Title of Invention

PROCESS FOR THE PREPARATION OF AN INTERMEDIATE FOR VENLAFAXINE

Abstract

Process for the preparation of l-cyano[(4-methoxyphenyl)methyl]-cyclohexanol of formula (I) of high purity, substantially free of impurities Comprising reaction of p-methoxy phenyl acetonitrile of formula (II)With cyclohexanone of formula (III)In an organic solvent selected from a lower aliphatic alcohol or an ether, in the presence of a base, without the aid of a catalyst. The reaction is carried out at a temperature in the range of -40º C to 30º C, and optionally in presence of water. When the organic solvent is a lower aliphatic alcohol, the base employed is an inorganic base and the reaction temperature is 0º C to 10º C. When the organic solvent is an ether, the base employed is an inorganic or organic base, and the reaction temperature is -35º C to -30º C. The compound of formula (I) may be crystallised using an aromatic hydrocarbon solvent

Full Text

FORM -2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See Section 10 ; rule 13) 1. TITLE OF INVENTION PROCESS FOR THE PREPARATION OF AN INTERMEDIATE FOR VENLAFAXINE 2. Applicant: LUPIN LTD, 159, CST Road, Kalina, Santacruz (East), Mumbal - 400 098, Maharashtra, India, an Indian company. The following specification particularly describes the nature of this invention and the manner in which it is to be performed. FIELD OF THE INVENTION The present invention relates to a process for preparation of 1-cyano [(4-methoxyphenyl) methyl]-cyclohexanol, a key intermediate for synthesis of the antidepressant drug, venlafaxine. BACKGROUND OF THE INVENTION 1-cyano [(4-methoxyphenyl) methyl]-cyclohexanol of formula (I) is an important precursor in the synthesis of venlafaxine, a central nervous system antidepressant. with cyclohexanone of formula (III) Compound of formula (I) is generally prepared by the condensation of p-methoxy phenyl acetonitrile of formula (II) in presence of a base. The earliest disclosure of such a condensation reaction was first reported by Archer and Rudy in US 2,647,122 (1953), wherein an aromatic mono-substituted nitrile was reacted with a cycloalkanone, in presence of a base catalyst such as sodium metal at reflux temperature to give an unsaturated compound of formula (IV) as shown hereinbelow. The reaction essentially proceeds via the formation of the tertiary alcohol of formula (V), which, under reflux conditions, loses a water molecule to give the unsaturated compound of formula (IV). There is, however, no mention of isolation of the intermediate alcohol (V) in US 2,647,122. Isolation of the compound of formula (V) and its use in preparation of venlafaxine and acid addition salts thereof was first disclosed in US 4,535,186 (Husbands et al.). This patent, which covers venlafaxine, also discloses a method for its synthesis comprising reaction of cyclohexanone (III) or cyclohexenone with p-methoxy phenyl acetonitrile (II) anion in the presence of a base to give compound of formula (I). The nitrile compound (I) is further reduced to the corresponding amino derivative, which on alkylation gives venlafaxine of formula (VI). The synthesis of venlafaxine via the intermediary of compound (I) described in US 4,535,186 is summarized hereinbelow. The base employed in the condensation of compound (II) and (III) to give compound (I), as per the method of US 4,535,186 is n-butyl lithium and the reaction is carried out in the presence of an organic solvent, like tetrahydrofuran or cyclohexane and at a temperature range of between -40° C to -70 ° C. However, the method embodied in US 4,535,186 suffers from several limitations, since it: a) utilizes expensive and hazardous n-butyl lithium; b) requires strictly anhydrous conditions and cryogenic temperatures, which if not adhered to leads to formation of the unsaturated compound (IV) in substantial amounts; and c) gives the product (I) in yields not exceeding 50%, thereby increasing the cost of manufacture, hazards in operability, overall renderuig the method not attractive on a commercial scale. GB 2,227,743 A (Shepherd) discloses an improved method over that reported in US 4,535,186 for preparation of compound (I), the improvement comprising carrying out the reaction of compound (II) and (III) in the presence aliphatic or aromatic hydrocarbon solvents like hexane, toluene or cyclohexane and at ambient temperature affording compound (I) in a yield of about 80%. However, this method utilizes lithium diisopropylamide instead of n-butyl lithium as the base, which again is not only expensive but also poses hazards in operability. US 6,504,044 (Chavan et. al) discloses another improved method for preparation of compound of formula (I) comprising reaction of compound (II) and compound (III) in presence of a cheaper and non-hazardous base, viz. an inorganic base such as sodium or potassium hydroxide, in the absence of a solvent or in presence of water as solvent and .in the presence or absence of a phase transfer catalyst at a temperature in the range of o" C to 15° C, giving the product in yields of greater than 90%. However, from the description of the process and the enabling disclosure given in the Examples of the US 6,504,044 specification, it would be apparent that the invention essentially teaches away from conducting the said reaction of compound (II) with (III) in the absence of a phase transfer catalyst and a solvent. This is substantiated by the fact that when the present inventors reacted compound (11) with compound (III) in the absence of a solvent and a phase transfer catalyst at 0*^ C exactly as per the method described in Example 6 of the said patent, the product i. e. compound (I) was obtained in a low yield of ca. 36% only. The probable reason for low yields is that at the temperature at which the reaction is carried out i. e. O" C, one of the starting materials, viz. p-methoxy phenyl acetonitrUe (II), by virtue of having a freezing point of 8° C is thrown out and is not effectively available for reaction with compound (III). This is further, substantiated by the fact that the isolated product was found to be contaminated with about 30%) of unreacted starting material (II). The abovementioned observations and results clearly indicate that contrary to the claims, the chemistry embodied in US 6,504,044 ought to be carried out in the presence of a phase transfer catalyst and in the presence of a solvent to obtain optimum yield and quality of compound (I). us 6,620,960 (Ekkundi et. al) discloses yet another a process for preparation of compound of formula (I) essentially similar to that disclosed in US 6,504,044 comprising reaction of compound (II) with compound (IE), however, specifically in the presence of an aqueous inorganic base and more specifically in the presence of a phase transfer catalyst. Although, the methods claimed in US 6,504,044 and US 6,620,960 overcome the limitations of the prior art methods to some extent, specially avoiding the use of hazardous organolithium bases and anhydrous solvents, however, they suffer from a major disadvantage in that in the reaction of compound of formula (II) with (III) in absence of a solvent, at the end of the reaction, the product separates out as a hard solid which has to be crushed to fine pieces as is evident from the description given in Example 2, column 3, of US 6,504,044. This would be highly cumbersome, if not impossible on large-scale production. Further, since the product (I) is obtained in the form of soUd lumps, repeated water washings have to be given to dislodge the excess alkali, which if not done properly would result in degradation of compound (I), thereby affecting the yield and quality. Moreover, use of expensive phase transfer catalyst not only adds to the cost of manufacture but also creates problems in their disposal in the effluent stream. To summarize, the prior art methods for preparation of l-cyano[(4-methoxyphenyl) methyl]-cyclohexanol of formula (I) are associated with the following limitations, viz. i) They utihze expensive and hazardous organolithium compounds like n-butyl lithium and lithium diisoproplyamide, adding to the cost of manufacture and hazards in operability; ii) Require anhydrous solvents and special precautions to exclude moisture fi^om the reaction medium as well as cryogenic temperatures, which if not adhered to strictly, lead to formation of substantial amounts of unsaturated compound of formula (IV), resulting in lower yield and quality, which in turn add to the cost of manufacture: iii) The product (I) is obtained as soUd lumps, which not only have to be crushed to fine pieces but also needs thorough washings to dislodge the alkali trapped within, which not only affects the yield and quality but also is impractical on a commercial scale; iv) Utilize expensive phase transfer catalysts, which not only adds to the cost of manufacture but also creates problems in their disposal in the effluent stream. There exists a need, therefore, for a simple, cost-effective and convenient process for preparation of compound (I), which overcomes the Umitations associated with the prior art methods. OBJECT OF THE INVENTION It is therefore a primary object of the present invention to provide a method for preparation of compound (I) in high yield and high purity, substantially free of impurjjtiesr which is simple, convenient and cost-effective and more importantly does not suffer from the Umitations associated with the prior art. It is a further object of the invention to provide a process for manufacture of compound (I) which avoids the use of hazardous and expensive chemicals. It is a still further object of the present invention to provide a method for preparation of compound (I) which should not be very sensitive to minor changes in reaction parameters and most importantly provide the object product in good yield and quality. It is another object of the present invention to provide a method for preparation of compound (I) which does away with the utilization of a phase transfer catalyst to thereby considerably minimize the cost of manufacture. The present inventors have found that the objects of the invention could be achieved through a careful selection of the reaction parameters, such as the reaction medium, the reaction temperature and the base used. " SUMMARY OF THE INVENTION Thus the present invention relates to a process for the preparation of l-cyano[(4-methoxyphenyl)methyl]-cyclohexanol of formula (I) of high purity, substantially free of impurities (I) comprising reaction of p-methoxy phenyl acetonitrile of formula (II) with cyclohexanone of formula (III) in an organic solvent selected from a lower aliphatic alcohol or an ether, in the presence of a base, without the aid of a catalyst, optionally in presence of water. comprising reaction of p-methoxy phenyl acetonitrile of formula (II) with cyclohexanone of formula (III) According to another aspect the invention relates to a process for the preparation of 1-cyano[(4-methoxyphenyl)methyl]-cyclohexanol of formula (I) of high purity, substantially free of impurities in an organic solvent selected from a lower aliphatic alcohol or an ether, in the presence of a base, without the aid of a catalyst at a temperature in the range of-40"" Cto30 C, and optionally in presence ofwater with the proviso that a) when the organic solvent is a lower aliphatic alcohol, the base employed is an inorganic base and the reaction temperature is 0° C to 100 C; and b) when the organic solvent is an ether, the base employed is an inorganic or organic base, and the reaction temperature is -35 C to -30 C, and optionally crystallizing compound of formula (I) using an aromatic hydrocarbon solvent. DETAILED DESCRIPTION OF THE INVENTION ^ Suitable bases inclTJt«i both organic and inorganic bases selected from alkyl amines like dimethylamine, diethylamine, trimethylamine, triethylamine, triisopropylamine and tertiarybutylamine; dialkylanilines like dimethylaniline and diethylaniline; dialkylamino pyridines like dimethylamino pyridine and diethylamino pyridine; alkali metal alkoxides like sodium methoxide, sodium ethoxide, lithium isopropoxide and potassium tertiarybutoxide; sterically hindered, strong tertiary amine bases such as l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU); alkali metal hydroxides like sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates hke sodium carbonate, potassium carbonate, lithium carbonate and the like. Only alkali metal alkoxides and alkali metal hydroxides give the most optimum conversion to the compound (I) thereby leading to its isolation in high yield and purity, substantially free of impurities, specially the unsaturated compound (IV). Further, the compatibility of an alkali metal alkoxide or an alkaU metal hydroxide as base with a solvent in achieving the optimum conversion to the object compound (I) was also found to be highly selective. 10 The organic solvents are selected from lower aliphatic alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tertiary butanol etc.; ahphatic and alicychc ketones such as acetone, methyl ethyl ketone, methyl iso-butyl ketone, cyclopentanone, cyclohexanone etc.; aliphatic and cyclic ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane etc.; alkyl acetates such as methyl acetate, ethyl acetate, butyl acetate etc.; amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and the like can be used for the reaction of compound (11) with compound (III), when an alkali metal alkoxide is used as the base. The most preferred solvent is ether which gives maximum conversion to compound (I). Among the ethers tetrahydrofuran and diisopropyl ether are preferred. Surprisingly very low conversion to compound (I) was observed when compound (II) was reacted with compound (III) in the presence of sodium methoxide or sodium ethoxide in methanol or ethanol as solvent. Similar selectivity in the choice of an ether or a lower ahphatic alcohol solvent was further observed when an alkah metal hydroxide was used as the base. However, among the ethers tetrahydroforan is the most preferred solvent. Further, of the lower aliphatic alcohols, methanol and ethanol are preferred. In particular, in the reaction of compound. (II) with compound (III) in the presence of an alkah metal alkoxide or alkali metal hydroxide as base and in the presence of an ether as solvent, the preferred temperature for conducting the said reaction was found to be m the range of between -35° C to -300 C. Similarly, in the reaction of compound (II) with compound (III) in the presence of an alkali metal hydroxide as base and in the presence of a lower alcohol as solvent, although the said reaction could be carried out at temperatures from ice bath to ambient temperatures, however, the preferred temperature is in the range of between 0° C to 15° C to obtain optimum conversion to compound (I). Another important aspect of the invention resides in the tolerabihty of the reaction conditions to the presence of water in the system. The presence of water in the system is detrimental to the reaction of compound (II) with compound (III) in the presence of an alkali metal alkoxide or alkali metal hydroxide as base and in the presence of an 11 ether as solvent. On the contrary the reaction of compound (II) with compound (III), in the presence of an alkah metal hydroxide as base and in the presence of a lower alcohol as solvent, presence of water up to equal amount of the solvent utilized is found not to affect the course of reaction as far as the conversion and formation of impurities are concerned. Most importantly, no formation of solid lumps was observed even when higher amounts of water were used as in the case of the prior art methods. The role of solvents, bases, temperature, catalysts etc. in the preparation of compound (I) by reaction of compound (II) with compound (III) are summarized in Table-I. 12 12 Table-I : Comparison of the results obtained in the reaction of p-methoxy phenyl acetonitrile of formula (II) with cyclohexanone (III) utilizing various solvents, bases, temperatures, catalysts for the preparation of 1-cyano [(4-meihoxyphenyl) methyl]-cyclohexanol (I) 13 Contd. Table-I (Contd...) Comparison of the results obtained in the reaction of p- 14 methoxy phenyl acetonitrile of formula (II) with cyclohexanone (III) utilizing various solvents, bases, temperatures, catalysts for the preparation of 1-cyano [(4-methoxyphenyl) methyl]-cyclohexanol (I) Table-I (Contd...) Comparison of the results obtained in the reaction of p- methoxy phenyl acetonitrile of formula (II) with cyclohexanone (III) utilizing various solvents, bases, temperatures, catalysts for the preparation of 1-cyano [(4-methoxyphenyl) methyl]-cyclohexanol (I) Abbr. THF= Tetrahydrofliran, DIPE= Diisopropyl ether, DEE= Diethyl ether, DME= Dimethyl ether, MeOH= Methanol, EtOH= Ethanol, IPA= Isopropyl alcohol, t-BuOH= tertiary butanol, n-BuLi=n-Butyl lithium, NaOH= Sodium hydroxide, NaOMe= Sodium methoxide, KOH= Potassium hydroxide, DBU= 1,8-diazabicyclo[5.4.0]undec-7-ene, TEA= Triethyl amine, In a typical method, when an ether is used as solvent, which is selected from either tetrahydrofiiran or diisopropyl ether, to a solution of 4-methoxy phenyl acetonitrile (II) in the ether solvent cooled to -40° C to -30° C is added the base, which is either selected from an alkali metal alkoxide or an alkali metal hydroxide in powdered form and the reaction mixture agitated at the same temperature for a period ranging from 30 minutes to 90 minutes. To the mixture is then added cyclohexanone (III), slowly over a period of 45 to 60 minutes and thereafter the reaction mixture was agitated at a temperature ranging between -35 C to -30 C till completion of reaction. 15 After the reaction is complete, water is added to the reaction mixture and agitated at room temperature for a period ranging between 45 to 60 minutes. The precipitated soUd is isolated by filtration and dried to give l-cyano[(4-methoxyphenyl)methyl]-cyclohexanol (I). Typical alkali metal alkoxides that can be employed include sodium methoxide, sodium ethoxide, lithium isopropoxide and potassium tertiarybutoxide. Typical alkali metal hydroxides that can be employed include sodium hydroxide, potassium hydroxide and hthium hydroxide. Of the alkali metal alkoxides, sodium methoxide and of the alkah metal hydroxides sodium hydroxide are preferred because of their low cost. Cyclohexanone (III) is employed in molar proportions of 1 to 2 moles per mole of compound (II), preferably in the range of 1 to 1.5 moles per mole of compound (II). The base can be employed in molar proportions of 0.5 to 3 moles per mole of compound (II), preferably in the range of 1 to 2 moles per mole of compound (II). The solvent can be employed in proportions of 2 to 10 times by volume of the weight of compound (II) taken, preferably it is employed in proportions of 2.5 to 5 times by volume of the weight of compound (II). In a typical method, when a lower aliphatic alcohol is used as solvent, which is selected from either methanol or ethanol, to a solution of 4-methoxy phenyl acetonitrile (II) in the alcohol solvent cooled to 0° C to 15° C is added the base, which is selected from an alkali metal hydroxide in powdered form and the reaction mixture agitated at the same temperature for a period ranging from 30 minutes to 90 minutes. To the mixture is then added cyclohexanone (III), slowly over a period of 45 to 60 minutes and thereafter the reaction mixture was agitated at a temperature ranging between 0° C to 30° C till completion of reaction. After the reaction is complete, water is added to the reaction mixture and agitated at room temperature for a period ranging between 45 to 60 muiutes. The precipitated 16 sohd is isolated by filtration and dried to give l-cyano[(4-methoxyphenyl)methyl]-cyclohexanol (I). The reaction can optionally be carried out using a mixture of methanol or ethanol with water. The amount of water employed can be between 1 % to 20% by volume of the volume of methanol or ethanol used. Preferably water can be employed between 1% to 50% by volume of the volume of methanol or ethanol used. Typical alkali metal hydroxides that can be employed include sodium hydroxide, potassium hydroxide and lithium hydroxide. Sodium hydroxide is preferred because ofits low cost. Cyclohexanone (III) is employed in molar proportions of 1 to 2 moles per mole of compound (II), preferably in the range of 1 to 1.5 moles per mole of compound (II), The base can be employed in molar proportions of 0.5 to 3 moles per mole of compound (II), preferably in the range of 1 to 2 moles per mole of compound (II). The solvent can be employed in proportions of 2 to 10 times by volume of the weight of compound (II) taken, preferably it is employed in proportions of 2.5 to 5 times by volume of the weight of compound (II). While both the abovementioned procedures give the object l-cyano[(4-methoxyphenyl)methyl]-cyclohexanol (I) of purity of above 98%, however, the compound (I) can additionally be further purified by dissolving the compound (I) under reflux in a hydrocarbon solvent and crystallizing the product on cooling. Suitable hydrocarbon solvents are selected from aromatic hydrocarbons such as benzene, toluene and xylene, of which toluene is preferred. Both the materials i. e. prior to and after crystallization are substantially free of impurities, especially the unsaturated compound (IV), which makes it specially suitable for manufacture of venlafaxine. The phrase "high purity" is defined to mean a purity level of greater than or equal to 98%, as exemplified in the examples below. The invention is fiirther illustrated by the following examples, which in no way should be construed as to limiting the scope of the invention. 17 The invention is fiirther illustrated by the following examples, which in no way should be construed as to hmiting the scope of the invention. Example 1 Powdered sodium hydroxide (45.0 g, 1.125 mole) was added to 4-methoxyphenylacetonitrile (II, 100 g, 0.68 mole) and stirred at 25-30" C for 1 hour. The reaction mass was cooled to O-1O0 C and methanol (250 ml) was added to it. Cyclohexanone (III, 83.5 g, 0.85 mol) was added slowly with stirring over a period of 50-60 minutes taking care to keep the temperature of the reaction between O-1O0 C. Stirring was continued for 6 hours while maintainmg the temperature at 0-10° C. When the reaction was complete, water (1000 ml) was added and the reaction mixture was stirred for 60 minutes at room temperature. The sohd was filtered, washed free of alkali with demineralized water and dried under vacuum at 55-60° C to give 161.Og (96.98%) of 1-cyano [(4-methoxyphenyl) methyl]-cyclohexanol (I) having a purity of 98.7%. Example 2 Powdered sodium hydroxide 7 (45.0 g, 1.125 mole) was added to 4-methoxyphenylacetonitrile (II 18 Example 3 Powdered sodium hydroxide (9.0 g, 0.225 mole) was added to 4-methoxyphenylacetonitrile (II, 20 g, 0.13 mole) and stirred at 25-300 C for 1 hour. The reaction mass was cooled to O-1O0 C and methanol (45 ml) and water (5 ml) were added to it. Cyclohexanone (III, 16.7 g, O.lTmol) was added slowly with stirring over a period of 50-60 minutes taking care to keep the temperature of the reaction between 0-10° C. Stirrmg was continued for 6 hours while maintaining the temperature at 0-10° C. When the reaction was complete, water (1000 ml) was added and the reaction mixture was stirred for 60 minutes at room temperature. The solid was filtered, washed free of alkali with demineralized water and dried to under vacuum at 55-600 C to give 31.98g (96.08%) of 1-cyano [(4-methoxyphenyl) methyl]-cyclohexanol (I) having a purity of 98.5%. Example 4 4-methoxyphenylacetonitrile (II, 100 g, 0.68 mole) was added to tetrahydrofuran (300 ml) and cooled to -30° C. Powdered sodium methoxide (44.0 g, 0.814 mole) was added and the reaction mass was stirred at -30° C for 1 hour. Cyclohexanone (III, 90.0 g, 0.91 mol) was added slowly with stirring over a period of 50-60 minutes taking care to keep the temperature of the reaction below -30° C. Stirring was continued for 6 hours while maintaining the temperature at -30° C. When the reaction was complete, water (1000 ml) was added and the reaction mixture was stirred for 60 minutes at room temperature. The soUd was filtered, washed free of alkali with demineralized water and driedpd^nder vacuum at 55-60° C to give 144.Og (86.70%) of 1-cyano [(4-methoxyphenyl) methylj-cyclohexanol (I) having a purity of 98.0%. Example 5 4-methoxyphenylacetonitrile (II, 100 g, 0.68 mole) was added to diisopropyl ether (800 ml) and cooled to -30° C . Powdered sodium methoxide (48.0 g, 0.89 mole) was added and the reaction mass was stirred at -30° C for 1 hour. Cyclohexanone (III, 78 g, 0.79 mol) was added slowly with stirring over a period of 50-60 minutes taking care to keep the temperature of the reaction below -30° C. Stirring was continued for 6 19 hrs while maintaining the temperature at -300 C. When the reaction was complete, water (lOOO ml) was added and the reaction mixture was stirred for 60 minutes at room temperature. The solid was filteied, washed ftee of alkali with deminexalized water and dried to under vacuum at 55-60"" C to give 142.0g (85.50%) of 1-cyano [(4-methoxyphenyl) methyl]-cyclohexanol (I) having a purity of98.00/0 20 in an organic solvent selected from a lower aliphatic alcohol or an ether, in the presence of a base, without the aid of a catalyst, optionally in presence of water and optionally crystallizing said compound of formula (I) using an aromatic hydrocarbon solvent. 2. A process as claimed in claim 1, wherein said process is carried out at a temperature in the range of- 40 to 300C with the proviso that; (a) when the organic solvent is a lower aliphatic alcohol, the base employed is an inorganic base and the reaction temperature is 0°C to 100C; and (b) when the organic solvent is an ether, the base employed is an inorganic or organic base, and the reaction temperature is - 35 to - 30°C. 3. A process according to anyone of claims 1 and 2, wherein cyclohexanone (HI) is employed in molar proportions of 1 to 2, preferably 1 to 1.5 moles per mole of compound (11). 4. A process according to anyone of claims 1 to 3 wherein the base can be employed in molar proportions of 0.5 to 3 moles, preferably 1 to 2 moles per mole of compoimd (II). 5. A process according to anyone of claims 1 to 4 wherein the solvent is used in proportions of 2 to 10 , preferably 2.5 to 5 times by volume of the weight of compound (II) . 6. A process according to anyone of claims 1 to 5, wherein, when the organic solvent is a lower aliphatic alcohol, the reaction is conducted in presence or absence of water. 21 7. A process according to anyone of claims Ito 5, wherein the lower aliphatic alcohol is methanol or ethanol. 8. A process according to anyone of claims 1 and 2, wherein the inorganic base is an alkali metal hydroxide, the alkali metal being sodium, potassium or lithium. 9. A process according to anyone of claims 1 and 2, wherein the ether is tetrahydrofuran or diisopropyl ether. 10. A process according to anyone of claims 1 and 2, wherein the organic base is an alkah metal alkoxide, the alkali metal being sodium or potassium. 11. A process according to anyone of claims 1,2 and 7, wherein the alkali metal alkoxide is sodium methoxide, sodium ethoxide and potassium tertiarybutoxide. 12. A process according to anyone of claims 1,2 and 3, wherein the proportion of water is between 1% to 50% volume by volume of methanol or ethanol. 13. A process according to claim 2, wherein the aromatic hydrocarbon solvent is selected from benzene, toluene and xylene. Dated this 31"" day of January 2004 22

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