PROCESS FOR THE PREPARATION OF CYCLOHEXANOL DERIVATIVES

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of cyclohexanol derivatives of the general formula (I).

More particularly, the present invention relates to a process for the preparation of cyclohexanol derivatives of the general formula (I), wherein R stands for a hydrogen atom or a methyl group.

According to the present invention the cyano compound of the general formula (II),

wherein R stands for a hydrogen atom or a methyl group, is transferred to a compound of the formula (I), wherein R stands for a hydrogen atom or a methyl group, in one reaction step by the reaction of the compound of the general formula (II) with dimethyl amine of the formula (IV)

H ₃ C. ,CH,

N ^' H

IV in the presence of a catalyst in hydrogen atmosphere. The obtained compound of the general formula (I) can be transferred to its acid addition salt if necessary.

The compounds of the general formula (I) are known antidepressant agents.

The compound of the formula (I), wherein R stands for hydrogen atom, is 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol), its INN name is desvenlafaxine. The compound of the formula (I), wherein R stands for a methyl group, is 1-[2-(dimethylamino)-1-(4-

methoxyphenyl)ethyl]-cyclohexanol), its INN name is venlafaxine. Desvenlafaxine is an active metabolite of venlafaxine.

TECHNICAL BACKGROUND OF THE INVENTION

Venlafaxine and desvenlafaxine were first disclosed as antipsychotic agents in the Hungarian patent No. 199 104. European patent No. 639 374 disclosed the use of venlafaxine and its analogues for the treatment of generalized anxiety disorder (GAD). The use of these compounds for the treatment of panic disorder is mentioned in European patent No. 1 153 603

The process for the preparation of the compounds of the formula (I) was first disclosed in the Hungarian patent No. 199104.

For the preparation of venlafaxine, numerous processes are known. According to the description of Hungarian patent No. 199 104, venlafaxine can be prepared by a two-step process from the cyano compound of the formula (II), wherein R stands for a methyl group. In the first reaction step, the cyano compound of the formula (II) is transformed to a primary amine compound of the formula (III),

wherein R stands for a methyl group, then it is dimethylated. In the course of the methylation reaction of primary amines, the product is a mixture of different alkylated products, which cannot be separated easily. During the methylation reaction, beside the preferred tertiary amine product different side products are formed.

According to the Hungarian patent No. 199 104, N ₁ N- dialkylation is carried out by using formaldehyde in formic acid and beside venlafaxine a large amount of side products is formed too.

According to the description of European patent application No. 1721889, venlafaxine is prepared from cyano compound of the formula (II), wherein R stands for a methyl group, which is transferred to a primary amine compound of the formula (III), wherein R stands for a methyl group, by a special reagent, then the product is methylated. The overall yield of the two-step process is 26%.

A one-pot reaction including the reduction and alkylation steps is disclosed in the description of the US patent application No. 6,350,912. The yield of the process is between 15-28%.

According to the international patent application No. WO 02/500017 the reduction is carried out in the presence of cobalt and Raney nickel catalysts.

According to the US patent application No. 20050033088, the reaction can be carried out in the presence of a palladium catalyst and organic acids. The yield is 45-55%.

The process for the preparation of the compound of the formula (I), wherein R stands for a hydrogen atom (desvenlafaxine), is more complicated because the phenolic hydroxyl group has to be protected until the end of the synthesis.

Desvenlafaxine is prepared according to the description of the Hungarian Patent No. 199104 by a multi-step reaction with a low overall yield (39%).

One of the drawbacks of the process is - as it is mentioned before - that the protection of the hydroxyl group of the phenol group has to be solved.

The product is obtained by debenzylation of the O-benzyl compound of the formula (V)

V

then the product is transferred to its fumarate salt.

A methyl group can protect the phenolic hydroxyl group, too. In this case the methoxy group of the phenyl group of venlafaxine is demethylated. For the demethylation several possibilities are mentioned in the literature.

According to the international patent application No. WO 00/59851, demethylation of venlafaxine is carried out by using a lithium diphenylphosphide reagent in tetrahydrofurane. The reagent is prepared from diphenylphosphine with n-butyl lithium at a temperature of -10 ⁰ C.

Although the final demethylation step is carried out in a considerably high yield (73%), the starting material, i.e. venlafaxine, can be prepared in several reaction steps from the appropriate cyano compound of the formula (II), wherein R stands for a methyl group.

The drawback of this demethylation process is the use of dangerous compounds, namely diphenylphosphine and n-butyl lithium.

Essentially the same process is disclosed for the preparation of enantiomeric forms of desvenlafaxine from enantiomeric forms of venlafaxine in the description of the international patent application No. WO2007/005961.

Demethylation can be carried out by using alkali metal salts of trialkyl borohydrides as it is disclosed in the description of European patent No. 1360169. In this case, the demethylation reaction takes a long time, e.g. 24 hours and the side products are poisonous compounds containing boron. The work-up of the reaction mixture is very difficult, the disposal of the side products containing boron requires special provisions, thereby increasing the cost of production.

A further process for the demethylation of venlafaxine is disclosed in the description of the international patent application No. WO 03/048104 and in US patent application No. 2003/236309. Demethylation is carried out at a high temperature (150-220 ⁰ C) with alkyl-, aryl- or aralkyl thiolates requiring generally a long reaction time. When using sodium sulphide in 1-methyl-pyrrolidone, the product is obtained after a 30-hour reaction time according to the international patent application No. WO 2007/071404.

Similarly, US patent application No. 2002/022662 discloses a process for the enantiomeric forms of desvenlafaxine by demethylation of enantiomeric forms of venlafaxine using alkyl- thiolates. The drawbacks of these processes are the high temperature used and the smelly reagents.

According to another process described in the patent application No. US 2002/022662, venlafaxine can be demethylated by using boron tribromide in dichloromethane at -40 ⁰ C. The use of the boron containing compound and the very low temperature are disadvantageous.

For the preparation of (dimethylamino)-ethyl-phenyl compounds having very different chemical structures, several further methods are known, which are different from the above mentioned processes. These processes provide said (dimethylamino)-ethyl-phenyl compounds in very low yields.

According to one of these processes the reaction of an alkyl nitrile compound with dimethyl amine of the formula (IV) is carried out under reductive conditions. This reaction is used only for the preparation of some particular types of compounds. For the preparation of desvenlafaxine and related compounds, this method has not been used. According to the literature, the reaction is carried out exclusively in alcohol type solvents..

Buck et al. (J. Am. Chem. Soc. 1938, 60, 1789) have prepared alkoxy-phenylethyl-λ/,λ/-dimethylamine compounds by the

reaction of the corresponding alkoxyphenyl acetonitrile with dimethylamine using palladium catalyst under reductive conditions. The yields of these processes are not mentioned.

According to the description of the German patent No. DE 711824, substituted phenyl-acetonitriles are reacted with dimethylamine in methanol under hydrogen atmosphere, in the presence of a palladium on charcoal catalyst and the corresponding phenyl-ethyl-λ/,/V-dimethylamine compounds are obtained in a yield between 28-47 %.

Similarly, (dimethyl-amino)-ethylindol compounds are prepared in a low yield (6-41 %) according to the US patent No. 5571833. The corresponding nitrile compounds are hydrogenated in methanol with addition of dimethylamine, in the presence of Raney nickel. The product is purified by chromatography.

According to the state of the art either venlafaxine or desvenlafaxine can be prepared using a multi-step synthesis from the corresponding compound of the formula (II), wherein R stands for a methyl group in case of venlafaxine and for hydrogen atom in case of desvenlafaxine.

Apart from the effectuation of the reduction of the nitrile group there is only one method disclosed in the literature for the subsequent reductive methylation, namely using a mixture of formaldehyde and formic acid. A common disadvantage of

these syntheses is the use of a strongly mutagenic compound - formaldehyde - especially in the last step of the synthesis of venlafaxine. The quality requirements are more and more severe in the pharmaceutical industry causing challenges to the pharmaceutical companies. Specifications of drug substances are always getting stricter, therefore the producers avoid the use of harmful reagents or solvents. In case the use of these compounds is necessary, the producers aspire to use them in the earliest possible step of the synthesis. Therefore, processes using poisonous or harmful reagents in the last step are less and less acceptable by the authorities, particularly, in case of genotoxic chemicals such as formaldehyde.

This tendency is realized in a guideline of CPMP/SWP/5199/02 (2007), which discloses very low limit values for genotoxic compounds (some ppm depending on the daily dose).

In case of the processes in which genotoxic compounds (e.g. formaldehyde) are used in the last reaction step compliance with the speficications requires the repeated purification of the product, which results in lower yield and higher costs. Further problems are arisen in case of using formaldehyde, namely the quantitative detection of formaldehyde in a concentration of some ppm may cause problems when using the generally applicable analytical methods.

The purpose of the present invention is to provide a process for the preparation of the products in a one-step synthesis from 1-

[cyano-(4-hydroxyphenyl)methyl]-cyclohexanol, or 1-[cyano-(4- methoxyphenyl)methyl]-cyclohexanol, which eliminates the drawbacks of the processes mentioned above, has a better yield and is more economic.

For the preparation of 1-[cyano-(4-hydroxyphenyl)methyl]- cyclohexanol a synthesis in good yield is disclosed in the description of US patent application No. 2007/0021627. The process for the preparation of 1-[cyano-(4- methoxyphenyl)methyl]-cyclohexanol is described in Hungarian patent No. 199 104.

SUMMARY OF THE INVENTION

The object of the present invention is a process in which the cyano compound of the formula (II), wherein R stands for a hydrogen atom or a methyl group, is reacted with dimethylamine of the formula (IV) in the presence of a hydrogenating catalyst in hydrogen atmosphere, then the obtained compound of the formula (I), wherein R stands for a hydrogen atom or a methyl group, is separated as a free base or in a form of its acid addition salt.

We found surprisingly that instead of alcohol type solvents mentioned in the prior art, the use of an ether or ester type solvent for the reaction of the compound of the general formula (II), wherein R stands for a hydrogen atom or a methyl group, with dimethylamine of the formula (IV) in the presence of a

hydrogenating catalyst and hydrogen atmosphere results in the corresponding compound of the formula (I) in a good yield.

In case of using the compound of the formula (II), wherein R stands for a hydrogen atom, the product is desvenlafaxine. In case of using the compound of the formula (M), wherein R stands for a methyl group, the product is venlafaxine.

DETAILED DESCRIPTION OF THE INVENTION

During the development we have carried out numerous experiments using different catalysts and conditions for the preparation of desvenlafaxine based on the teaching of the prior art.

In the reaction of the compound of the formula (II), wherein R stands for a hydrogen atom, with dimethylamine in methanol in the presence of palladium on charcoal catalyst under a pressure of 5 bar hydrogen gas the main product is surprisingly the compound of the formula (Vl),

Vl wherein R stands for a hydrogen atom, (4-(2- dimethylaminoethyl)-phenol). The desired desvenlafaxine could

be detected by HPLC (High Pressure Liquid Chromatography) only as a minor product from a mixture of products.

The results were the same when ethanol was used instead of methanol. In this case the product mixture contained 55 % of the compound (Vl), wherein R stands for a hydrogen atom, and only 34 % of desvenlafaxine.

When using an aqueous solution of dimethylamine instead of dimethylamine gas, the yields are even lower. Only 12 % of desvenlafaxine was present in the product, based on HPLC test. Neither in case of using dimethylamine gas nor Raney nickel catalyst led to a higher yield.

In the reaction of the compound of the formula (II), wherein R stands for a methyl group, with dimethylamine in methanol in the presence of a palladium on charcoal catalyst under 5 bar pressure of hydrogen, the main product is surprisingly the compound of the formula (Vl), wherein R stands for a methyl group. The desired venlafaxine could be detected by HPLC (High Pressure Liquid Chromatography) only as a minor product in the mixture of products.

Although according to the literature, the reaction of the cyano compounds with dimethylamine is carried out always in an alcohol type solvent we tried to use a dipolar aprotic solvent instead. We found that when using either dimethylformamide (DMF) or λ/-methyl-2-pyrrolidone (NMP) as solvent, the

reaction of the nitrile compound of the formula (II), wherein R stands for hydrogen atom, with dimethylamine gas in the presence of a palladium on charcoal catalyst under hydrogen atmosphere at 50 ⁰ C takes a very long time. Even after 24 hours 2-10 % of desvenlafaxine was in the reaction mixture beside 87-96 % of the starting compound according to the measurements by HPLC.

We found it surprising that -contrary to the data -in the literature use of ether or ester type solvents instead of an alcohol type solvent in the reaction of a cyano compound of the general formula (II) with dimethylamine of the formula (IV) under hydrogen atmosphere, in the presence of a hydrogenating catalyst results in a compound of the general formula (I) in a high yield.

In other words the base form or acid addition salts of the compounds of the formula (I), wherein R stands for a hydrogen atom or a methyl group, can be prepared by the reaction of a compound of the general formula (II) with dimethylamine of the formula (IV) under hydrogen atmosphere, in the presence of a hydrogenating catalyst in an ether or in an ester type solvent, then the obtained product can be transformed to an acid addition salt if necessary.

Particularly, the reaction can be carried out in straight or branched saturated aliphatic or cyclic ethers. Such ether type

solvents are preferably tetrahydrofurane, dioxane or the tert- butyl methyl ether (MTBE).

Furthermore, the reaction can also be carried out in ester type solvents, preferably ethyl acetate.

As hydrogenating catalyst e.g. palladium on coal, on charcoal or platinum can be used. Preferably palladium on charcoal is used as catalyst. The use of nickel containing catalyst, such as Raney nickel is not suitable because of the formation of side products.

According to the present invention 1.0 - 20.0 moles of dimethylamine based on one mol of 1-[cyano-(4- hydroxyphenyl)methyl]-cyclohexanol or 1-[cyano-(4- methoxyphenyl)methyl]-cyclohexanol of the general formula (II) are used.

The reaction is carried out in a pressure-tight vessel under an overpressure of hydrogen between 0-100 bar, preferably 1-10 bar, more preferably under an overpressure of 5 bar.

The reaction is carried out at a temperature between 0 ⁰ C and 100 ⁰ C, preferably between 20 ⁰ C and 80 ⁰ C, most preferably between 50 ⁰ C and 80 °C.

According to the most preferable embodiment of the present invention, 1-[cyano-(4-hydroxyphenyl)methyl]-cyclohexanol of

the general formula (M) ₁ wherein R stands for a hydrogen atom, is suspended in an ether type solvent, preferably in dioxane or tetrahydrofurane, most preferably in dioxane, the mixture of dimethylamine of the formula (IV) and an ether type solvent, preferably dioxane or tetrahydrofurane, most preferably dioxane, and a catalyst containing palladium are added to the reaction mixture, then the mixture is kept under 3-10 bar, preferably 5-10 bar hydrogen pressure for 8-20 hours, preferably 10-20 hours, at a temperature between 40-60 ⁰ C until the decrease of hydrogen pressure is stopped, then the catalyst is filtered off , the reaction mixture is evaporated and the obtained product (desvenlafaxine) is recrystallized in a known manner and/or transformed to an acid addition salt if necessary.

The obtained desvenlafaxine base can be transformed to its acid addition salt if necessary in a known manner. The obtained acid addition salt can be recrystallized and/or transferred to another salt. Either the base or the acid addition salts can be purified by known methods. Such purification methods are recrystallization or chromatography. The acid addition salt can be transferred to the base if necessary.

According to another preferable embodiment of the present invention 1-[cyano-(4-methoxyphenyl)methyl]-cyclohexanol of the general formula (II), wherein R stands for a methyl group, is suspended in an ether type solvent, preferably in dioxane or tetrahydrofurane, most preferably in dioxane, the mixture of

dimethylamine of the formula (IV) and an ether type solvent, preferably dioxane or tetrahydrofurane, most preferably dioxane, and a catalyst containing palladium are added to the reaction mixture, then the mixture is kept under 3-10 bar, preferably 5-10 bar pressure of a hydrogen atmosphere for 8-20 hours, preferably 10-20 hours at a temperature between 40-60 ⁰ C until the decrease of hydrogen pressure is stopped, then the catalyst is filtered off, the reaction mixture is evaporated and the obtained product (venlafaxine) is recrystallized in a known manner and/or transformed to an acid addition salt if necessary.

The obtained venlafaxine base can be transformed to its acid addition salt if necessary in a known manner. The obtained acid addition salt can be recrystallized and/or transferred to another salt. Either the base or the acid addition salts can be purified by known methods. Such purification methods are e.g. recrystallization and chromatography. The acid addition salt can be transferred to the base if necessary.

For the preparation of the acid addition salts according to the present invention, any organic or inorganic acid used generally in the pharmaceutical industry can be used. Such inorganic acids are e.g. hydrochloric acid, hydrogen bromide, sulphuric acid, phosphoric acid. Such organic acids are aliphatic or aromatic mono- di- tri- or polycarboxylic acids, e.g. acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, benzoic acid etc., or aryl- or alkylsulfonic acids, e.g. benzene sulfonic acid or

methane sulfonic acid etc. In case of use of organic or inorganic polybasic acids, acidic salts can also be formed, e.g. hydrogen sulfate salt, or hydrogen fumarate salt.

Venlafaxine or desvenlafaxine according to the present invention can be used as pharmaceutical active ingredient either in a form of a base or a salt.

The advantage of the present invention is that venlafaxine or desvenlafaxine can be prepared in a one-step process using the corresponding cyano compound of the formula (II), wherein R stands for a hydrogen atom or a methyl group, depending on the desired product.

The process according to the present invention is advantageous because according to the prior art the phenolic hydroxyl group had to be protected during the preparation of desvenlafaxine and the protecting group had to be removed in the last step of the process. Furthermore the transformation of the corresponding cyano compound to a dimethylamino compound requires two reaction steps according to the prior art either in case of the preparation of desvenlafaxine or venlafaxine.

Furthermore, the use of the one-step synthesis has another advantage, namely it makes the use of genotoxic formaldehyde unnecessary.

A further advantage of the present invention is the high yield of the process for the preparation of venlafaxine or desvenlafaxine even on industrial scale. Toxic (e.g. phosphides, trialkyl borohydrides) or smelly (e.g. thiolates) chemicals are not used. The process steps can be carried out easily on industrial scale and do not require high temperature.

Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples.

Example 1

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a hydrogen atom (desvenlafaxine)]

In a pressure-tight vessel, 6.9 g (0.03 mol) of 1-[cyano-(4- hydroxyphenyl)methyl]-cyclohexanol are suspended in 100 ml of tetrahydrofurane, then a mixture of 9.5 g (0.21 mol) of dimethylamine and 60 ml of tetrahydrofurane and 2.5 g of palladium on charcoal catalyst is added. The vessel is purged twice with nitrogen, twice with hydrogen, then the reaction mixture is kept at 50 °C and hydrogenated under a pressure of 5 bar hydrogen for 10 hours, until the decrease of hydrogen pressure is stopped. The reaction mixture is cooled to room temperature, the catalyst is filtered off and washed with tetrahydrofurane. The filtrate and the washing solvent are united and evaporated in vacuo. The residue, the crude product is suspended with 30 ml of tert butyl methyl ether, filtered, washed and dried. Thus 5.5 g (70%) of title product are obtained.

Melting point: 223-225 ⁰ C.

IR (KBr): 3425, 2939, 1517, 1272, 843 cm ^"1 .

¹ H-NMR (DMSO-de, 500 MHz): 9.11 (br s, 1 H), 6.96 (d, J=8.6 Hz, 2H), 6.63 (d, J=8.6 Hz ₁ 2H), 5.40 (br s, 1H) ₁ 2.99 (m, 1H), 2.71 (m, 1H), 2.34 (m, 1H) ₁ 2.14 (s, 6H) ₁ 0.8-1.6 (m, 10H) ppm.

¹³ C-NMR (DMSO-de, 125 MHz): 155.7, 131.9, 130.2, 114.6, 72.7, 60.6, 51.8, 45.5, 37.3, 32.6, 25.9, 21.5, 21.4 ppm.

Elementary analysis based on the formula C1 ₆ H ₂₅ NO ₂ :

Calculated: C % = 72.97; H % = 9.57; N % = 5.32 Measured: C % = 72.80; H % = 9.64; N % = 5.19.

Example 2

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a hydrogen atom (desvenlafaxine)]

Example 1 is repeated with the exception that the reaction is carried out at a room temperature instead of 50 ⁰ C and takes 20 hours.

Thus 6.1 g (77%) of title product are obtained.

The properties of the product correspond to the product of

Example 1.

Example 3

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a hydrogen atom (desvenlafaxine)]

Example 1 is repeated with the exception that the reaction is carried out at a temperature of 80 ⁰ C instead of 50 °C and takes

8 hours.

Thus 4.8 g (60%) of title product are obtained.

The properties of the product correspond to the product of

Example 1.

Example 4

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a hydrogen atom (desvenlafaxine)]

Example 1 is repeated with the exception that 1.40 g (0.03 mol) of dimethylamine are used.

Thus 5.4 g (68%) of title product are obtained.

The properties of the product correspond to the product of

Example 1.

Example 5

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a hydrogen atom (desvenlafaxine)]

Example 1 is repeated with the exception that 14.0 g (0.31 mol) of dimethylamine are used.

Thus 5.8 g (73%) of title product are obtained.

The properties of the product correspond to the product of Example 1.

Example 6

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a hydrogen atom (desvenlafaxine)]

Example 1 is repeated with the exception that instead of tetrahydrofurane dioxane is used.

Thus 6.2 g (79%) of title product are obtained.

The properties of the product correspond to the product of

Example 1.

Example 7

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I) ₁ wherein R stands for a hydrogen atom (desvenlafaxine)]

Example 1 is repeated with the exception that instead of tetrahydrofurane tert butyl methyl- ether (MTBE) is used. Thus 5.2 g (66%) of title product are obtained. The properties of the product correspond to the product of Example 1.

Example 8 (Comparative example)

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a hydrogen atom (desvenlafaxine)]

Example 1 is repeated with the exception that instead of tetrahydrofurane ethanol is used. The product is a mixture with a composition as follows (based on HPLC measurements):

34 % of 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]- cyclohexanol, and

55 % 4-[2-(dimethylamino)-ethyl]-phenol.

The products are separated, purified and their chemical structures are identified. Spectral data of the separated compound of the formula 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol correspond to the data of the product of Example 1. The melting point and spectral data of the separated compound of the formula 4-[2-

(dimethylamino)-ethyl]-phenol correspond to the data of the prior art (Tetrahedron 1990, 46, 7105).

Example 9 (Comparative example)

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a hydrogen atom (desvenlafaxine)]

Example 1 is repeated with the exception that instead of tetrahydrofurane ethanol is used. Furthermore, a 60% aqueous solution of dimethylamine is used as dimethylamine source.

The product is a mixture with a composition as follows (based on HPLC measurements):

12 % of 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]- cyclohexanol, and

85 % 4-[2-(dimethylamino)-ethyl]-phenol.

The products are separated, purified and their chemical structures are identified. Spectral data of the separated compound of the formula 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol correspond to the data of the product of Example 1. The melting point and spectral data of the separated compound of the formula 4-[2-

(dimethylamino)-ethyl]-phenol correspond to the data of the prior art (Tetrahedron 1990, 46, 7105).

Example 10 (Comparative example)

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a hydrogen atom (desvenlafaxine)]

Example 1 is repeated with the exception that instead of palladium on charcoal catalyst 2.5 g of Raney nickel are used.

The product is a mixture with a composition as follows (based on HPLC measurements):

17 % of 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]- cyclohexanol, and

79 % of 4-[2-(dimethylamino)-ethyl]-phenol.

The products are separated, purified and their chemical structures are identified. Spectral data of the separated compound of the formula 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol correspond to the data of the product of Example 1. The melting point and spectral data of the separated compound of the formula 4-[2- (dimethylamino)-ethyl]-phenol correspond to the data of the prior art (Tetrahedron 1990, 46, 7105).

Example 11 (Comparative example)

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a hydrogen atom (desvenlafaxine)]

Example 1 is repeated with the exception that instead of tetrahydrofurane 30 ml of λ/,λ/-dimethylformamide (DMF) are used. The product is a mixture with a composition as follows

(based on HPLC measurements):

2 % of 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]- cyclohexanol, and

96 % of 1-[cyano-(4-hydroxyphenyl)methyl]-cyclohexanol.

Spectral data of the separated compound of the formula 1-[2- (dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol correspond to the data of the product of Example 1.

Example 12 (Comparative example)

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I) ₁ wherein R stands for a hydrogen atom (desvenlafaxine)]

Example 1 is repeated with the exception that instead of tetrahydrofurane 30 ml of λ/-methyl-2-pyrrolidone (NMP) are used. The product is a mixture with a composition as follows

(based on HPLC measurements):

10 % of 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]- cyclohexanol, and

87 % of 1-[cyano-(4-hydroxyphenyl)methyl]-cyclohexanol.

Spectral data of the separated compound of the formula 1-[2- (dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol correspond to the data of the product of Example 1.

Example 13

Process for the preparation of 1-[2-(dimethylamino)-1-(4- methoxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a methyl group (venlafaxine)]

In a pressure-tight vessel 7.4 g (0.03 mol) of 1-[cyano-(4- methoxyphenyl)methyl]-cyclohexanol are suspended in 100 ml of tetrahydrofurane, then a mixture of 9.5 g (0.21 mol) of dimethylamine and 60 ml of tetrahydrofurane and 2.5 g of palladium on charcoal catalyst is added.

The vessel is purged twice with nitrogen, twice with hydrogen, and then the reaction mixture is kept at 50 ^C C and hydrogenated under a pressure of 5 bar of hydrogen for 10 hours, until the decrease of hydrogen pressure is stopped. The reaction mixture is cooled to room temperature, the catalyst is filtered off and washed with tetrahydrofurane. The filtrate and the washing solvent are united and evaporated in vacuo. The raw product is suspended with 20 ml of methyl-tert. butyl ether, filtered, washed and dried. Thus 5.4 g (65%) of title product are obtained.

Melting point: 78-79 ⁰ C.

IR (KBr): 3158, 2944, 1514 crτϊ ¹ .

¹ H-NMR (DMSO-cfe, 400 MHz): 7.05 (d, J=8.7 Hz, 2H), 6.82 (d,

J=8.7 Hz, 2H), 3.79 (s, 3H) ₁ 3.32 (t, J=12.4 Hz, 1 H), 2.97 (dd,

J=3,4 Hz, 12.0 Hz, 1H), 2.34 (s, 6H), 2.34 (m, 1H), 1.69 (m,

3H), 1.52 (m, 3H), 1.37 (m, 1H), 1.29 (m, 1H) ₁ 0.98 (m, 1H),

0.87 (m, 1 H) ppm.

¹³ C-NMR (DMSO-cfe, 125 MHz): 158.3, 132.7, 130.1 , 113.3, 74.2, 61.2, 55.2, 51.7, 45.4, 38.0, 31.2, 25.9, 21.6, 21.3 ppm.

Elementary analysis based on the formula Ci ₇ H ₂₇ NO ₂ :

calculated: C % = 73.61 ; H % = 9.81 ; N % = 5.05 measured: C % = 73.42; H % = 9.70; N % = 5.09.

Example 14 (Comparative example)

Process for the preparation of 1-[2-(dimethylamino)-1-(4- methoxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a methyl group (venlafaxine)]

Example 13 is repeated with the exception that instead of tetrahydrofurane ethanol is used. The product is a mixture with a composition as follows (based on HPLC measurements):

30 % of 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]- cyclohexanol, and

48 % of 4-methoxyphenethyl-dimethylamine.

The products are separated, purified and their chemical structures are identified. Spectral data of the separated compound of the formula 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol correspond to the data of the product of Example 13. The boiling point and spectral data of the separated compound of the formula 4-methoxyphenethyl- dimethylamine correspond to the data of the prior art (J. Org.

Chem., 1976, 41, 3653).

Example 15

Process for the preparation of 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]-cyclohexanol [of the general formula (I), wherein R stands for a hydrogen atom (desvenlafaxine)]

Example 1 is repeated with the exception that instead of tetrahydrofurane ethyl acetate is used. Thus 5.1 g (65%) of title product are obtained.

The properties of the product correspond to the product of Example 1.