Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF 1-[2-DIMETHY LAMINO-(4-METHOXY PHENYEL)-ETHYL]CYCLOHEXANOL

Abstract The present invention relates to an improved process for the preparation of 1 -[2-dimethylamino-(4-methoxyhenyl) cyclohexanol of formula 1, The product is commonly known as Venlafaxine and also as effexor. In the process a one pot synthesis of compound of formula 1 from 1 [Cyano(4-methoxyphenyl) -cyclo-hexanol having formula 2 is carried out in presence of formylating agent such as formalin, catalyst-raney nickel and protic solvent. The compound of formula 2 is prepared by a single step conversion comprising the condensation of 4-methoxyphenylacetonitrile with cyclohexanone in the presence of a convenient base like sodium hydroxide
Full Text The present invention relates to an improved process for the preparation of 1-[2-dimethylamino-(4-methoxyphenyl)ethyl]cyclohexanol of formula 1. l-[2-dimethylamino-(4-methoxyphenyl)ethyl]cyclohexanol of formula 1 is commonly known as Venlafaxine and also as effexor. More particularly, the present invention relates to a one pot synthesis of compound of formula 1 from l[Cyano(4-methoxyphenyl)methyl]-cyclo-hexanol having formula 2 which is in turn prepared by a single step conversion comprising the condensation of 4-methoxyphenylacetonitrile with cyclohexanone in the presence of a convenient base like sodium hydroxide
(Formula Removed)
Venlafaxine having formula 1 and its pharmaceutically acceptable salts thereof are important antidepressants of the central nervous system developed by Wyeth-Ayerat & Company in 1993 [Zhou Jinpei, Zhang Huibin, Huang Xuezhe Huang Wenlong J, China Pharm. Univ. 1999, 30(4) P.249-50].
In the prior art [Husbands et al. U.S. Patent No.4, 535, 186 (1985)] compound of the formula 1 is prepared by reaction of p-methoxy phenyl acetonitrile at -78°C, with cyclohexanone under the influence of n-butyl lithium, following available methods [Sauvetre et al. Tetrahedron 34 2135 (1978)] followed by reduction under high pressure using Rhodium on alumina as the catalyst obtained through Lou-c-kart reaction. Symmetrical N-methylation is accomplished via modified Eschweiler -Clarkes procedure employing formalin, formic acid and a large excess of water as illustrated by Tilford et all [J.A.C.S. 76, 2431 (1954)]. Alternatively, the procedure of Borch and Hassid using sodium cyano borohydride and formaldehyde is employed.
In another prior art [Robin Gerald Shepherd UK Patent No GB 2 227 743 A (1990)] the condensation of 4-methoxyphenylacetonitrile with cyclohexanone is accomplished by the use of lithiumdiisopropylamide in hydrocarbon solvents like
hexane toluene or cyclohexane at ambient temperature thereby improving the yield to 79% and further reduction of 2 to the amine followed by protection of the arnine to the required compound of formula 1.
In yet another prior art [Zhou Jinpei, Zhang Huibin, Huang Xuezhen, Huang Wenlong J, China Pharm. Univ. 1999, 30(4) P.249-50], anisole is acylated to the chloroacetyl derivative and aminated using N,N Dimethylamine, the carbonyl group of this compound reduced to alcohol using KBH4 and converted to the bromo derivative using PBr3 which in turn when reacted with Mg and then cyclohexanone underwent a Grignard reaction to provide Venlafaxine.
The use of reagents like butyllithium and lithiumdiisopropylamide, Rhodium on alumina and chloroacetylchloride poses severe drawbacks because of their hazardous nature. More over the solvents used are also hazardous and inconvenient in the large- scale preparation of compound of formula 1.
Objects of the invention
The object of the present invention is to provide a simple and convenient method of synthesis of venlafaxine using easily available raw materials.
Accordingly, the present invention relates to an improved process for the preparation of 2-[dimethylamino-(4-methoxyphenyl)ethyl]-cyclohexanol of formula 1 which comprises reducing l-[cyano(4-methoxyphenyl)-methyl] cyclohexanol of formula 2
(Formula Removed)
characterised in that with a formulating agent in a protic solvent such as methanol in the presence of a catalyst at a temperature in the range between 30-60°C for a time period in the range of 6-16 hours at a pressure in the range of 100 to 400 psi of hydrogen, removing the catalyst by filtration, isolating and purifying the compound of formula 1 by any conventional method.
In one embodiment of the inventions, the formulating agent comprises 35% formalin. In a further embodiment of the invention, the catalyst is Raney nickel.
In another embodiment of the present invention, compound of formula 2 is prepared by treatment of cyclohexanone with 4-methoxy phenyl acetonitrile in the presence of base by the process described in our copending patent application number 232del2001.
In an another embodiment of the present invention, the Raney nickel used is in the ratio ranging from 1:1 to 3:1 (w/v) as that of the starting material.
In yet another embodiment of the present invention, the pressure used is preferably 200 psi of hydrogen.
In still another embodiment of the present invention the reaction time is preferably 10 hours.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed as limit to the scope of the reaction in any manner.
Bxample 1
To a solution of l[Cyano (4-methoxyphenyl) methyljcyclohexanol having formula (2) (5.0 parts, 0.02 mole) in methanol (100 parts) was added formalin (35%soln, 25
parts) and Raney nickel (5 ml, settled material). The mixture was hydrogenated under pressure (200 psi) at 60°C for 6 hrs. The reaction was removed, filtered, the Raney nickel washed with methanol, (4 x 25 parts) the combined filtrates concentrated to an oily residue. It was then dissolved in ethyl acetate (100 parts) and partitioned between 10% dil HC1. The aqueous layer was washed with ethyl acetate, basified to pH 10 using 25% aqueous sodium hydroxide solution, saturated with sodium chloride and extracted with ethyl acetate, after washing with brine (2 x 25 parts) and drying over Na2SO4 was concentrated on rotaevaporator to get a bright white solid m.p. 74-6°C. Yield 1.6 parts (28%).
The acid insoluble portion after washing and drying was concentrated to get the unreacted nitrile (3 parts, 60%).
'HNMR CDC13) 6(ppm): 7.32-6.98 (4H, q, p-substituted aromatic) 3.78 (3H, s, OCH3) 3.64 (2H, m, CH2 N(CH3)2 3.06 (1H, m, CH-CH2N-(CH3) 2.74 (6H, s, N(CH3)2: 1.38 (10H, Br m, aliphatic cyclohexyl)
Example 2
To a solution of l[Cyano(4-methoxyphenyl)methyl]cyclohexanol having formula (2) (5.0 parts, 0.02 mole) in methanol (100 parts) was added formalin (35%soln, 25 parts) and Raney nickel (5 ml, settled material). The mixture was hydrogenated under pressure (200 psi) at 30°C for 16 hrs. The reaction was removed, filtered, the Raney nickel washed with methanol, (4 x 25 parts) the combined filtrates concentrated to an oily residue. It was then dissolved in ethyl acetate (100 parts) and partitioned between 10% dil HC1. The aqueous layer was washed with ethyl acetate, basified to pH 10 using 25% aqueous sodium hydroxide solution, saturated with sodium chloride and extracted with ethyl acetate, after washing with brine (2 x 25 parts) and drying (Na2SO4) was concentrated on a rotaevaporator to get a bright white solid m.p. 74-6°C. Yield 0.85 parts (15%). The acid insoluble portion after washing and drying was concentrated to get the unreacted nitrile 2 -3 parts, 60%).
Example 3
To a solution of 1 [Cyano(4-methoxyphenyl)methyl]cyclohexanol having formula (2) (5.0 parts, 0.02 mole) in methanol (100 parts) was added formalin (35%soln, 25 parts) and Raney nickel (1.25 ml, settled material). The mixture was hydrogenated
under pressure (200 psi) at 60°C for 16 hrs. The reaction was removed, filtered, the Raney nickel washed with methanol, (4 x 25 parts) and the combined filtrates concentrated to an oily residue. It was then dissolved in ethyl acetate (100 parts) and partitioned between 10% dil HC1. The aqueous layer was washed with ethyl acetate, basified to pH 10 using 25% aqueous sodium hydroxide solution, saturated with sodium chloride and extracted into ethyl acetate, after washing with brine (2 x 25 parts) and drying (Na2SO4) was concentrated on a rotaevaporator to get a bright white solid m.p. 74-6°C. Yield 0.85 parts (15%). The acid insoluble portion after washing and drying was concentrated to get the unreacted nitrile 2 (3.2 parts, 64%).
Example 4
To a solution of 1 [Cyano(4-methoxyphenyl)methyl]cyclohexanol having formula (2) (5.0 parts, 0.02 mole) in methanol (100 parts) was added formalin (35%soln, 25 parts) and Raney nickel (2.5 ml, settled material). The mixture was hydrogenated under pressure (400 psi) at 60°C for 10 hrs. The reaction was removed, filtered, the Raney nickel washed with methanol, (4 x 25 parts) the combined filtrates concentrated to an oily residue. It was then dissolved in ethyl acetate (100 parts) and partitioned between 10% dil HC1. The aqueous layer was washed with ethyl acetate, basified to pH 10 using 25% aqueous sodium hydroxide solution, saturated with sodium chloride and reextracted into ethyl acetate, after washing with brine (2 x 25 parts) and drying (NaiSC^) was concentrated on a rotaevaporator to get a bright white solid m.p. 74-6°C. Yield 1.6 parts,30%. The ethyl acetate portion after washing with water (2x20 parts) and drying was concentrated to get the unreacted nitrile 2 (3.2 parts, 64%)


We Claim:
I. An improved process for the preparation of l-2-[dimethylamino-(4-methoxyphenyl ]-cyclohexanol of formula 1 which comprises reducing l-[cyano(4-methoxyphenyl)-methyl]cyclohexanol of formula 2
(Formula Removed)
characterised in that with a formulating agent in a protic solvent such as methanol in the presence of a catalyst at a temperature in the range between 30-60°C for a time period in the range of 6-16 hours at a pressure in the range of 100 to 400 psi of hydrogen, removing the catalyst by filtration, isolating and purifying the compound of formula 1 by any conventional method.
2. An improved process as claimed in claim 1 wherein the formulating agent used
comprises 35% formalin.
3. An improved process as claimed in claims 1 to 2 wherein the catalyst used is Raney
nickel.
4. An improved process as claimed in claims 1-3, wherein the Raney nickel used is in the
ratio ranging from 1:1 to 3:1 (w/v) as that of the starting material.
5. An improved process as claimed in claims 1-4, wherein the pressure used is preferably
200 psi of hydrogen.
6. An improved process as claimed in claims 1-5, wherein the reaction time used is
preferably 10 hours.An improved process as claimed in claims 1-6 wherein the unreacted starting material
used is fully recovered and recycled.
8. An improved process for the preparation of l-2-[dimethylamino-(4-methoxyphenyl)-cyclohexanol of formula 1 substantially as herein described with reference to the examples.



Documents:

232-del-2001-abstract.pdf

232-del-2001-claims.pdf

232-del-2001-correspondence-others.pdf

232-del-2001-correspondence-po.pdf

232-del-2001-description (complete).pdf

232-del-2001-form-1.pdf

232-del-2001-form-19.pdf

232-del-2001-form-2.pdf

232-del-2001-form-3.pdf

232-del-2001-petition-138.pdf


Patent Number 208858
Indian Patent Application Number 0232/DEL/2001
PG Journal Number 33/2007
Publication Date 17-Aug-2007
Grant Date 13-Aug-2007
Date of Filing 28-Feb-2001
Name of Patentee COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH
Applicant Address RAFI MARG NEW DELHI-110 001,India
Inventors:
# Inventor's Name Inventor's Address
1 SUBHASH PRATAPRAO CHAVAN NATIONAL CHEMICAL LABORATORY,PUNE-411008,MAHARASTRA,INDIA
2 SUBHASH KRISHNAJI KAMAT NATIONAL CHEMICAL LABORATORY,PUNE-411 008,MAHARASTRA,INDIA
3 LATHA SIV ADASAN NATIONAL CHEMICAL LABORATORY,PUNE-411 008,MAHARASTRA,INDIA
4 DUSHANT ANANDRAO KHOBRAGADE NATIONAL CHEMICAL LABORATORY,PUNE-411 008,MAHARASTRA,INDIA
5 THOTTAPPILLIL RAVINDRANATHAN NATIONAL CHEMICAL LABORATORY,PUNE-411 008,MAHARASTRA,INDIA
6 KAMALAM BALAKRISHNAN NATIONAL CHEMICAL LABORATORY,PUNE-411 008,MAHARASTRA,INDIA
7 MUKUND KESHAO GURJAR NATIONAL CHEMICAL LABORATORY,PUNE-411 008,MAHARASTRA,INDIA
8 UTTAM RAMRAO KALKOTE NATIONAL CHEMICAL LABORATORY,PUNE-411 008,MAHARASTRA,INDIA
PCT International Classification Number C07C 213/10
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 09/796082 2001-02-28 U.S.A.