Title of Invention

IMPROVED PROCESS FOR PREPARATION OF PAROXETINE INTERMEDIATE

Abstract

A process for preparation of paroxetine and intermediates thereof is disclosed herein. More particularly, this invention discloses an improved procedure of reduction with diborane as also a novel solvent mix for the manufacture of a trans (-) carbinol. This invention further discloses recycling of the unwanted waste (+) trans isomer to the (-) form by using a novel and convenient process of racemization.

Full Text

THE PATENTS ACT, 1970 (39 of 1970) COMPLTE SPECIFICATION [See section 10;rule 13] "IMPROVED PROCESS FOR PREPARATION OF PAROXETINE INTERMEDIATE" (a) IPCA LABORATORIES LTD. (b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of this invention and the manner in which it is to be performed: FIELD OF INVENTION: The present invention relates to an improved process for preparation of paroxetine and intermediates thereof. More particularly, this invention relates to an improved procedure of reduction with diborane as also a novel solvent mix for the manufacture of a trans (-) carbinol. This invention further relates to recycling of the unwanted waste (+) trans isomer to the (-) form by using a novel and convenient process of racemization. BACKGROUND AND PRIOR ART: Paroxetine is a compound identified chemically as (-) - trans-4-(4"-fluro phenyl) -3-[[3, 4-metheline dioxy) phenoxy] methyl] - piperidine and (3S-trans)-3-[(l, 3-benzodioxol-5-yl-oxy) methyl]-4-(4-fluorophenyl) piperidine. Paroxetine is a preferred medication administered for depression, anxiety, panic disorders and post- trauma stress disorders. Paroxetine belong to a class of compounds that are inhibitors of 5-hydroxy tryptamine (5 HT) uptake and, thus of therapeutic use, typically administered as hemihydrate hydrochloride salt because of its physiological and pharmaceutical acceptability. Paroxetine is known by trade name Paxil in USA and Seroxat in Europe. Paroxetine was first reported (in Ferrosan Patent) in US Patents 3,912,743 and 4,007,196.the corresponding patent in UK being GB-B-1422263. Paroxetine was referred as the maleate salt. US 3,912,743 describes the process for preparation of 3-methoxy methyl -l-methyl-4-phenylpiperidine which comprises i) converting 3-hydroxymethyl-1 -methyl-4-phenylpiperidine into its methanes ulfonic ester using methane sulfochloride at 10°C-15°C and further reacting with sodium methoxide to yield racemic 3- methoxymethyl-1-methyl-l-methyl-4-phenylpiperidine, which is further resolved using (-)dibenzoyltartaric acid, or ii) treating 3-hydroxymethyl-l-methyl-4-phenylpiperidine sodium hydride in dimethylformamide in presence of methylbromide at 25°C or iii) treating 3-hydroxymethyl-l-methyl-4-phenylpiperidine with 4-methoxyphenol in presence of dicyclohexylcarbodiimide at 160°C-180° C. EP 0219934 discloses a process for preparation of (+/-)-cis-4-(4"-Fluorophenyl)-3- methoxycarbonyl-1 -methyl-piperidine by catalytic hydrogenation of 4-(4"- Fluorophenyl)-3-methoxycarbonyl-l-methylpyridinium bromide using platinum oxide and further isomerising into (+/-)-trans-4-(4"-fluorophenyl)-3-methoxycarbonyl-l-methylpiperidine in presence of sodium methoxide in toluene which may be further reduced using lithium aluminium hydride to corresponding carbinol intermediate used in the preparation of paroxetine. EP 0223334 describes the reduction of 4-aryl-2,6-dioxo-3-piperidinecarboxylic acid ester with lithium aluminium hydride to 4-aryl-3-hydroxymethyl-l-alkyl piperidine in presence of inert solvent such as tetrahydrofuran. EP 0223403 mainly claims the process for preparation of a crystalline paroxetine hydrochloride hemihydrate using paroxetine base, compositions containing the same and its therapeutic use as an anti-depressant. EP 0300617 mainly discloses the process for preparation of aryl piperidine carbinol intermediate which comprises reduction of 4-p-Fluorophenyl-3-formylpyridine hydrochloride to 4-p-Fluorophenyl-3-hydroxymethylpyridine by catalytic hydrogenation or using sodium borohydride in presence of alcohol and further converted to 4-p-Fluorophenyl-3-hydroxymethyl-l-alkylpyridinium bromide using alkyl bromide and further catalytically hydrogenated to (+/-)-cis-4-p-Fluorophenyl-3-hydroxymethyl-l-alkylpiperidine. WO 02102382 describes process for preparing paroxetine HC1 which comprises reacting paroxetine base with HCI and further re-crystallizing the paroxetine HCI in toluene and separating the paroxetine HCI substantially free of pink-colored compound as an impurity. WO-A-00/08017 (equivalent to EP-A-1100796) claims the process for preparing paroxetine hydrochloride anhydrate which comprises heating a paroxetine hydrochloride solvate to remove the solvating solvent and increasing the temperature of the heating as the amount of solvent remaining in the solvate decreases. US 6, 33,289 (equivalent to EP-A-1300144) relates to the treatment and/or prevention of depression using paroxetine hydrochloride hemihydrate. EP-A-1042318 discloses a process for preparation of paroxetine hydrochloride propan-2-ol solvate comprises forming a solution of paroxetine hydrochloride in a mixture of propan-2-ol and an effective co-solvent such as toluene, heptane or hexane, which was used to prepare crystalline anhydrate form of paroxetine hydrochloride. WO-A-00/32597 (equivalent to EP-A-1135384) concerned with a process for obtaining crystalline paroxetine hydrochloride propan-2-ol solvate which comprises providing a solution of paroxetine hydrochloride in propan-2-ol, and crystallising paroxetine hydrchloride propan-2-ol solvate under conditions of intense insonation or in a continuous crystalliser. WOA-01/02346 provides a process for the isolation of a single diastereomer of 2-cyano-3-arylglutarate ester as a single diastereomer from a mixture of 2-cyano-3-arylglutarate ester diastereoisomers. This intermediate is further converted into paroxetine. WO 0146148 describes the process for isolation of (-) trans4- (4"-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine) from a mixture of racemic trans 4- (4fluorophenyl)-3-hydroxymethyl-1-methylpiperidine using (-)ditoluoyltartaric acid in presence of mixture of solvent viz.,acetone and water. US 2002099219 disclose preparation of tosylate salt of 4-fluorophenyl-3-carbinol piperidine by reacting carbinol with tosyl halide such as p-toluene sulphonyl chloride in presence of ethyl acetate and converting the tosylate salt to paroxetine further processing paroxetine to form paroxetine hydrochloride or paroxetine mesylate.. US 20020082277 discloses the process for preparation of racemic trans(+-)-l-methyl-4- (p-fluorophenyl)piperidine-3-carbinol (N-methylparoxol) by reduction of ethyl trans (+- )-l-methyl-2,6-dioxo-4-(p-fluorophenyl)piperidine-3-carboxylate using lithium aluminium hydride in toluene/tetrahydrofurane and resolving (-)trans-l-methyl-4-(p-fluorophenyl)piperidine-3-carbinol by treating with (-)-0,0-di-p-toluoyltartaric acid in presence of acetone and further converted into a tosylate salt of 4-fluorophenyl-3-carbinol piperidine by reacting with toluene sulfonic acid to minimize the content of des-fluoro impurities. US 5681962 mainly describes a process for the preparation of (±)-trans-4-(4"- fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine by reducing (±)-trans-3- Ethoxy/methoxycarbonyl-4-(4"-fluorophenyl)-N-methyl piperidine-2,6-dione in presence of diborane (generated insitu) at reduced temperature such as -10°C to 20°C in an inert solvent such as tetrahydrofuran or dimethoxyethane. US 6172233 claims a process for preparation of cis/trans l-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine by reacting 4-fluorophenylmagnesium bromide (Gridgnard compound) in diethyl ether with arecoline at -5 to -10 DEG C in a suitable non-ether solvent or in a mixture of such a solvent with diethyl ether which may be resolved to the (-) trans isomer using nitro tartranilic acid. The novel use of the solvent mix used for resolving the racemic trans carbinol to isolate the desired salt of (-) trans carbinol in high state of optical purity and yield as now found to be unexpectedly advantageous is not appreciated in the prior art, particularly in making paroxetine as described herein. Further, the present invention provides recycling of the wasteful trans (+) carbinol (la) by oxidation and racemization methods which further leads to the formation of N-oxide so as to give the trans(+) carboxylic acid (II) in high state of purity was not described in the prior process of preparation of aryl piperidine carbinol. SUMMARY OF INVENTION In the present invention an improved process for the reduction of the ester dione (IV) is described with diborane. A novel combination of solvents, acetone and methanol is used in the preparation of (-) trans carbinol (I) with DPTTA in very high purity and yield. This invention also relates to the recycling of wasteful trans (+) carbinol (la) by novel oxidation & racemization method which uses conventional oxidizing agent. DETAILED DESCRIPTION Paroxetine is prepared by typical process wherein 4- fluro ethyl cinnamate which in turn made from 4-fluro benzaldehyde with the reaction of ethyl acetate and followed by isolation of cinnamate ester which in turn reacted with thionyl chloride and monomethyl amine to generate the 4-fluro N- methyl cinnamate. i This 4- fluro N- methyl cinnamide is further condensed with expensive base namely sodium tertiary butoxide and diethyl malonate to generate the ester dione (IV) which in turn is reduced by BF3 etherate and sodium borohydride to generate the trans(±)racemic carbinol(Ib). This trans carbinol is separated into the desired isomer the (-) form by resolution with (L) di-para toluyl tartaric Acid (DPTTA). The above process generates an important waste, trans (+) carbinol which constitutes a major cost factor and disposal hazard of the toxic enantiomer. WO 9322284 discloses the selective hydrolysis of the desired isomer of a key intermediate by porcine liver esterase enzyme. The enzyme in the desired purity is not available and the acetone extract of the porcine liver leads to poor isomer selectivity thus limiting the scope of invention. The raw material so used by the enzyme route is generated from arecoline which is potentially 6 toxic thus limiting the scope of the process proposed to recycle the undesired (+) trans isomer. The present process discloses the unique potential of reducing the ester dione (IV) by a novel scheme of addition to prevent reductive dehydrogenation leading to the des flurocarbinol(V) by reacting with a pre generated diborane solution in solvents like THF, dioxane, methylal, ethylal to generate the racemic trans carbinol with a much improved quality and yield. The process for preparation of paroxetine and its intermediates which comprises: a) reducing the ester dione of formula IV, by reacting with pregenerated diborane solution in organic solvent to generate the racemic trans carbinol in an improved quality and yield; and b) resolving the said racemic trans carbinol with di-para toluyl tartaric acid (DPTTA) by using a combination of solvent mixture of acetone and methanol in ratio of 70:30 to 99:1 to give the desired salt of (-) trans carbinol in high state of optical purity and yield. The invention further relates to the use of a novel combination of acetone and methanol in ratio of 70:30 to 99:1 and more preferably in the ration of 85:15 to 95:5 of the solvent mix to give the desired salt of (-) trans carbinol (I) with DPTTA in very high state of optical purity and yield. This invention also relates to the recycling of the wasteful trans (+) carbinol (la) by a novel oxidation and racemization methods which uses conventional oxidizing agents such as Jones reagent and pyridinium chloro chromate.The undesired isomer (la), further leads to the formation of N-oxide so as to give the trans(+) carboxylic acid (II) in high state of purity. A process for recyclisation of the wasterfuil trans (+) carbinol to (-) carbinol wherein the said process comprises, a) treating the wasteful carbinol with conventional oxidizing agents to form trans carboxylic acid, b) esterifying the trans carboxylic acid in ethanol, c) racemizing the ester with base at a temperature of 60-120°C to give racemic ester, d) adding this ester to any fresh batch of dione ester with calculated additional quantity of the diborane solution to effect the reduction of the ester. The intermediate (II) is esterified in ethanol and racemized with bases like sodium hydride, sodium rnethoxide, sodium amide, lithium isopropyl amide, potassium methoxide and other strong bases at temperature of 60°C to 120°C and more preferably 60°C to 80°C to give racemic ester(III). The intermediate (Hi) can also be added to any fresh batch of dione ester (IV) with calculated additional quantity of the diborane solution to effect reduction of the ester. The racemic ester has hitherto been synthesized from the toxic arecoline route thus can now synthesized and reduced with the diborane solution as said above to the desired racemic carbinol. While the present invention as described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting scope of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims. The invention is illustrated by the following Examples: Example 1 Preparation of (±)-trans-4-(4"-Fluorophenyl)-3-hydroxymethyl-N-methyIpiperidine (formula lb). A solution of diborane in tetrahydrofuran (21.6 ml; 21.6 mmol) added slowly to a solution of trans-4-(4,.fluorophenyl)-N-methylpiperidin-2, 6-dione -3 carboxylic acid ethyl ester (formula IV) (0.616g, 2 mmole) in tetrahydrofuran (20 ml) at temperature below 40°C over a period of 1 hour. When addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched carefully by adding water (30 ml) followed by 10% aqueous, sodium hydroxide solution. The separated aqueous layer was extracted with ethyl acetate and the solvent was evaporated to obtain the product. Example 2 Resolution of (±) tranS-4-(4"-Fluorophenyl)-3-hydroxymethyl-N-methyIpiperidine. A solution of 100 g of compound (formula la) dissolved in 1600 ml acetone and 400 ml methanol was prepared and added to a cooled solution of (L) di-para toluyl tartaric acid (DPTTA) (190.4 grn in 2000 ml acetone) over a period of 2 hours maintaining the temperature of the reaction mixture between 20-25 °C, after addition the reaction mass was cooled to 0-5° C; for 1 hour and the desired isomer (-) carbinol precipitates out as a salt which was filtered and (+) isomer of carbinol remains in the mother liquor. The precipitated salt was purified by refluxing in 1L of acetone for 30 min. The reaction mass was then cooled to 20°C for 1 hour and washed with 50 ml of acetone and dried at 40-45°C under vacuum (75-100 mm) to yield (-) trans carbinol salt (96-100 gm)the mother. Example 3 Isolation of (-)-trans-4-(4"-Fluorophenyl)-3-hydroxymethyl-N-methylpiperidine (formula 50 gm of the (-) trans carbinol salt was charged with 150 ml of DM water and to this solution ethyl acetate (150 ml) was added and the reaction mass was stirred and cooled to 10-15 °C. Slowly 30% of hydrochloric acid was added to the above prepared solution maintaining the same temperature. The reaction mixture was stirred for 25-30 minutes till the clear solution obtained. Separated organic layer was extracted with 60 ml of ethyl acetate thrice and the combined ethyl acetate layer was washed with 10% HCL. Sodium hydroxide solution (50%) was added to the combined acidic extract at temperature 10-15°C and stirred well and extracted thrice with 80 ml of ethyl acetate each. The ethyl acetate layer was washed with 20ml of sodium chloride solution (10%), then with water and separated ethyl acetate layer was distilled out at 45-50°C under reduced pressure varying from 100-20 mm of Hg cooled to 35°C to obtain the title compound (16-17.5 gm). Example 4 Preparation of (+)-trans-4-(4"-Fluorophenyl)- N-methylpiperidine-3-carboxylic acid (formula II). A solution composed of 0.99g of sodium dichromate and 1.33g of concentrated sulfuric acid dissolved in 4.46ml of water was added slowly with stirring to a solution of 2.23 g of (+) carbinol (formula la) in 4.7ml of acetone at room temperature. The mixture was then stirred at room temperature for 4-6 hours and then diluted with 40ml of water, made alkaline with sodium hydroxide solution and washed with water. The resulting mixture was stirred for 30 min. The separated aqueous layer was extracted thrice with 20 ml of ethyl acetate and the solvent was distilled out under reduced pressure to obtain the title compound. Example 5 Preparation of (±)-trans-4-(4"-FIuorophenyI) - N-methylpiperidine-3-carboxylic acid ethyl ester (formula III). 2.37 gm (+) trans carboxylic acid (formula II) was charged in 100ml round bottom flask. 25 ml of ethanol and dilute hydrochloric acid ( 0.5 ml, IN) was added and the solution was refluxed for 4 hours to complete the reaction. After completion of the reaction, the reaction mass was neutralized with sodium hydroxide solution (10%, 5 ml). The resultant reaction mass was extracted with ethyl acetate and distilled the solvent to obtain the titled product. This racemic carboxylic ester thus obtained can be further added to any fresh batch of dione ester (formula IV) for reduction with calculated additional quantity of the pregenerated diborane solution to yield (±)-trans-4-(4"-Fluorophenyl)-3-hydroxymethyl-N-methylpiperidine( formula I). We claim 1. A improved process for preparation of paroxetine intermediate, (-)-trans-4-(4"-Flurophenyl)-3-hydroxymethyl-N-methyl piperidine comprising the steps of: a) reducing the ester dione of formula IV. by reacting with pregenerated diborane solution in organic solvent to generate the racemic trans carbinol in an improved quality and yield; IV b) resolving the said racemic trans carbinol with di-para toluyl tartaric acid (DPTTA) by using a combination of solvent mix of acetone and methanol in ratio of 70:30 to 99:1 to give the desired salt of (-) trans carbinol in high state of optical purity and yield and c) recycling the wasteful trans (+) carbinol to desired (-) carbinol. 2. The process as claimed in claim 1, wherein said organic solvent is selected from THF, dioxane, methylal or ethylal. 3. The process as claimed in claim 1, wherein said solvent mix is preferably 95:5 to 85:15. 4. A process for recyclisation of the wasteful trans (+) carbinol to (-) carbinol as claimed in claim 1, wherein the said process comprises: a) treating the wasteful carbinol with conventional oxidizing agents to form trans carboxylic acid; b) esterifying the trans carboxylic acid in ethanol; c) racemizing the ester with base at a temperature of 60-120°C to give racemic ester and d) adding this ester to any fresh batch of dione ester with calculated additional quantity of the diborane solution to effect the reduction of the ester. 5. The process as claimed in claim 4, wherein said oxidizing reagent is selected from Jones reagent, or piridinium chloro chromate. 6. The process as claimed in claim 4, wherein said base used for racemization is selected from sodium hydroxide, sodium methoxide, sodium amide, lithium isopropyl amide, potassium methoxide or other strong bases. 7. The process as claimed in claim 4, wherein the temperature used for racemization is preferably at 60-80°C. Dated this the 12th day of October 2004 Dr. Gopakumar G. Nair Agent for the Applicant

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1075-mum-2003-cancelled pages(3-1-2007).pdf

1075-mum-2003-claims(granted)-(12-10-2004).pdf

1075-mum-2003-claims.doc

1075-mum-2003-claims.pdf

1075-mum-2003-correspondence(5-1-2007).pdf

1075-mum-2003-correspondence(ipo)-(24-12-2007).pdf

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1075-mum-2003-correspondence.pdf

1075-mum-2003-description(granted).doc

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1075-mum-2003-form 1(16-10-2003).pdf

1075-mum-2003-form 1(24-11-2003).pdf

1075-mum-2003-form 1(5-1-2007).pdf

1075-mum-2003-form 1-5-jan-2007.pdf

1075-mum-2003-form 1.pdf

1075-mum-2003-form 18(28-9-2005).pdf

1075-mum-2003-form 18.pdf

1075-mum-2003-form 2(granted)-(3-1-2007).pdf

1075-mum-2003-form 2(granted)-(5-1-2007).doc

1075-mum-2003-form 2(granted).doc

1075-mum-2003-form 2(granted).pdf

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