FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
As amended by the Patents (Amendment) Act, 2005
&
The Patents Rules, 2003
As amended by the Patents (Amendment) Rules, 2005
PROVISIONAL SPECIFICATION (See section 10 and rule 13)
1.TITLE OF THE INVENTION
AN IMPROVED PROCESS FOR THE PREPARATION OF CYCLOHEXANOL COMPOUNDS
2.APPLICANTS
Aarti Healthcare Limited, An Indian Company Registered under Indian Companies Act 1960, Having its registered Office at 71, Udyog Kshetra, 2nd Floor, Mulund-Goregaon link Road, Mulund (West), Mumbai- 400080, Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification describes the invention:

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of cyclohexanol compounds e.g. the compound l-[cyano-l-(p-methoxy phenyl)methyl]cyclohexanol of formula (5) which represents an important preparation of venlafaxine of formula (A).
BACKGROND OF THE INVENTION
Cyclohexanol compounds are known in the prior art. Cyclohexanol compounds of formula (1) are known for being particularly useful as synthesis intermediates for preparing pharmaceutical active substances which are antidepressants.
CN
CN O
R R
1 2 3
Wherein, R1 is hydrogen or (C1-C4) alkoxy and R2 is hydrogen, (C1-C4)alkyl or (C1- C4) alkoxy.
General process for preparation of cyclohexanol compounds of formula (1) for the
below mentioned prior art can be represented as scheme-1.
Scheme-1:
CN

CN 0
R ^^ R
2 3 1
Wherein, R1 is hydrogen or (C1-C4) alkoxy and R2 is hydrogen, (C1-C4)alkyl or (C1-C4) alkoxy.
General process for preparation l-[cyano-l-(p-methoxy phenyl)methyl]cyclohexanol of formula (5) can be shown as scheme-2.


Scheme-2:

CN

HO
H3CO

H3C0

An important substance is venlafaxine of formula (A). Preparation of venlafaxine of formula (A) and venlafaxine HC1 salt of formula (B) is described in US patent US 4535186.
/CH3 ^CH3

"CH,

-CH,

HO
HO
H3CO

H3CO

.HCI

A

B

US patent No. 4535186 and EP 0112669 have described various cyclohexanol
compounds of formula (1) wherein they were prepared with less than 50% yield by
the condensation of substituted acetonitrile having of formula (2) with
cyclohexanone of formula (3) using n-butyl lithium as the base at -70°C.
As butyl lithium is very hazardous, the use of butyl lithium causes great inconvenience in large scale production. The need for setting up plants for operating at very low temperatures combined with the high cost of butyl lithium make this method unacceptable for industrial preparation.
GB patent GB 227743 A has disclosed the condensation of compounds having of formula (2) with cyclohexanone of formula (3) using lithium diisopropyl amide in hydrocarbon solvents like hexane, toluene or cyclohexane at ambient temperature thereby improving the yield to 79%.
Chinese patent CN 1225356 has disclosed the use of organic bases in the reaction of a 4-methoxy phenyl acetonitrile with cyclohexanone, to produce l-[2-amino-l-(p-methoxybenzyl)ethyl]cyclohexanol. The reaction additionally requires the use of NaBH4 and BF3.


PCT application 97/20810 has disclosed a process for the preparation arylbutylnitrile derivatives which involves reaction of a solution of a 1, 3 di-halopropane and a cyanobenzyl derivative in a substantially dimethyl sulphoxide-free solvent with a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
European patent EP 1238967, PCT application WO 02/18325 and PCT application WO 03/080565 have disclosed the process for the preparation of cyclohexanol derivatives wherein aqueous basic material such as sodium hydroxide and a small amount of phase transfer catalyst are used in an aqueous solution. But in the above processes, while reaction is in progress, all reactants or large amount of reactants may be solidified in the reactor Thus there will be yield loss or the above methods further require a process of grinding the solidified reactants and therefore are unsuitable for mass production and are difficult to use industrially.
Further the prior art can be described with the following references:
European patent EP1313698 Bl has disclosed the process for the preparation of 1-
[cyano-(4-methoxyphenyl)methyl]cyclohexanol wherein cyclohexanone is reacted
with phenyl acetonitrile in presence of aqueous base and phase transfer catalyst to
give cyano-alcohol derivative. PTCs like quaternary ammonium salts, quaternary
phosphonium salts and crown ethers are reported in the patent.
The yield is about 90-95% and reaction hrs are about 6-8 hrs at 18-25°C.
The major drawbacks of this patent are as follows:
1. Reaction hrs are more than 6 hrs and the base quantity is also higher (about 0.5 equivalent with respect to p-methoxy phenyl acetonitrile).
2. It is also required to carry out the purification of the product obtained by the above process using large volume of solvents which leads to the unnecessary use of solvents and environmental pollution.
3. Cyclohexanone in the reaction is also used in the excess quantity (1.3-1.4
equivalent with respect to p-methoxy phenylacetonitrile) which also required an extra
solvent purification to remove the excess of cyclohexanone from the product which
leads to the product loss hence the process is not industrially viable.


European patent EP1671944 Al has claimed the process for the preparation of 1-[cyano-(4-methoxyphenyl)methyl]cyclohexanol of formula (5). According to the claims, cyclohexanone is reacted with p-methoxy phenyl acetonitrile in presence of aqueous inorganic base and aqueous alcohol to give the Cyano product.
By the above described method, low yield of the final product is obtained and further large volume of solvents like dichloro methane and heptane is used to remove the traces of cyclohexanone and p-methoxy phenyl acetonitrile which causes yield loss and thus the process may not be feasible industrially.
US patent US 2004/0106818 has claimed the process for the preparation of l-[2-amino-l-(p-methoxyphenyl)ethyl]cyclohexanol. According to the claims, cyclohexanone is reacted with phenyl acetonitrile in presence of metal hydride in a solvent to give l-[cyano-(4-methoxyphenyl)methyl]cyclohexanol which is further hydrogenated using raney nickel in solvent to give l-[2-amino-l-(p-methoxyphenyl)ethyl] cyclohexanol.
Metal hydrides are very hazardous and inflammable if come in contact with air. The use of metal hydride needs very highly systematic plant facilities and also requires much better awareness for using them thus the use of metal hydrides in commercial production should be avoided as it is very difficult to handle.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide an environmental friendly, non-polluting, simple and convenient method for the preparation of cyclohexanol compounds of formula (1).
It is another object of the invention to provide a process that avoids the use of expensive and hazardous reagents like metal hydrides, n-butyl lithium, and lithium di-isopropylamide.
It is yet another object of the invention to provide a process that does not require elaborate work up or purification processes like chromatography for the isolation of


products or purification in solvent which leads to a lengthy process thus minimizing the yield of the product.
It is a further object of the invention to provide a process by which 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, non-hazardous so that large scale production is possible.
It is yet another object of the invention to provide a process by which more than 99.5% of purity and more than 98% yield of the cyclohexanol compounds of formula (l)are obtained.
It is yet another object to provide an efficient process wherein substituted acetonitrile compound of formula (2) is reacted with cyclohexanone of formula (3) in presence of dual catalyst wherein first catalyst is selected from inorganic base and another one is selected from substituted polyoxyethylene ether of formula (4) in presence or absence of solvent. As the reaction is carried out in solvent minimizing environment, the ratio of solvent used in the reaction should not be more than 1:1 with compare to the starting material i.e. substituted phenyl acetonitrile of formula (2).
It is also an object to provide a process for the preparation of l-[cyano-(4-methoxyphenyl)methyl]cyclohexanol of formula (5) which can be used for the preparation of venlafaxine of formula (A) and its HC1 salt of formula (B).
It is yet another object to provide an improved process for the preparation of venlafaxine HC1 of formula (B) which comprises:
a. Reacting p-methoxy phenyl acetonitrile of formula (6) with cyclohexanone of
formula (3) in presence of surfactant of formula (4) and an inorganic base to obtain 1-
[cyano-(4-methoxyphenyl)methyl]cyclohexanol of formula (5).
b. Hydrogenating l-[cyano-(4-methoxyphenyl)methyl]cyclohexanol of formula (5)
using Pd/C in formic acid as solvent and worked it up to obtain an organic layer
c. Reacting an organic layer with paraformaldehyde at reflux temperature for 4-6 hrs
and worked it up to obtain organic ethyl acetate layer of pure venlafaxine of formula
(A) which is not isolated


d. Adding IPA.HCl to the organic ethyl acetate layer to obtain venlafaxine HCl of formula (B).
It is an object to provide a process for the preparation of venlafaxine HCl of formula (B) using l-[cyano-(4-methoxyphenyl)methyl]cyclohexanol of formula (5) obtained by the above process which comprises:
1. l-[cyano-(4-methoxyphenyl)methyl]cyclohexanol of formula (5) obtained by the above process is hydrogenated in presence of Pd/C in formic acid as solvent.
2. Formic acid is distilled out to keep the required quantity of formic acid in reaction mass for N-alkylation in step-3.
3. Formaldehyde is added in the above reaction mass of step-2 and refluxed it till reaction completion.
4. Solvents are distilled out from step- 3.
5. pH=l-2 is adjusted using aqueous acid.
6. Reaction mass is extracted with ethyl acetate to remove impurities wherein product is in aqueous layer.
7. pH=10-l 1 of the aqueous layer is adjusted using aqueous base
8. Aqeous layer is extracted with ethyl acetate and distilled out ethyl acetate and left required quantity of ethyl acetate in the reaction mass for further reaction.
9. pH=l-1.5 of ethyl acetate layer is adjusted using IPA HCl.

10. Methanol is added in the reaction mass.
11. Reaction mass is then refluxed, cooled, filtered, washed with any of the solvent used in the reaction and dried it to obtained venlafaxine HCl of formula (B).
It is an object to provide a process for the preparation of venlafaxine HCl of formula (B) using l-[cyano-(4-methoxyphenyl)methyl]cyclohexanol of formula (5) obtained by the above process which comprises:
1. l-[cyano-(4-methoxyphenyl)methyl]cyclohexanol of formula (5) obtained by the above process is hydrogenated in presence of Pd/C in formic acid as solvent.
2. Formic acid is distilled out to keep the required quantity of formic acid in reaction mass for N-alkylation in step-3.
3. Paraformaldehyde is added in the above reaction mass of step-2 and refluxed it for 4-6 hrs.
4. pH=10-l 1 of the aqueous layer is adjusted using aqueous base


5. Aqeous layer is extracted with ethyl acetate and distilled out ethyl acetate and left required quantity of ethyl acetate in the reaction mass for further reaction.
6. pH=l-1.5 of ethyl acetate layer is adjusted using IPA HC1.

7. Methanol is added in the reaction mass.
8. Reaction mass is then refluxed, cooled, filtered, washed with any of the solvent used in the reaction and dried it to obtained venlafaxine HC1 of formula (B).
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of cyclohexanol compounds of formula (1). The reaction is conducted in a dual catalytic system. The catalytic system includes substituted polyoxy ethylene ether of formula (4) and inorganic base i.e. inorganic metal reagent.
R ^ y (OCH2CH2)x—OH
4 Wherein
R is an aryl, alkyl or arylalkyl group having from 1 to 20 carbon atoms and x
has an average value between from about 9 to about 150.
In the method of the invention, at least one inorganic metal reagent is brought into contact with substituted phenyl acetonitrile of formula (2) in the presence of substituted polyoxyethylene ether of formula (4).
The inorganic metal reagent may works as a co-catalyst. The reaction is conducted until the substituted polyoxyethylene ether at least partially complexes the metal of the inorganic metal reagent.
By using catalytic amounts of surfactant compounds, it is possible to synthesize the target cyclohexanol compounds of formula (1) in a solvent minimized environment.
Cyclohexanol compounds of formula (1) can be produced by a one step using substituted phenyl acetonitrile derivative of formula (2) and cyclohexanone of formula (3).


Treatment of the substituted phenyl acetonitrile compounds of formula (2) with cyclohexanone and an inorganic base in the presence of substituted polyoxyethylene ether produces cyclohexanol compounds of formula (1) by a nucleophilic addition reaction.
The process for the preparation of cyclohexanol compounds of formula (1) which are useful synthetic intermediates for the preparation of pharmaceutical active ingredients, proceeds to near quantitative yield and is practical and economically attractive.
Cyclohexanol compounds produced by the above process can be useful in the preparation of the pharmaceutical active ingredients for eg. l-[cyano-(4-methoxyphenyl)methyl]-cyclohexanol of formula (5) can be used as an intermediate in the process for the preparation of venlafaxine of formula (A) and its HCl salt of formula (B).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method for producing cyclohexanol compounds of formula (1) which can be prepared by a process wherein an inorganic metal reagent serves as the catalyst. The method of the invention proceeds neatly, in a solvent minimized environment, under homogeneous or heterogeneous conditions and in the presence of a catalytic amount of substituted polyoxyethylene ether of formula (4).
In one of the embodiment of the invention, the process employs a dual catalytic system whereby the substituted polyoxyethylene ether of formula (4) is used as co-catalyst in conjugation with the traditional metal reagent which works as catalyst. The substituted polyoxyethylene ether of formula (4) offers the capability to increase liquid-liquid interface area. In addition it enables selective complexation of metal ions, thereby resulting in solubilization of the traditional metal reagent in the substituted polyoxyethylene ether media.
The resulting product can be separated from the catalyst by simple filtration without any additional work up which makes the process simple, relatively waste free, environment friendly, economic process.


The present invention thus provides a process for preparing cyclohexanol compounds of formula (1) in a solvent minimized environment by using catalytic amount of substituted polyoxyethylene ether of formula (4). The term "solvent minimized" is a functional term and is meant to include those reactions which either no traditional solvent or such a minimal amount that the solvent would not function as a significant or controlling part of the reaction. Preferably, the solvent ratio in the reaction should not be more than 1:1 compared to the ratio of solvent: substituted phenyl acetonitrile of formula (2), more preferably 0.5:1 compared to the starting material i.e. substituted phenyl acetonitrile compounds of formula (2). The reaction can be carried out using excess of solvent i.e. more than 1:1 compared to the starting material i.e. substituted phenyl acetonitrile of formula (2).
The cyclohexanol compounds of formula (1) synthesis of the present invention can be represented as scheme 3:
Scheme-3:
CN

Base, surfactant below 10C

As per the scheme-3, substituted phenyl acetonitrile of formula (2) is reacted with cyclohexanone of formula (3) in presence of dual catalyst {inorganic base and surfactant i.e. substituted polyoxyethylene ether of formula (4)} to give the cyclohexanol compound of formula (1).
The reaction is carried out in presence or absence of solvent at below 10°C, preferably -10°C to 10°C, more preferably at -5 °C to 0°C which goes to completion within 30 minutes to 2 hrs. The solvent used in the minimized quantity can be selected from polar solvents, non-polar solvents, polar aprotic solvents or mixtures thereof for eg. C1-C4 alcohol, DMF, DMSO, N-methyl pyrolidinone (NMP), chlorinated solvents like chloroform, MDC, toluene, benzene, hexane, water or mixtures thereof can be used without limiting the invention.
Preferred substituted polyoxyethylene ethers (surfactant) are selected from the formula (4).


R