Title of Invention

AN IMPROVED PROCESS FOR PREPARING OPTICALLY PURE PIPERIDINE CARBINOL

Abstract

The present invention relates to an improved process of preparing optically pure piperidine carbinol, namely, (-)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-Nmethylpiperidine of Formula I which comprises, combining racemic trans-piperidine carbinol and (-)-dip-toluoyltartaric acid in a mixture of organic solvents selected from the group consisting of ketones and alcohols, crystallizing selectively the (-)-di-p-toluoyltartaric acid salt of (-)-(3S,4R)piperidine carbinol from the above solution,treating (-)-di-p-toluoyltartaric acid salt of (-)- (3S,4R)- piperidine carbinol in water and a water immiscible solvent with a mineral acid, such as hydrochloric acid to recover (-)-di-p-toluoyltartaric acid in water immiscible solvent and regenerating and extracting (-)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl -Nmethylpiperidine of Formula I from the aqueous layer at a pH of 12.0 to 12.5.

Full Text

FIELD OF THE INVENTION The present invention is directed to an industrially advantageous preparation of an optically pure piperidine carbinol. More specifically, the present invention relates to a process for the preparation of (-) - (3S",4R)-4-(4-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine of Formula I which is an important intermediate in the preparation of antidepressant drug Paroxetine of Formula II BACKGROUND OF THE INVENTION Paroxetine of Formula II is a Serotonin (5-hydroxytryptamine, 5HT) reuptake inhibitor and is chemically known as (-) - (35",4i?)-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)piperidine. It is orally administered for the treatment of depression, social anxiety disorder, obsessive-compulsive disorder, panic disorder and post traumatic stress disorder. Various processes have been described for the preparation of Paroxetine, for example, in US 4,007,196, EP 0 223 403. A particularly useful starting material employed in the processes described therein is (-) - (3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine of Formula I. In the process described in US Patent 4,902,801, a racemic trans-piperidine carbinol of Formula I is resolved by conversion to a salt with chiral acids such as (+)-2"-nitrotartranilic acid or (-) di-p-toluoyltartaric acid. The chiral (+)-2"-nitrotartranilic acid resolving agent is not commercially available and the synthesis of this acid requires a number of steps, therefore it is not suited to a large scale manufacture of (-)-(3S",4R)-piperidine carbinol. However, (-)-di-;p-toluoyltartaric acid is commercially available and has been used in acetone to resolve racemic trans-piperidine carbinol. But it has been observed that the process described therein is difficult to control on a large scale, giving inconsistent yields and unacceptable level of impurities. A major problem which has been encountered is the co-crystallization of (-)-di-p-toluoyltartaric acid salt of the unwanted (+)-(3R,4S)-piperidine carbinol enantiomer. In PCT application WO 00/37443 the resolution of racemic piperidine carbinol of Formula I has also been carried out using (-)-di-p-toluoyltartaric acid in acetone. Further, in European pharmacopoeia, the limit for the Paroxetine enantiomer present in Paroxetine is restricted to not more than 0.2%, and therefore optically pure (-)-(3S,4R)-piperidine carbinol is required to prepare Paroxetine meeting EP Pharmacopoeial specifications. Regeneration of (-)-(3S",4R)-piperidine carbinol from the (-)-di-N-toluoyltartaric acid sah has been accomplished in US Application 2003/0004352 Al by adjusting the pH to 10.5 to 11.5 by adding sodium hydroxide. We have found that the alkaline pH is detrimental to (-)-di-p-toluoyltartaric acid, as the extended reaction times during large scale operation cause appreciable hydrolysis of the di-p-toluoyltartaric acid, thereby generating monotoluoyltartaric acid, toluic acid and tartaric acid. These hydrolyzed products contaminate (-)-di-p-toluoyltartaric acid making it unsuitable for recycling it in the process. Furthermore, this hydrolysis reaction destroys (-)-di-p-toluoyltartaric acid resulting in significant addition to the cost of (-)-(3S,4R)-piperidine carbinol manufacture. In view of the above, the present invention has been developed with the aim of improving the chiral purity of (-)-(3S",4R)-piperidine carbinol of Formula I. Further, the present invention provides an efficient commercial process to recover pure (-)-di-p-toluoyltartaric acid wherein hydrolysis reaction to produce monotoluoyltartaric acid, toluic acid and tartaric acid has been restricted SUMMARY OF THE INVENTION The present invention relates to an improved process of preparing optically pure piperidine carbinol, namely (-)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-N"- methylpiperidine of Formula I which comprises, (i) combining racemic trans-piperidine carbinol and (-)-di-p-toluoyltartaric acid in a mixture of organic solvents selected from the group consisting of ketones and alcohols, (ii) crystallizing selectively the (-)-di-p-toluoyltartaric acid salt of (-)-(3S",4R)-piperidine carbinol from the above solution, (iii) treating (-)-di-p-toluoyltartaric acid salt of (-)-(3S",4R)-piperidine carbinol in water and a water immiscible solvent with a mineral acid to recover (-)-di-p-toluoyltartaric acid in water immiscible solvent and (iv) regenerating and extracting (-)-(3S",4R)-4-(4-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine of Formula I from the aqueous layer at a pH of 12.0 to 12.5. DETAILED DESCRIPTION OF THE INVENTION The object of the present invention is to produce optically pure (-)-(3S",4R)-4-(4-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine of Formula I from a racemic trans-piperidine carbinol without the disadvantages encountered in the prior art. Racemic trans-piperidine carbinol can be prepared using the reactions and the techniques described in the US patent 4,902,801 and US patent 5,681,962. The example to resolve piperidine carbinol described in US Patent 4,902,801 makes use of acetone as the solvent and specifies anhydrous conditions. We have surprisingly found that presence of limited amount of an alcohol in acetone is beneficial. We have found that the presence of methanol in acetone avoids the precipitation of unwanted (-)-di-p-toluoyltartaric acid salt of (+)-(3R,4S)-piperidine carbinol. Thus, in the improved process, the racemic trans-piperidine carbinol of Formula I is dissolved in acetone preferably containing 10% v/v methanol. This is treated at 20-25°C with a solution of (-)-di-p-toluoyltartaric acid dissolved in acetone containing 10% v/v methanol and holding the crystallization mixture at 20-25°C, preferably for 1 hour, to consolidate the crystallization. The crystallization is completed by cooling the mixture to preferably between 5°C and 10°C and preferably maintaining at this temperature for 1 hour. Precipitated (-)-di-p-toluoyltartaric acid salt is isolated at 5-10°C, washed with 9:1 v/v acetone-methanol mixture and dried at 40-45 °C under vacuum to obtain (-)-di-p-toluoyltartaric acid salt of (-)-(3S,4R)-piperidine carbinol having a minimum of 99.8% chiral purity by HPLC. The mother liquor containing (-)-di-p-toluoyltartaric acid salt of the unwanted {+)-(3R,4S)-piperidine carbinol enantiomer is concentrated under vacuum and (-)-di-p-toluoyltartaric acid is recovered from the residue by the procedure described in the following paragraph. In the present invention, the recovery of (-)-di-p-toluoyltartaric acid from the corresponding (-)-di-p-toluoyltartaric acid salt of (-)-(3S",4R)-piperidine carbinol is achieved by dissolving the salt in water and adding water immiscible organic solvent, preferably ethyl acetate or toluene and treating it with a suitable mineral acid, preferably hydrochloric acid and extracting the regenerated (-)-di-p-toluoyltartaric acid into the organic layer. From this organic layer pure (-)-di-p-toluoyltartaric acid can be recovered by concentration under vacuum. It has been observed that (-)-di-p-toluoyltartaric acid is rapidly hydrolyzed in basic pH than in the acidic conditions. Therefore, treating (-)-di-p-toluoyltartaric acid salt of piperidine carbinol with mineral acid in the present invention provides almost quantitative recovery of (-)-di-/»-toluoyltartaric acid which can be reused. Thereafter, (-)-(3S",4R)-piperidine carbinol is obtained from the aqueous layer by raising the pH to 12.0-12.5 with aqueous sodium hydroxide and extracting the released carbinol into an organic solvent, which is dichloromethane, toluene or ethyl acetate, preferably ethyl acetate, at a temperature in the range 10 to 20°C. In the present process, the organic extract of (-)-(3S",4R)-piperidine carbinol is concentrated under vacuum and hexanes are added to the concentrated mass at elevated temperature, preferably at 50 to 60°C, to obtain a clear solution, which is slowly cooled to 10 to 20°C to produce optically pure crystalline (-)-(3S",4R)-piperidine carbinol which has very low level of impurities and that can be readily isolated and dried. Major advantage of the present invention is the high optical purity of (-)-{3S,4R)-piperidine carbinol in which the unwanted (+)-(3R,4iS)-enantiomer is less than 0.2%. The improvement realized in the present invention as compared to the prior art process is the high recovery of pure (-)-di-p-toluoyltartaric acid by releasing it in an acidic medium to avoid its hydrolysis to monotoluoyltartaric acid, toluic acid and tartaric acid. The recovered (-)-di-p-toluoyltartaric acid can be recycled in the process which is of significant value in the large scale manufacture of (-)-(3S",4R)-piperidine carbinol. (-)-(3S",4R)-piperidine carbinol of the present invention can be used for the preparation of Paroxetine or a pharmaceutical acceptable salt thereof, and specially the hydrochloride hemihydrate. This comprises coupling of (-)-(35",4i?)-piperidine carbinol with sesamol, and then demethylation, to produce Paroxetine of Formula II and optionally forming a pharmaceutically acceptable salt as described in US patent 4,721,723 and US Patent 4,007,196. Further the invention is illustrated by the following example without limiting it. STEP! PREPARATION OF (-)-DI-P-TOLUOYLTARTARIC ACID SALT OF (-)-(3S,4R)-PIPERIDINE CARBINOL (+)-trans-4-(4-Fluorophenyl)-hydroxymethyl-N-methylpiperidine (50 g) was dissolved in 9:1 v/v mixture of acetone and methanol (1800 ml). Thereafter, solution of (-)-di-(P)-toluoyltartaric acid (103.85 g) in 200 ml of 9:1 v/v acetone and methanol mixture was added slowly in 1 hour maintaining the temperature between 20 and 25°C. The crystallization mixture was stirred for 1 hour at 20-25°C and then cooled to S-10°C and continued stirring for 1 hour. The product was filtered, washed with acetone (200 ml) and dried at 40-45°C under reduced pressure to obtain 50 g of title compound having chiral purity 99.8% by HPLC. STEP II PREPARATION OF (-)(3S,4R)-4-(4-FLUOROPHENYL)-3-HYDROXY - METHYL-N-METHYLPIPERIDINE 25 g of (-)-di-p-toluoyltartaric acid salt of (-)-(3S,4R)-piperidine carbinol was suspended in a mixture of DM water (75 ml) and ethyl acetate (75 ml) and cooled to 10-20°C. pH was adjusted to 0.6-0.8 with concentrated hydrochloric acid and mixture stirred for 15 minutes. Thereafter, layers were separated and aqueous layer extracted with 50 ml of ethyl acetate. The combined ethyl acetate extract was concentrated under vacuum to recover (-)-di-p-toluoyltartaric acid. The aqueous layer was treated at 10-20°C with sodium hydroxide solution to raise the pH to 12.0-12.5 and the liberated (-)-(3S",4R)-piperidine carbinol was extracted with ethyl acetate (2x100 ml). The combined ethyl acetate extract was washed with aqueous brine and concentrated under vacuum to distil ethyl acetate. The residue was diluted with hexanes (200 ml) at 55-60°C and then slowly cooled to 10-20°C for crystallization. The crystallized product was filtered, washed with hexanes (10 ml) and dried to obtain 8.5 g of (-)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-//-methylpiperidine having chiral purity 99.8% by GC. WE CLAIM: 1. The present invention relates to an improved process of preparing optically pure piperidine carbinol, namely (-)-(3S",4R)-4-(4-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine of Formula I which comprises, (J) combining racemic trans-pipevidinG carbinol and (-)-di-p-toluoyltartaric acid in a mixture of organic solvents selected from the group consisting of ketones and alcohols, (ii) crystallizing selectively the (-)-di-p-toluoyltartaric acid salt of (-)-(3S",4i?)-piperidine carbinol from the above solution, (iii) treating (-)-di-p-toluoyltartaric acid salt of (-)- (35,4/?)- piperidine carbinol in water and a water immiscible solvent with a mineral acid, such as hydrochloric acid to recover (-)-di-p-toluoyltartaric acid in water immiscible solvent and (iv) regenerating and extracting (-)-(3S",4R)-4-(4-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine of Formula I from the aqueous layer at a pH of 12.0 to 12.5. 2. The process according claim 1 wherein a mixture of acetone and methanol is preferably used to selectively crystallize (-)-di-p-toluoyltartaric acid salt of (-)- (3S",4R)-piperidine carbinol. 3. The process according claim 2 wherein acetone and methanol are in the ratio of 9:1 by volume. 4. The process according claim 1 wherein the water immiscible organic solvent is toluene or ethyl acetate, and preferably ethyl acetate. 5. The process according claim 1 wherein the product obtained has a minimum of 99.8% chiral purity.

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