Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF 1-[CYANO(ARYL) METHYL] CYCLOHEXANOL

Abstract This invention provides an improved process for the preparation of l-[(cyano) aryl methyl] cyclohexanol of the general formula 1 wherein RI = H, or OMe and R2 = H, OMe, or cyclopentyloxy, from arylacetonitriles of the general formula 3 wherein RI = H, or OMe and R2 = H, OMe, or cyclopentyloxy. More particularly the present invention provides an improved process for the preparation of of l-[cyano (4-methoxyphenyl) methyl] cyclohexanol of the formula Ib wherein Rl =OMe, R2 = H which is a key intermediate for the preparation of Venlafaxine of the general formula 2b wherein RI =OMe and R2 =H and salts thereof which are well known antidepressants of the central nervous system.
Full Text This invention relates to an improved process for the preparation of l-[(cyano) aryl methyl] cyclohexanol of the general formula 1 wherein RI = H, or OMe and R2 = H, OMe, or cyclopentyloxy, from arylacetonitriles of the general formula 3 wherein RI = H, or OMe and R2 = H, OMe, or cyclopentyloxy. More particularly the present invention relates to the preparation of l-[cyano (4-methoxyphenyl) methyl] cyclohexanol of the formula Ib wherein Rl =OMe, R2.=.H which is a key intermediate for the preparation of Venlafaxine of the general formula 2b wherein RI =OMe and R2 =H and salts thereof which are well known antidepressants of the central nervous system.
(Formula Removed)
In the prior art [Husbands et al. U.S. Patent No.4, 535, 186 (1985) and EP 0112669B] various 2-aryl- (l-hydroxycyclohexyl)-acetonitriles having formula (1) were prepared with 50% yield by the condensation of arylacetonitriles having formula (3) with cyclohexanone using n-butyl lithium as the base at -70°C [Sauvetre et al. Tetrahedron 34 2135 (1978)].
Peter Gerald Shepherd UK Patent No GB 2 227 743 A (1990) discloses the Midensation of compounds having formula 3 with cyclohexanone using lithium Uiisopropylamide in hydrocarbon solvents like hexane, toluene or cyclohexane at ambient temperature thereby improving the yield to 79%.
The use of butyllithium causes great inconvenience in large-scale preparation since jbutyllithium is very hazardous. The need for setting up plants for operating at very low temperatures combined with the high cost of butyllithium make this method unacceptable for industrial preparations.

The object of tht present invention is to provide a simple and convenient method of preparation of compounds having formula 1 (a-d) using simple inexpensive and easily available reagents.
Accordingly, the present invention relates to an improved process for the preparation of 1-[(cyano) aryl methyl] cyclohexanol of the general formula 1 wherein RI = H, or OMe and R2 = H, OMe, or cyclopentyloxy which comprises; reacting cyclohexanone with carbanion of an aryl acetonitrile of general formula 3 (a-d), (Formula Removed)
Rl= H,R2 = H
e) Rl=OMeR2 = H
f) Rl=OMeR2 = OMe
h) Rl = OMe R2 = cyclopentyloxy
using a base in the range of 0.25 mole to 1 mole optionally in the presence of a phase transfer catalyst at a temperature in the range of 0-15°C for a time period in the range of 15 minutes to 120 minutes, isolating the compound of formula 1 by any conventional method and purifying the resultant compound by simple crystallization
In an embodiment of the present invention the base used is selected form the group consisting of powdered sodium hydroxide, powdered potassium hydroxide, 10% aqueous sodium hydroxide solution, 10% aqueous potassium hydroxide solution and 50% sodium hydroxide solution.
In yet another embodiment the quantity of base used is in the range of 0.25 mole to 1 mole In yet another embodiment the quantity of base used is preferably 0.5 mole.
In yet another embodiment the phase transfer catalyst used is selected from the group consisting of tetrabutylammonium hydrogensulphate, tetrabutylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium iodide and triethylbenzyl ammonium chloride.
In yet another embodiment the aryl acetonitrile of formula 3 used is selected from the group consisting of phenylacetonitrile, 4-methoxyphenylacetonitrile, 3,4-dimethoxy phenylacetonitrile and 3-cyclopentyloxy, 4-methoxy phenylacetonitrile.
In yet another embodiment the solvent used is water.
In yet another embodiment the amount of base used is in a catalytic amount.
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. Example 1
Phenylacetonitrile 3a (11.7 parts, 0.1 moles) was placed in a beaker and cooled to 0°C. Powdered potassium hydroxide (0.28 parts, 0.05 moles catalytic quantity) and tetrabutylammonium iodide (0.37 parts, 0.01 moles) was added and mixed thoroughly. After 5 minutes, cyclohexanone (9.8 parts, 0.1 moles) was added slowly at 0°C. The mixture on stirring vigorously for 15 minutes solidified suddenly. Water (100 parts) was added at this stage and the reaction mixture stirred for an hour to complete the reaction. The product- 1-cyano [(aryl) methyl] cyclohexanol la was filtered by suction, washed with water (3x100 parts) and dried to constant weight. 18.7 parts, (87%). Crystallized from ethyl acetate pet ether to yield shining white crystals Mp. 101-2 °C. NMR (200 MHz., CDC13) 8 7.4(s, 5H, aromatic); 3.80 (s, 1H CH CN); 1.59 (m, 10H cyclohexyl); 1.24 (br s, 1H). M+215
Example 2
4-Methoxyphenylacetonitrile 3b (147 parts, 1 mole) was cooled to 0°C, and stirred vigorously with a solution of 10% aqueous sodium hydroxide solution (100 parts, 0.25 mol). Tetrabutyl ammonium hydrogen sulphate (4.0 parts, 0.1 mol) was added in one lot while stirring. The reaction was warmed to 15°C after which, cyclohexanone (100 parts 1.02 mol) was added rapidly in 10 minutes taking care to keep the temperature of the reaction below 15°C. A thick
smooth solid separates. At this stage the solid was crushed to fine pieces and water (1000 parts) was added to facilitate stirring. Stirring was continued for 2 hrs. When the reaction was over, (monitored by tic) the solid was filtered, washed free of alkali and dried to constant weight. Yield 162 parts (97.6%) .The product 1-cyano [(4-methoxyphenyl) methyl]-cyclohexanol Ib was crystallized from ethylacetate petether to obtain shining white needles of >99% purity on HPLC M.p. 125-6°C. (litt. mp 123-5°). !HNMR (CDC13) 8 7.32,6.95 (4H, q, p-substituted aromatic), 3.8 (3H, s - OCH3); 3.76 (1H, s, CH CN 1.56 (10 H, m, aliphatic cyclohexyl); M*245
Example 3
3,4-Dimethoxyphenylactonitrile 3c (0.885 parts, 0.005 moles) was cooled to 15°C in a beaker and stirred vigorously with powdered sodium hydroxide (0.100 parts 0.25 mol). Trimethylbenzylammonium chloride (0.028 parts, 0.003 moles) was added to this mixture followed by cyclohexanone (0.5 parts, 0.005 moles). Stirring was continued for 2 hrs and the reaction was left overnight at 0°C. Water (5ml) was added after which the solid that separated was filtered, washed with water and dried 0.976 parts (71%). The product 1-cyano [(3,4-dimrthoxyphenyl) methyl] acetonitrile Ic was crystallised from ethylacetate to fine needles. Mp.l34-5° C. NMR: (CDC13) 8 6.85 (m, 3H, aromatic). 3.87(s, 3H O CH3); 3.86(s, 3H 0 CH3); 3.69(s, 1H, CH CN); 1.59 (m, 10H, cyclohexyl); 1.24 (bs, 1H, OH); M+275
Example 4
3-cyclopentyloxy, 4-methoxy phenylacetonitrile 3d (0.3 parts, 0.00129 mols) was cooled to 0°C and stirred with a 50% solution of sodium hydroxide (0.1 part, 0.00125 moles) and tetrabutylammoniumhydrogensulphate (0.044 parts, 0.000129 mol). Cyclohexanone (0.129 parts 0.0013 moles) was added after 10 minutes and stirring continued for 2 hours to ensure completion of the reaction. The product 1-cyano- [(3-cyclopentyloxy, 4methoxyphenyl) methyl] cyclohexanol Id was isolated by filtration, washing and drying as a low melting solid. NMR (CDC13) 8 (6.8 (m, 3H, aromatic); 4.75 (br. S, 1H, O-CH-); 3.6 (s 3H, OMe); 3.59 (s, 1H CH-CN); 1.5-2 (m, 18H, cyclopentyl and cyclohexyl). M+ 329
Example 5
4-Methoxyphenylacetonitrile Ib (1.47parts, O.lmol) was cooled to 0°C and stirred with powdered sodium hydroxide (.0.02 parts 0.05 mol). Tetrabutylammoniumiodide (0.036 parts 0.01 mol) was added to this mixture and condensed with cyclohexanone (0.98 parts, 0.1 mol)
as described above. The product Ib was isolated by filtration, washing and drying of the solid obtained after stirring the reaction mixture for 10 minutes. (2.2 parts, 89.7%)
Example 6
4-Methoxyphenylacetonitrile Ib (1.47parts, O.lmol) was cooled to 0°C and stirred with powdered sodium hydroxide (0.100 parts.0.025 mol) without any phase transfer catalyst. When the reaction became thick, cyclohexanone (0.98 parts, 0.1 mol) was added and the reaction stirred for another 10 minutes till solid separated. The product Ib was isolated as described above. (1.91 part, 78%)
The advantages of the present invention are as follows:
The present invention avoids the use of expensive and hazardous reagents like n-butyl lithium, lithiumdiisopropylamide etc.
The present invention also avoids the use of dry solvents like THF and diethyl ether, which are also expensive and hazardous. The present method can be conducted in water or even under solvent free conditions.
The present invention does not involve elaborate work up or purification processes like chromatography for the isolation of products.
The present invention avoids the inconvenience of carrying out reactions at very low temperatures.
The present invention does not require the use of inert atmosphere.
The present invention describes a process by which near quantitative yields of the product are obtained.
The present invention describes a process, which is simple, easy to handle, and non-hazardous so that large-scale production is possible.
The present invention presents a very convenient method of preparation of 1 through a simple short and cost effective process.



We Claim:
1. An improved process for the preparation of l-[(cyano) aryl methyl] cyclohexanol of the general formula 1 wherein RI = H, or OMe and Ra = H, OMe, or cyclopentyloxy which comprises; reacting cyclohexanone with carbanion of an aryl acetonitrile of general formula 3 (a-d),(Formula Removed)Rl= H,R2 = H Rl=OMe R2 = H Rl=OMe R2 = OMe Rl=OMe R2 = cyclopentyloxy using a base in the range of 0.25 mole to 1 mole optionally in the presence of a phase transfer catalyst at a temperature in the range of 0-15°C for a time period in the range of 15 minutes to 120 minutes, isolating the compound of formula 1 by any conventional method and purifying the resultant compound by simple crystallization.
2. An improved process as claimed in claim 1 wherein the base used is selected form the group consisting of powdered sodium hydroxide, powdered potassium hydroxide, 10% aqueous sodium hydroxide solution, 10% aqueous potassium hydroxide solution and 50% sodium hydroxide solution.

3. An improved process as claimed in claim 1 to 2, wherein the quantity of base used is
preferably 0.5 moles.
4. An improved process as claimed in claims 1-3, wherein the phase transfer catalyst used
is selected from the group consisting of tetrabutylammonium hydrogensulphate,
tetrabutylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium
iodide and triethylbenzyl ammonium chloride.
5. An improved process as claimed in claims 1-4, wherein the aryl acetonitrile of formula 3
used is selected from the group consisting of phenylacetonitrile, 4-
methoxyphenylacetonitrile, 3,4-dimethoxy phenylacetonitrile and 3-cyclopentyloxy, 4-
methoxy phenylacetonitrile.
6. An improved process as claimed in claims 1-5, wherein the solvent used is water.
7. An improved process for the preparation of l-[(cyano) aryl methyl] cyclohexanol of the
general formula 1 substantially as described hereinbefore with reference to the foregoing
examples.

Documents:

231-del-2001-abstract.pdf

231-del-2001-claims.pdf

231-del-2001-correspondence-others.pdf

231-del-2001-correspondence-po.pdf

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

231-del-2001-form-1.pdf

231-del-2001-form-19.pdf

231-del-2001-form-2.pdf

231-del-2001-form-3.pdf

231-del-2001-petition-138.pdf

abstract.jpg


Patent Number 242409
Indian Patent Application Number 231/DEL/2001
PG Journal Number 35/2010
Publication Date 27-Aug-2010
Grant Date 25-Aug-2010
Date of Filing 28-Feb-2001
Name of Patentee COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110001, 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-411008, MAHARASTRA, INDIA.
3 LATHA SIVADASAN NATIONAL CHEMICAL LABORATORY, PUNE-411008, MAHARASTRA, INDIA.
4 KAMALAM BALAKRISHNAN NATIONAL CHEMICAL LABORATORY, PUNE-411008, MAHARASTRA, INDIA.
5 DUSHANT ANANDRAO KHOBRAGADE NATIONAL CHEMICAL LABORATORY, PUNE-411008, MAHARASTRA, INDIA.
6 THOTTAPPILLIL RAVINDRANATHAN NATIONAL CHEMICAL LABORATORY, PUNE-411008, MAHARASTRA, INDIA.
7 MUKUND KESHAO GURJAR NATIONAL CHEMICAL LABORATORY, PUNE-411008, MAHARASTRA, INDIA.
8 UTTAM RAMRAO KALKOTE NATIONAL CHEMICAL LABORATORY, PUNE-411008, MAHARASTRA, INDIA.
PCT International Classification Number C07C 29/04
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA