| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | February 11, 2003 |
| PATENT TITLE |
Process for the production of 1-(aminomethyl)-cyclohexyl-acetic acid in pure form |
| PATENT ABSTRACT | A process for the production and purification of gabapentin, i.e. 1-(aminomethyl)cyclohexyl-acetic acid, which comprises hydrolysis of 2-aza-spiro[4.5]decan-3-one with HCl, treatment of the resulting product and filtration with acetone, dissolution in water at isoelectric pH and crystallization or digestion in the hot in mixtures of diisopropyl ether with ethanol or methanol |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | June 14, 2002 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A process for the preparation of 1-(aminomethyl)cyclohexyl-acetic acid in pure form, which comprises the following steps: a) hydrolysis of 2-aza-spiro[4.5]decan-3-one with diluted aqueous HCl and recovery of the resulting 1-(aminomethyl)cyclohexyl-acetic acid hydrochloride by filtration and washing on the filter with acetone; b) removal of the residual hydrochloric acid from the product obtained in a) by digestion in acetone, filtration and drying; c) treatment of an aqueous solution of the product obtained in b) with bases to reach the isoelectric point (pH 7.1-7.2), filtration of the resulting 1-(aminomethyl)cyclohexyl-acetic acid and washing on the filter with aqueous ethanol; d) crystallization of 1-(aminomethyl)cyclohexyl-acetic acid obtained in c) from deionized water; or, alternatively to d) e) digestion in the hot of 1-(aminomethyl)cyclohexyl-acetic acid obtained in c) in ethanol/diisopropyl ether or methanol/diisopropyl ether and filtration in the cold. 2. A process as claimed in claim 1, wherein step b) is carried out with about 3 parts by volume of acetone per one part by weight of 1-(aminomethyl)cyclohexyl-acetic acid hydrochloride. 3. A process as claimed in claim 1, wherein step b) is carried out at about 40-45.degree. C. 4. A process as claimed in claim 1, wherein step c) is carried out by adding 30% NaOH to a solution of one part by weight of 1-(aminomethyl)cyclohexyl-acetic acid hydrochloride in about 2.4 parts by weight of water. 5. A process as claimed in claim 1, wherein step d) is carried out by crystallization of one part by weight of 1-(aminomethyl)cyclohexyl-acetic acid from about three parts by weight of deionized water. 6. A process as claimed in claim 1, wherein step e) is carried out by digestion of one part by weight of 1-(aminomethyl)cyclohexyl-acetic acid in 2.2-2.4 parts by weight of a mixture of 8.5-10 parts by weight of ethanol and one part by weight of diisopropyl ether. 7. A process as claimed in claim 1, wherein step e) is carried out by digestion of one part by weight of 1-(aminomethyl)cyclohexyl-acetic acid in 2.5-3 parts by weight of a mixture of one part by weight of methanol and 1.3-1.4 parts by weight of diisopropyl ether. 8. A process as claimed in claim 6, characterized in that filtration is carried out at a temperature of 0-5.degree. C. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
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.sub.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. ##STR1## 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.ltoreq.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". |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
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