Preparation of gabapentin

Details Preparation of gabapentin Preparation of gabapentin

1999-06-22

2001-07-03

Shippen, Michael L. (Department: 1621)

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

Organic compounds

Carboxylic acids and salts thereof

Reexamination Certificate

active

06255526

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a new process for converting gabapentin hydrochloride salt to gabapentin via a novel polymorphic form of gabapentin.
BACKGROUND OF THE INVENTION
Gabapentin is 1-(aminomethyl)-1-cyclohexaneacetic acid, having the chemical structure:
Gabapentin is used in the treatment of cerebral diseases such as epilepsy. The literature describes many ways of preparing gabapentin from a variety of starting materials. U.S. Pat. No. 4,024,175 describes at least three methods of preparing gabapentin from cyclohexyl-1,1-diacetic acid. Each of these methods results in the formation of gabapentin hydrochloride salt, which may be converted to 1-(aminomethyl)-1-cyclohexaneacetic acid by treatment with a basic ion exchanger and then crystallized from a solvent such as ethanol/ether.
U.S. Pat. No. 4,894,476 specifically discloses an improved method for converting the hydrochloride salt into the free amino acid. This involves pouring a deionized water solution of the salt over an ion exchange column, eluting with deionized water, producing a slurry from the eluate, adding an alcohol to the slurry, centrifuging and drying the slurry to obtain the free amino acid.
Alternative methods for preparing gabapentin have been described that do not proceed via the hydrochloride or any other mineral acid salt. Such methods include those described in U.S. Pat. Nos. 5,132,451, 5,095,148, 5,068,413. Each of these methods involve a cyanic intermediate which is hydrogenated under severe conditions to produce the free amino acid.
These methods are industrially impractical. Those methods comprising ion exchange columns require the use of large amounts of ion exchanger for lengthy periods of time to lower the level of chloride ions to the desired level. The alternative methods involve further more demanding steps.
Commercially available gabapentin is crystalline and exhibits an X-ray diffraction pattern with peaks of 2-theta values at 7.8, 13.3, 15.0, 17.0, 20.4, 21.3, 23.1, 23.6, 25.7, 27.0 and 28.2 degrees. Hereinafter, the commercially available polymorphic form of gabapentin is referred to as polymorph form “II”.
SUMMARY OF THE INVENTION
The present invention relates to an improved method for purifying gabapentin comprising converting gabapentin hydrochloride salt to gabapentin form II. The present invention avoids the disadvantages associated with prior art methods, by adding alternative steps and by proceeding via a novel polymorphic form of gabapentin.
Accordingly, the present invention relates to a method of converting gabapentin hydrochloride salt to gabapentin form II, comprising reacting a solution of gabapentin hydrochloride with an additional amine in a first solvent to produce a novel polymorphic form as a precipitate, thereafter, converting the novel polymorphic form to form II by forming a suspension and/or a solution of the precipitate in methanol, and then recovering gabapentin form II.
The present invention further relates to a novel polymorphic form of gabapentin designated as gabapentin form III. The polymorph may be identified by its unique X-ray diffraction pattern.
A further aspect of the present invention relates to the novel polymorphic form of gabapentin that is of use as an intermediate in the preparation of polymorphic form II.


REFERENCES:
patent: 4024175 (1977-05-01), Satzinger et al.
patent: 4894476 (1990-01-01), Butler et al.
patent: 4960931 (1990-10-01), Butler et al.
patent: 5068413 (1991-11-01), Steiner et al.
patent: 5095148 (1992-03-01), Mettler, et al.
patent: 5132451 (1992-07-01), Jennings et al.

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