WO2008093360A2 - A process for preparation of (s)-(+)-n-methyl-3(1-naphthyloxy)-3(2-thienyl)propylamine hydrochloride - Google Patents

A process for preparation of (s)-(+)-n-methyl-3(1-naphthyloxy)-3(2-thienyl)propylamine hydrochloride Download PDF

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WO2008093360A2
WO2008093360A2 PCT/IN2008/000062 IN2008000062W WO2008093360A2 WO 2008093360 A2 WO2008093360 A2 WO 2008093360A2 IN 2008000062 W IN2008000062 W IN 2008000062W WO 2008093360 A2 WO2008093360 A2 WO 2008093360A2
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compound
process
ml
thienyl
water
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WO2008093360A3 (en
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Venkatasubramanian Radhakrishnan Tarur
Nandu Baban Bhise
Dhananjay Govind Sathe
Neeraj Srivastava
Chhayendra Janardan Choudhari
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Usv Limited
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulfur
    • C07D333/06Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulfur with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Abstract

The present invention provides an improved process for preparation of intermediate of Duloxetine base and hydrochloride salt thereof.

Description

Technical Held:

The present invention relates to an improved process for the preparation of (S)-(+)-N- methyl-3-(l -naphthalenyloxy)-3-(2-thienyl)propylamine hydrochloride also known as Duloxetine hydrochloride of formula I.

Figure imgf000002_0001

Formula (I)

Background of invention:

Duloxetine hydrochloride is a selective serotonin norepinephrine reuptake inhibitor indicated for the treatment of major depressive disorder.

US 5023269 describes process for the preparation of racemic N-methyl-3-(l- naphthalenyloxy)-3-(2-thienyl)propylamine, compound (7) comprising reaction of 2- acetyl thiophene (2) with paraformaldehyde and dimethyl amine hydrochloride to get 3- dimethylamino-l-(2-thienyl)-l-propanone (3). The obtained compound (3) was reduced using sodium borohydride to get racemic alcohol (4) which was treated with metal hydride and 1 -fluoronaphthalene in N,N-dimethylacetamide to obtain oxalate salt of N5N- dimethyl-3-(l- naphthalenyloxy)-3-(2-thienyl)propanamine (6). The oxalate salt was demethylated using phenyl chloroformate in toluene to obtain free base of racemic Duloxetine (7). Duloxetine base thus obtained was further converted into the pharmaceutically acceptable acid addition salts by treating with equimolar or excess amount of acid.

US 5362886 describes preparation of Duloxetine hydrochloride by reacting 2-acetyl thiophene (2) with dimethyl amine HCl and paraformaldehyde in isopropanol and the resulting keto compound (3) which was reduced by sodium borohydride to get racemic compound ∞-[2-(dimethylamino)ethyl]-2-thiophene methanol (4). The compound (4) was resolved by (S)-(+)-Mandelic acid in ethanol and methyl tert butyl ether to get (S)-(-)- N,N-dimethyl-3-hydroxy-3-(2-thienyl)-propanamine (5) followed by condensation using 1-fluoronaphthalene in presence of sodium hydride and potassium benzoate in dimethyl sulphoxide to get compound (6). Compound (6) was further demethylated by phenyl chloroformate and diisopropyl ethylamine in toluene and subsequently hydrolyzed by alkali metal hydroxides to get Duloxetine base (7). Compound (7) thus obtained was treated with concentrated HCl and inoculating crystal of the compound (1) was added to the reaction mixture to get Duloxetine hydrochloride as represented by the scheme below. However, reproduction of the desired product by using this process resulted in poor yield of the product.

Scheme I

Figure imgf000003_0001

1-fluoro naphthalene NaH

Figure imgf000003_0002

Phenyl clilorofcmiate

Figure imgf000003_0004
Figure imgf000003_0003
WO2006045255 describes process for preparation of Duloxetine base by demethylating the compound 6 with phenyl chloroformate and diisopropyl ethyl amine in toluene then hydrolyzing with alkali metal hydroxides to get Duloxetine base (7). Duloxetine Base (7) thus obtained was heated with ammonium chloride to get compound (1) (yield 55%).

WO2006027798 describes the preparation of Duloxetine base by resolving the N5N- dimethyl-3-(l- naphthalenyloxy)-3-(2-thienyl)propanamine by Di-para-toluoyl-L-tartaric acid to get tartaric acid salt of the N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2- thienyl)propanamine which was further basified followed by demethylation and hydrolysis. This Duloxetine base in methanol was treated with ammonium chloride to get Duloxetine HCl.

WO2006071868 discloses process for preparation of Duloxetine hydrochloride via preparation of (S)-Duloxetine ethyl carbamate from oxalate salt of N,N-Dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl) propanamine. Duloxetine hydrochloride obtained with yield of 56%.

WO2004056795 describes process of preparation of (S) -Duloxetine or its acid addition salts from racemic Duloxetine . Duloxetine hydrochloride was obtained by treating the racemic base with hydrochloric acid which provides 99% required enantiomer.

WO2006126213 discloses process for preparing Duloxetine, or its acid addition salt, comprising condensation of (S)-(-)-N, N,-dimethyl-3-(2-thienyl)-3-hydroxy propanamine with 1 -fluoronaphthalene followed by demethylation or condensation of N, N-dimethyl-3- (2-thienyl)-3-hydroxy propanamine with 1 -fluoronaphthalene followed by resolution and demethylation; and converting Duloxetine to its hydrochloride salt by treatment with IPA- HCl (yield 53%).

Objectives of the invention:

Λn object of the present invention is to provide process for the preparation of (S)-(+)-N- methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propylamine hydrochloride (I) in high yield and purity.

Another object of the invention is to provide a simple, economical and industrially feasible process for the preparation of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2- thienyl) propylamine hydrochloride (I).

Summary of the invention:

The present invention discloses an improved process for the preparation of Duloxetine hydrochloride (I) comprising: a) reacting 2-acetyl thiophene (2) with paraformaldehyde and dimethyl amine hydrochloride to form 3-dimethylamino-l-(2-thienyl)-l-propanone hydrochloride (3); b) adding sodium borohydride in water or alcoholic solvents to compound (3) in step a) to get compound (4); c) resolving compound (4) using chiral resolving agent into compound (8); d) condensing compound (5) with 1-fluoro naphthalene in presence of sodium hydride in dimethyl sulphoxide (DMSO) to get S-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3- (2-thienyl) propanamine (6); e) demethylating compound (6) using phenyl chloroformate in presence of diisopropyl ethylamine to get Duloxetine carbamate; f) hydrolyzing the obtained Duloxetine carbamate using sodium hydroxide in dimethyl sulphoxide to get Duloxetine base (7); g) treating Duloxetine base (7) with chlorinating agent and alcohol to get Duloxetine HCl and h) optionally purifying Duloxetine HCl (1) to get ICH quality material.

According to another aspect of the present invention Duloxetine hydrochloride is purified using suitable alcoholic solvent to get Duloxetine HCl (1).

According to another aspect of the present invention Duloxetine hydrochloride is purified by dissolving DuIo hydrochloride in suitable solvent and then solvent is distilled out completely. Then anti-solvent is added to precipitate the Duloxetine HCl (1). Detailed description of the invention:

The present invention provides process for preparation of Duloxetine, (S)-(+)- N- methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride, of formula I which comprises the steps of ;

a) reacting 2- acetyl thiophene with N, N- dimethyl amine hydrochloride, paraformaldehyde in presence of hydrochloric acid in suitable solvent, adding sodium borohydride in alcohol to get 3-(dimethylamino)-l-(2-thienyl)-l-propanol

(4). b) purifying compound (4) by acid base treatment;

Figure imgf000006_0001

(4)

c) resolving the compound (4) with chiral resolving agent in suitable solvent to get compound (5) and compound (8);

Figure imgf000006_0002

(5) (8) d) optionally recycling the unwanted R-isomer (8) by treating the resolution mother liquor of step (b) with acid to get compound (4); e) condensing the compound (5) with 1-halo naphthalenes in presence of sodium hydride in DMSO to get the crude compound (6); f) basifying the obtained organic acid salt followed by extraction with water immiscible solvents to obtain the pure compound (6)

Figure imgf000007_0001

31 1 .48

(6) g) demethylating compound (6) with phenyl chloroformate, diisopropyl ethylamine in toluene and isolating the compound (7)and hydrolyzing the resulting carbamate with sodium hydroxide in DMSO;

Figure imgf000007_0002

(7) h) treating compound (7) with alcohols and chlorinating reagent to provide the compound of formula (I).

Figure imgf000007_0003

(1) In preferred embodiment of the present invention, process for the preparation of

Duloxetine hydrochloride (I) comprises refluxing the mixture of 2-acetyl thiophene, dimethyl amine hydrochloride, paraformaldehyde and concentrated HCl in alcohol for 4 h. After completion of reaction the reaction mixture is cooled to the room temperature and water is added followed by addition of alcohol and cooled to 5-10° C. Aqueous sodium hydroxide solution is added to adjust the pH 7-8 of the reaction mixture. The resultant reaction mixture is reduced in-situ by addition of reducing agent in small lots at 5-10° C. After complete addition of sodium borohydride. the reaction mixture is stirred for 30 minutes at 5-10° C and further stirred at room temperature for 12-15 h. The reaction mixture is concentrated to obtain oily residue. The residue obtained is treated with water immiscible solvent, washed with water and brine solution. The separated ethyl acetate layer is concentrated to obtain oil, which solidifies on standing to white solid of 3- (dimethylamino)- 1 -(2-thienyl)- 1 -propanol (4).

Alternately, after completion of reaction, alcoholic solvent is distilled out and compound is precipitated by addition of water to the reaction mass. The solid obtained is filtered, washed with water and dried to get the 3-(dimethylamino)-l -(2-thienyl)- 1 -propanol (4).

The compound (4) is further purified by acid-base treatment. The acid used is selected from Ci-C4 aliphatic o'rganic acids and the base is selected from the group consisting of sodium hydroxide, potassium hydroxide and sodium carbonate.

3-(dimethylamino)-l -(2-thienyl)- 1 -propanol (4) obtained above is resolved by heating in mehyl tertiary butyl ether at temperature 45-50° C and solution of chiral acid in presence of non polar solvent is added in a drop wise manner followed by stirring for 45 minutes at 45-50° C. After completion of reaction the reaction mass is cooled to room temperature and the solid obtained is filtered, washed with water immiscible solvent to obtain the chiral salt of (S)- 3 -(dimethylamino)-l -(2-thienyl)- 1 -propanol (5) which is crystallized in organic solvent to get pure compound (5).

The mother liquor containing unwanted isomer (8) is concentrated, basified and extracted with ethyl acetate to get the oily residue which solidified on standing. In another embodiment, unwanted isomer, (R)-3-(dimethylamino)-l -(2-thienyl)- 1 -propanol (8) from the resolution mother liquor is recycled into 3-(dimethylamino)-l -(2-thienyl)- 1 -propanol (4) by adding solution of hydrochloric acid at 20-25°C to compound (8) which is isolated from the mother liquor. The reaction mixture is stirred for 8 hrs at 20-250C and basified with aqueous NaOH to attain pH 9-10. The reaction mass is extracted with water immiscible solvent and concentrated the solvent under reduced pressure to get oil of 3- (dimethylamino)-l-(2-thienyl)-l-propanol (4) which solidifies on standing.

In another embodiment of the present invention the obtained pure compound (5) is basified and extracted with water immiscible solvent to obtain (S)- 3-(dimethylamino)-l- (2-thienyl)-l-propanol (5) as oil, which solidified on standing.

The compound (5) thus obtained is coupled with 1- halonaphthalenes with sodium hydride in presence of dimethyl sulphoxide. After completion of reaction, the reaction mixture is quenched with water and the crude compound is extracted with water immiscible solvent. The crude compound is then treated with organic acid in water to form the water soluble organic acid salt of compound (6). Then the aqueous layer is washed with water immiscible solvent and basified. The reaction mixture is extracted with water immiscible solvent and concentrated to get oil of the pure compound (6). In another embodiment of the present invention compound (6) is demethylated by treating with phenyl chloroformate in toluene in presence of diisopropyl ethylamine at 65-70° C to yield the carbamate which is isolated and hydrolyzed in dimethyl sulphoxide and aqueous sodium hydroxide solution to obtain crude Duloxetine base (7). The crude base is further purified by converting into its corresponding acetate salt using aqueous acetic acid and washing the aqueous layer by water immiscible solvent to remove the organic impurities then basifying the aqueous layer and finally extracting the pure Duloxetine base in ethyl acetate.

In yet another embodiment of the present invention the obtained Duloxetine base in ethyl acetate is reacted with chlorinating agent and alcohol selected from CpC4 alcohols. The advantage of this process is that the product is obtained in good yield.

In another embodiment of the present invention the compound (3) is in situ reduced with sodium borohydride in ethanol and/or water to obtain compound (4) and compound (4) is in situ resolved with chiral resolving reagent in a non polar solvent.

The alcohol used is selected from methanol, ethanol and isopropanol. The water immiscible solvent used is selected from ethyl acetate, toluene, methyl tertiary butyl ether.

The chiral resolving agent is selected from the group consisting of mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid and camphor sulphonic acid.

The non polar solvent is selected from the group consisting of aromatic hydrocarbons, C1- C4 esters and C2-C8 ethers such as methyl tertiary butyl ether, ketonic solvent such as acetone preferably acetone. The advantage is the process avoids use of expensive methyl tertiary butyl ether (which is used in high volume) and alcohol. Single solvent acetone is used, which can be recycled.

The organic acid used is selected from formic acid, acetic acid, propanoic acid, methane sulphonic acid or PTSA more preferably acetic acid.

The water immiscible solvent is selected from methyl tert butyl ether, ethyl acetate, toluene or chlorinated solvents preferably MDC.

The chlorinating agent used for preparation of Duloxetine hydrochloride is preferably thionyl chloride and alcohol used is selected from Ci-C4 alcohols preferably IPA. Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art may 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 following 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 arc described in numerous publications.

Example 1

(S)- 3-(dimethylamino)-l-(2-thienyl)-l-propanol (5): Λ mixture of 2-acetyl thiophene (250 g, 1.98 mol), dimethyl amine hydrochloride (21 O g, 2.57 mole), paraformaldehyde (78.44 g, 0.871 mole) and concentrated HCl (3.97 ml) in ethanol (317 ml) was refluxed for 4 h. The reaction mixture was cooled to the room temperature and water (700 ml) was added, followed by addition of methanol (1.6 L) at room temperature. The reaction mixture was cooled to 5-10° C and basified with aqueous sodium hydroxide solution to adjust the pH 7-8. Then sodium borohydride (81 g, 2.18 mole) was added in small lots at 5-10° C. After completion of addition of sodium borohydride, reaction mixture was stirred for 30 minutes at 5-10° C. Then it was stirred at room temperature for 12-15 h. The reaction mixture was concentrated to obtain oily residue. The residue was treated with ethyl acetate (3.0 L) and washed with water (3x500 ml) and brine solution (500 ml). The ethyl acetate layer was separated, dried over sodium sulphate, and concentrated to obtain oil which solidified on standing to white solid (210 g). This solid was taken in methyl tert butyl ether (3.15 L) and heated to 45-50° C and a solution of (S)-(+)-Mandelic acid (86.27 g. 0.567 mole) in ethanol (250 ml) was added in a dropwise manner. The reaction mixture was stirred for 45 minutes at 45-50° C and cooled to room temperature. The solid obtained was filtered and washed with methyl tert butyl ether to obtain Mandelate salt (112 g). This salt was crystallized using acetone to get pure Mandelate salt (96 g). The Mandelate salt was basified with sodium hydroxide followed by extraction with dichloromethane to obtain (S)- 3-(dimethylamino)-l-(2- thienyl)-l-propanol as oil which solidified on standing. Yield 50g.

Example 2

(S)- 3-(dimethylamino)-l-(2-thienyl)-l-propanol (5):

Λ mixture of 2-acetyl thiophene (25Og, 1.98 mole), dimethyl amine hydrochloride (21 O g, 2.57 mole), paraformaldehyde (78.44 g, 0.871 mole) and concentrated HCl (3.97 ml) in ethanol (317 ml) was refluxed for 4 h. The reaction mixture was cooled to the room temperature and water (700 ml) was added followed by addition of methanol (1.6 L) at room temperature. The reaction mixture was cooled to 5-10° C and basified with aqueous sodium hydroxide solution to adjust pH 7-8. Then sodium borohydride (81 g, 2.18 mole) was added in small lots at 5-10° C. After completion of addition of sodium borohydride, reaction mixture was stirred for 30 minutes at 5-10° C. Then it was stirred at room temperature for 12-15 h. After completion of reaction, acetone (240 ml) was added to quench the excess borohydride. The reaction mixture was concentrated to obtain oily residue. To this residue dilute aqueous HCl solution (250 ml cone HCl in 250 ml water) was added to form the hydrochloride salt. This aqueous solution was washed with toluene (2x200 ml) to remove organic impurities. Washed aqueous solution was basified with aqueous alkali solution to pH 10-11. This alkaline solution was then extracted with methyl tert butyl ether (3x750 ml). The organic layer was then washed with water and dried over sodium sulphate. The organic layer was heated to 45-50° C and a solution of (S)-(+)-Mandelic acid (86.27 g, 0.567 mole) in ethanol (250 ml.) was added in a dropwise manner. The reaction mixture was stirred for 45 minutes at 45-50° C and cooled to room temperature. The solid obtained was filtered and washed with acetone to obtain Mandelate salt. This salt was leached in acetone at reflux temperature to get pure Mandelate salt (98 g). The Mandelate salt was basified with sodium hydroxide followed by extraction with dichloromethane to obtain (S)- 3-(dimethylamino)-l-(2-thienyl)-l- propanol as oil which solidified on standing. Yield 52 g.

Example 3

(S)- 3-(dimethylamino)-l-(2-thienyl)-l-propanol (5):

A mixture of 2-acetyl thiophene (100 g, 0.793 mole), dimethyl amine hydrochloride (81.5 g, 1 mole), paraformaldehyde (35.5 g, 0.394 mole) and concentrated HCl (4.0 ml) in ethanol (250 ml) was refluxed for 5 h. The reaction mixture was cooled to room temperature and diluted with ethanol (250 ml). The reaction mixture was cooled to 5-10° C and basified with ethanolic sodium hydroxide solution (32 g NaOH in 450 ml ethanol) to pH 8-10. The sodium borohydride (35 g, 0.92mol) was added portionwise into the reaction mixture at 5-100C for 30 minutes. The reaction mixture was stirred at room temperature for 6 h. Then glacial acetic acid (165 ml) was added into it to adjust pH 5-6 to get a white solid which was filtered and washed with ethanol (300 ml). The filtrate was basified with 20% aqueous NaOH (140 ml) to pH 7.5-8 and concentrated to obtain oily residue (112 g). The residue was dissolved in acetone (700 ml) at 45-500C and a solution of (S)-(+)-Mandelic acid (47 g, 0.31 mole) in acetone (100 ml) was added in a drop wise manner at 45-500C. The reaction mixture was stirred for 45 min at 45-50° C and was further cooled to room temperature. The solid obtained was filtered and washed with acetone to obtain Mandelate salt of the desired isomer (43 g). The Mandelate salt was basified with sodium hydroxide and extracted with dichloromethane to obtain (S)- 3- (dimethylamino)-l-(2-thienyl)-l-propanol as oil which solidified on standing. Yield 22g. The mother liquor containing the unwanted isomer (8) was concentrated, basified and extracted with ethyl acetate to get the oily residue which solidified on standing.

Example 4

(S)- 3-(dimcthylamino)-l-(2-thienyl)-l-propanol (5):

A mixture of 2-acetyl thiophene (100 g, 0.793 mole), dimethylamine hydrochloride (81.5 g, 1 mole), paraformaldehyde (35.5 g, 0.394 mole) and concentrated HCl (4.0 ml) in isopropanol (IPA) (250 ml) was refluxed for 6 h. The reaction mixture was cooled to room temperature and IPA was removed by distillation. Water (600 ml) was added to the residue. A solution of sodium borohydride (15 g) in 10% aqueous sodium hydroxide solution (41 g, NaOH in 410 ml water) was slowly added to the reaction mixture at 30-350C. The reaction mixture was stirred at room temperature for 6 h. Then aqueous HCl (Cone HCl 150 ml in 300 ml water) was added to get a clear solution. The reaction' mass was then washed with toluene (2x300 ml) to remove organic impurities. The reaction mass was again basified by adding sodium hydroxide solution (75 g NaOH in 150 ml water). This basic solution was extracted with methyl tert butyl ether (3x300 ml). The ethereal layer was washed with water and dried over sodium sulphate. This organic layer was heated to 50-550C and a solution of (S)-(+)-Mandelic acid (44 g) in ethanol (44 ml) was added. The reaction mass was heated at this temperature for 1 h and cooled to rt and filtered to get chiral Mandelate salt. This crude salt was taken in acetone (900 ml) and the mixture was heated at reflux temperature for 3 h. Then reaction mixture was cooled and filtered to get the pure Mandelate salt of the compound 5 (84 g). The Mandelate salt was basified with sodium hydroxide and extracted with dichloromethane to obtain (S)- 3- (dimethylamino)-l-(2-thienyl)-l-propanol as oil, which solidified on standing. Yield 42 g. The mother liquor containing the unwanted isomer (8) was concentrated, basified and extracted with ethyl acetate to get the oily residue which solidified on standing. Example 5

(S)- 3-(dimethylamino)-l-(2-thienyl)-l-propanol (5)

A mixture of 2-acetyl thiophene (100 g, 0.793 mole), dimethyl amine hydrochloride (81.5 g, 1 mole), paraformaldehyde (35.5 g, 0.394 mole) and concentrated HCl (4.0 ml) in isopropanol (250 ml) was refluxed for 6 h. The reaction mixture was cooled to 5-100C and filtered and washed with IPA to get a white colored solid. This solid (150 g) was dissolved in water (600 ml). A solution of sodium borohydride (12.5 g, 0.342 mole) in 10% aqueous sodium hydroxide solution (41 g, NaOH in 410 mL water) was slowly added to the reaction mixture at 30-350C. The reaction mixture was stirred at room temperature for 6 h. Then aqueous HCl (150 ml cone HCl in 300 ml water) was added to get a clear solution. The reaction mass was then washed with toluene (2x300 ml) to remove organic impurities. The reaction mass was then basified using sodium hydroxide solution (75 g NaOH in 150 ml water) and then extracted using methyl tert butyl ether. (3x300 ml). The ethereal layer was washed with water and dried over sodium sulphate. This organic layer was heated to 50-550C and a solution of (S)-(+)-Mandelic acid (44 g, 0.289 mole) in ethanol (44 ml) was added. The reaction mass was heated at this temperature for 1 h, cooled to rt and filtered to get crude Mandelate salt. This crude salt was taken in acetone (900 ml) and the mixture was heated at reflux temperature for 3 h. Then reaction mixture was cooled and filtered to get the pure Mandelate salt of the compound 5 (84 g). The Mandelate salt was basified with sodium hydroxide and extracted with dichloromethane to obtain (S)- 3-(dimethylamino)-l-(2-thienyl)-l- propanol as oil which solidified on standing. Yield 42 g.

The mother liquor containing the unwanted isomer (8) was concentrated, basified and extracted with ethyl acetate to get the oily residue which solidified on standing.

Example 6 3-(dimethylamino)-l-(2-thienyl)-l-propanol (4):

To a solution of the solid obtained from the resolution mother liquor [containing the unwanted isomer, compound (8), (55 g)] in toluene (450 ml). 1.5 M solution of hydrochloric acid (890 ml) was added at 20-250C. The reaction mixture was stirred for 8 h at 20-250C. The reaction mixture was basified with aqueous NaOH to pH 9-10 and extracted with ethyl acetate. The ethyl acetate layer was washed with water till neutral pH, dried over sodium sulphate and concentrated under reduced pressure to get 3- (dimethylamino)-l-(2-thienyl)-l-propanol (4) as oil which solidified on standing. Yield: 35 g

Example 7

(S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanaminc (6) :

Λ solution of (S)-(-)-3-(dimethylamino)-l-(2-thienyl)-l-propanol (175 g, 0.945 mole) in dimethyl sulphoxide (750 ml) was added lot wise to a mixture of 60% sodium hydride (47.3 g, 1.18 mole) in dimethyl sulphoxide (475 ml) at 30-350C. This mixture was stirred for 30 min and the temperature was raised to 60-65° C followed by dropwise addition of 1 -fluoronaphthalene (152 g, 1.04 mole). Reaction mixture was stirred for 6-8 hrs. After cooling, methanol was added to quench the excess sodium hydride followed by addition of water (4.9 L) to the reaction mass and extraction with ethyl acetate. The combined organic extracts were washed with water and dried over sodium sulphate. The organic layer was concentrated under reduced pressure to get oil (298 g). 8 % aqueous solution of acetic acid (1.49 L) was added to this oil and stirred for 30 min. Aqueous mixture was washed with methyl tert butyl ether (3x1.49 L). Aqueous layer was then basified with 5 % aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and concentrated under reduced pressure to get (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine as oil. Yield: 192 g (65%).

Example 8

(S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanaminc (6) :

To the solution of (S)-(-)-3-(dimethylamino)-l-(2-thienyl)-l-propanol (175 g, 0.945 mole) in dimethyl sulphoxide (1225 ml), 60% sodium hydride (47.3 g, 1.18 mole) was added lot wise at 30-350C. This mixture was stirred for 30 minutes. The temperature was raised to 60-65° C and 1 -fluoronaphthalene (152 g, 1.04 mole) was added drop wise. Reaction mixture was stirred for 6-8 h. After cooling methanol was added to quench the excess sodium hydride followed by addition of ethyl acetate (250 ml) and water (4.9 L) . Layers were separated and lower aqueous layer was extracted with ethyl acetate (2x250 ml). The combined organic extracts were washed with water. 8 % aqueous solution of acetic acid (1.49 L) was added to this layer and stirred for 30 min. Aqueous layer was basified with 5 % aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and concentrated under reduced pressure to get (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine as oil. Yield: 19O g (65%).

Example 9

(S)-(+)-N, N-dimethyI-3-(l-naphthalenyloxy)-3-(2-thienyl) propanaminc (7): To the solution of (S)-(-)-3-(dimethylamino)-l-(2-thienyl)-l-propanol (175 g, 0.945 mole) in dimethyl sulphoxide (1225 ml), 60% sodium hydride (47.3 g, 1.18 mole) was added lot wise at 30-350C. This mixture was stirred for 30 minutes. Then raised temperature to 60-65° C and 1 -fluoronaphthalene (152 g, 1.04 mole) was added drop wise. Reaction mixture was stirred for 6-8 hrs. After cooling methanol is added to quench the excess sodium hydride then ethyl acetate (250 ml) followed by water (4.9 L) was added to the reaction mass. Layers were separated and lower aq. layer was extracted with ethyl acetate (2X250 ml). The combined organic extracts were washed with water. 8 % aqueous solution of acetic acid (1.49 L) was added to this organic layer and stirred the mixture for 30 minutes. Separated aqueous layer was basified with 5 % aqueous sodium hydroxide solution and extracted with toluene (3X175 ml). The organic layer was washed with water, dried over sodium sulphate.

To this organic layer Diisopropyl ethyl amine (134 g, 1.04 mole) was added at room temperature. To this solution phenyl chloroformate (163 g, 1.04 mole) in Toluene (190 ml) was added drop wise. The reaction mixture was heated to 65-70° C for 7 hr and cooled the reaction mass to 30° C and quenched it with 5% aqueous sodium hydroxide solution. Stirred the mass for 15 minutes and separated the layers. The organic layer was further washed with water (3x1.5 L) then with 1 N Hydrochloric acid solution and finally with water. The organic layer was concentrated under reduced pressure to get crude carbamate (300 g). This oil was taken in dimethyl sulphoxide (1.5 L) and a solution of sodium hydroxide (132 g) in water (792 ml) was added. Resulting solution was heated to 70-75° C for 7-8 hr. The reaction mixture was cooled, diluted with water (6 L) then extracted with ethyl acetate (3x1.5L). The organic layer was washed with water, dried over sodium sulphate and finally concentrated under vacuum to obtain oil. To this oily compound 10% aqueous solution of acetic acid (3.35 L) was added and the mixture was stirred for 30 minutes. This aqueous solution was washed with Methyl tert butyl ether (4x1.2 L). The washed aqueous layer was basified with 5% aqueous sodium hydroxide solution and extracted with ethyl acetate (3x 1.2L). The combined organic layer was washed with water till neutral pH, dried over sodium sulphate and concentrated under reduced pressure to get (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine as oil. Yield: 14O g (50 %).

Example 10

(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine:

(S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (90 g, 0.0289 mole) was taken in toluene (540 ml) and diisopropyl ethyl amine (56 g, 0.434 mole) was added to the mixture at room temperature. To this solution phenyl chloroformate (68 g, 0.434 mole) in toluene (90 ml) was added drop wise. Then heated the reaction mixture to 65-70° C for 7 hr. Then cooled the reaction mass to 30° C and quenched it with 5% aqueous sodium hydroxide solution. Stirred the mass for 15 minutes and separated the layers. The organic layer was further washed with water (3x700 ml) then with 1 N Hydrochloric acid solution and finally with water. The organic layer was concentrated under reduced pressure to get crude carbamate (137 g). This oil was taken in dimethyl sulphoxide (675 ml) and a solution of sodium hydroxide (48 g) in water (290 ml) was added. Resulting solution was heated to 70-75° C for 7-8 hr. The reaction mixture was cooled, diluted with water (2.7 L) then extracted with ethyl acetate (3x1 L). The organic layer was washed with water, dried over sodium sulphate and finally concentrated under vacuum to obtain oil (122 g). To this oily compound 10% aqueous solution of acetic acid (1220 ml) was added and the mixture was stirred for 30 minutes. This aqueous solution was washed with Methyl tert butyl ether (4x600 ml). The washed aqueous layer was basified with 5% aqueous sodium hydroxide solution and extracted with ethyl acetate (3x600 ml). The combined organic layer was washed with water till neutral pH, dried over sodium sulphate and concentrated under reduced pressure to get (S)-(+)-N- methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine as oil. Yield: 59 g (68%).

Example 11

(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride

0):

(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (5 g 0.0168 mol) was taken in ethyl acetate (35 ml) and ethanol (1.2 ml, 0.02mol) was added to it. Then the reaction mixture was chilled to -5 to 0° C and thionyl chloride (2.45 g, 0.02 moles) was slowly added to the mixture at -5-O0C. The precipitated reaction mass was stirred for 1 hr at -5-00C. Then filtered under reduced pressure, washed with ethyl acetate and dried to get the title compound. Yield: 4 g (71%). This compound was recrystallized in IPA to get the pure compound.

Example 12

(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride

(1):

(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (5 g 0.0168 mole) was taken in ethyl acetate (60 ml) and IPA (1.2 ml, 0.02mole) was added to it. Then the reaction mixture was chilled to -5 to 0° C and thionyl chloride (1.9 g, 0.016 moles) was slowly added to the mixture at -5-00C. The precipitated reaction mass was stirred for 1 hr at -5-O0C. Then filtered under reduced pressure, washed with ethyl acetate and dried to get the title compound. Yield: 4.1 g (73%). This compound was crystallized in isopropyl alcohol to get the pure compound.

Example 13

(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride

(1):

(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (5 g 0.0168 mole) was taken in ethyl acetate (60 ml) and ethanol (5 ml) was added to it. Then the reaction mixture was chilled to -5 to 0° C and thionyl chloride (1.9 g, 0.016 moles) was slowly added to the mixture at -5-00C. The precipitated reaction mass was stirred for 1 hr at -5-O0C. Then filtered under reduced pressure, washed with ethyl acetate to get the title compound. Yield: 4 g (71%). This compound was crystallized in IPA to get the pure compound.

Example 14

Purification of Duloxetine hydrochloride:

This crude compound (4 g) was taken in IPA (30 mL) and refluxed to get the clear solution. To this clear solution activated carbon was added and stirred the reaction mass for 15 minutes. The reaction mass was filtered over celite. The clear filtrate was concentrated to half of its volume then cooled to rt and another IPA (15 ml ) was added. Then mixture was chilled to 5-1O0C, then filtered and washed with lot of IPA to get the pure (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl propanamine hydrochloride (1) of ICH purity (3.4 g) (85%).

Example 15

Purification of Duloxetine hydrochloride:

(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride (5 g) was dissolved in Methanol (25 mL) at 5O0C, charcoalized and filtered through celite. Celite bed was washed with Methanol (10 mL). Clear filtrate was concentrated to dryness and Toluene (100 mL) was added to it. Mixture was stirred for 1 hr and filtered. Wet cake was washed with Toluene (50 mL) followed by Hexanes (50 mL). White coloured product was dried at 60-650C. Yield : 4.5 g (90%).

Example 16

Purification of Duloxetine hydrochloride:

(S)-(-t-)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride (5 g) was dissolved in Methanol (25 mL) at 5O0C, charcoalized and filtered through celite. Celite bed was washed with Methanol (10 mL). Clear filtrate was concentrated to dryness and Acetone was added to it. Mixture was stirred for 1 hr and filtered. Wet cake was washed with Acetone. White to off white coloured product was dried at 60-650C. Yield : 3 g (60%).

Example 17

Purification of Duloxetine hydrochloride:

(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride (5 g) was dissolved in Methanol (25 mL) at 5O0C, charcoalized and filtered through celite. Celite bed was washed with Methanol (10 mL). Clear filtrate was concentrated to dryness and Methylene dichloride (25 mL) followed by Hexanes (150 mL) was added to it. Mixture was stirred for 1 hr and filtered. Wet cake was washed with Hexanes. White coloured product was dried at 60-650C. Yield : 4.0 g (80%).

Claims

We claim:
1. An improved process for preparing (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3- (2-thienyl) propanamine hydrochloride (1) comprising:
Figure imgf000021_0001
(1) a) reacting 2-acetyl thiophene with paraformaldehyde, dimethyl amine hydrochloride and concentrated HCl to obtain compound (3);
Figure imgf000021_0002
(3) b) reducing compound (3) with sodium borohydride in alcohol and/or water to obtain the racemic alcohol (4);
Figure imgf000021_0003
(4) c) resolving compound (4) with chiral resolving agent to obtain compound (5);
Figure imgf000021_0004
GH
(5) d) condensing compound (5) with 1-halo naphthalene in presence of sodium hydride in dimethyl sulphoxide to obtain compound (6);
Figure imgf000022_0001
(6) e) demethylating compound (6) with phenyl chloroformate followed by hydrolysis with aqueous alkali to obtain compound (7);
Figure imgf000022_0002
(7) f) treating compound (7) with alcohol and chlorinating reagent to obtain compound (1) and g) optionally purifying compound (1) using alcohol to get pure compound (1).
2. The process as claimed in claim 1 wherein compound (3) is in situ reduced with sodium borohydride in ethanol and/or water to obtain compound (4).
3. The process as claimed in claim 1 wherein compound (4) is purified by acid-base treatment.
4. The process as claimed in claim 1 wherein compound (4) is in situ resolved with chiral resolving reagent in presence of non polar solvent.
5. The process as claimed in claim 3 wherein acid used is selected from CpC4 aliphatic organic acids and the base is selected from the group consisting of sodium hydroxide, potassium hydroxide and sodium carbonate.
6. The process as claimed in claim 1 wherein chiral resolving agent is selected from the group consisting of mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid and camphor sulphonic acid.
7. The process as claimed in claim 4 wherein non polar solvent is selected from the group consisting of aromatic hydrocarbons, ketones, Ci-C4 esters and C2-C8 ethers .
8. A process for the preparation of hydrochloride salt of 3- aryloxy -3- arylpropanamines (IA)
Figure imgf000023_0001
IA where Ar is phenyl or 2-thienyl
ArI is 1-naphthyl, 2-methoxyphenyl,
2-thiomethoxyphenyl, 2-methylphenyl or 4-trifluoromethylphenyl
G is hydrogen or methyl which comprises treating compound IA with chlorinating agent and alcohol.
9. The process as claimed in claim 1 or 8 wherein chlorinating agent is thionyl chloride.
10. The process as claimed in claim 1 or 8 wherein alcohol is selected from the group consisting Of Ci-C4 alcohols.
1 1. The process as claimed in claim 1 wherein the alcohol used for purifying compound (1) is selected from C1-C4 alcohols preferably IPA.
12. The process as claimed in claim 1 wherein the purification of compound (1) comprises solvent antisolvent method.
13. The process as claimed in claim 12 wherein the solvent used is methanol.
14. The process as claimed in claim 12 wherein the antisolvent used is selected from hexane and acetone.
15. The process as claimed in claim 1 to 14 as substantially described herein with reference to the forgoing examples 1 to 17
PCT/IN2008/000062 2007-01-31 2008-01-31 A process for preparation of (s)-(+)-n-methyl-3(1-naphthyloxy)-3(2-thienyl)propylamine hydrochloride WO2008093360A2 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009150238A2 (en) * 2008-06-13 2009-12-17 Krka, D.D. Novo Mesto Gastro-resistant pharmaceutical oral compositions comprising duloxetine or its pharmaceutically acceptable derivatives
WO2011033366A3 (en) * 2009-09-16 2011-09-01 Jubilant Life Sciences Limited Process for the preparation of duloxetine hydrochloride and its precursors
EP2376471A2 (en) * 2009-01-06 2011-10-19 Alembic Limited An improved process for the preparation of duloxetine and salts thereof

Citations (3)

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Publication number Priority date Publication date Assignee Title
US5362886A (en) * 1993-10-12 1994-11-08 Eli Lilly And Company Asymmetric synthesis
WO2006045255A1 (en) * 2004-10-26 2006-05-04 Zentiva, A.S. Method of manufacturing (s)-n-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (duloxetine)
US20060194869A1 (en) * 2004-12-23 2006-08-31 Santiago Ini Process for preparing pharmaceutically acceptable salts of duloxetine and intermediates thereof

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US5362886A (en) * 1993-10-12 1994-11-08 Eli Lilly And Company Asymmetric synthesis
WO2006045255A1 (en) * 2004-10-26 2006-05-04 Zentiva, A.S. Method of manufacturing (s)-n-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (duloxetine)
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009150238A2 (en) * 2008-06-13 2009-12-17 Krka, D.D. Novo Mesto Gastro-resistant pharmaceutical oral compositions comprising duloxetine or its pharmaceutically acceptable derivatives
WO2009150238A3 (en) * 2008-06-13 2010-07-01 Krka, D.D. Novo Mesto Gastro-resistant pharmaceutical oral compositions comprising duloxetine or its pharmaceutically acceptable derivatives
EP2376471A2 (en) * 2009-01-06 2011-10-19 Alembic Limited An improved process for the preparation of duloxetine and salts thereof
EP2376471A4 (en) * 2009-01-06 2012-09-12 Alembic Ltd An improved process for the preparation of duloxetine and salts thereof
WO2011033366A3 (en) * 2009-09-16 2011-09-01 Jubilant Life Sciences Limited Process for the preparation of duloxetine hydrochloride and its precursors

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