Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-06-14
2003-02-11
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C548S543000, C548S558000
Reexamination Certificate
active
06518456
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation and the purification of 1-(aminomethyl)cyclohexyl-acetic acid (gabapentin) (see formula I below), which process overcomes several problems involved in the methods known in patent literature.
Gabapentin is used in the treatment of some cerebral diseases, such as epilepsy, and of diseases typical of the elderly, since it improves brain functionality: see, for example, U.S. Pat. Nos. 5,084,479, 5,025,035, 5,510,381. Furthermore, this medicament has extremely low toxicity (LD
50
>8000 mg/kg).
DISCLOSURE OF THE PRIOR ART
A number of processes for the preparation and purification of gabapentin are known in patent literature, see for instance U.S. Pat. Nos. 4,024,175, 4,152,326, 5,068,413, 6,054,482, 5,091,567, 5,132,451, 5,362,883, 6,255,526, WO 0058268.
Most patents disclose the preparation of gabapentin hydrochloride, from which the free amino acid is obtained by passing an aqueous solution on an anionic resin; gabapentin is subsequently recovered by concentration and precipitation with solvents. These processes involve large volumes and massive amounts of ion exchange resin. On the other hand, an alternative process comprising high-pressure filtration through porous membranes requires specific apparatuses, high pressures and large dilutions. In a further process, the amino acid is freed from its hydrochloride by means of some amines in organic solvents mixtures. Alternative processes involving neither the hydrochloride nor other salts, require however the hydrogenation of intermediates under drastic conditions and can hardly be used on an industrial scale.
DISCLOSURE OF THE INVENTION
The present invention relates to a process for the preparation and purification of Gabapentin of formula (I), 1-(aminomethyl)cyclohexyl-acetic acid), substantially free from the “lactam” of formula (II) (2-Aza-spiro[4.5]decan-3-one) and from inorganic salts.
Said process mainly uses water and small amounts of organic solvents; furthermore, neither ion exchange resins nor the specific industrial apparatuses involved are required.
DETAILED DISCLOSURE OF THE PROCESS
The process of the invention comprises the following steps.
1. Gabapentin hydrochloride is obtained by refluxing 2-aza-spiro[4.5]decan-3-one (“lactam”), for a given time, in a hydrochloric acid aqueous solution. A first crop, obtained upon cooling, is recovered by filtration; the mother liquors are then concentrated to obtain further crops. The recovered product has high purity and contains small amounts of the starting “lactam”, moreover the recovery yield is higher than 85%.
2. Crude gabapentin hydrochloride is digested in acetone to remove hydrochloric acid, while further reducing the amount of “lactam” still present. The hemihydrate hydrochloride is obtained after drying.
3. Gabapentin is obtained by treating a hot concentrated aqueous solution of gabapentin hydrochloride with sodium hydroxide to the amino acid isoelectric point, then cooling and filtering the precipitated gabapentin, which is washed with an ethanol/water mixture thereby obtaining a product with sodium chloride content even lower than 1%. The mother liquors are concentrated to obtain further crops, until a 90% overall yield.
4. Gabapentin is crystallized from deionized water, further reducing the content of inorganic salts still present.
5. Crystallization from water is not always necessary, in that sodium chloride concentration can be brought below 0.02% (corresponding to Cl ion≦0.01%) by hot digestion in an ethanol/isopropyl ether or methanol/isopropyl ether mixture. The mixture is then cooled, filtered and dried to obtain almost quantitatively highly pure, anhydrous gabapentin having low content in inorganic salts.
The process of the invention for the preparation of anhydrous gabapentin is a remarkable improvement over the known processes, in that:
1. required reaction times are shorter and procedures are easier, there is no need for ion exchange resins or complex industrial apparatuses for high-pressure filtration through porous membranes, and smaller volumes are necessary per kg of gabapentin obtained.
2. yield is on the average higher than in the known processes involving the acid hydrolysis of the “lactam”.
REFERENCES:
patent: 4024175 (1977-05-01), Satzinger et al.
patent: 4152326 (1979-05-01), Hartenstein et al.
patent: 5025035 (1991-06-01), Wallace
patent: 5068413 (1991-11-01), Steiner et al.
patent: 5084479 (1992-01-01), Woodruff
patent: 5091567 (1992-02-01), Geibel et al.
patent: 5132451 (1992-07-01), Jennings et al.
patent: 5362883 (1994-11-01), Jennings et al.
patent: 5510381 (1996-04-01), Pande
patent: 6054482 (2000-04-01), Augart et al.
patent: 6255526 (2001-07-01), Pesachovich et al.
patent: 00/58268 (2000-10-01), None
Fornaroli Mirco
Peverali Diego
Velardi Francesco
Killos Paul J.
Procos S.p.A.
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