Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2001-02-28
2003-01-07
Siegel, Alan (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
Reexamination Certificate
active
06504044
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 1-[(cyano)arylmethyl] cyclohexanol of the general formula 1 from arylacetonitriles of the general formula 3. More particularly the present invention relates to the preparation of 1-[cyano (4-methoxyphenyl) methyl] cyclohexanol of the formula 1b wherein R1=OMe, R
2
=H which is a key intermediate for the preparation of Venlafaxine of the general formula 2b wherein R1=OMe and R2=H and salts thereof which are well known antidepressants of the central nervous system.
a) R1=H, R2=H
b) R1=OMe R2=H
c) R1=OMe R2=OMe
d) R1=OMe R2=cyclopentyloxy
BACKGROUND OF THE INVENTION
In the prior art [Husbands et al. U.S. Pat. No. 4,535,186 (1985) and EP 0112669B] various 2-aryl-(1-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)].
UK Patent No GB 2 227 743 A (1990) of Peter Gerald Shepherd discloses the condensation of compounds having formula 3 with cyclohexanone using lithium diisopropylamide 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 butyllithium 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.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a simple and convenient method of preparation of compounds having formula 1(a-d).
It is another object of the invention to provide a process that avoids the use of expensive and hazardous reagents like n-butyl lithium, lithiumdiisopropylamide.
It is still another object of the invention to provide a process that avoids the use of dry solvents like THF and diethyl ether that are expensive and hazardous.
It is yet another objective of the invention to provide a process that does not require elaborate work up or purification processes like chromatography for the isolation of products.
It is a further object of the invention to provide a process by which near quantitative yields of the product are obtained.
It is another object of the invention to provide a process which is simple, easy to handle, inexpensive and non-hazardous so that large-scale production is possible.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to a process for the preparation of 1-(cyano)arylmethyl] cyclohexanol of the general formula 1(1a-d), said process comprising reacting cyclohexanone with the carbanions of an aryl acetonitrile of the general formula 3 (3a-d),
a) R1=H, R2=H
b) R1=OMe R2=H
c) R1=OMe R2=OMe
d) R1=OMe R2=cyclopentyloxy
using a base, at temperature in the range of 0-15° for a time period in the range of 15 minutes to 120 minutes, isolating the compound of formula 1 and purifying the compound of formula 1(1a-d) by crystallisation.
In one embodiment of the 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 another embodiment of the invention the quantity of base used is in the range of 0.25 mole to 1 mole.
In a further embodiment of the invention the quantity of base used is 0.5 mole.
In another embodiment of the invention, the reaction is carried out in the presence of or absence of a phase transfer catalyst.
In another embodiment of the present invention, the phase transfer catalyst used is selected from the group consisting of tetrabutylammonium hydrogensulphate, tetrabutylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium iodide or benzyltriethyl ammonium chloride.
In still another embodiment of the present invention, the aryl acetonitrile of formula 3 used is selected from the group consisting of phenylacetonitrile, 4-methoxyphenylacetonitrile, 3,4-dimethoxy phenylacetonitrile or 3-cyclopentyloxy, 4-methoxy phenylacetonitrile.
DETAILED DESCRIPTION OF THE INVENTION
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.
REFERENCES:
patent: 4535186 (1985-08-01), Husbands et al.
patent: 5043466 (1991-08-01), Shepard
patent: 1 382 753 (1950-08-01), None
patent: 2 227 743 (1990-08-01), None
patent: WO 97/20810 (1997-06-01), None
Chemical Abstract 133:17266, 1999, Cheng, G & Zhuo, C, XP002168521.
Balakrishnan Kamalam
Chavan Subhash Prataprao
Gurjar Mukund Keshao
Kalkote Uttam Ramrao
Kamat Subhash Krishnaji
Council of Scientific and Industrial Research
Darby & Darby
Siegel Alan
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