| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | February 25, 1992 |
| PATENT TITLE |
Process for the preparation of 1-aminomethyl-1-cyclohexaneacetic acid |
| PATENT ABSTRACT | The instant invention concerns a novel process for the preparation of 1-aminomethyl-1-cyclohexaneacetic acid (gabapentin), a known compound useful for treating certain cerebral diseases such as epilepsy and dizziness |
| 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 REFERENCES CITED |
Journal of the American Chemical Society, v. 83, No. 7, Apr. 19, 1961, pp. 1733-1738, W. S. Wadsworth et al., "The Utility of Phosphanate Carbanions in Olefin Synthesis". Organic Preparations and Procedures International, v. 19, No. 6, 1987, pp. 471-475, Richard A. Bunce et al, "Michael Reaction of Nitromethane with Beta, Beta-Disubstituted Acrylate Esters". Copending U.S. Application 399056, Filed 8-25-89. |
| PATENT CLAIMS |
We claim: 1. A process for the preparation of ##STR6## which comprises: (a) reacting cyclohexanone with a phosphonoacetic acid ester and a base to produce the corresponding cyclohexylideneacetic acid ester, (b) reacting the cyclohexylideneacetic acid ester from Step (a) with nitromethane in the presence of a basic catalyst to produce the corresponding 1-nitromethyl-1-cyclohexaneacetic acid ester, (c) reducing the 1-nitromethyl-1-cyclohexaneacetic acid ester from Step (b) with hydrogen in the presence of a noble metal catalyst to the corresponding 1-aminomethyl-1-cyclohexaneacetic acid ester and 2-aza-spiro[4,5]-decan-3-one, (d) converting the products of Step (c), 1-aminomethyl-1-cyclohexaneacetic acid ester and 2-aza-spiro[4,5]-decan-3-one, into 1-aminomethyl-1-cyclohexaneacetic acid salt using a dilute acid, and (e) converting the salt from Step (d) to the 1-aminomethyl-1-cyclohexaneacetic acid. 2. A process according to claim 1 wherein in Step (a) cyclohexanone is reacted with a base at about ambient temperature before reacting it with a phosphonoacetic acid ester. 3. A process according to claim 2 wherein the base is selected from sodium hydride, sodium hydroxide, and potassium hydroxide. 4. A process according to claim 1 wherein in Step (b) dimethyl sulphoxide is used as a solvent and an alkali metal carbonate is used as a catalyst. 5. A process according to claim 1 wherein in Step (c) the reduction is carried out at a temperature of from about 100.degree. C. to about 125.degree. C., with a noble metal catalyst. 6. A process according to claim 3 wherein the base is potassium hydrodroxide. 7. A process according to claim 4 wherein in Step (b) the alkali metal carbonate is selected from the group consisting of potassium carbonate and sodium carbonate. 8. A process according to claim 7 wherein the alkali metal carbonate is potassium carbonate. 9. A process according to claim 5 wherein in Step (c) the reduction is carried out at a temperature of about 125.degree. C. 10. A process according to claim 1 wherein the Step (b) the cyclohexylideneacetic acid ester is ethyl cyclohexylideneacetate. 11. A process according to claim 1 wherein in step (c) the noble metal catalyst is palladium on active carbon. 12. A process according to claim 1 wherein in step (d) the dilute acid is hydrochloric acid. 13. A process according to claim 1 wherein in step (e) an aqueous solution of 1-aminomethyl-1-cyclohexaneacetic acid hydrochloride is passed over a column filled with a weakly basic anion exchanger to afford 1-aminomethyl-1-cyclohexaneacetic acid. 14. A process according to claim 1 wherein in 1-aminomethyl-1-cyclohexaneacetic acid is converted to a pharmaceutically acceptable acid salt thereof. |
| 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, hypokinesia, 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. U.S. Pat. No. 4,894,476 describes gabapentin monohydrate and a process for producing it. These patents are 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. Examples of the syntheses end in an isocyanate or urethane that can be converted into the desired (1-aminomethyl)-1-cyclohexaneacetic acid by acidic hydrolysis to give an acid or basic hydrolysis to give a basic salt or followed by acidification to give an acid salt. DETAILED DESCRIPTION OF THE INVENTION The present invention is concerned with a process for the preparation of gabapentin (1-aminomethyl-1-cyclohexaneacetic acid). ##STR3## Gabapentin is a medicament described in Germany Patents 24 60 891 and 25 43 821 for the therapy of certain cerebral diseases, for example epilepsy and cases of dizziness. Various processes are known for the preparation of gabapentin and related compounds. For example, gabapentin can be prepared by converting 1,1-cyclohexanediacetic acid, via a reactive acid derivative, into the azide which is subsequently subjected by thermal decomposition to a Curtius reaction. For reasons of safety, the process is not very suitable for technical use since the azide formed can easily explode in the case of heating or working up (stirring with acid). Gabapentin can also be obtained by the Lossen rearrangement of the corresponding hydroxamic acid. The process previously known for the preparation of gabapentin via the Lossen rearrangement takes place via the following eight reaction steps: ##STR4## The above process has some serious disadvantages which are briefly as follows: the total yield over all of the steps is only 30%; because of the many reaction steps, the process requires a relatively large expenditure of time and labor and therefore a high production cost; in reaction Step 1, work is carried out with large amounts of gaseous ammonia at low temperatures; in reaction Step 2, 80% sulphuric acid is used as 10 solvent at 160.degree. C.; the removal of this and of further acids used in the process of production results in toxic waste water; the process requires, in part, expensive adjuvant reagents which are not incorporated into the end product and thus contribute substantially to the high costs of production. The instant invention provides a new process for the preparation of gabapentin which: (1) involves fewer reaction steps and thus requires shorter time and less labor; (2) the total yield is greater than that of the known process; (3) the costs of production are lower; (4) the process should be useful on an industrial scale; (5) the process should ensure a minimum danger to people and have a small impact on the environment. The present invention, provides a process for the preparation of gabapentin according to the principle of a Michael condensation, which is characterized by the following reaction steps: (a) reaction of cyclohexanone with a phosphonic acid ester compound to give a cyclohexylideneacetic acid ester; (b) reaction of the cyclohexylideneacetic acid ester with nitromethane to give the corresponding 1-nitro-methylcyclohexaneacetic acid ester; (c) reduction of the 1-nitromethylcyclohexaneacetic acid ester to the corresponding 1-aminomethylcyclohexene-acetic acid ester and 2-aza-spiro[4,5]decan-3-one; (d) conversion of the products obtained in Step c into 1-aminomethyl-1-cyclohexaneacetic acid salt by means of dilute acid; (e) liberation of the 1-aminomethyl-1-cyclohexaneacetic acid from the salt by means of ion exchangers, wherein in Step (a) the cyclohexanone is first reacted at ambient temperature with potassium hydroxide before the phosphonic acid ester is added thereto; in Step (b) dimethyl sulphoxide is used as solvent and an alkali metal carbonate as catalyst; and in Step (c) work is carried out at an elevated temperature above 100.degree. C. The cyclohexylideneacetic acid ester is a lower alkyl ester with alkyl from 1 to 6 carbon atoms, preferred is the ethyl ester. The process of the present invention is a simple, quick and cost-effective preparation of gabapentin. The process consists of five reaction steps and gives a total yield of about 50%, in comparison with 30% in the case of the known process. By recycling of unreacted starting material in reaction Step (d) to the reaction process, the yield can be further increased by up to 15%. The process according to the present invention is superior to the known process due to the short and simple procedures involved. All reactions are complete after a maximum of 4 hours. The reaction in Step 1 takes place at ambient temperature. All the reaction products are extracted from the reaction mixture or are obtained directly by removal of the solvent. The material isolated in Step (d) is pure according to HPLC and the purity of the products of the other steps is greater than 95% so that no purification operations are necessary. The new, optimized process according to the present invention is illustrated by the following Scheme I. ##STR5## In reaction Step (a) of the process according to the present invention, cyclohexanone is reacted to give cyclohexylideneacetic acid ester. For this purpose, the phospho-organic compound is first reacted with a base, for example, sodium hydride, and subsequently with cyclohexanone. Instead of sodium hydride, sodium hydroxide or potassium hydroxide can be used and thus more safely handled. Loss of yield and by-products (ester cleavage and decomposition) then take place. Surprisingly, it has been found that by an altered course of the reaction, even with the use of potassium hydroxide, the yield of product and the purity can be greatly increased and the formation of by-products can be avoided. In this way, it becomes possible to avoid more laborious purification operations (vacuum distillation). In the case of this altered course of the reaction, cyclohexanone is first reacted at ambient temperature with potassium hydroxide before the phosphonic acid ester is added. After a short post-reaction at ambient temperature, the reaction is quenched by the addition of water and the product is extracted from the aqueous solution with petroleum ether. After removal of the solvent, the product is obtained in a yield of more than 90% and with a purity of 98%. In reaction Step 2 of the process of the present invention, a Michael condensation of nitromethane to the product of Step 1 with base catalysis takes place. The addition of nitromethane to .beta.,.beta.-disubstituted aorylic acid esters like the product of Step 1 (cyclohexylideneacetic acid ester) is made difficult by the insufficient activation by one ester group and by the steric hindrance of the substituents. It is known in the art that, in the case of less activated reaction components, nitromethane in large excess with or without solvent, usually under reflux can be used. In J. Org. Chem., 50, 2806/1985 the Michael condensation of acrylic acid esters without using an excess of nitromethane is described. However, first the stoichiometric formation of the salt of nitromethane with bases, such as potassium hydroxide or potassium tert.-butylate, is necessary. Furthermore, in the case of the described .beta.,.beta.-disubstituted compounds, the double bond is to be activated by a further electron-attracting group. The Michael condensation requires the presence of basic catalysts, for example potassium hydroxide, various amines, alcoholates, metal fluorides or the like. Tetraalkylammonium fluorides are also very effective catalysts for the Michael condensation. Under such conditions, i.e., with a large excess of nitromethane, the described reaction with the product of Step 1 can be carried out on a laboratory scale, in which case tetraethylammonium fluoride or potassium hydroxide are the catalysts of choice. However, these conditions could not be used for the process according to the present invention since, as is known, nitromethane forms compounds capable of explosion with strong bases and is capable of explosion with the help of primers. Nitromethane exists in a tautomeric equilibrium with the corresponding nitronic acid. With potassium hydroxide, nitronic acid forms an extremely unstable salt which is highly sensitive to impact. Amines in turn also give a detonation-sensitiva mixture. In general, alkaline solutions of nitromethane are known not to be stable when they are heated or stored for a comparatively long time. Another reason for the non-usability of the above conditions for the process according to the present invention is, on the one hand, the cleavage of the products of Step 1 by strong bases to give a carboxylic acid and, on the other hand, the fact that, in this special case, strong bases, such as potassium hydroxide and tetraalkylammonium fluorides, catalyze the rearrangement of the double bond in the ring. The formation of the compounds with a rearranged double bond in the ring is almost quantitative. It is thermodynamically preferred in comparison with the product of Step 1 with conjugation of the double bond and ester function. In the case of the absence of nitromethane, the product of Step 1 reacts, with base catalysis, in less than 15 minutes to the more stable by-product 1-cyclohexeneacetic acid ester. In the presence of equimolar amounts of nitromethane, the by-product formation in comparison with the formation of the product of Step 2 is still preferred and, after working up, about 10% of the desired product of Step 2 is obtained and about 90% 1-cyclohexeneacetic acid ester. Because of the potential danger of nitromethane, on the one hand, and the undesirable side reactions, on the other hand, an attempt must be made, a) to avoid the use of strong bases and, b) to reduce the proportion of nitromethane if possible to the proportion necessary for the reaction, i.e., to the equivalent amount. Accordingly, it was quite unexpected to have the reaction take place with such good yields when the proportion of nitromethane is reduced to the necessary minimum amount, weak bases are used as catalysts and an additional solvent is used. Surprisingly, it has been found that in reaction Step 2, in spite of the limited conditions, yields of 90% and purities of .gtoreq.90% can be achieved and no by-products are formed when dimethyl sulphoxide is used as solvent in conjunction with catalytic amounts (10-50 mole%) of potassium carbonate or sodium carbonate as basic catalyst. In detail, the procedure is such that nitromethane is added slowly and continuously in equimolar amount (with 10% to 50% 10 excess), together with the product of Step 1, to a reaction mixture of solvent and catalyst at 95.degree. to 100.degree. C. However, nitromethane can also be added continuously alone to a reaction mixture of solvent, catalyst and the product of Step 1 at 95.degree. to 100.degree. C. However, by-products are formed. In any case, by the continuous addition of nitromethane, it is ensured that nitromethane always reacts away and can at no time exist in comparatively large amounts from which a potential danger could result. The third reaction step of the process according to the present invention is the catalytic reduction of the nitro group to the amino group. For this purpose, the product of reaction Step 2 is reacted with hydrogen in the presence of a noble metal catalyst, for example palladium on active carbon. As solvent, acetic acid, ethanol or also ethanol with aqueous hydrochloric acid can be used. From this reaction there normally results two products, the cyclized product (lactam) and ethyl 1-aminomethyl-1-cyclohexaneacetate. We have found that, at a sufficiently high temperature, preferably at 100.degree. to 125.degree. C., the "lactam" is obtained exclusively in a yield of more than 90%. After removal of the catalyst and of the solvent, the lactam is, without further purification, hydrolyzed in reaction Step 4 of the process according to the present invention with aqueous hydrochloric acid at boiling temperature to give gabapentin hydrochloride. Depending upon the acid concentration, there is a conversion into up to 80% gabapentin hydrochloride. The unreacted lactam is recovered by extraction and again subjected to the hydrolysis. From the remaining aqueous solution, gabapentin hydrochloride is obtained in 60% to 70% yield with a purity of 99%. The purity achieved makes further purification superfluous so that, in reaction Step 5 of the process according to the present invention, the free amino acid gabapentin can be obtained directly from the hydrochloride. For this purpose, a 20% aqueous solution of gabapentin hydrochloride is passed over a column filled with a weakly basic anion exchanger. From the resulting aqueous solution, by gentle evaporation in a vacuum and subsequent crystallization from methanol, gabapentin can be obtained with high purity in a yield of 80% to 90%. In an especially preferred Step 1, the cyclohexanone and the phosphonic acid ester are taken and potassium hydroxide is introduced, while stirring, into this homogeneous phase. In a rapid and exothermal reaction, which is kept at 30.degree. to 40.degree. C. by cooling and a measured rate of introduction of the potassium hydroxide, the reaction is practically complete. Furthermore, we have ascertained that the catalytic hydrogenation in ethanol as solvent already leads quickly and practically to the lactam even at temperatures above 60.degree. C. |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |