Title of Invention	NOVEL PROCESS FOR THE PREPARATION OF 1-[2-AMINO-1-(P-METHOXY PHENYL)ETHYL] CYCLOHEXANOL
Abstract	A process for the manufacture of 1-[2-amino-(p-methoxyphenyl)ethyl] cyclohexanol of the structural formula (II) or its pharmaceutically acceptable salt by catalytic hydrogenation of 2-(4 methoxy phenyl)-1-oxa-spiro [2,5] octane-2-carbonitrile( I) in a suitable solvent in presence of ammonia or acids in presence of hydrogenating catalyst selected from Raney Ni or Noble metals and hydrogen.

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FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION [See sections 10] NOVEL PROCESS FOR THE PREPARATION OF 1-[2-AMINO-1- (P-METHOXYPHENYL) ETHYL]CYCLOHEXANOL. ALEMBIC LIMITED; ALEMBIC ROAD; VADODARA-390003 GUJARAT. INDIA The following specification particularly describes and ascertains the nature of the invention, and the manner in which it is to be performed. 13 NOV 2002 NOVEL PROCESS FOR THE PREPARATION OF ( 1-[2-AMINO-1-(P-METHOXYPHENLYL)ETHYL]CYCLOHEXANOL. TECHNICAL FIELD : The present invention relates to an improved process for the preparation of 1-[2-Amino-1-(p-methoxyphenyl)ethyl] cyclohexanol of formula (II) from 2-(4 methoxy phenyl)-1-oxo-spiro[2-5]octane-2-carbonitrile formula (I) by catalytic hydrogenation using Raney Nickel in ammoniacal alcohol or nobel metal catalyst in acidic alcohol. BACKGROUND OF THE INVENTION : 1-[2-Amino-1-(p-methoxyphenyl)ethyl] cyclohexanol is one of the key intermediate for the synthesis of well known antidepressant drug Venlafaxine Hydrochloride. The prior art [Husbands et al. EP 0112669 (US 4535186)] discloses a preparation of 1-[2-Amino-1-(p-methoxyphenyl)ethyl] cyclohexanol [Formula II] from 1-[cyano-(p-methoxyphenyl ) methyl ] cyclohexanol [Formula I] by reduction using Rhodium on alumina as the catalyst. The prior art WO 02/50017A1 discloses a preparation of 1-[2-Amino-1-(p- methoxyphenyl)ethyl] cyclohexanol [Formula II] from 1-[cyano-(p- methoxyphenyl ) methyl ] cyclohexanol [Formula I] by reduction using pre-treated catalyst (i.e. Raney-Ni) and methanol with ammonia concentration. These known synthetic routes tend to involve the use of hazardous, costly and moisture sensitive reagents. For example, the synthesis described in EP 0,112,669 requires a very low reaction temperature (-50°C to -70°C), and hydrogenation step which uses expensive and not readily available rhodium catalyst. WO 02/50017A1 discloses 1-[2-Amino-1-(p-methoxyphenyl)ethyl] cyclohexanol [Formula II] from 1-[cyano-(p-methoxyphenyl ) methyl ] cyclohexanol [Formula I] by reduction using pre-treated catalyst. In this method first the catalyst is treated with carboxylic acid or a salt or an hydride or with an ammonium salt and then after carry out the reaction in methanol with ammonia concentration. Therefore, an objective of the present invention is to provide a simple synthetic route for the preparation of 1-[2-Amino-1-(p-methoxyphenyl)ethyl] cyclohexanol, a key intermediate for the synthesis of Venlafaxine, starts from a novel intermediate 2-(4 methoxy phenyl)-1-oxo-spiro[2-5]octane-2-carbonitrile and employs mild and simple reaction conditions. SUMMARY OF THE INVENTION : The present invention provides a process for the manufacture of 1-[2-amino-(p-methoxyphenyl)ethyll cyclohexanol of the structural formula (II) which comprises the reduction of 2-(4 methoxy phenyl)-1-oxo-spiro[2-5] octane-2-carbonitrile in a suitable solvent in the presence of a hydrogenating catalysts at a temperature in the range between 20-70°C. Time taken for reduction is in the range of 10-26 hours while hydrogen pressure is in the range of 0.5 to 5 kg of hydrogen. The same is depicted in Scheme II. Scheme - II In one embodiment of the invention, the hydrogenation catalyst comprises Raney Nickel or Nobel metal catalysts such as Palladium on carbon, Platinum on carbon and Platinum Dioxide and Rhodium on Alumina. In another embodiment of the invention, the suitable solvent comprises ammoniacal alcohols such as methanol, ethanol, propanol or butanol more preferably methanol when Raney Nickel or other nobel metal catalysis mentioned as above. In another embodiment of the invention where in the Raney nickel or modified raney nickel used , the hydrogenations is performed in ammonical alcohols. In another embodiment of the invention where in the suitable solvent comprises acidic alcohols such as methanol, ethanol, propanol or butanol more preferably methanol when nobel metal catalysts is used as the catalyst. DETAILED DESCRIPTION OF THE INVENTION : The present invention achieved the foregoing object and found that 2-(4 methoxy phenyl)-1-oxo-spiro [2-5] octane-2-carbonitrile can be reduced to 1-[2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol ( II ) by catalytic hydrogenation using a hydrogenation catalyst Raney Nickel or nobel metal catalysts such as Palladium or Platinum in a suitable polar solvent containing acid or base. When hydrogenation catalyst is Raney Nickel or Rhodium on Aluminapreferably the solvent used is an ammoniacal alcohol such as methanol, ethanol, propanol or butanol more preferably methanol. The concentration of ammonia in alcohol is preferably 5.0% to 10% (W / V). When hydrogenation catalyst is noble metal catalyst such as the above alcoholic solvents containing organic acid or mineral acid can be used. 1-[2-amino-1-(p-methoxyphenyl)ethylJcyclohexanol (II) so produced by the process of the invention can be converted in to Venlafaxine Hydrochloride by the prior art process reported in EP 0112699. The process of the invention will now be described in greater detail making reference to the following examples. The illustrated examples, however should not be construed to limit the scope of the invention: Example: 1 2-(4 methoxyphenyl)-1-oxo-spiro[2-5] octane-2-carbonitrile (100g) was dissolved in methanol (1000 ml) containing 90 gm ammonia ( concentration of ammonia = 5% to 10% W/V) and hydrogenated in an autoclave over 100 gm Raney Ni at 50 psi pressure of hydrogen for 10-14 hours at room temperature. The catalyst was filtered, washed with methanol and the combined filtrate evaporated and dried under reduced pressure to furnish free base of 1-[2-Amino-1-(p-methoxyphenyl)ethylJ cyclohexanol. The residue was dissolved in isopropanol 100 ml and treated with iso-propanolic HCI . Isopropanol was distilled out and the residue was treated with ethyacetate & slurry is stirred 1 hour. The product was filtered, washed with ethyl acetate and dried under vacuum at 60° C to obtain 66 g 1-[2-Amino-1-(p-methoxy phenyl)ethyl] cyclohexanol hydrochloride. M. P.170°C-1730C. IR: (cm-1) 3421,2954,1614,1514,1250,1153,1028, 964, 839, 830. 1H NMR (DMSO-d6) 8 7.96 (s, 3H,NH3), 7.2 (d, 2H, aromatic), 6.87 (d, 2H, aromatic), 3.69 (s, 3H, OCH3), 3.14 (m, 3H, CHCH2), 1.2 (m, 10H, cyclohexyl H). 13C NMR (DMSO-c6) 5 159.1, 131.56, 131.04, 114.33, 72.62, 55.85, 53.15, 37.19, 34.46, 26.18, 22.29, 21.97. MS:250(M++1) Example: 2 2-(4 methoxyphenyl)-1-oxo-spiro[2-5] octane-2-carbonitrile (100g) was dissolved in methanol (1000 ml) containing 95 gm ammonia ( concentration of ammonia -5% to 10% W/V) and hydrogenated in an autoclave over 85 gm Raney Ni at 50 psi pressure of hydrogen for 10-14 hours at room temperature. The catalyst was filtered, washed with methanol and the combined filtrate evaporated and dried under reduced pressure to furnish free base of 1-[2-Amino-1-(p-methoxyphenyl)ethyl] cyclohexanol. The residue was dissolved in isopropanol 100 ml and treated with iso-propanolic HCI . Isopropanol was distilled out and the residue was treated with ethyacetate & slurry is stirred 1 hour. The product was filtered, washed with ethyl acetate and dried under vacuum at 60° C to obtain 66 g 1-[2-Amino-1-(p-methoxy phenyl)ethyl] cyclohexanol hydrochloride. M. P. 170°C-173°C. IR : (cm1) 3421, 2954, 1614, 1514, 1250,1153, 1028, 964, 839, 830. fH NMR (DMSO-c6) 5 7.96 (s, 3H, NH3+), 7.2 (d, 2H, aromatic), 6.87 (d, 2H, aromatic), 3.69 (s, 3H, OCH3), 3.14 (m, 3H, CHCH2), 1.2 (m, 10H, cyclohexyl H). 13C NMR (DMSO-d6) 8 159.1, 131.56, 131.04, 114.33, 72.62, 55.85, 53.15, 37.19, 34.46, 26.18, 22.29, 21.97. MS:250(M++1) Example : 3 2-(4 methoxy phenyl)-1-oxo-spiro[2-5] octane-2-carbonitrile (10g) was dissolved in methanol (100 ml) add 10 ml Acetic acid and 2 gm Platinum Oxide and hydrogenated in an autoclave at 50 psi pressure of hydrogen for 5-9 hours at room temperature. The catalyst was filtered, washed well with methanol and the combined filtrate evaporated and dried under reduced pressure yielding residue. The residue was dissolved in 20-ml ethylacetate and treated with iso-propanolic HCI. The slurry is stirred at 10°C for 1 hour. The product is filtered , washed with ethyl acetate and dried under vacuum at 60° C gives 7-8 gm 1-[2-Amino-1-(p-methoxyphenyl)ethyl]cyclohexanol hydrochloride. M. P. 170°C-173°C. IR : ( cm1) 3421, 2954, 1614, 1514, 1250,1153, 1028, 964, 839, 830. 1H NMR (DMSO-cfe) 8 7.96 (s, 3H, NH3+), 7.2 (d, 2H, aromatic), 6.87 (d, 2H, aromatic), 3.69 (s, 3H, OCH3), 3.14 (m, 3H, CHCH2), 1.2 (m, 10H, cyclohexyl H). 13C NMR (DMSO-cfe) 5 159.1, 131.56, 131.04, 114.33, 72.62, 55.85, 53.15, 37.19, 34.46, 26.18, 22.29, 21.97. MS: 250 (M+ + 1) Example: 4 2-(4 methoxy phenyl)-1-oxo-spiro[2-5] octane-2-carbonitrile (10g) was dissolved in methanol (100 ml), to this was added 10 ml Acetic acid and 5 gm 10% Palladium on carbon and hydrogenated in an autoclave at 5-7 kg pressure of hydrogen for 12-15 hours at room temperature. The catalyst was filtered, washed well with methanol and the combined filtrate evaporated and dried under reduced pressure yielding residue. The residue was dissolved in 20-ml ethylacetate and treated with iso-propanolic HCI to set pH 2 of the mass on pH paper. The slurry is stirred at 10°C for 1 hour. The product is filtered , washed with ethyl acetate and dried under vacuum at 60° C gives 7-8 gm 1-[2-Amino-1-(p-methoxyphenyl)ethyl]cyclohexanol hydrochloride after purification. M. P. 170°C-173°C. IR : (cm-1) 3421, 2954, 1614,1514,1250,1153,1028, 964, 839, 830. 1H NMR (DMSO-cfe) 5 7.96 (s, 3H, NH3+), 7.2 (d, 2H, aromatic), 6.87 (d, 2H, aromatic), 3.69 (s, 3H, OCH3), 3.14 (m, 3H, CHCH2), 1.2 (m, 10H, cyclohexyl H). 13C NMR (DMSO-cfe) 5 159.1, 131.56, 131.04, 114.33, 72.62, 55.85, 53.15, 37.19, 34.46, 26.18, 22.29, 21.97. MS:250(M++1) Example: 5 2-(4 methoxy phenyl)-1-oxo-spiro[2-5] octane-2-carbonitrile (10g) was dissolved in methanol (100 ml) to this was added 10 ml Acetic acid and 8 gm 10% Platinum on carbon and hydrogenated in an autoclave at 5-7 kg pressure of hydrogen for 12-15 hours at room temperature. The catalyst was filtered, washed well with methanol and the combined filtrate evaporated and dried under reduced pressure yielding residue. The residue was dissolved in 20-ml ethylacetate and treated with iso-propanolic HCI to set pH 2 of the mass on pH paper. The slurry is stirred at 10°C for 1 hour. The product is filtered, washed with ethyl acetate and dried under vacuum at 60°C to obtain 7-8 gm 1-[2-Amino-1-(p- methoxyphenyl)ethyl]cyclohexanol hydrochloride after purify by column chromatography. M. P. 170°C-173°C. IR : (cm"1) 3421, 2954, 1614, 1514, 1250,1153, 1028, 964, 839, 830. 1H NMR (DMSO-c6) 6 7.96 (s, 3H, NH3+), 7.2 (d, 2H, aromatic), 6.87 (d, 2H, aromatic), 3.69 (s, 3H, OCH3), 3.14 (m, 3H, CHCH2), 1.2 (m, 10H, cyclohexyl H). 13C NMR (DMSO-cfe) 8 159.1, 131.56, 131.04, 114.33, 72.62, 55.85, 53.15, 37.19, 34.46, 26.18, 22.29, 21.97. MS:250(M+ + 1) Example: 6 2-(4 methoxy phenyl)-1-oxo-spiro[2-5] octane-2-carbonitrile (10g) was dissolved in methanol (100 ml) containing 9g ammonia and hydrogenated in an autoclave over 5 g 5% Rhodium on Alumina at 3-5 kg pressure of hydrogen for 8-10 hours at room temperature. The catalyst was filtered, washed well with methanol and the combined filtrate evaporated and dried under reduced pressure yielding residue. The residue was dissolved in 100-ml isopropanol and treated with iso- propanolic HCI. Isopropanol was distilled out completely and the residue was treated with 200-ml ethyacetate & slurry is stirred at 10°C for 1 hour. The product was filtered, washed with ethyl acetate and dried under vacuum at 60° C gives 6.6 gm 1-[2-Amino-1-(p-methoxy phenyl)ethyl] cyclohexanol hydrochloride after purification. M. P. 170°C-173°C. IR : ( cm1) 3421, 2954, 1614, 1514, 1250,1153, 1028, 964, 839, 830. 1H NMR (DMSO-d6) 5 7.96 (s, 3H, NH3+), 7.2 (d, 2H, aromatic), 6.87 (d, 2H, aromatic), 3.69 (s, 3H, OCH3), 3.14 (m, 3H, CHCH2), 1.2 (m, 10H, cyclohexyl H). 13C NMR (DMSO-de) 8 159.1, 131.56, 131.04, 114.33, 72.62, 55.85, 53.15, 37.19, 34.46, 26.18, 22.29,21.97. MS:250(M++1) We claim - 1. A process for the manufacture of 1-[2-amino-(p-methoxyphenyl)ethyl] cyclohexanol of the structural formula (II) or its pharmaceutically acceptable salt by catalytic hydrogenation of 2-(4 methoxy phenyl)-1-oxa-spiro [2,5] octane-2-carbonitrile( I) in a suitable solvent in presence of ammonia or acids in presence of hydrogenating catalyst selected from Raney Ni or Noble metals and hydrogen. 2. A process as claimed in claim 1 wherein nobel metal catalyst is selected from the group comprising Palladium on carbon, Platinum on carbon and Platinum Dioxide and Rhodium on Alumina. 3. A process as claimed in claim 1 wherein the solvent is THF and an alcoholic solvent such as methanol, ethanol, propanol or butanol. 4. A process as claimed in claim 1, wherein the solvent is ammoniacal alcohol preferably methanol or ethanol when Raney Ni or Rhodium on Alumina is used as catalyst. 5. A process as claimed in claim 4, wherein the concentration of ammonia in methanol is between 1.0% to 6.0% (W/V). 6. A process as claimed in claim 3, wherein the solvent is alcohol when Nobel metal catalyst is used. 7. A process as claimed in claim 3 wherein the alcohol is methanol, ethanol or isopropanol. 8. A process as claimed in claim 1 wherein the acid is selected from organic acid, mineral acid. 9. A process as claimed in claim 1 wherein the temperature is in the range between 20- 70°C. 10. A process as claimed in claim 9 wherein the temperature is preferably 20-40°C. 11. A process as claimed in claim 1 wherein the hydrogen pressure is in the range of 0.5 to 5 kg. Dated this 13th day of November 2002 Meghna Vaidya Of S. Majumdar & CO. Applicant's Agent

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