(+)-N,N- dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine to remove the R isomer of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and (S)-(+)-N,N- dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine avoiding removing R isomer impurity without resolution through formation of chiral salt.

Description

NOVEL PROCESS FOR PREPARATION OF DULOXETINE AND INTERMEDIATES FOR USE THEREIN

FIELD OF INVENTION:

Disclosed herein is a novel process for the preparation of substantially pure (S)-(+)-N- methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine hydrochloride of Formula-I hereinafter referred as Duloxetine hydrochloride comprising the preparation of substantially pure S isomer of lewis acid salts of Duloxetine of the formula- II which owing to difference in selectivity of R and S isomers towards Lewis acid thereby resulting into enrichment of S isomer. Lewis salt of Duloxetine in organic solvent selectively gets enriched in S isomer by minimizing the unwanted R isomer obtained as impurity due to epimerization during the arylation of (S)-(+)-N,N-dimethyl-3-Hydroxy-3-(2-thiophenyl) propanamine of Formula-Ill with 1-Fluoro naphthalene. The lewis acid salt of the Duloxetine can be converted into substantially pure Duloxetine hydrochloride by converting the lewis acid salt to free base which is converted into the corresponding hydrochloride salt or optionally converting the lewis acid salt of Duloxetine into corresponding hydrochloride salt in situ without the isolation of the free base.

Further disclosed herein is a novel process for the preparation of substantially pure (S)-(+)- N,N-dimethyl-3-( 1 -naphthalenyloxy)-3-(2-thiophenyl)-propanamine of Formula-IV comprising the preparation of substantially pure S isomer of lewis acid salts of formula- IV(a) which owing to difference in selectivity of R and S isomers towards Lewis acid. This results into the enrichment of S isomer. Therefore lewis salt of (S)-(+)-N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl)-propanamine in organic solvent gets enriched in S isomer by minimizing the unwanted R isomer obtained as an impurity due to epimerization during the arylation of (S)-(+)-N,N-dimethyl-3-Hydroxy-3-(2-thiophenyl) propanamine of Formula III with 1-Fluoro naphthalene.

Furthermore, disclosed herein is a novel process for the preparation of substantially pure (S)- (+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine hydrochloride of Formula-I comprising demethylation of enriched lewis acid salt of (S)-(+)-N,N-dimethyl-3- (l-naphthalenyloxy)-3-(2-thiophenyl) propanamine of formula IV(a).The said lewis acid salt of (S)-(+)-N,-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine can be converted into Duloxetine hydrochloride by its conversion into free base which is then further converted into the corresponding hydrochloride salt or optionally converting the lewis acid salt of Duloxetine into corresponding hydrochloride salt in situ without the isolation of the free base. Another aspect of the invention is a novel process for the preparation of substantially pure (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyI) propanamine hydrochloride of Formula-I comprising converting the said lewis acid salt of (S)-(+)-N,-methyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine into Duloxetine hydrochloride by its conversion into free base which is then further converted into the corresponding hydrochloride salt or optionally converting the lewis acid salt of Duloxetine into corresponding hydrochloride salt in situ without the isolation of the free base.

BACKGROUND OF INVENTION:

(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine of the Formula Ia is known as Duloxetine under the International Nonproprietary Name.

Duloxetine is a selective inhibitor of serotonin and nor epinephrine uptake in the human body. It is used as antidepressant in the clinical practice. Duloxetine is an efficient active pharmaceutical ingredient, which inhibits the metabolism of serotonin, the decreased level of which is responsible for depression and anxiety. Duloxetine hydrochloride salt of Formula I is most suitable for use in clinical practice as antidepressant.

The synthesis of Duloxetine was discussed by Deerer, et. al, in Tetrahedron Letters, 31(49), 7101-04 (1990).

US5023269 and US4956388 disclose chemical synthesis of Duloxetine. These describe the use of optically active precursor key intermediate or resolution of racemates of Duloxetine. US5491243 discloses a stereospecific process for the synthesis of dimethyl precursor of Duloxetine (Formula- IV) and isolating it as a phosphoric acid salt (98.1% potency, adjusted yield of 79.6% with EE % 91. The obtained phosphoric acid salt is then converted into corresponding base followed by demethylation to get Duloxetine and isolating it as hydrochloride with potency of 99.8%. However, there is no mention of chiral purity.

WO2004/056795 discloses resolution of racemic Duloxetine using various chiral acids like mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid and camphor sulphonic acid with preference to di-p-toluyl tartaric acid and conversion of these salts either into free base or other addition salts like hydrochloride as appropriate. It also describes racemisation and recycling of the non-desired enantiomer thereby increasing the economy of the process.

WO 2007/105021 discloses fumarate, citrate or mandelate salts of (S)-(+)-N-methyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine .

US 2007/0191616 discloses process for obtaining optically pure (S)-(+)-N-methyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine and acid addition salts which also provides for racemic resolution of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine to obtain S-enantiomer with di-para-toluyl-L-tartaric acid.

US5362886 discloses a process for the preparation of (S)-(+)-N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine by arylation of (S)-(+)-N,N-dimethyl-3-(l- hydroxy )-3-(2-thiophenyl) propanamine with 1- fluoronaphthalene using sodium hydride in presence of certain potassium salts in an organic solvent and recovering the product as the phosphoric acid salt.

Thus the prior art discloses that enantiomerically pure Duloxetine is obtained by the methods summarized below: a) Chiral resolution of 3-(N,N-Dimethylamino)-l-(2-thienyl)-l-propanol, followed by converting it into Duloxetine. b) Asymmetric reduction of 3-(N,N-Dimethylamino)-l-(2-thienyl)-l-propanone to get the corresponding alcohol, followed by converting it into Duloxetine. c) Chiral resolution of 3-N-methylamino-l-(2-thienyl)-l-propanol, followed by converting it into Duloxetine. d) Chiral resolution of racemic Duloxetine. e) Chiral resolution of racemic (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2- thiophenyl) propanamine followed by its conversion into duloxetine.

The processes for preparation S)-(+)-N-methyI-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine disclosed in the prior art results in the formation of R isomer of N-methyl-3-(l- naphthalenyloxy)-3-(2-thiophenyI) propanamine formed during the arylation of S-(+)-3- N,N-dimethylamino-l-(2-thienyl)-l-propanol with 1-fluoro naphthalene in presence of strong base like sodium hydride and then carry forwarded. The substantially pure S)-(+)-N-methyl- 3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine can only be obtained if R impurity is removed from the mixture. The Prior art also discloses the phenomenon of racemisation during the arylation of 3 -hydroxy propanamine with 1-fluoro naphthalene in presence of strong base like sodium hydride that attribute towards R isomer as an impurity. This recurrence of R-isomer motivated the inventors to give a method that minimizes this impurity resulting into enhancement of chiral purity.

Several criteria set forth by the health authorities with regard to the active pharmaceutical ingredient used in the medicinal product is related with chemical purity. Therefore salt preparation is preferable as a way of purification Transformation of the crude base of the active ingredient into salt is advantageous in following aspects. In general, salts have higher melting temperatures than the corresponding bases; therefore salts can be isolated and purified more efficiently and conveniently. The convenience of the purification process is justified by the strict requirements towards purity of the active pharmaceutical ingredient. The second advantage of the present invention in using Lewis acid more preferably Zinc chloride salts resides in fact that two optical enantiomeric Zinc chloride salts of N-methyl-3- (l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine differ in their selectivity towards Lewis acid in the given solvent. This feature enables to minimize the undesired R isomer in both cases mentioned herein thereby resulting into enrichment of S isomer.

During the process of stability testing, identification and concentration of individual impurities present in the Active pharmaceutical ingredient are determined as the function of time and storage conditions. In the aforementioned tests, generally high performance liquid chromatography and mass spectrometry are used as analytical methods. During our investigations regarding Duloxetine and its precursor intermediate, we have found that (S)- (+)-N,N-dimethyl-3-(l -naphthalenyloxy)-3-(2-thiophenyl)propanamine isolated as phosphoric acid salts changes its physical state on keeping for about nine months. On the other hand Zinc chloride salt of the said precursor maintains its physical state kept for same span of time. Thus third advantage of the present invention is the stability of Zinc chloride salts of Duloxetine and its intermediates.

Thus, the disadvantage associated with methods used in state of art to get the stereo specific enantiomer is the high cost of the chiral acids used for isolating the chiral salts of Duloxetine or precursors thereby requiring enhanced raw material consumption, conversion of chiral salts into Duloxetine base, its isolation and further conversion into addition salts increases unit operation beside the problems like racemisation and yield loss. In case where phosphoric acid salts is used, the associated problem is its stability. It has been observed by the present invertors that (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophen) propanamine phosphoric acid salt gets detonated to 94% from 98% HPLC purity in about nine months duration with change in color against 97% from 98% in case of (S)-(+)-N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thiophen) propanamine Zinc chloride salt with no difference in color. Moreover the commercial available phosphoric acid contains 15% water. This requires an additional operation of drying. Therefore Lewis acid preferably Zinc chloride benefits on industrial scale owing to its easy availability in anhydrous form along with stability that is imparted to its salts with Duloxetine and its precursor intermediate.

Thus there is a need of a process which will be more cost effective and industrially more beneficial.

Process disclosed in the prior art comprises the reaction between molecules of structure III and V via IV to give the Duloxetine free base as shown below. During the process of making Duloxetine using substantially pure S isomer of Structure III, epimerization takes place which results in the formation of R isomer which is carried forward till the formation of free base.

In the present invention provides a novel method of preparing Duloxetine comprising formation of lewis acid salt of molecules of structures IV or Ia. The lewis acid salt of R isomer formed as an impurity during the condensation process to form IV or in Ia is selectively removed in organic solvent during their lewis acid salt formation thereby causing the enrichment of S isomer either at stage IV or Ia resulting in the formation of substantially pure S isomer of Duloxetine free from the R impurity formed during the formation of molecule of structure IV or Ia. Preparation of Zinc chloride salts with (S)-(+)-N-methyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine and also in its precursor intermediate (S)- (+)-N,N-dimethyl-3-( 1 -naphthalenyloxy)-3-(2-thiophenyl)propanamine increases the enantiomeric purity. The present inventors while working have found that the use of salts of (S)-(+)-N-methyl-3- (l-naphthalenyloxy)-3-(2-thiophen) propanamine and (S)-(+)-N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thiophen) propanamine more particularly Lewis acid salts renders the invention cost effective and industrially more acceptable resulting into the formation of substantially pure (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophen) propanamine and (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophen) propanamine in good yield avoiding additional step to remove the R -isomer of respective compounds formed during the arylation of (S)-(+)-N,N-dimethyl-3-(l-hydroxy)-3-(2-thiophenyl)propanamine with 1- fluoronaphthalene.

The present invention has following advantages over the existing prior art, namely:

1. Easy availability and low cost material making the process commercially effective.

2. The resultant product thus obtained is of high chiral and chemical purity with good yield.

3. There is in-situ conversion of Lewis acid salts e.g. zinc chloride salt of (S)-(+)-N- methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine into Duloxetine hydrochloride is achieved by using another simple chemical IPA. HCl. Thus, the total number of steps is reduced as it does not involve the isolation of the Duloxetine base.

4. Stable and insitu conversion of Zinc chloride salt of (S)-(+)-N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine without isolating demethylated product resulting into monomethylated compound followed by its conversion into Duloxetine worked efficiently.

5. Easy handling of solids isolated as precursors with better stability.

6. Enhancement of chiral purity of Duloxetine by using Lewis acid.

In summary, processes disclosed in prior art for the preparation of Duloxetine hydrochloride, are tedious, time consuming and operationally difficult at industrial scale. Therefore, there exists a need for improvement in the process which is devoid of the above mentioned drawbacks. OBJECT OF THE INVENTION:

It is an object of the present invention to provide salts particularly Lewis acid salts more particularly Zinc chloride salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine.

One of the embodiments of the present invention comprises a process for preparing substantially pure (+) Duloxetine Hydrochloride of high optical purity comprising use of Lewis acid salts. Lewis acid salt can be Aluminium chloride, Stannic chloride, Ferric chloride preferably Zinc chloride salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2- thiophenyl) propanamine or (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine.

Another embodiment of the present invention is to provide Lewis acid salts more particularly Zinc chloride salt of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine.

Further embodiment of the present invention includes a process for the preparation of Lewis acid salts preferably zinc chloride salts of (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2- thiophenyl) propanamine which is an important intermediate for preparing Duloxetine free base or other acid addition salts as appropriate.

Another embodiment of the present invention to enhance the chiral purity of Duloxetine or other intermediates thereof by using Lewis acids preferably Zinc chloride salts.

It is yet another object of the present invention to provide the process for preparing Duloxetine hydrochloride of the formula II optionally isolating Duloxetine base from salts preferably Lewis acid salts preferably Zinc chloride salt of (S)-(+)-N-methyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine. It is a further object of the present invention to provide a cost effective process for preparing Duloxetine hydrochloride of the formula II.

SUMMARY OF THE INVENTION:

The present invention provides a process for preparing the substantially pure S-enantiomer that will be free from R-enantiomer as an impurity both in (S)-(+)-N-methyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine and also in its precursor intermediate (S)- (+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine. The advantage of the present invention is found in its ability to prepare the desired product in high yield of about 82% with high purity (99.75% HPLC purity, Chiral purity 99.91%) with selective isolation avoiding the standard process of resolution comprising formation of salt with a specific isomeric salt. The standard resolution process results in the lower yield of the desired product.

An embodiment comprises arylation of (S)-(+)-N,N-dimethyl-3-(l-hydroxy)-3-(2- thiophenyl) propanamine) with 1-fluoro naphthalene using sodium hydride as a base and DMSO as solvent. The said arylation process results in racemisation (more preferably to say epimerization) resulting into the formation of about 3% of R isomer as an impurity. The present invention provides a novel method of preparing substantially pure (S)-(+)-N-methyl- 3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and (S)-(+)-N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine comprising the formation of Lewis acid salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and (S)-(+)-N,N- dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine preferably zinc chloride salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and (S)-(+)-N,N- dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine. The R and S isomers of the said lewis acid salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and (S)-(+)-N,N-dimethyl-3-( 1 -naphthalenyloxy)-3-(2-thiophenyl) propanamine differ in their selectivity pattern towards lewis acid in an organic solvent. Lewis acid salt of R isomer of N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine which is formed as an impurity is selectively minimized during lewis acid salt itself in an organic solvent thereby enriching the S isomer. Organic solvent can be selected from aliphatic alcohol, aliphatic ketone or aliphatic ester and the like. Preferably the organic solvent is aliphatic alcohol or aliphatic ester. More preferably organic solvent is aliphatic alcohol. Most preferable is isopropyl alcohol.

In an embodiment for preparing (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2- thiophenyl) propanamine, (S)-(+)-N,N-dimethyI-3-(l -hydroxy)-3-(2-thiophenyl) propanamine is subjected to arylation with 1-fluoro naphthalene in presence of sodium hydride as base during which epimerization takes place resulting into about 3 % of unwanted R epimer that is carry forwarded till end if not care taken of. In the present invention this unwanted R epimer is selectively minimised by Lewis salt preferably Zinc chloride at this stage. The enriched S epimer thus obtained is then taken for demethylation using organic haloformates preferably phenyl chloroformate with optional isolation.

In another embodiment (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and lewis acid preferably Zinc chloride salts obtained either from (S)-(+)-N,N- dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine or from (S)-(+)-N-methyl-3- (l-naphthaleny!oxy)-3-(2-thiophenyl) propanamine are converted into the corresponding hydrochloride salt either by treating the respective Zinc chloride salt directly with IPA/HC1 or optionally by isolating Duloxetine base by treating with an inorganic base

The (S)-(+)-N,N-dimethyl-3-(l-hydroxy)-3-(2-thiophenyl) propanamine used in the present invention can be prepared by any of the process available in the prior art and forms no part of the present invention. DETAILED DESCRIPTION:

As disclosed in the prior art the arylation of (S)-(+)-N,N-dimethyl-3-(l-hydroxy)-3-(2- thiophenyl) propanamine) with 1-fluoro naphthalene using sodium hydride as a base and DMSO as solvent. The said arylation process results in racemisation (more preferably to say epimerization) resulting into the formation of about 3% of R isomer as an impurity However there are no methods available in the prior art that talks about selective removal of R-isomer that is generated during arylation.

The present invention provides a novel method of preparing substantially pure (S)-(+)-N- methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and (S)-(+)-N,N-dimethyl-3- (l-naphthalenyIoxy)-3-(2-thiophenyl) propanamine comprising the formation of Lewis acid salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and (S)-(+)- N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine preferably zinc chloride salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and (S)-(+)- N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine. The R and S isomers of the said lewis acid salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and (S)-(+)-N,N-dimethyl-3-(l -naphthalenyloxy)-3-(2-thiophenyl) propanamine differ in their selectivity pattern towards lewis acid by resulting into enrichment of S isomer in an organic solvent. Lewis acid salt of R isomer of (S)-(+)-N-methyl-3-(l- naphthalenyloxy)-3-(2-thiophenyI) propanamine and . (S)-(+)-N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine formed as an impurity is selectively minimised thereby resulting into the enrichment of S isomer during salt formation with Lewis acid preferably Zinc chloride with the said mixture containing R isomer of the said product as an impurity in an organic solvent. Organic solvent can be selected from aliphatic alcohol, aliphatic ketone or aliphatic ester and the like. Preferably the organic solvent is aliphatic primary alcohol of primary aliphatic ester. More preferably the organic solvent is aliphatic primary alcohol. Most preferable is isopropanol. The lewis acid salt is selected from aluminium chloride, tin chloride, zinc chloride, Ferric chloride and the like. More preferably the lewis acid salt is zinc chloride of (S)-(+)-N- methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine hereinbefore and hereinafter referred as Duloxetine lewis acid can be converted into corresponding Duloxetine hydrochloride salt comprising either by treating the said lewis acid salt with a base, preferably with an inorganic base into the corresponding free base which can be converted into the corresponding hydrochloride salt optionally insitu or by isolating the free base by treating the said Duloxetine base with hydrochloric said in an organic solvent preferably aliphatic alcoholic solvent or by directly treating with alcoholic HCl preferably isopropanolic HCl.

In an embodiment for making Duloxetine hydrochloride comprises:

1) Reacting(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propan- amine with Lewis acid preferably Zinc chloride resulting into (S)-(+)-N-methyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine Zinc chloride.

2) Adding IPA.HC1 into above salt to get said Duloxetine Hydrochloride optionally isolating Duloxetine base that again comprises treatment of an inorganic base with (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine Zinc chloride.

In another embodiment process for making Duloxetine hydrochloride comprises:

1) Reacting(S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine with Lewis acid like Zinc chloride resulting into (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3- (2-thiophenyl) propanamine Zinc chloride.

2) Above said salt is demethylated resulting into (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3- (2-thiophenyl) propanamine Zinc chloride optionally isolating it. 3) Adding IPA.HC1 into the said salt to get the said Duloxetine Hydrochloride optionally isolating Duloxetine base that again comprises treatment of an inorganic base with (S)-(+)-N- methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine Zinc chloride.

Entire schematic representation for the preparation of Duloxetine is shown below, however chemistry of the present invention can be summarized as shown in A and B.

Whe eferable Lewis acid is Zinc chloride

The (S)-(+)-N,N-dimethyl-3-(l-hydroxy)-3-(2-thiophenyl) propanamine used in the present invention can be prepared by any of the process available in the prior art. The Invention can be best understood by the following non limiting examples.

Examples:

Duloxetine base required for the purpose was prepared from the process available in the prior art.

Example -1:

Preparation of (S)-(+)-N, N-Dimethyl -3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1- amine

To a 1 lt/4 neck round bottom flask fitted with a mechanical stirrer, reflux condenser and calcium chloride drying tube under an atmosphere of nitrogen gas were charged dimethyl sulphoxide (DMSO) (225 ml) and (S)-(-)-3-methylamino-l-(thio[phene-2-yl) propan-1-ol and the colorless solution cooled to 10-15^οC. The solution when cooled sodium hydride (12.5 gm, 60% dispersion) was added lot wise over a period of 60 minutes keeping the temperature at 10-20°C and the contents were stirred for 30 minutes at the same temperature. Slowly heat the reaction mixture to 60-65°C and charge drop wise 1-Fluoronaphthalene (50 gm). The solution was stirred at 60^οC to 65^οC and the progress of the reaction was monitored by TLC. After complete conversion, cooled the reaction mass followed by the reaction mixture was poured into mixture of 10 ml acetic acid in 1000 ml water. Allow the temperature raise to ambient temperature. 10^οC to 20^οC and stirred for 15 to 20 minutes. Adjust the pH of the reaction mixture to 12 using 30% caustic solution. Extract the reaction mixture with toluene (3 X 150 ml). Combined organic layer washed with water (1 X 50 ml). Dry over anhydrous sodium sulphate. Use the organic layer as such for the next step.

Example -2:

Preparation of (S)-(+)-N-methyl -3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine, zinc chloride salt To a 1 lt/4 neck round bottom flask fitted with a mechanical stirrer, reflux condenser and calcium chloride drying tube under an atmosphere of nitrogen gas were charged above toluene layer, diisopropyl ethyl amine (70 ml), and the colorless solution heated to 5O^οC. To the solution phenyl chloroformate (105 gm) was added. lot wise over a period of 120 minutes keeping the temperature at 50-55°C. The solution was stirred at the same temperature and the progress of the reaction was monitored by TLC. After complete conversion, the reaction mass was cooled to ambient temperature. To the reaction mixture charged caustic solution (700 ml, 10% in water) stirred for 15 to 20 minutes. The layers were separated. Potassium hydroxide (133 gm) was charged to the reaction mixture. The reaction mixture was heated to reflux and maintained for 3 hours. The progress of the reaction was monitored by TLC. After complete conversion, the reaction mass was cooled to ambient temperature. Adjust the pH of the reaction mixture to 12 by using potassium hydroxide (20 ml, 50%). The layers were separated. Washed the organic layer with water (1 x 100 ml). Complete recovery of toluene under vacuum at 45° to 50°C, followed by stripping of toluene (50 ml) provided dark brown colored oil. (83.6 gms) which was dissolved in methanol (400 ml) at 50-60^οC. Cooled to ambient temperature followed by to 0°C. To this added a solution of zinc chloride in methanol over a period of 30 mins. The precipitated product was further cooled to 0-5°C and maintained for one hour. The precipitated solid was filtered, washed with cold methanol (25 ml) and dried at 45 to 50°C for 4 to 6 hours to provide (S)-(+)-Methyl -3-(naphthalene-l- yloxy)-3-thiophen-2-yl) propan-1 -amine, zinc chloride salt as a off white to brown colored powder.

DXT - ZnCI₂ data: IR absorption frequencies in cm^"1:

3499, 3477, 3053, 2812, 1680, 1506, 1461, 1396, 1263, 1236, 1094, 1058, 904, 855, 836, M.P. by DSC - 163-165°C

Example -3:

A) Preparation of (S)-(+)-N-methyl -3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 - amine, hydrochloride To a 1 lt/4 neck round bottom flask fitted with a mechanical stirrer, reflux condenser and calcium chloride drying tube under an atmosphere of nitrogen gas were charged with 50.Og above zinc chloride salt ( from example 2) in IPA. Stirred to suspend. To the suspension charged 15% IPA.HC1 to get clear solution. The clear reaction mixture was stirred for 8 hrs. The precipitated product was further cooled to 0-5^οC and maintained for one hour. The precipitated solid was filtered, washed with cold IPA (25 ml) and dried at 45 to 50^οC for 4 to 6 hours to provide (S)-(+)-N-methyl-3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 - amine, hydrochloride as a off white to white colored powder. This product was then purified from isopropanol resulting into 20 g (S)-(+)-N-methyl-3-(naphthalene-l-yloxy)-3-thiophen- 2-yl) propan-1 -amine, hydrochloride.

B) To a 1 lt/4 neck round bottom flask fitted with a mechanical stirrer, reflux condenser and calcium chloride drying tube under an atmosphere of nitrogen gas were charged with 50.0g above zinc chloride salt ( from example 2) in IPA. Stirred to suspend. To the suspension charged 15% IPA.HC1 to get clear solution. The clear reaction mixture was quenched over ice. The precipitated product was further cooled to 0-5^οC and maintained for one hour. The precipitated solid was filtered, washed with cold IPA (25 ml) and dried at 45 to 50^οC for 4 to 6 hours to provide (S)-(+)-Methyl-3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine, hydrochloride as a off white to white colored powder. This product was then purified from isopropanol resulting into 21 g (S)-(+)-N-methyl-3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine, hydrochloride.

C) To a suspension of salt 50.0g from example 2 in water was added 50% NaOH solution at 0-5^οC till the pH reached 11-12. Reaction mass so obtained was further extracted with methylene dichloride. Oil obtained by distillation of solvents is taken in isopropanol was added with IPA/HC1 at 0-5^οC is filtered off to get 32.7g (S)-(+)-N-methyl -3-(naphthalene-l- yloxy)-3-thiophen-2-yl) propan-1 -amine, hydrochloride. Example 4: Preparation of (S)-(+)-N,N-dimethyl -3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine, zinc chloride salt

A) To a solution of 100.Og (S)-(+)-N,N-dimethyl -3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine in 200ml isopropanol was added a suspension of ZnC12(53g) in 300 ml IPA at 25-30 ° and stirred overnight. The solid was washed with ethyl acetate and dried at 50- 55^οC yielded 122.Og of titled product.

XRD data:

2 theta values: 10.86, 12.04, 12.30, 13.02, 13.82, 15.22, 15.74, 16.28, 16.6, 17.2, 19.46,

19.78, 21.78, 22.16, 22.58, 32.86, 33.54

IR absorption frequencies in cm^-1:

3504, 3051, 1576, 1262, 1235, 773

B) To a solution of 100.Og (S)-(+)-N, N-dimethyl -3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine in 200ml ethyl acetate was added a suspension of ZnC12(53g) in 300 ml IPA at 25-30 ° and stirred overnight. The solid was washed with ethyl acetate and dried at 50- 55^οC yielded 122.Og of titled product.

Example 5: of (S)-(+)-N-methyl -3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine, hydrochloride

100.0 g salt obtained from example 4 was suspended in 250 ml water was added 50% NaOH till pH reached 12.0. The reaction mass was extracted with toluene. Toluene layer thus obtained was the added with 70.0 ml Diethyl isopropyl amine followed by 36.7 g of phenyl chloroformate. After the completion of the reaction organic layer was subjected to hydrolysis in the presence of potassium hydroxide. Organic layer was evaporated after successive water washing yielded oil which was taken into 125_ml IPA followed by addition of IPA/HC1. Solid was filtered and dried to get 67.0 g which was further recrystallised from IPA. HPLC purity: 99.75% Chiral purity: 99.91% XRD data: 2 theta values: 9.54, 13.84, 18.02, 18.80, 19.20, 20.80, 22.08, 23.28, 26.38, 27.36, 27.88, 30.36,

¹HNMR data: δ values (D₂O); 2.06-2.14 (IH, m, J= 4.8Hz), 2.23-2.32 (IH, m, J=), 2.72-2.79 (IH, m, J=4.8Hz), 2.86-2.93(1H, m, J=4.4Hz), 5.47-5.5(1H, dd, J= 4.8Hz), 6.54-6.56( IH, t, 3.6Hz), 6.58-6.6( IH, d, J=7.6Hz), 6.76-6.78(1H, d, J=4Hz), 6.84-6.85(1H, d, J=5.6Hz), 6.87-6.89(1H, d, J=8Hz), 7.01-7.03(1H, d, J=8Hz), 7.11-7.15(1H, t, J=7.2Hz), 7.19-7.23(1H, t, J=8.4), 7.38-7.4(1H, d, J=8Hz), 8.01-8.03(1H, d, J=8Hz). IR absorption frequencies in cm^-1: 3062, 2960, 1596, 1263, 1236

Claims

WE CLAIM:

1) Lewis acid salt of (S)-(+)-N-methyl-3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1- amine of the formula II

2) Lewis acid salts of (S)-(+)-N,N-dimethyl-3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine of the formula IVa

3) Lewis acid as claimed in claim 1 and 2 are selected from the group of Zinc chloride, Aluminium chloride, Tin chloride and Ferric chloride.

4) Lewis acid as claimed in any of the preceding claims is Zinc chloride.

5) A process for the preparation of Lewis acid salts of (S)-(+)-N-methyl-3-(naphthalene-l- yloxy)-3-thiophen-2-yl) propan-1 -amine of the formula II comprising reaction of (S)-(+)-N- methyl-3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine of the formula Ia and lewis acid in an organic solvent.

6) A process for the preparation of (S)-(+)-N-methyl-3 -(naphthalene- l-yloxy)-3 -thiophen-2- yl) propan-1 -amine hydrochloride of the formula I comprising reacting the said lewis acid salt with a base to obtain (S)-(+)-N-methyl-3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine free base which is converted into the corresponding hydrochloride .

7) Lewis acid as claimed in preceding claim 5 and 6 is Zinc chloride.

8) Process for the preparation of Lewis acid salts of (S)-(+)-N,N-dimethyl-3-(naphthalene-l- yloxy)-3-thiophen-2-yl) propan-1 -amine of the formula IVa comprising reaction of (S)-(+)- N,N-dimethyl-3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine of formula IV with lewis acid in an organic solvent

9) Organic solvent as claimed in claim 5 and 7 is selected from the group of alcoholic, ester, ketonic solvent or mixture thereof.

10) Organic solvent as claimed in claim 9 is aliphatic alcoholic solvent.

11. Organic solvent as claimed in claim 10 is Isopropyl alcohol.