Process for production of gabapentin intermediate

Details Process for production of gabapentin intermediate Process for production of gabapentin intermediate

2001-10-26

2003-09-02

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C568S376000

Reexamination Certificate

active

06613904

ABSTRACT:

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 &agr;,&agr;′,dicyano-&bgr;,&bgr;-pentamethyleneglutarimide, and a process for manufacturing &agr;,&agr;′,dicyano-&bgr;,&bgr;-pentamethyleneglutarimide.
BACKGROUND OF THE INVENTION
Gabapentin, 1-(aminomethyl)-1-cyclohexaneacetic acid, has the chemical structure of formula II:
Gabapentin is use 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 (IT) 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, &agr;,&agr;′,dicyano-&bgr;,&bgr;-pentamethyleneglutarimide (formula I)
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
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
3
in ethanol on a large scale.
SUMMARY OF THE INVENTION
The present invention relates to a process for producing &agr;,&agr;′,dicyano-&bgr;,&bgr;-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
3
can be replaced in the reaction of &agr;,&agr;′,dicyano-&bgr;,&bgr;-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
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.
The embodiments of the present invention are further described in the following example.


REFERENCES:
patent: 4024175 (1977-05-01), Satzinger et al.
patent: WO97/33858 (1997-09-01), None
Holder, R. W. et al., “Geminate-Substituted Cyclopentadienes. 1. Synthesis of 5,5-Dialkylcyclopentadienes via 4,4-Dialkylcyclopent-2-en-1-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 &bgr;&bgr;-Substituted Glutaric Acids. J. Chem. Soc., 1934, pp. 1758-1765.

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