| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | November 26, 1991 |
| PATENT TITLE |
Process for the preparation of cyclic amino acids and intermediates useful in the process |
| PATENT ABSTRACT | Processes for the preparation of cyclic amino acid derivatives useful in the treatment of cerebral diseases such as epilepsy are disclosed. Novel intermediates useful in processes are also disclosed |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | August 21, 1990 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. A process for the preparation of a compound formula ##STR10## or a pharmaceutically acceptable salt thereof, wherein n is an integer of from 1 to 3 comprising: (a) converting a malonic ester of formula ##STR11## wherein R is an alkyl of from 1 to 5 carbon atoms and n is as described above by alkaline hydrolysis into a cyanocycloalkylmalonic acid derivative of formula ##STR12## (b) diacarboxylating gently the cyanocycloalkylmalonic acid of step (a) to produce a 1-cyanocycloalkylacetic acid of formula ##STR13## (c) hydrogenating the acetic acid from step (b) in an alkanol solvent using a catalyst to produce a compound of formula I above. 2. A process according to claim 1, wherein in step (c) the catalyst is selected from Raney nickel, Raney cobalt or noble metal catalysts. 3. A process according to claim 1, wherein in step (b) the temperature is from about ambient to about 80.degree. C. at a pressure of from about 1 to 50 KPa. 4. A process according to claim 1, wherein in step (c) the alcohol solvent is ethanol, isopropanol or butanol. 5. A process according to claim 1, wherein in step (b) decarboxylation takes place in the melt. 6. A process according to claim 1, wherein in step (b) decarboxylation takes place in an organic solvent. 7. A process according to claim 6, wherein the organic solvent is ethyl acetate, toluene, methyl ethyl ketone, dioxane, hexane, an alkanol of from 1 to integer 6 carbon atoms or a halogenated hydrocarbon. 8. A process according to claim 1, wherein in step (a) alkaline hydrolysis is carried out in an alkanol of from 1 to 4 carbon atoms or a mixture of the alkanol and water. 9. A process according to claim 1, wherein the product formed is gabapentin. 10. A process according to claim 1, wherein said compound of formula I is converted to a pharmaceutically acceptable salt. 11. A process for the preparation of a compound formula ##STR14## or a pharmaceutically acceptable salt thereof, wherein n is an integer of from 1 to 3 comprising: (a) catalytic hydrogenation at an elevated temperature of a cyanocycloalkylmalonic acid of the formula ##STR15## wherein n is as described above, to a cyclic lactam of the formula ##STR16## wherein n is as described above, and (b) the lactam of formula V is converted by acid hydrolysis to a compound of formula I. 12. A process according to claim 11, wherein said compound of formula I is converted to a pharmaceutically acceptable salt. 13. A process according to claim 11, wherein the hydrogenation is carried out at a pressure of from 1 to 50 KPa at a temperature of from about 50-120.degree. C. 14. A process according to claim 11, wherein the hydrogenation catalyst is selected from Raney nickel, Raney cobalt or platinum, palladium, or rhodium. 15. A process according to claim 11, wherein the acid hydrolysis of the lactam utilizes hydrochloric acid or sulfuric acid. |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION Gabapentin is a generic term used to identify the chemical compound (1-aminomethyl)-1-cyclohexaneacetic acid. ##STR1## It is useful in therapy of certain cerebral disorders such as certain forms of epilepsy, faintness attacks, hypokinesis and cranial traumas. U.S. Pat. Nos. 4,024,175 and 4,087,544 cover the compound and its uses. They also disclose an acid salt, i.e. gabapentin hydrochloride hydrate in a ratio of 4:4:1 and a sodium salt of gabapentin hydrate in a ratio of 2:1. These patents are hereby incorporated by reference. The patents describe various processes for the preparation of this and similar compounds of general formula ##STR2## wherein R.sub.1 is a hydrogen atom or a lower alkyl radical and n is 4, 5, or 6 and the pharmaceutically acceptable salts thereof, which depend upon known methods used for the preparation of primary amines or amino acids. All examples of the syntheses end in an isocyanate or urethane that can easily be converted into the desired (1-aminomethyl)-1-cyclohexaneacetic acid by acidic hydrolysis (preferred) to give an acid or basic hydrolysis to give a basic salt or followed by acidification to give an acid salt. U.S. Pat. No. 4,894,476 covers crystalline gabapentin monohydrate and methods for producing the same. This patent is hereby incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION The present invention is concerned with a process for the preparation of cyclic amino acid derivatives of formula ##STR3## in which n is 1, 2 or 3 and preferably 2, and of the pharmacologically acceptable salts thereof. The process for the preparation comprises converting a malonic ester derivative of formula ##STR4## in which R is an alkyl radical containing up from 1 to 5 carbon atoms and preferably an ethyl radical and n has the above meaning, by alkaline hydrolysis into a cyanocycloalkylmalonic acid derivative of the formula ##STR5## in which n has the above meaning. This is then decarboxylated either directly (Scheme II) or via an intermediate (Scheme I) of the formula ##STR6## in which n has the above meaning, and the nitrile group is hydrogenated in the presence of a catalyst. The lactam of formula ##STR7## in which n has the above meaning, is formed as a main product or as a by-product, and is then optionally separated off the compound of formula (I) and converted by hydrolysis into a compound of formula (I) or a desired salt thereof. A compound of formula (I) in which n is 2 (gabapentin, Drugs of the Future, Vol. 9, No. 6, pp. 418-419/1984) is well known. Starting from cyclohexanone, it was prepared by a laborious 7- or 8-step synthesis. Known processes for the preparation of gabapentin include a synthesis intermediate which must be converted into gabapentin hydrochloride by acid hydrolysis in an aqueous medium. By splitting off water and intramolecular cyclization, there is formed from gabapentin a lactam (2-aza-spiro-[4,5]decan-3-one) of formula V. The gabapentin hydrochloride obtained must then be converted into gabapentin in dilute aqueous solution by means of an ion exchanger. The gabapentin can then be obtained from the aqueous solution without appreciable lactam formation by means of technically laborious methods. The laboriousness of the synthesis, the undesired lactam formation, as well as the laborious isolation of gabapentin from aqueous solutions consequently give rise to a high cost of preparation for gabapentin. It is an object of the present invention to provide an economical process for the preparation of compounds of formula (I) and especially of gabapentin which can be carried out on a large scale. The number of synthesis steps needs to be reduced and the undesired formation of lactam needs to be suppressed. Furthermore, a process is needed which permits the isolation of gabapentin from nonaqueous solutions. Surprisingly, it has been found that the problem was solved by the reaction steps described above and in the instant claims. After the almost quantitative conversion of the malonic acid ester derivatives (II) by alkaline hydrolysis into the 1-cyanocycloalkylalonic acid derivatives (III) and by gentle decarboxylation into the 1-cyanocycloalkylacetic acid derivatives (IV), these can be hydrogenated in alcoholic solvents by means of catalysts to give the compounds of formula (I) directly. By means of the reaction conditions of the present invention, the formation of a lactam of formula (V) can thereby be prevented. In this new process, the conversion of salts of formula (I) into the corresponding bases, as well as the laborious isolation of the latter from aqueous solutions (see the following Scheme I). The process according to the present invention is illustrated by the following reaction Scheme I. ##STR8## Raney nickel, Raney cobalt or noble metal catalysts, for example rhodium or palladium, optionally in a carrier, such as carbon are used. Surprisingly, it has been found that cyanocycloalkylmalonic acid derivatives of formula (III) can, in the case of the catalytic hydrogenation at an elevated temperature, with the splitting off of carbon dioxide, be converted into a cyclic lactam of formula (V). This lactam can be converted by acid hydrolysis into the desired end product (I) according to the following Scheme II. ##STR9## The alkaline hydrolysis of the compounds (II), and the conversion thereof into cyanocycloalkylmalonic acid derivatives of formula (III) usually takes place either by means of alkali metal or alkaline earth metal hydroxides or by means of salts thereof with weak acids, for example acetic acid or carbonic acid. Raney nickel, Raney cobalt or noble metals, for example platinum, palladium or rhodium, optionally on conventional carrier materials are used. The hydrolysis of the compounds (V) takes place by means of strong mineral acids, for example hydrochloric acid or sulfuric acid. The decarboxylation of compounds of formula (III) takes place either in the melt or in an organic solvent, for example ethyl acetate, toluene, methyl ethyl ketone, dioxane or hexane, an alcohol containing up to eight carbon atoms or a halogenated hydrocarbon, for example 3,3-trichloroethylene. The alkaline hydrolysis of the compounds (II) is preferably carried out in an alcohol containing up to four carbon atoms or in a mixture thereof with water. The hydrogenation of compounds (III) and (IV) is carried out at a pressure of 1 to 50 KPa and in a relatively wide temperature range of from ambient temperature to 80.degree. C. if the hydrogenation starts from compounds (IV). If, on the other hand, compounds (III) are used as starting materials with the inclusion of the decarboxylation and avoidance of the intermediate (IV), the temperatures under the same pressure conditions are preferably higher and are in the range of 50 to l20.degree. C. The alcohol used is preferably ethanol, isopropanol or butanol. |
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