Title of Invention

A NOVEL MANUFACTURING PROCESS FOR CRYSTALLINE AND OPTICALLY PURE TRANS -(3S,4R)-(-)-N-METHYL-4-(4'-FLUOROPHENYL)-3-HYDROXY METHYL PIPERIDINE

Abstract

The invention relates to a process for the manufacturing enantiomerically pure intermediate of Paroxetine hydrochloride i.e. trans-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine by resolving trans-(±)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl-piperidine using most economically viable resolving agents like D-(-)-tartaric acid to form a mixture of diastereomeric salts, separating the diastereomeric salts by fractional crystallization in a mixture of solvent systems of the kind such as described herein, in the specified time and temperature range to provide said trans-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patent Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION "A NOVEL MANUFACTURING PROCESS FOR CRYSTALLINE AND OPTICALLY PURE TRANS- (3S,4R)-(-)-N-METHYL-4-(4'-FLUOROPHENYL)-3-HYDROXY METHYL PIPERIDINE" We, CADILA HEALTHCARE LTD., a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad - 380 015, Gujarat, India, The following specification particularly describes the nature of the invention and the manner in which it is performed: A novel manufacturing process for crystalline and optically pure Trans- (3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine. FIELD OF THE INVENTION: The present invention relates to manufacturing crystalline and optically pure intermediate of Paroxetine hydrochloride, characterized by Formula- (I) by using novel resolving agents such as D-(-), D - or L- mandelic acid, D- or L-Glutamic acid and D-(+)-Camphorsulphonic acid, which enables resolution of ?ram.-(+)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine in such a way that affords optically pure compound trans-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine (I) that is free from its enantiomeric as well as other process related impurities. Thus obtained pure crystalline compound of the Formula- (I) is most suitable for preparing active drug substance Paroxetine hydrochloride. (1) (II) (III) BACKGROUND OF THE INVENTION: Pharmaceutical products with antidepressant and anti-Parkinson properties are described in US-3912743 and US-4007196. An especially important compound among those disclosed is Paroxetine, the trans isomer of N-methyl-4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy-phenoxy methyl) piperidine (II). This compound is used in therapy as the hydrochloride salt for the treatment and prophylaxis of inter alia depression, obsessive compulsive disorder (OCD) and panic disorder. In US 6,316,628B1, describes the resolution of trans,-(+)-N-benzyl-4-(4'-fluorophenyl)-3-hydroxy methyl-piperidine by L-Tartaric acid using methanol as a single solvent or a mix 1 solvent of methanol and at least one compound selected from the group consisting of isopropyl alcohol and acetone. Using the exemplified data it has been observed that the L-Tartarate of ?ram,-(-)-N-benzyl-4-(4,-fluorophenyl)-3-hydroxy methyl-piperidine compound can not be precipitated as crystals by reacting the ^raw-(±)-N-benzyl-4-(4'-fluorophenyl)-3 -hydroxy methyl-piperidine compound with L-Tartaric acid. So, the disclosed resolving agent L-Tartaric acid is not the write choice to resolve trans-(+)-N-benzyl-4-(4'-fiuorophenyl)-3-hydroxy methyl-piperidine compound. In US-4902801 and US-4007196, Paroxetine is prepared from a trans-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine (I). The pyridine carbinol compound of formula (I) is in-turn prepared by reduction of a racemic trans ester precursor compound of formula (III). In which R= CH3 or C2H5. The reduction is carried out conventionally using metalhydride, in an inert solvent. Following reduction of the trans ester precursor compound of formula (III), the precursor compound of formula (I) is obtained in the trans configuration but as a mixture of trans-(3S,4R) and trans-(3R,4S) enantiomers. In the above mentioned prior art as well as in EP 374674 resolution of compound of formula (I) is enabled by using salts with chiral acids such as, (+)-2'-nitrotartaric acid, (-)-di-p-tolyl-D-tartaric acid and (-)-benzyl-D-tartaric acid. A research article Chem. Pharm. Bull.48 (4) 529-536 (2000) discloses resolution of trans-(+)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine with the help of L-o-chlorotartranilic acid. In WO 98/01424, describes the resolution of trans-(+)-N-benzyl-4-(4'-fiuorophenyl)-3-hydroxy methyl-piperidine by (-)-L-dibenzyl tartaric acid monohydrate and by (+)-D-dibenzyl tartaric acid monohydrate. Whereas, WO98/02556 and WO 93/22284 relates to resolution of compound of Formula- (III) using various enzymes to achieve enantiomerically pure compound of its precursor Formula- (III), which can be useful for preparing Paroxetine hydrochloride via intermediate step of Formula-(II). These mentioned resolving agents have the disadvantages like (i) Being expensive (ii) High recovery cost, in case of the Enzymatic resolution preliminary investment cost is also very high and the are enzymes sensitive to pH, temperature, water contaminants etc. 2 SUMMARY OF THE INVENTION: Thus, it would be a significant contribution to the art to provide an efficient process for resolving compound of Formula- (I), which is suitable for large-scale production i.e. the process of the present invention is suitable to unit process and unit operations for manufacturing title compound. This objective of the present invention is achieved by using the resolving agents, which are readily available at low cost like, D-(-)-tartaric acid, D - or L- mandelic acid, D- or L-Glutamic acid and D-(+)-Camphorsulphonic acid, which are useful for preparing diastereomeric salt of (+)-N-methyl-4-(4'-fluorophenyl)-3 -hydroxy methyl piperidine, whose differential solubility properties can be exploited in a suitable solvent system at an appropriate temperature range to obtain desired optically pure trans-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine (I) in minimum possible unit operations. It is an another object of an invention to choose resolving agents, which are recovered by simple and cost effective unit process and operation. The reagents those are used for enabling the invention are easy to recover by simpler technique like neutralization with base, extraction of process related impurity with organic solvents and by adjusting the pH that provides high recovery at plant scale. Yet another object of this invention is to achieve crystalline compound of the Formula-(I) in high purity i.e. the resultant product of the resolution process affords compound of Formula- (I), which is free form its enantiomeric impurity as well as other process related impurities. Another embodiment of this invention relates to the state of the resultant product of Formula- (I), which is obtained as end result of the resolution process described herein this invention. When an intermediate step useful for preparing drug substance is having low bulk density or having amorphous nature it causes dusting problem, which is not suitable for plant scale operation. This causes not only the installation of various equipment to take care of safety precautions since the dusting of the compound may increases health hazards. DETAILED DESCRIPTION: Accordingly, the present invention provides a process for the manufacture of optically pure diastereomeric salts of e.g. D-(-)-tartrate salt of ?ram,-(+)-N-methyl-4-(4'-fiuorophenyl)-3-hydroxy methyl piperidine, The diastereomeric salt is then basified to generate trans-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine (I). 3 The molar ratio of trans-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine to the acid resolving agents is 1:1 to 1:1.5, preferably 1:1.1. The diastereomeric salt formation as well as resolution is preferably carried out in the same solvent or a mixture of solvent system. We have observed that the resolution of trans-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl-piperidine with above mentioned resolving agents, most preferably with D-(-)-tartaric acid is found to be largely governed by the polarity of the solvent system used. Preferred solvent system for the purpose of this invention comprises use of polar protic or polar aprotic solvent mixture. Most preferably, water or alcohols having branched or straight carbon atom chain of C1-C4 carbon atom or aprotic polar solvents such as DMF, DMSO, pyrolidone, DMAC or mixture thereof. Preferably methanol alone or in combination with other recommended solvents is used for salt formation as well as resolution at ambient temperature, however in order to obtain optimum yield, optical purity and desired state of the compound of Formula- (I). The temperature also plays a key role in fractional crystallization for obtaining the optically pure trans-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl-piperidine. It has been also observed that if the resolution is carried out at 0-70°C temperature, the desired product is obtained in a higher optical purity. Most preferred range of the temperature is between 0-45°C range that provides the best results and optimum purity as well as desired state of the compound of the Formula- (I). The reaction time may also vary between 0 to 26 hrs after the addition of the trans-(±)-N-methyl-4-(4'-fluorophenyl)-3 -hydroxy methyl piperidine to the D-(-)-tartaric acid; however under optimal reaction conditions, the preferred reaction time is 1-10 hrs to obtain the optimum yield with desired optical purity. The separated diastereomeric salt (3S, 4R: 2R, 3R) from the reaction mass is isolated by filtration. Moderately resolved diastereomeric salt may also be further slurried using same solvent system, under similar operational conditions, the purified salt is then treated with a base, i.e. alkali hydroxides, carbonates and hydrogen carbonates, preferably sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, etc. Most preferably sodium hydroxide is used for achieving pH in the range 11-12 to obtain transit S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine. 4 The mother liquor obtained from slurry wash contains 45-65% trans-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine as tartarate salt, that can be purified to enhance the productivity. The resolving agent, which is selected for the purpose of enabling this invention for example D-(-)-tartaric acid can be recovered from the aqueous mother liquor by usual known methods, as reported in literature and reused for the same resolution. Besides D-(-)-tartaric acid other organic acids mentioned above such as D - or L-mandelic acid, D- or L-Glutamic acid and D-(+)-Camphorsulphonic acid are also be used as a resolving agent. The resolution of trans-(+)-N-methyl-4-(4'-fluorophenyl)-3 -hydroxy methyl piperidine using L-(+)-tartaric acid is also carried out. However in this case, (3S, 4R: 2S, 3S) diastereomeric salt isolated from the mother liquor, which after some purification and desalting gives the trans-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine. In a preferred embodiment, trans-(+)-N-methyl-4-(4'-fluorophenyl)-3 -hydroxy methyl piperidine is treated with 1.1 molar ratio of D-(-)-tartaric acid in 5.0 volumes of methanol at 25-30°C and same temperature is maintained for 2 hours. The reaction mixture is further cooled to 0-10°C and same temperature is maintained for 2 hours. Solid is filtered at 0-10°C. The wet cake is slurried with 3.0 volume of methanol, filtered and washed with 0.25 volumes of methanol. The wet product thus obtained is dried at 50-55°C till constant weight to give 80-90% yield of diastereomeric salt, containing Specific Optical Rotation; -32.0° to -34.0° at 25°C and 1% w/w solution in methanol. Following examples are illustrative of the instant invention. These examples are not intended to limit the scope of the invention as defined herein above. The scope of the invention is not limited by results or the illustrated examples, but as defined in the detailed description of the invention; all the embodiments of the said above invention i.e. state of the substance, which is characterized by various physical properties as well as the purity profile of the substance of Formula- (I) is a part of present invention. Examples: [A] Preparation of D-(-)-Tartrate salt 5 Experiment-1 Preparation of Trans-(3S,4R)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine tartrate Dissolve 185.1 g. of D-(-)-Tartaric acid by stirring into 1250.0 ml of methanol at 25-30°C. Add in the clear solution, 250 g of Trans-(+)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine in single lot at 25-30°C. Stir for 15 minutes to get a clear solution. In the clear solution thus obtained, add as seed 1.0 g of pure Trans-(3S,4R)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine tartrate. After 5-15 minutes solid product precipitates. Stir the reaction mass for 2 hours at 25-30°C. Thereafter cool the reaction mixture to 0-10°C and maintain at the same temperature for 2 hours. Filter the crystals so obtained. Separate the wet crystals so obtained and suspend in 750 ml of methanol. Stir the suspension for half an hour. Filter the solid and wash with methanol to afford 187.5 g. tartarate salt of Trans-(3S,4R)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine. Melting point: 167-169 °C; Trans (3S, 4R) isomer by chiral HPLC Puritv: 99.95%. Experiment-2 Preparation of Trans-(3S,4R)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine tartrate Suspend 185.1 g. of D-(-)-Tartaric acid in 1250.0 ml of methanol at 25-30°C. Stir to get clear solution. Add 250 g of Trans-(+)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine in reaction vessel in single lot at 25-30°C. Stir for 15 minutes to obtain clear solution. Stir continuously for 9 hours at same condition, to separate-out solid product from the solution. Stir the reaction mass for 4 hours at 25-30°C. Filter the crystals. Separate the wet crystals, and suspend in 750 ml of methanol and stir for half an hour. Filter the solid product and wash with methanol to afford 187.0 g. tartrate salt of Trans-(3S,4R)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine. Melting point: 167-169°C; Trans (3S, 4R) isomer by chiral HPLC Purity: 99.97% 6 Experiment-3 Preparation of Trans-(3S,4R)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine tartrate Dissolve 22.2 Kg. of D-(-)-Tartaric acid by stirring into 150.0 L of methanol at 25-30°C. Add in the clear solution, 30.0 Kg of Trans-(+)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine in single lot at 25-30°C. Stir for 15 minutes to get a clear solution. In the clear solution thus obtained, add as seed 120.0 g of pure Trans-(3S,4R)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine tartrate. After 5-15 minutes solid product precipitates. Stir the reaction mass for 2 hours at 25-30°C. Thereafter cool the reaction mixture to 0-10°C and maintain at the same temperature for 2 hours. Filter the crystals so obtained. Separate the wet crystals so obtained and suspend in 90.0 L of methanol. Stir the suspension for half an hour. Filter the solid and wash with methanol to afford 22.5 Kg. tartarate salt of Trans-(3S,4R)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine. Melting point: 167-169 °C; Trans (3S, 4R) isomer by chiral HPLC Purity: 99.96%. [B] Desalting of Tartrate salt Preparation of Trans-(3S,4R)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine Dissolve 180.0 g of Trans-(3S,4R)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine tartrate in 1000.0 ml of water. Add aqueous solution of 40% sodium hydroxide to adjust pH = 11-12. Extract the aqueous solution by adding 1250.0 ml of Toluene. Separate layers and extract the aqueous layer twice with 625.0 ml of Toluene. Combine the toluene layers and pass through Hyflosupercel bed. Distil off toluene completely. After distillation of toluene crystallize the material from 750.0 ml of n-Hexane. Filter the solid product and wash with n-Hexane, to afford 100.0 g of Trans-(3S,4R)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine. Melting point: 97-98 °C; Trans (3S, 4R) isomer by chiral HPLC Purity: 99.97%. 7 We Claim: 1. Highly optically pure trans-(3S,4R)-(-)-Af-methyl-4-(4'-flourophenyl)-3-hy droxymethylpiperidine. 2. A process for the manufacture of highly optical pure trans-(3S,4R)-(-) or trans-(3R,4S)-(+)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine which comprises (a) Resolution of trans-(+)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine with D-(-)-tartaric acid to form a mixture of diastereomeric salts. (b) separating the diastereomeric salt by filtration at desired temperature range. (c) purifying said diastereomeric salt in described solvent system. (d) liberating of optically pure trans-(3S,4R)-(-) or trans-(3R,4S)-(+)-N-methyl-4-(4'- fluorophenyl)-3-hydroxy methyl piperidine with optical purity more than 99.5-99.9%. 3. A process as claimed in claim 1(a), wherein the resolving agent is D-(-)-tartaric acid. 4. A process as claimed in claim 2, wherein D-(-)-tartaric acid is employed in 1-1.5 molar ratio preferably, 1.1 molar ratio, with that of trans-(+)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine. 5. A process as claimed in claim 1(a), wherein protic solvents containing C1-C6 are employed for resolution alone or along with varying proportions of dipolar solvents like N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrilodone and water. 6. A process as claimed in claim 5, wherein methanol, ethanol, 1-propanol and 2-propanol are preferably used as protic solvents for resolution alone or along with varying proportions of dipolar solvents like N,N-dimethylformamide, water, dimethylsulfoxide, and N-methyl-2-pyrrilodone. 7. A process as claimed in claim 6, wherein ratio of the dipolar solvent to alcoholic solvent varies from 5-20% (v/v) is used for resolution. 8. A process as claimed in claim 7, wherein amount of a single solvent or a solvents combination employed as that of trans-(+)-N-methyl-4-(4'-fluorophenyl)-3 -hydroxy methyl piperidine is 1-15 volume. 8 9. A process as claimed in claim 8, wherein the most preferably amount of methanol and N,N-dimethylformamide employed as that of trans-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine is 8.5 and 1.7 volumes respectively. 10. A process as claimed in claim 9, wherein resolution is carried out at temperature 0-70 C, preferably, 0-45°C. 11. A process as claimed in claim 11, wherein the reaction mixture is stirred for 0-26 hours, preferably, 1-10 hours. 12. A process as claimed in claim 1(a), wherein the diastereomeric salt contains the trans-(3S,4R)-isomer 60-100%, preferably, 80-100% and trans-(3R,4S)-isomer 40-0%, preferably, 20-0%. 13. A process as claimed in claim 1(b), wherein diastereomeric salt is separated by filtration over Nutsche filter or by centrifugation at temperature 0-70°C preferably, 0-45°C. 14. A process as claimed in claim 1(c), wherein purification of moderately resolved diastereomeric salt is accomplished in 0-10 volumes of a single solvent or a solvent mixture containing primary, secondary or tertiary alcohol (C1-C6) with water to get desired optical purity. 15. A process as claimed in claim 14, wherein purification of moderately resolved diastereomeric salt is accomplished in solvent mixture of 0-5 volumes of methanol and 0-5 volumes of water to get desired optical purity. 16. A process as claimed in claim 1(c), wherein the purification is carried out at 0-70 C, preferably, 0-45°C 17. A process as claimed in claim 1(c), wherein reaction mixture is stirred for 0.5-4 hours, preferably, 0.5 to 1 hour before filtration. 18. A process as claimed in claim 17, wherein the diastereomeric salt contains trans-(3S,4R)-isomer is 93-100% and trans-(3R,4S)- isomer is 7-0%, preferably, 2-0%. 19. A process as claimed in claim 1(c), wherein purified diastereomeric salt has required 1-2 more purification in same condition as claimed in preceding claims, to get desired optical purity (>99.5 %) depending upon the ratio of alcohol and dipolar solvents in solvent system, preferably one more purification is required to get desired optical purity. 20. A process as claimed in claim 26, wherein the optical purity of trans-(3S,4R)-(-)-isomer of N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine is enhanced from 98 to 99.95%. 9 21. A process as claimed in claim 1(d), wherein pure diastereomeric salts having optical purity >99.5% is treated with aqueous solution of base i.e. alkali metal hydroxides, carbonates and bicarbonates to get free trans-(3S,4R)-(-) or trans-(3R,4S)-(+)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine with optical purity between 99.5-99.9%, but most preferably aqueous sodium hydroxide solution is used. 22. A process as claimed in preceding claims, wherein the mother liquor obtained from purification contains diastereomeric salts, having optical purity 45-65% of trans-(3S,4R)-(-) or trans-(3R,4S)-(+)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine, that can be purified to enhance the productivity. 10 Abstract: The invention relates to a process for the manufacturing enantionierically pure intermediate of Paroxetine hydrochloride i.e. ^ram-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine by resolving ?ram,-(+)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl-piperidine using most economically viable resolving agents like D-(-)-tartaric acid to form a mixture of diastereomeric salts, separating the diastereomeric salts by fractional crystallization in a mixture of solvent systems of the kind such as described herein, in the specified time and temperature range to provide said trans-(3S,4R)-(-)-N-methyl-4-(4'-fluorophenyl)-3-hydroxy methyl piperidine. 11

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