Process for the preparation of phenethylamine derivatives

Description

The present invention provides a process for the preparation of phenethylamine derivatives, which comprises hydrogenating a phenylacetonitrile in the presence of a nickel or cobalt catalyst. Compounds of formula (1) are known to be particularly useful as intermediates in the preparation of antidepressants acting on the central nervous system. One such important compound is Venlaaxin (Merck Index, 12th edition, 1996, No. 10079). The preparation of the compound is described in US-A-4,535,186. According to Example 2 of said patent, the intermediate of formula (1) is prepared by hydrogenation in the presence of a rhodium catalyst. The use of a rhodium catalyst has economic disadvantages, and this catalyst must therefore be recovered, which requires an additional purification step and involves the possibility of varying the catalytic activity of the recovered catalyst. The present invention relates to a high-yield process for the preparation of phenethylamine derivatives, meeting the requirements of economy. The present invention provides a process for the preparation of a compound of general formula (1) - where R-ι represents a hydrogen atom, hydroxyl, unsubstituted or substituted alkyl or alkoxy group; R2 represents a hydrogen atom or a substituent which can be replaced by a hydrogen atom; n is 0, 1 or 2 for the preparation of compounds or salts thereof, which consists in hydrogenating the compound of general formula (2) - where R1, R2 and n are as defined above - in the presence of a nickel or cobalt catalyst. The alkyl group represented as Rt substituent may be straight or branched, preferably a group having 1-4 carbon atoms, such as methyl, ethyl, η-propyl, isopropyl, η-butyl, sec-butyl, tert-butyl. Said groups may be unsubstituted or substituted. Their substituent may be, for example, a phenyl group. The alkoxy group represented as R-ι substituent may be a straight or branched chain, preferably a group having 1 to 4 carbon atoms, such as alkoxy, ethoxy, n-propoxy, isopropoxy, η-butoxy, sec-butoxy, tert-butoxy. The methoxy group is preferred. The groups mentioned may be unsubstituted or substituted, for example with a phenyl group. R-ι preferably represents a hydroxyl group or a C1-C4 alkoxy group, of which methoxy is most preferred. It is preferred that the R! group is attached to the benzene ring in the para-position. The R2 substituent which can be replaced by a hydrogen atom is, for example, a silyl, benzyl, formyl or C2-C6 alkanoyl group. The conversion can be carried out by known methods. R2 is preferably formyl or alkanoyl group of 2-6 carbon atoms, or most preferably hydrogen, n is preferably 1. In a preferred embodiment of the present invention, R-ι is a methoxy group, R2 is a hydrogen atom and n is 1. The nickel or cobalt catalysts used in the present invention are well known and can be used in the conventional manner in hydrogenation. The nickel catalyst can be prepared, for example, by thermal decomposition of nickel formate or other heat-stable nickel salts, for example in fatty oil, or by precipitation of a nickel salt on an inert support, followed by reduction with hydrazine or hydrogen gas. The nickel catalyst can also be prepared by treatment of electrically precipitated nickel hydroxide. In the preparation of nickel hydroxide, a current is passed directly through a cell, the anode of which is made of nickel, and the electrolyte is a dilute solution of an alkaline salt of a weak acid. The nickel hydroxide thus obtained is reduced in the usual manner, for example with hydrogen gas or hydrazine. The activity of the nickel or cobalt catalyst can be enhanced in conventional manner, for example by using Group VIB metals or compounds thereof which can be reduced with hydrogen to the corresponding elemental metal, or by using manganese or iron promoters. Such Group VIB metals or hydrogen-reducible metal compounds include, for example, elemental chromium, chromium acetate, chromium chloride, chromium oxide, elemental molybdenum, molybdenum hydroxide, molybdenum oxide, elemental tungsten, tungsten chloride, tungsten oxide and the like, or mixtures of any two or more of the foregoing. The weight ratio of the Group VIB component to the nickel or cobalt catalyst can be any suitable value, but is generally in the range of 0.001:1 to 0.2:1, preferably 0.005:1 to 0.1:1. The catalyst may be supported or unsupported. Typical supports include carbon, alumina, silica, chlorine trioxide, titanium dioxide, zirconium dioxide, zinc oxide, calcium oxide, magnesium oxide, barium sulfate, calcium carbonate, or aluminum phosphate. The nickel or cobalt catalyst may be bound to the support in an amount of, for example, 1.0 to 20.0% by weight. Preferred catalysts are Raney nickel and Raney cobalt. Such catalysts can be prepared, for example, by treating a mixture of nickel and aluminum or cobalt and aluminum with a suitable base, such as sodium hydroxide, to remove the aluminum to yield a highly reactive nickel or cobalt metal catalyst. In all cases, the use of a nickel catalyst, and in particular Raney nickel, is preferred. In a preferred embodiment of the present invention, the nickel or cobalt catalyst is preferably pretreated with a carboxylic acid, its salt, its anhydride, an ammonium salt, a vanadium, tungsten or molybdenum compound. Mixtures containing at least two of the aforementioned compounds may also be used. Carboxylic acids having 1 to 8 carbon atoms, especially 2 to 8 carbon atoms, including polycarboxylic acids are preferred. Carboxylic acids may be unsubstituted or substituted, for example, by a hydroxyl group or a halogen atom (for example, a fluorine atom). Examples of such carboxylic acids include formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, citric acid, tartaric acid, trifluoroacetic acid; anhydrides, for example, acetic anhydride, propionic anhydride, etc. HU 225 019 Β1 are anhydrides of the above-mentioned acids. Examples of carboxylic acid salts include alkali metal salts, such as sodium salts. Carboxylic acids having 2 to 4, especially 2 carbon atoms, are preferred. These carboxylic acids may be unsubstituted or substituted as described above. The term also includes salts and anhydrides of the acids. Acetic acid and its salts and anhydrides are most preferred. Ammonium salts are, for example, halides such as ammonium chloride and especially ammonium fluoride. Vanadium salts in which the oxidation state of vanadium is 0, 2, 3, 4 or 5 are preferred. Elemental vanadium is also suitable. Examples of such compounds are V2O5, VOCl3, V2O4, NH4VO3. Acetylacetonates (acac), such as V(acac)3, VO(acac)2, are particularly preferred. The vanadium compounds are used in catalytic amounts in dissolved or dispersed form. Preferred are tungsten or cobalt compounds in which the metal has an oxidation state of 0, 2, 3, 4, 5 or 6, such as H,WO4, H3[P(W3O11)4], H2MoO4, H3[P(MO3O10)4]. For the pretreatment of nickel or cobalt catalysts, it is preferred to use carboxylic acids, their salts or anhydrides or acetyl acetates. Carboxylic acids are most preferred. The pretreatment is preferably carried out in an aqueous medium. The aqueous medium usually contains the nickel or cobalt catalyst and the agent used for the treatment. The treatment is usually carried out at room temperature, but the process can also be carried out at lower or higher temperatures. The conditions of the reduction - time, temperature and pressure - can vary within a wide range, as will be apparent to those skilled in the art. The hydrogenation is preferably carried out in an organic solvent, for example an alcohol (methanol, but especially ethanol). It is also preferred to carry out the hydrogenation in the presence of a base (for example NH3, NH4OH or NaOH). The catalysts mentioned are present in the reaction mixture in an amount of 0.1-500% by weight, preferably 20-200% by weight, based on the amount of starting material used. The educt may be present in the reaction mixture in an amount of 0.1-80, preferably 5-20, weight % relative to the weight of the reaction mixture. The temperature used in the reaction may be, for example, 0-200°C, preferably 20-120°C, most preferably 20-80°C. The reaction time can vary, generally from 0.1 to 24, preferably from 0.1 to 14, particularly preferably from 0.1 to 4 hours. The pressure of the hydrogen gas is, for example, 1-200 bar, in particular 1-100 bar, preferably 20-60 bar. The catalysts can be reused 1-100 times, especially 1-10 times; surprisingly, the catalysts can be reused without further treatment, and the reused catalyst shows no decrease in either its activity or selectivity. After the reaction, the product can be purified by known methods, for example, by dissolving the obtained product in an organic solvent (e.g. diisopropyl ether), adding acid and filtering off the corresponding salt. Preferably, the product can be purified by adding a hydrogen halide (e.g. hydrogen chloride) or a C1-6 carboxylic acid (e.g. formic acid). It is particularly preferred to use formic acid and separate the obtained compound of general formula (1a) by filtration. The present invention further provides compounds of formula (1a). The conditions given above are used for their preparation. Compounds of formula (1a) do not require any special treatment to be further converted into compounds of formula (3). Alternatively, the product can be used directly without purification in the reactions described below. The present invention further provides a process for the preparation of a compound of formula (3) wherein R1, R2 and n are as defined above, which comprises hydrogenating a compound of formula (2) in the presence of a nickel or cobalt catalyst to a compound of formula (1) and converting the compound of formula (1) to a compound of formula (3). The meanings of R1, R2 and n and the statements relating thereto are the same as those defined above. The conversion of compound (1) to compound (3) can be carried out by known methods, as described in US-A-4,535,186 (especially Example 3). The conversion can generally be carried out by the reaction shown in Figure 1 (Step A), followed by the preparation of the corresponding hydrochloride salt (Step B). In step A, the compound of general formula (1) is reacted with, for example, formaldehyde, formic acid in a large excess of water. Step B is carried out in the usual manner, preferably with an equimolar amount of hydrochloric acid to form the acid addition salt. The process of the present invention allows the compound of formula (1) to be obtained in high yield and eliminates the need for expensive catalysts. The following examples are provided to illustrate the above. The examples are for illustrative purposes only and do not limit the scope of the invention. Example 1 a) Catalyst pretreatment 135 g of Raney nickel is washed three times with 135 ml of water each time, then with 250 ml of 5% (v / v) aqueous acetic acid solution, finishing the washing with 3*1000 ml of water. b) Hydrogenation 180 g of 1-[cyano-(4-methoxyphenyl)methyl]cyclohexanol, 2400 ml of methanol, 600 ml of 25% (v / v) aqueous ammonia solution and 135 g of Raney nickel pretreated as described above are weighed into a 1-liter autoclave. The reaction mixture is hydrogenated at 27-30 °C under 120 psi of hydrogen gas for 9-10 hours. The reaction mixture is filtered through 100 g of celite, the filtered catalyst is washed with 700 ml of methanol. The filtrates are evaporated to give 167.1 g of crude product HU 225 019 Β1 in the form of an oily residue. 1.1 g of crude product was dissolved in 2 ml of anhydrous ethyl acetate and 2 ml of isopropanol hydrochloric acid solution was added (the solution had a pH of approximately 2). The solvent was removed under highly reduced pressure to give 1.14 g of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride. Example 2 a) Pretreatment of the catalyst ml of 5% (v / v) aqueous acetic acid solution is added to 5 g of Raney nickel [60% (w / w) catalyst suspension]. The resulting suspension is stirred at room temperature for 10-15 minutes. After separation, the catalyst is washed four times with deionized water. b) Hydrogenation 1.2 g of 1-[cyano-(4-methoxyphenyl)methyl]cyclohexanol, Raney nickel obtained as above, 24 ml of ethanol and 6 ml of 25% (v / v) aqueous ammonia solution are weighed into an autoclave. The reaction mixture is hydrogenated at 60 °C under 4 MPa (40 bar) hydrogen gas for 140 minutes. The catalyst is filtered off and washed with ethanol. The filtrate and ethanol washings are combined and evaporated under reduced pressure to give 1.2 g of crude product as an oily residue. The crude product contains 79% (w / w) of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (according to HPLC analysis). The crude product obtained was dissolved in diisopropyl ether and hydrochloric acid was added to give the hydrochloride addition salt. The salt was filtered off, washed with diisopropyl ether and dried under reduced pressure. 1.23 g of the salt was obtained as a white crystalline solid. The product obtained contained 84% (w / w) of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride (HPLC analysis). Melting point: 169 °C. Example 3 The procedure of Example 2 was repeated except that twice the amount of Raney nickel was used, the hydrogenation was continued for 70 minutes, and the formation of the hydrochloride salt was omitted. 1.2 g of crude product was obtained, containing 86% (w / w) of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride (HPLC analysis). Example 4 The procedure of Example 2 was repeated except that Raney cobalt was used in the same amount instead of Raney nickel, the hydrogenation was continued for 90 minutes, and the formation of the hydrochloride salt was omitted. 1.2 g of crude product was obtained, containing 92% (w / w) of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (HPLC analysis). Example 5 a) Catalyst pretreatment To a saturated solution of V(acac)3[acac=acetylacetonate] in 500 ml of deionized water, 50 g of Raney nickel (60% suspension) was added. The resulting suspension was stirred at room temperature for 15-20 minutes. The separated catalyst was washed five times with 500 ml of deionized water. b) Hydrogenation 33 g of 1-(cyano-(4-methoxyphenyl)methyl]cyclohexanol, the Raney nickel catalyst pretreated as above, 320 ml of ethanol and 80 ml of 25% (v / v) aqueous ammonia solution are weighed into an autoclave. The reaction mixture is hydrogenated at 60 °C under 4 MPa (40 bar) hydrogen gas for 640 minutes. The catalyst is filtered off and washed with ethanol. The filtrate and ethanol wash are combined and evaporated to give 33 g of crude product as an oily residue. The crude product contains 93% (w / w) 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (according to HPLC analysis). The crude product can be used directly to produce the hydrochloride addition salt. Example 6 a) Pretreatment of the catalyst 1 ml of 0.5% (vol) H3[PW3O10)4]xH2O aqueous solution is added to 5 g of Raney nickel (60% suspension). The resulting suspension is stirred at room temperature for 15-20 minutes. After separation, the catalyst is washed five times with deionized water. b) Hydrogenation 1.2 g of 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol, Raney nickel pretreated as above, 24 ml of ethanol and 6 ml of 25% aqueous ammonia solution are weighed into an autoclave. The reaction mixture is hydrogenated at 60 °C and 4 MPa (40 bar) of hydrogen gas for 300 minutes. The catalyst is filtered off and washed with ethanol. The filtrate and ethanol wash are combined and evaporated to give 1.2 g of crude product as an oily residue. The crude product contains 90% (w / w) of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (according to HPLC analysis). Example 7 a) Preparation of 1-[2-amino-1-(methoxyphenyl)ethyl]cyclohexanol formic acid salt 49.8 g of crude 1-[2-amino-1-(methoxyphenyl)ethyl]cyclohexanol obtained by hydrogenation of the nitrile was suspended in 250 ml of ethyl acetate and 12 ml of formic acid (98-100%) was added in one portion. The reaction mixture was heated to reflux with stirring and then cooled to room temperature. The product was filtered off, washed with 100 ml of hexane and dried under reduced pressure to give 48.1 g (82%) of crude formate salt. b) Purification of the formate salt The crude formate salt was suspended in 1 liter of ethyl acetate, heated at reflux for 1 hour, then cooled to room temperature and filtered. At this step, a more purified product was obtained (>98% product by HPLC analysis). The purification procedure was repeated, and the final product was dried at 40 °C under reduced pressure to give 29.6 g (50%) of product as a white crystalline solid. The purity of the product was >98% by HPLC analysis. HU 225 019 B1 Example 8 Reductive methylation of 1-[2-amino-1-(methoxyphenyl)ethyl]cyclohexanol formate salt 29.6 g of the formate salt obtained as above are mixed with 100 ml of water, 17 ml of formic acid (98-100%) and 26 ml of formaldehyde (37%) and heated under reflux for 20 hours. The reaction mixture is cooled to room temperature, acidified with 4N hydrochloric acid to pH>1 and extracted five times with 50 ml of ethyl acetate. The aqueous phase is adjusted to pH>12 with 30% aqueous sodium hydroxide solution and 150 ml of toluene are added. The mixture is passed through an R3 filter, the phases are separated and the aqueous phase is extracted again with 50 ml of toluene. The combined organic extracts are washed with 100 ml of water. 30 ml of 4.2N hydrochloric acid in dioxane were added to the solution with stirring over 56 minutes and the resulting suspension was stirred for 1 hour. The product was filtered, washed with 2*50 ml of hexane, and dried under reduced pressure at 40 °C to give 26.9 g of the hydrochloride salt (86%) as white crystals, which were pure by HPLC analysis. Example 9 a) Catalyst pretreatment 6.00 kg of Raney nickel are placed in a 50 ml steel autoclave. 40 liters of an aqueous solution containing 115.2 g of VO(acac)2 are added to the catalyst. The mixture is stirred at room temperature for 30 minutes, then the aqueous phase is removed. b) Hydrogenation 4.00 kg of 1-[cyano-(4-methoxyphenyl)methyl]cyclohexanol are suspended in 5 liters of ethanol and the suspension is transferred to the autoclave containing Raney nickel. 22 liters of ethanol are added to the mixture, the autoclave is sealed and its tightness is checked. Then 6 liters of 25% aqueous ammonium hydroxide are added to the reaction mixture via the metering device. The autoclave is flushed three times with nitrogen gas and then three times with hydrogen gas. The autoclave is pressurized to 4 MPa (40 bar) and the reaction is started by starting stirring. The reaction mixture is heated to 60 °C for 20 minutes and then maintained at 60 °C for a further 2 hours. The contents of the autoclave are cooled to room temperature, the hydrogen gas is replaced with nitrogen gas, and the autoclave is opened. After filtering off the catalyst, the filtrate is evaporated to dryness under reduced pressure. According to HPLC analysis, the desired 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol is obtained in 93% yield. Example 10 a) Catalyst pretreatment 22.5 g of Raney nickel are placed in a 300 ml steel autoclave fitted with a sintered filter. 220 ml of a saturated aqueous solution of V(acac)3 is added to the catalyst and the mixture is stirred for 30 minutes. The reaction mixture is left to stand overnight, then the water is removed through a filter and the catalyst is washed with 50 ml of water and 3x50 ml of ethanol. b) Hydrogenation g 1-[cyano-(4-methoxyphenyl)methyl]cyclohexanol is suspended in 50 ml of ethanol and the suspension is transferred to a 0.3 liter autoclave containing the modified Raney nickel. 50 ml of ethanol is added to the mixture, the autoclave is sealed and its tightness is checked. Then 30 ml of 25% aqueous ammonium hydroxide is added to the reaction mixture via the metering device, the autoclave is flushed three times with nitrogen gas and then three times with hydrogen gas. The autoclave is pressurized to 4.5 MPa (45 bar) and the reaction is started with stirring. The reaction mixture is heated at 60 °C for 20 minutes and then maintained at 60 °C for a further 2 hours. The contents of the autoclave were cooled to room temperature, the hydrogen gas was replaced with nitrogen gas, and the autoclave was opened. HPLC analysis showed that the desired 1-[2-amino-(4-methoxyphenyl)ethyl]cyclohexanol was obtained with a selectivity of 86%. c) Hydrogenation with reused catalyst The catalyst recovered from the above procedure is washed with 50 ml of ethanol, and then the hydrogenation procedure described above is exactly repeated with this catalyst, using the same reaction times. According to HPLC analysis, the desired 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol is obtained with a selectivity of 85%. In the subsequent procedures, the selectivity is also 85-87%, and no noticeable deactivation of the catalyst is observed even after four reuses. The vanadium content of the product is always <2 ppm, and the nickel content varies between 1-3 ppm.

Claims

1. Process for the preparation of a compound of general formula (1) - where in the formula R1 represents a hydrogen atom, a hydroxyl group or an unsubstituted or substituted alkyl or alkoxy group; R2 represents a hydrogen atom or a group replaceable by a hydrogen atom; n represents 0, 1 or 2 or its salts, characterized in that the compound of general formula (2) - where R1, R2 and n are as defined above - is hydrogenated in the presence of a nickel or cobalt catalyst.

2. The process according to claim 1, characterized in that R2 represents a hydroxyl group or an unsubstituted or phenyl-substituted C1-C4 alkoxy group, preferably a methoxy group.

3. The process according to claim 1 or 2, characterized in that the R-1 group is attached in the para-position.

4. The process according to any one of claims 1-3, characterized in that R2 represents a hydrogen atom, a silyl, benzyl, formyl or a C2-C6 alkanoyl group, preferably a hydrogen atom.

5. The method according to any one of claims 1-4, characterized in that n is 1.

6. The process according to claim 1, characterized in that Rt represents a methoxy group, R2 represents a hydrogen atom and n represents 1. HU 225 019 Β1 7. The process according to any one of claims 1-6, characterized in that the nickel or cobalt catalyst is pretreated with a carboxylic acid, its salt or anhydride, or its ammonium salt, or with a vanadium, tungsten or molybdenum compound, or with a mixture of at least two of said compounds.

8. The process according to claim 7, characterized in that a carboxylic acid having 1-8 carbon atoms, preferably acetic acid, is used.

9. The process according to claim 7, characterized in that a vanadium compound containing acetylacetonate is used.

10. The method according to any one of claims 7-9, characterized in that the pretreatment is carried out in an aqueous medium.

11. The process according to any one of claims 1-10, characterized in that the catalyst is Raney nickel or Raney cobalt.

12. The process according to any one of claims 1-11, characterized in that a nickel catalyst, preferably Raney nickel, is used.

13. The process according to any one of claims 1-12, characterized in that the hydrogenation is carried out in an organic solvent, preferably an alcohol.

14. The process according to any one of claims 1-13, characterized in that a recycled catalyst is used.

15. The process according to claim 1, characterized in that after hydrogenation the product is purified by reacting with formic acid to obtain a compound of general formula (1a) - where R1, R2 and n are as defined in claim 1.

16. A compound of formula (1a), wherein R1, R2 and n are as defined in claim 1.

17. A process for preparing a compound of general formula (3) - wherein Rt represents a hydrogen atom, a hydroxyl group or an unsubstituted or substituted alkyl or alkoxy group; and R2 represents a hydrogen atom or a group replaceable with a hydrogen atom, n represents 0, 1 or 2, characterized in that a compound of general formula (2) - wherein R4, R2 and n are as defined above - is hydrogenated in the presence of a nickel or cobalt catalyst to obtain a compound of general formula (1) - wherein R,, R2 and n are as defined above - and the compound of general formula (1) is converted into a compound of general formula (3).

18. The process according to claim 17, characterized in that the nickel or cobalt catalyst used is pretreated with a carboxylic acid, its salt or anhydride, or an ammonium salt, or a vanadium, tungsten or molybdenum compound, or a mixture of at least two of said compounds.

19. The process according to any one of claims 17-18, characterized in that R4 represents a methoxy group, R2 represents a hydrogen atom and n represents 1.