Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF VENLAFAXINE

Abstract

The invention discloses a process for the preparation of 1-[2-(dimethylamino)- 1-(4-methoxyphenyl) ethyl] cyclohexanol (I), Venlafaxine and its pharmaceutically acceptable salts, which comprises the steps of (a)condensing 4-methoxy phenyl acetonitrile (II) with cyclohexanone (III) using a base in an alcoholic solvent at a temperature range of -5° to 15° C to produce 1-[cyano(4-methoxyphenyl) methyl] cyclohexanol (IV) (b)reducing the 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV) with NaBH4 in presence of a carboxylic acid in an aprotic solvent at a temperature range of 25° to 80°C to prepare 1-[2-amino-1-(4-methoxyphenyl) ethyl]cyclohexanol (V) (c)converting the 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (V) in to Venlafaxine (I) and its pharmaceutical salts by manner known per se. The invention is also for preparation of intermediate compound (v) above by novel process steps (a) and (b) as stated.

Full Text

The invention relates to an improved process for the preparation of venlafaxine i.e 1-[2(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol Venlafaxine i.e. 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanoll (I) and its pharmaceutically acceptable salts, such as hydrochloride, are widely used for the treatment of depression. Venlafaxine is phenylethylamine derivative possessing a neuropharmacological profile, which differs from that of tricyclic antidepressant drugs. Venlafaxine is a departure from the earlier classes of antidepressants, offering equivalent or even better efficacy, while improving on many of undesirable side effects of the earlier classes. Venlafaxine inhibits the synaptosomal reuptake of both serotonin and noradrenaline and is also a weak inhibitor of dopamine reuptake (Stephen M. Hollyday and Paul Benfield; Drugs 49(2): 280-294; 1995). Background of the invention In literature, it is known that Venlafaxine i.e. 1-[2-(dimethylamino)-1-(4- methoxyphenyl) ethyl]cyclohexanol (I) and its pharmaceutically acceptable salts can be prepared by - (a) condensing 4-methoxy phenyl acetonitrile (II) with cyclohexanone (III) to prepare 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV) as shown in Scheme -1 (b) reducing the 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV) to prepare 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (V) as shown in Scheme-2. ( c) The intermediate 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (V) as obtained by reduction of (IV) in Scheme 2 above is further converted to Venlafaxine (I). As disclosed in US 4535186, 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV) is prepared by condensation of 4-methoxy phenyl acetonitrile (II) with cyclohexanone (III) by using n-butyl lithium. The draw back of this condensation process lies in the use of the n-butyl lithium, which is a highly flammable, pyrophoric, moisture sensitive and corrosive in nature. Also, the reaction is carried out at very low temperature i.e. -50°C to -70° C. Maintaing such low temperature is not convenient on commercial scale. Moreover, yield quoted for the condensation is below 50%. To avoid the use of n-butyl lithium and improve the yield for above condensation process, lithium diisopropylamide was used in WO 00/32556. Though, it improved the yield, but the reaction was carried out at low temperature of -65° C to -78° C. Maintaining such low temperature and handling the lithium diisopropylamide, which is corrosive in nature, are not convenient at commercial level. Also, the improved yield (80.7%) is still not satisfactory for commercial exploitation. In attempt to avoid low temperature, CN 1225356 used organic base like sodium methoxide, sodium ethoxide, sodium hydride for the above condensation process. However, the handling of such hazardous bases are inconvenient. Also, there is a need to have the higher yields on commercial production scale. In WO 02/18325, 10% aqueous sodium hydroxide used for the condensation of 4-methoxy phenyl acetonitrile (II) with cyciohexanone (III) in presence of phase transfer catalyst (PTC) like tetra butyl ammonium bromide. However, the use of such catalyst at commercial level makes the process costlier. Also, EP 1238967 disclose the condensation process by using aq. NaOH/KOH or powdered NaOH/KOH in presence or absence of PTC. However, much lower yield (78%) is obtained in absence of PTC. Also, the addition of powdered NaOH/KOH is exothermic, which increases the impurities. Thus there is a need for an improved process for condensing 4-methoxy phenyl acetonitrile (II) with cyciohexanone (III) to prepare 1-[cyano(4- methoxyphenyl)methyl]cyclohexanol (IV) that avoids any hazardous and toxic chemicals . Also, the reaction should be easy to operate and eco-friendly with higher yield. Further, 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV) is reduced over rhodium on alumina, to prepare 1-[2-amino-1-(4-methoxyphenyl)ethyl] cyclohexanol (V) according to Scheme -2 as disclosed in US 4535186. The main drawback of this reaction lies in the use of rhodium on alumina, which is hazardous in nature and is a costly chemical. Also, the reaction is carried out in parr apparatus under high pressure. Maintaining such high pressure makes the process critical and requires special equipment, which is not economical on commercial scale. To avoid the use of hazardous rhodium as reducing agent, Raney Nickel is used at 30°-60° C in parr apparatus as disclosed in US 6350912 B1. But maintaining such temperature under high pressure is difficult to handle and may be explosive. Yet in another attempt to solve the problem associated with the above reduction process, CN 1225356 used 40-50% BF3 - etherate solution as reducing agent. However, the use of BF3 as reducing agent, which is highly toxic in nature should better be avoided for commercial production of Venlafaxine. Also, to solve the problem associated with the use of parr apparatus in reduction process of 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV), WO 0032555 disclosed the use of sodium borohydride in presence of cobalt chloride as reducing agent. However, the main drawback of this process is in use of cobalt chloride, which is carcinogenic and toxic in nature. Also, the reported yield is low. Considering the potential use of the drug venlafaxine, there is a demand for a cost effective process for the synthesis of venlafaxine on commercial scale with higher yield. Also, process to be economical should dispense with special equipment like parr apparatus and without any costly catalyst. The process should be easy to operate on commercial scale. Also, the method needs to be using reagents which are non toxic, non- hazardous and easy-to-handle on a commercial scale, and thus the process needs to avoid reagents such as n- butyl lithium, lithium diisopropylamide, rhodium on alumina, BF3 and the like. OBJECT OF THE INVENTION The first object of the invention is to provide an improved, cost effective and simple process, for production of Venlafaxine i.e. 1-[2-(dimethylamino)-1-(4- methoxyphenyl)ethyl]cyclohexanol (I) or its pharmaceutically acceptable salt in higher yield. The second object of the invention is to provide an improved process for production of 1-[2-amino-1-(4-methoxyphenyl) ethyl]cyclohexanol (V) a key intermediate in the production of Venlafaxine. The third object of the invention to provide a cost effective process to prepare 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV) an early intermediate in production of Venfalxine by condensing 4-methoxy phenyl acetonitrile (II) with cyclohexanone (III) while avoiding very low temperature and use of hazardous chemical like n- butyl lithium, lithium diisopropyl amide as condensation reagent. These and other objects of the present invention will become apparent with reference to the following description and claims. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to process for the preparation of biologically active phenylethyl amine i.e. 1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl] cyclohexanol (I), Venlafaxine and its pharmaceutically acceptable salts, which comprises the steps of (a)condensing 4-methoxy phenyl acetonitrile (II) with cyclohexanone (III) using a base in an alcoholic solvent at a temperature range of -5 ° to 15 ° C to produce 1-[cyano(4-methoxyphenyl) methyl] cyclohexanol (IV) (b)reducing the 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV) with NaBH4 in presence of a carboxylic acid in an aprotic solvent at a temperature range of 25° to 80°C to prepare 1-[2-amino-1-(4-methoxyphenyl) ethyl] cyclohexanol (V) (c)converting the 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (V) in to Venlafaxine (I) and its pharmaceutical salts by manner known per se for example by methods of US 4535186 ; J. Med. Chem. 1990, 33, 2899-2905. The base used in the step (a) is an alkali hydroxide selected from sodium hydroxide, potassium hydroxide, or cerium hydroxide. The preferred base is sodium hydroxide. The alcoholic solvent used in the step (a) is an alcohol selected from methanol, ethanol, isopropyl alcohol and n-butanol or a combination thereof. The preferred alcoholic solvent is selected from methanol, ethanol and isopropylalcohol. The most preferred alcoholic solvent is methanol. The reaction step (a) is carried out at a temperature range of -5 ° to 15°C. The preferred temperature range is -5 ° to 5°C. The most preferred temperature range is -5° to 0°C. The reaction step (a) is carried for 2 to 4 hrs. The carboxylic acid used in the step (b) is selected from acetic acid, trifluoroacetic acid, trichloroacetic acid and the like. The preferred carboxylic acid is trifluoroacetic acid. The aprotic solvent in the step (b) is selected from the group consisting of ether, ester, ketone and halogenated solvents or combination thereof. The preferred aprotic solvent is selected from the group consisting of tetrahydrofuran, ethyl acetate, dioxane and methylene dichloride. The most preferred aprotic solvent is tetrahydrofuran. The reaction step (b) is carried out at a temperature range of 25° to 80°C. The preferred temperature range is of 25 ° to 60°C. The reaction step (b) is carried out for 24 to 36 hrs. According to the present invention, Venlafaxine Hydrochloride (VI), which is a marketed salt of Venlafaxine (I), is prepared as shown in Scheme- 4. Scheme- 4 Accordingly the present invention provides for an improved process for the preparation of Venlafaxine i.e. 1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl]cyclohexanol of formula (I) and its pharmaceutically acceptable salts, which comprises the steps of (a) condensing 4-methoxy phenyl acetonitrile (II) with cyclohexanone (III) using base such as herein described in an alcoholic solvent such as herein described at a temperature range of -5° to 15°C to produce 1-[cyano(4- methoxyphenyl) methyl] cyclohexanol (IV) (b) reducing the 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV) with NaBH4 in presence of carboxylic acid such as herein described in an aprotic solvent such as herein described at a temperature range of 25° to 80°C to prepare 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (V) c) converting the 1-[2-amino-1-(4-methoxyphenyl) ethyl]cyclohexanol (V) in to Venlafaxine (I) or its pharmaceutically salts like hydrochloride by manner known per se. The present invention further provides for a process for preparation of 1-[2- amino-1-(4-methoxyphenyl)ethyl] cyclohexanol (v) the key intermediate in the process for the preparation of Venlafaxine i.e. 1-[2-(dimethylamino)-1-(4- methoxyphenyl) ethyl] cyclohexanol and its pharmaceutically acceptable salts which comprises the steps of : (a) condensing 4-methoxy phenyl acetonitrile (II) with cyclohexanone (III) using base such as herein described in an alcoholic solvent such as herein described at a temperature range of -5 ° to 15°C to produce 1-[ cyano (4- methoxyphenyl) methyl] cyclohexanol (IV) (b) reducing the 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV) with NaBH4 in presence of carboxylic acid such as herein described in an aprotic solvent such as herein described at a temperature range of 25 ° to 80 ° C to prepare 1-[2-amino-1-(4- methoxyphenyl) ethyl] cyclohexanol (V) In the following section a preferred embodiments are described by way of examples to illustrate the process of this invention. However, this is not intended in any way to limit the scope of the present invention. PREPARATORY EXAMPLE Example 1 Preparation of 1-[cyano(4-methoxyphenyl) methyl] cyclohexanol (IV): In a 1 It. 4-neck round bottom flask equipped with stirrer, thermometer, ice- bath tub, 50gm of 4-methoxyphenyl acetonitrile and 49.25gm of cyclohexanone were charged. Further the reaction mixture cooled at -5 ° to 0°C and clear solution of sodium hydroxide in methanol (13.60 gm NaOH in 136ml of methanol) was slowly added. It was maintained for 2 to 4 hours at -5 ° to 0°C and 500ml DM water added. The reaction mixture is further filtered, washed and recrystallized with isopropanol below 30°Cto obtain 82gm of 1-[cyano(4-methoxyphenyl) methyl] cyclohexanol (IV). Yield: 98.5%. Example 2 Preparation of 1-[2-amino-1-(4-methoxyphenyl) ethyl] cyclohexanol (V): In a 2 It. 4-neck round bottom flask equipped with stirrer, condenser and CaCl2 guard tube, 685 ml of tetrahydrofuran (THF) was charged. Further 40gm of NaBH4 added under stirring for half an hour and 120gm of trifluoroacetic acid added slowly within 1.5 hour. The reaction mixture is further stirred for 2 hours and the clear solution of 100gm of 1-[cyano(4-methoxyphenyl) methyl] cyclohexanol (IV) in 257 ml of tetrahydrofuran added and maintained for 24 hours at 20 to 25°C. Further it is maintained for 4 hours at 40 to 45°C and ice water added below 10°C. The reaction mixture filtered and washed with THF and THF distilled out below 65°C. Further 1000ml deminerlized (DM) water added. The PH of the reaction mixture was adjusted to 1 with con. HCI and stirred for 15 minutes. The pH was further adjusted to 10- 10.5 with liquor ammonia and stirred for 30 minutes and extracted with methylene dichloride. Organic layer was dried over Na2SO4 and filtered and washed with dichloromethane to obtain 100gm of oily 1-[2-amino-1-(4-methoxyphenyl) ethyl] cyclohexanol (V). Yield: 98.4 %. Example 3 Preparation of Venlafaxine hydrochloride (VI): In a 2 It. 4-neck round bottom flask equipped with stirrer and condenser, 110gm of 1-[2-amino-1-(4-methoxyphenyl) ethyl] cyclohexanol (V) was charged. It was treated with 110.5 ml of formic acid and 137.5 ml of formaldehyde under stirring and 1100ml of water added and refluxed for 24 hours and the water distilled. The reaction mixture cooled to 30-35°C. 500ml of DM water added and pH was adjusted to 1 with dil.HCI and extracted with ethyl acetate. The extract was discarded. The aqueous residue was basified by sodium hydroxide and thrice extracted with ethyl acetate and the organic layer washed with saturated sodium chloride and separated and dried over Na2SO4. The reaction mixture is filtered and evaporated to oil. It was then charged in a 2lit. 4-neck round bottom flask with 500ml of ethyl acetate and 10gm of activated charcoal and refluxed for half an hour and filtered through hyflow. In filtrate 100ml of IPA HCI added at 50°C and maintained at 5 to 10°C for 2 hours. The reaction mixture was filtered, washed and dried to obtain 55.5 gm of venlafaxine hydrochloride. Yield: 40.1% 50.0 gm of compound was further recrystallized in 1400 ml mixture of methanol / ethyl acetate (3:25) to yield 47 gm (94%) Venlafaxine Hydrochloride having HPLC purity >99.8%. Venlafaxine Hydrochloride characterized by infrared absorption bands (cm-1) at 3801.4, 3743.6, 3672.2, 3349.2, 2935.5, 2858.3, 2836.1, 2579.6, 2479.3, 2422.4, 2361.7, 2336.6, 1611.4, 1511.1, 1468.7, 1434.9, 1398.3, 1307.6, 1245.0, 1178.4, 1146.6, 1109.0, 1038.6, 972.1, 908.4, 836.1, 811.0, 769.5, 738.7. Venlafaxine Hydrochloride characterized by powder X-ray diffraction peaks expressed in degrees 2-thieta values at 6.7, 8.3, 10.2, 12.7, 13.5, 15.6, 16.3, 16.8, 18.9, 19.7, 20.3, 21.1, 21.7, 25.0, 25.6, 26.2, 28.5, 31.0, 31.6, 33.9, 35.1. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to the person skilled in the art and are intended to be included within the scope of the present invention. We claim: 1. An improved process for the preparation of Venlafaxine i.e. 1-[2- (dimethylamino)-1-(4-methoxyphenyl) ethyl]cyclohexanol of formula (I) and its pharmaceutically acceptable salts, which comprises the steps of (a) condensing 4-methoxy phenyl acetonitrile (II) with cyclohexanone (III) using base such as herein described in an alcoholic solvent such as herein described at a temperature range of -5° to 15°C to produce 1-[cyano(4- methoxyphenyl) methyl] cyclohexanol (IV) (b) reducing the 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV) with NaBH4 in presence of carboxylic acid such as herein described in an aprotic solvent such as herein described at a temperature range of 25°to 80°C to prepare 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (V) c) converting the 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (V) in to Venlafaxine (I) or its pharmaceutically salts like hydrochloride by manner known per se. 2. A process for preparation of 1-[2-amino-1-(4-methoxyphenyl)ethyl] cyclohexanol (v), the key intermediate in the process for the preparation of Venlafaxine i.e. 1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl]cyclohexanol and its pharmaceutically acceptable salts which comprises the steps of (a) condensing 4-methoxy phenyl acetonitrile (II) with cyclohexanone (III) using base such as herein described in an alcoholic solvent such as herein described at a temperature of -5° to 15°C to produce 1-[cyano(4- methoxyphenyl) methyl] cyclohexanol (IV) (b) reducing the 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV) with NaBH4 in presence of carboxylic acid such as herein described in an aprotic solvent such as herein described at a temperature range of 25° to 80°C to prepare 1-[2-amino-1-(4-methoxyphenyl) ethyl] cyclohexanol (V). 3. A process as claimed in claim 1, wherein the pharmaceutical salt is hydrochloride. 4. A process as claimed in claim 1, wherein the said base in step (a) is an alkalii metal hydroxide. 5. A process as claimed in claim 4, wherein the said alkali metal hydroxide in step (a) is selected from the group comprising NaOH and KOH. 6. The process as claimed in claim 5, wherein the alkali metal hydroxide is NaOH. 7. A process as claimed in claim 1, wherein the said alcoholic solvent in step (a) is selected from the group comprising of methanol, ethanol, isopropyl alcohol, n-butanol or mixture thereof. 8. A process as claimed in claim 7, wherein the solvent is methanol. 9. A process as claimed in claim 1, wherein the step (a) is carried out at a temperature range of -5° to 5° C. 10. A process as claimed in claim 7, wherein the preferred temperature range is -5° to 0° C. 11. A process as claimed in claim 1, wherein the step (a) is carried out for 2 hrs to 4 hrs. 12. A process as claimed in claim 1, wherein the said carboxylic acid in step (b) is selected from the group consisting of acetic acid, trifluoroacetic acid and trichloroacetic acid. 13. A process as claimed in claim 12, wherein the carboxylic acid is trifluoro acetic acid. 14. A process as clamed in claim 1, wherein the aprotic solvent used in step (b) is selected from ether, ester, ketone, halogenated solvents or mixtures thereof. 15. A process as clamed in claim 14, wherein the aprotic solvent used in step (b) is selected from the group consisting of tetrahydrofuran, ethyl acetate, dioxane and methylene dichloride. 16. A process as claimed in claim 15, wherein the aprotic solvent is tetrahydrofuran. 17. A process as claimed in claim 1, wherein the temperature range is 25° to 60° C. 18. A process as claimed in claim 1, wherein the step (b) is carried out for 24 to 36 hours. 19. A process as claimed in claim 1, wherein compound (IV) obtained in step (a) is purified with isopropanol at the temperature below 30°C. 20. A process for the production of 1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl]cyclohexanol i.e. Venlafaxine of formula (I), and its pharmaceutically acceptable salts substantially as herein described particularly with reference to the foregoing example. 21. A process for the production of 1-[2-amino-1-(4-methoxy phenyl) ethyl] cyclohexanol of formula (V) substantially as herein described particularly with reference to the foregoing example. The invention discloses a process for the preparation of 1-[2-(dimethylamino)- 1-(4-methoxyphenyl) ethyl] cyclohexanol (I), Venlafaxine and its pharmaceutically acceptable salts, which comprises the steps of (a)condensing 4-methoxy phenyl acetonitrile (II) with cyclohexanone (III) using a base in an alcoholic solvent at a temperature range of -5° to 15° C to produce 1-[cyano(4-methoxyphenyl) methyl] cyclohexanol (IV) (b)reducing the 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (IV) with NaBH4 in presence of a carboxylic acid in an aprotic solvent at a temperature range of 25° to 80°C to prepare 1-[2-amino-1-(4-methoxyphenyl) ethyl]cyclohexanol (V) (c)converting the 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (V) in to Venlafaxine (I) and its pharmaceutical salts by manner known per se. The invention is also for preparation of intermediate compound (v) above by novel process steps (a) and (b) as stated.

Documents:

78-kol-2003-assignment.pdf

78-kol-2003-correspondence.pdf

78-kol-2003-examination report.pdf

78-kol-2003-form 18.pdf

78-kol-2003-form 2.pdf

78-kol-2003-form 24.pdf

78-kol-2003-form 3.pdf

78-kol-2003-form 4.pdf

78-kol-2003-form 7.pdf

78-kol-2003-form 9.pdf

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78-kol-2003-gpa.pdf

78-kol-2003-granted-abstract.pdf

78-kol-2003-granted-claims.pdf

78-kol-2003-granted-description (complete).pdf

78-kol-2003-granted-form 1.pdf

78-kol-2003-granted-specification.pdf

78-kol-2003-oposition others 1.pdf

78-kol-2003-oposition others 2.pdf

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78-kol-2003-oposition others 4.pdf

78-kol-2003-oposition others 5.pdf

78-kol-2003-oposition others 6.pdf

78-kol-2003-others.pdf

78-kol-2003-pa.pdf

78-kol-2003-reply to examination report.pdf