| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | April 19, 2005 |
| PATENT TITLE |
Process for production of gabapentin intermediate |
| PATENT ABSTRACT | The invention relates to a novel process for producing a the intermediary compound .alpha.,.alpha.',dicyano-.beta.,.beta.-pentamethyleneglutarimide. The process includes the steps of reacting a ketone such as cyclohexanone with ethylcyanoacetate in the presence of ammonium hydroxide |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | June 6, 2003 |
| PATENT REFERENCES CITED |
Holder, R. W. et al., "Geminate-Substituted Cyclopentadienes. 1. Synthesis of 5,5-Dialkylcyclopentadienes via 4,4-Dialkylcyclopent-2-en-l-ones", J. Org. Chem. 1982, vol. 47, pp. 1445-1451. Thorpe et al.; paper entitled, The Formation and Reactions of Imino Compounds: Part XVIII. The Condensation of cycloHexanones with Cyanoacetamide Involving the Displacement of an Alkyl Group. J. Chem. Soc. 1913, pp. 1586-1600. Vogel, A.I., paper entitled Physical Properties and Chemical Constitution: Part II. Esters of .beta..beta.-Substituted Glutaric Acids. J. Chem. Soc., 1934, pp. 1758-1765. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method of synthesizing pentamethylene glutarimides comprising: reacting a ketone and ethylcyanoacetate under the reaction conditions of the Guareschi reaction in the presence of water and ammonium hydroxide for a time less than 36 to 48 hours. 2. The method according to claim 1, wherein the reaction conditions of the Guareschi reaction comprise a suitable temperature. 3. The method according to claim 1, wherein the ketone is cyclohexanone. 4. The method according to claim 1, wherein the suitable time is from 24 hours to 36 hours. 5. The method according to claim 1, wherein the suitable amount of time is less than 24 hours. 6. The method according to claim 1, wherein the molar ratio of ethylcyanoacetate to ketone is in the range of 1:2. 7. The method according to claim 1, wherein the reaction solvent is methanol or ethanol. 8. The method according to claim 2, wherein the temperature comprises an addition temperature and a reaction temperature. 9. The method according to claim 8, wherein the addition temperature is 8.degree. C. to 10.degree. C. 10. The method according to claim 8, wherein the reaction temperature is 25.degree. C. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The present invention relates to a compound that is used as an intermediate in the production of gabapentin, and a process for production thereof. More particularly, the present invention relates to .alpha.,.alpha.',dicyano-.beta.,.beta.-pentamethyleneglutarimide, and a process for manufacturing .alpha.,.alpha.',dicyano-.beta.,.beta.-pentamethyleneglutarimide. BACKGROUND OF THE INVENTION Gabapentin, 1-(aminomethyl)-1-cyclohexaneacetic acid, has the chemical structure of formula II: ##STR1## Gabapentin is used for treating cerebral diseases such as epilepsy, faintness attacks, hypokinesis and cranial traumas. U.S. Pat. No. 4,024,175 to Satzinger et al., incorporated herein by reference, discloses that gabapentin of formula (II) shows hypothermal and, in some cases, narcosis-potentiating or sedating properties as well as protective effect against cardiozole cramp in animals. Gabapentin is the active ingredient in Neurontin, marketed by Warner Lambert, and approved by the Food and Drug Administration as an anti-epileptic, anti-seizure, or anti-convulsant medication. As such, there has been a need for producing pure and stable gabapentin. In one process for the preparation of gabapentin, an intermediary, .alpha.,.alpha.',dicyano-.beta.,.beta.-pentamethyleneglutarimide (formula I) ##STR2## is produced by the Guareschi reaction in the following manner. Cyclohexanone and ethylcyanoacetate are reacted in an anhydrous environment in the presence of gaseous ammonia dissolved in ethanol. The reaction is represented as ##STR3## The Guareschi reaction is inefficient as the reaction requires at least 48 hours to proceed to completion, and more typically between 48-168 hours for completion. In addition, current environmental regulations make it impractical to produce gaseous NH.sub.3 in ethanol on a large scale. SUMMARY OF THE INVENTION The present invention relates to a process for producing .alpha.,.alpha.',dicyano-.beta.,.beta.-pentamethyleneglutarimide (formula I) by reacting cyclohexanone and ethylcyanoacetate in the presence of ammonium hydroxide. The process of the present invention can be substantially completed in less than 24 hours. The reaction of the present invention can be processed in an aqueous environment and may include at least one solvent. The solvent can be methanol, ethanol or any similar solvent not having adverse affect on the reaction. Most importantly, a reaction of the present invention need not be conducted in an anhydrous environment. DETAILED DESCRIPTION We have discovered that contrary to previous practice in the art, the Guareschi reaction may be performed in the presence of water. Consequently, gaseous NH.sub.3 can be replaced in the reaction of .alpha.,.alpha.',dicyano-.beta.,.beta.-pentamethyleneglutarimide by, for example, an aqueous solution of ammonium hydroxide. Such aqueous solutions are significantly easier to handle since they avoid many of the environmental concerns that would arise from handling gaseous NH.sub.3 in ethanol. Accordingly, in one embodiment of the invention a ketone is condensed with ethylcyanoacetate in the presence of ammonium hydroxide. In another embodiment of the invention, the ketone is cyclohexanone. A reaction according to the present invention is substantially complete in less than 36 to 48 hours. In one embodiment of the invention, the reaction process is substantially completed in 24 to 36 hours. In a preferred embodiment, a reaction according to the present invention is substantially completed in less than 24 hours. In one embodiment of the present invention, a molar ratio of ethylcyanoacetate:ketone is in the range of 1:0.5 to 4:2. In a preferred embodiment of the present invention, a molar ratio of ethylcyanoacetate:cyclohexanone is 2:1. The organic solvent used in the Guareschi reaction can be an alcohol or another polar solvent. In a preferred embodiment the solvents are be methanol and ethanol. In addition, esters of cyanoacetate acid, such as for example, methylcyanoacetate can be used to replace ethylcyanoacetate in the Guareschi reaction. |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
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