| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | July 14, 1992 |
| PATENT TITLE |
Process for the production of 1-(aminomethyl) cyclohexane acetic acid |
| PATENT ABSTRACT | A new process is described for the production of 1-(aminomethyl)cyclohexane acetic acid, a pharmaceutical agent used as an anticonvulsant. For this purpose a (1-cyanocyclohexyl)-malonic acid dialkyl ester is decarbalkoxylated to the corresponding (1-cyanocyclohexyl)acetic acid alkyl ester, then transesterified with a benzyl alcohol and finally hydrogenated to form the end product |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | July 10, 1991 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
Krapcho et al., Synthesis, (1982), pp. 805-821; pp. 893 to 914. New et al., Synthesis (1983), pp. 388 to 389. Drugs of the Future, vol. 9, No. 6, (1984), pp. 418 and 419. Aneya et al., Tetrahedron Letters, vol. 24, No. 23, (1983), pp. 4641 and 4644. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. (1-Cyanocyclohexyl)acetic acid ester of the formula: ##STR13## wherein R.sub.2 is a benzyl radical of the formula: ##STR14## wherein R is H, an alkoxy group, a nitro group or a halogen. 2. The ester according to claim 1 wherein R.sub.1 is H. 3. The ester according to claim 1 wherein R.sub.1 is an alkoxy group. 4. The ester according to claim 1 wherein R.sub.1 is a nitro group. 5. The ester according to claim 1 wherein R.sub.1 is a halogen |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION 1. Field of the Invention The invention relates to a new process for the production of 1(aminomethyl)cyclohexane acetic acid as well as to (1-cyanocyclohexyl)acetic acid ester as new intermediate products in the process according to the invention. 2. Description of Related Art 1-(Aminomethyl)cyclohexane acetic acid is used under the name Gabapentin in medicine as an anticonvulsant. Gabapentin, its use and production are described in Drugs of the Future, Vol. 9, No. 6, 1984, pp. 418 to 419, as well as in U.S. Pat. Nos. 4,024,175 and 4,152,326, which are hereby incorporated by reference in their entireties. Production of Gabapentin under these known methods is very expensive, however, and includes seven to eight technically difficult and error-prone steps. SUMMARY OF THE INVENTION Therefore the object was to find a process that excludes said drawbacks. This object was able to be obtained with a process for the production of 1-(aminomethyl)cyclohexane acetic acid of the formula: ##STR1## The process is characterized in that in a first step a (1-cyanocyclohexyl) malonic acid dialkyl ester of the general formula: ##STR2## in which R is an alkyl with 1 to 4 carbon atoms, is decarbalkoxylated to the corresponding (1-cyanocyclohexyl)acetic acid alkyl ester of the general formula: ##STR3## in which R is defined as above. In a second step, the alkyl ester is transesterified with a benzyl alcohol of the general formula: ##STR4## i.e., in which R.sub.1 is H, an alkoxy group, a nitro group or a halogen, in the presence of a basic catalyst to form a (1-cyanocyclohexyl)acetic acid benzyl ester of the general formula: ##STR5## in which R.sub.1 is defined as above. Finally the benzyl ester is hydrogenated in the presence of a hydrogenating catalyst to form the end product with hydrogen. DESCRIPTION OF THE PREFERRED EMBODIMENTS The initial products in the process according to the invention are (1-cyanocyclohexyl)malonic acid dialkyl esters of the general formula: ##STR6## in which R means an alkyl with 1 to 4 carbon atoms. These compounds are described in Swiss Patent Application CH 3127/88, which is hereby incorporated by reference in its entirety, and are accessible in a simple way from cyclohexanone. The methyl or ethyl esters preferably are used for the process according to the invention. In the first process step, the initial product is decarbalkoxylated to a (1-cyanocyclohexyl)acetic acid alkyl ester of the general formula: ##STR7## in which R means an alkyl with 1 to 4 carbon atoms. These compounds have not been described up to now. The decarbalkoxylation can be performed according to methods known in the literature, e.g., according to Krapcho et al., Synthesis 1982, pages 805 to 921 and 893 to 914, or according to Aneya et al., Tetrahedron Letters 1983, Vol. 24, No. 43 pages 4641 to 4644, which are hereby incorporated by reference in their entirety. Then suitably the operation is performed in boric anhydride or in dipolar aprotic solvents such as dimethyl sulfoxide, in combination with water as reaction medium at temperatures between 100.degree. and 250.degree. C. Optionally the reaction can be performed in the presence of alkali or alkaline-earth salts, such as alkali or alkaline-earth chlorides, cyanides, or acetates. The resulting (1-cyanocyclohexyl)acetic acid alkyl ester is suitably isolated and purified by distillation. Alternatively, it is also possible to produce the (1-cyanocyclohexyl)acetic acid alkyl esters by alcoholysis of (1-cyanocyclohexyl)acetonitrile of the general formula: ##STR8## with a lower aliphatic alcohol in the presence of a mineral acid and then hydrolyzing the mixture with water. In this case, the (1-cyanocyclohexyl)acetonitrile is accessible according to New et al., Synthesis 1983, pages 388-389, which is hereby incorporated by reference in its entirety, from the corresponding cyclohexylidene malonic acid ester. The alcoholysis is performed with a lower alcohol, preferably with methanol or ethanol, in the presence of a mineral acid from the series hydrogen chloride, hydrogen bromide or anhydrous sulfuric acid. Both the alcohol and the mineral acid are suitably used in amounts of 1 to 100 equivalents relative to the nitrile. The reaction temperature is suitably between -20.degree. and 50.degree. C., the pressure between 1 and 10 bars. Optionally, an additional aprotic solvent, such as, e.g., an aliphatic or aromatic hydrocarbon, an ether, ester, or a halogenated hydrocarbon can be used as reactant together with the alcohol. The intermediate product (Imidat) occurring in the alcoholysis is not isolated but is directly hydrolyzed with water, preferably in excess, at temperatures between -20.degree. and 100.degree. C. to form the (1-cyanocyclohexyl)acetic acid alkyl ester. In the subsequent step, the alkyl ester is transesterified with a benzyl alcohol of the general formula: ##STR9## in which R.sub.1 means H or an alkoxy group, a nitro group or a halogen in the presence of a catalyst to form a (1-cyanocyclohexyl)acetic acid benzyl ester of the general formula: ##STR10## in which R.sub.1 means H or an alkoxy group, a nitro group or a halogen. These compounds have not been described up to now. The transesterification is preferably performed with benzyl alcohol in the presence of a base as catalyst. Suitable bases are the cyanides such as, e.g., potassium cyanide, alcoholates such as, e.g., sodium methylate or potassium tert-butylate or tertiary amines such as, e.g., triethylamine or N,N-dimethylaminopyridine. The catalyst is suitably used in amounts between 0.01 and 10 mol percent, preferably between 0.2 and 3 mol percent. Advantageously, the operation is performed in the presence of an aprotic solvent, such as dimethyl ether or tetrahydrofuran, or an aromatic or aliphatic hydrocarbon, such as toluene or hexane. The reaction temperature for the transesterification is suitably between 0.degree. C. and the boiling point of the benzyl alcohol used. The reaction product is suitably isolated and purified by distillation. Alternatively, the (1-cyanocyclohexyl)acetic acid benzyl ester may also be produced by alcoholysis of (1-cyanocyclohexyl)acetonitrile of the general formula: ##STR11## with a benzyl alcohol of the general formula: ##STR12## in which R.sub.1 means H or an alkoxy group, a nitro group or halogen, preferably benzyl alcohol, in the presence of a mineral acid, preferably from the series hydrogen chloride, hydrogen bromide or anhydrous sulfuric acid. Both the benzyl alcohol and the mineral acid are suitably used in amounts from 1 to 100 equivalents, relative to the nitrile. The reaction temperature is suitably between -20.degree. and 50.degree. C., the pressure is suitably between 1 and 10 bars. Optionally an additional aprotic solvent, such as, e.g., an aliphatic or aromatic hydrocarbon, an ether, ester, or a halogenated hydrocarbon can be used as reactant together with the alcohol. The intermediate product (Imidat) occurring in the alcoholysis is not isolated but is directly hydrolyzed with water, preferably in excess, at temperatures between -20.degree. and 100.degree. C. to form the (1-cyanocyclohexyl)acetic acid benzyl ester. In the last step, the catalytic hydrogenation of the benzyl ester with hydrogen to the desired end product, 1(aminomethyl)cyclohexane acetic acid, takes place. Noble metal catalysts such as platinum, palladium, rhodium, ruthenium catalysts, optionally applied to inert supports such as activated carbon or aluminum oxide or Raney catalysts such as, e.g., Raney nickel or Raney cobalt catalysts, or (noble) metal oxides, such as, e.g., nickel oxide or platinum oxide can be used as a hydrogenating catalyst. Suitably, the amount of catalyst varies between 1 and 50 percent by weight, relative to the benzyl ester used. Advantageously, the benzyl ester is hydrogenated in the presence of a suitable solvent, such as a lower alcohol, e.g., ethanol, methanol; a carboxylic acid, e.g., acetic acid; an ester, e.g., ethyl acetate; or an ether or alcohol in combination with ammonia. The pressure suitably varies in the range of 1 to 100 bars, preferably between 2 and 10 bars, the temperature suitably varies between 0.degree. and 100.degree. C. The optimal temperature is largely dependent on the catalyst used. The desired product already precipitates in great purity, but optionally can be further purified by recrystallization |
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| PATENT PHOTOCOPY | available on request |
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