JP2007297386A - Method for preparing gabapentin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially advantageous method for preparing gabapentin namely [1-(aminomethyl)-cyclohexane acetic acid]. <P>SOLUTION: The one-pot synthesis method of preparing 1-(aminomethyl)-cyclohexane acetic acid comprises a step of preparing a 1-cyanocyclohexane acetic acid salt by hydrolyzing a 1-cyanocyclohexane acetic acid ethyl ester using potassium hydroxide, sodium hydroxide, or lithium hydroxide, a step of preparing 1-(aminomethyl)-cyclohexane acetic acid in-situ by hydrogenating the resulting 1-cyanocyclohexane acetic acid salt in the presence of a catalyst, and a step of isolating 1-(aminomethyl)-cyclohexane acetic acid. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to an improved method for producing gabapentin.
US Pat. Nos. 4,024,175 and 4,087,544 include novel cyclic amino acids having the chemical formula A:

[Wherein R ₁ is a hydrogen atom or a lower alkyl group, and n is 4, 5 or 6]
And pharmacologically compatible salts thereof have been disclosed.

  The compounds disclosed in the above U.S. patents are useful in the treatment of certain cerebral diseases, e.g., they are used to treat certain types of epilepsy, dizziness, motor impairment and cranial trauma. Is possible. In addition, they are useful in the treatment of elderly patients because they provide improved cerebral function. Particularly useful is 1- (aminomethyl) -cyclohexaneacetic acid (gabapentin).

  γ-Aminobutyric acid (GABA) is an inhibitory amino acid found in the mammalian central nervous system (CNS). Dysfunction of GABA neurotransmission in the CNS may contribute to or even cause mental disorders such as epilepsy, schizophrenia, Parkinson's disease, Huntington's chorea and dyskinesia (Saletu B. et al., International Journal of Clinical Pharmacology, Therapy and Toxicology. 1986; 24: 362-373). Gabapentin was designed as a GABA analog that would cross the blood brain barrier. Gabapentin has been found to have anticonvulsant and antispasmodic effects and very low toxicity in humans.

  U.S. Pat. Is disclosed. These methods require many steps and in some cases may utilize uneconomic large amounts of reagents and harmful solvents.

There is a need to improve methods for more efficiently producing gabapentin on a large scale.
DESCRIPTION OF THE INVENTION According to the present invention, a process for producing 1- (aminomethyl) -cyclohexaneacetic acid or a pharmaceutically acceptable salt thereof in one pot, comprising:
Hydrolyzing 1-cyanocyclohexaneacetic acid ethyl ester with potassium hydroxide, sodium or lithium to form 1-cyanocyclohexaneacetic acid salt;
Hydrogenating 1-cyanocyclohexaneacetate in-situ in the presence of a catalyst to form 1- (aminomethyl) -cyclohexaneacetic acid;
Isolating 1- (aminomethyl) -cyclohexaneacetic acid;
A method as described above comprising is provided.

In one embodiment of the invention, the method is performed in an aqueous environment.
In one embodiment of the invention, after hydrolysis, the solution is washed with a water-immiscible solvent. Preferably, the water immiscible solvent is toluene or MTBE.

In one embodiment of the invention, the hydrolysis is performed at a temperature of about 80 ° C. for approximately 3 hours.
Hydrolysis may be performed at room temperature.
In one embodiment of the invention, the hydrogenation is carried out at approximately 30 ° C. for up to 20 hours. Preferably, the hydrogenation is carried out for approximately 14 hours.

In one embodiment of the invention, the catalyst is Raney nickel.
In another embodiment of the invention, the solution is filtered to remove the catalyst.
In another embodiment of the invention, the filtered catalyst is reused.

In one embodiment of the invention,
Adding a weak acid; and
Isolating 1- (aminomethyl) -cyclohexaneacetic acid;
The product is isolated by

Preferably the weak acid is acetic acid.
In one embodiment of the invention, gabapentin is seeded into the solution after the acid is added.
Preferably, the method comprises the step of stirring the product at 0, 10 ° C. for approximately 4 hours.

  In one embodiment of the invention, the isolated 1- (aminomethyl) -cyclohexaneacetic acid is washed with alcohol. Preferably, the alcohol is isopropyl alcohol (IPA).

In one embodiment of the invention, 1- (aminomethyl) -cyclohexaneacetic acid is recrystallized.
In one embodiment of the invention, 1- (aminomethyl) -cyclohexaneacetic acid is dissolved in methanol and water.

In another embodiment of the invention, 1- (aminomethyl) -cyclohexaneacetic acid is dissolved in methanol and water, isopropyl alcohol is added, and the solution is distilled under vacuum.
In a further embodiment of the invention, the product is washed with isopropyl alcohol and dried under vacuum.

The present invention also provides the potassium salt of 1- (aminomethyl) -cyclohexaneacetic acid.
The present invention further provides 1- (aminomethyl) -cyclohexaneacetic acid containing less than 0.01% by weight of potassium acetate.

DETAILED DESCRIPTION We have developed an improved method for producing gabapentin. This method comprises a one-pot reaction that requires fewer unit operations than conventional production methods. Since this reaction is carried out in water, the product yield is high and it is an environmentally friendly method. This method is shown in Scheme 1 below.

The method of the present invention has many advantages over known methods for producing gabapentin as follows.
Isolation of the intermediate cyano acid (1-cyanocyclohexaneacetic acid) is not required. This offers significant advantages over existing pathways because this material is unstable and requires refrigerated storage. Since the hydrogenation step is performed in a pure aqueous solvent, the cost of the solvent is reduced and the environmental load is reduced. In addition, the Raney nickel catalyst may be removed at the end of the process and further reused directly in subsequent processes.

According to the method of the present invention, the throughput is doubled compared to currently known methods for producing gabapentin.
1-Cyanocyclohexaneacetic acid ethyl ester is heated to high temperature (about 80 ° C.) with potassium hydroxide during the hydrolysis step (approximately 3 hours). This has been found to result in a very reproducible hydrogenation and overall a very efficient process. Reproducibility is a very important factor when manufacturing gabapentin on a large plant scale. However, the method of the present invention can be performed even at room temperature.

  Because the cyano acid potassium salt is hydrogenated (compared to free cyano acid as used in other methods), Raney nickel used is at least 50% less compared to other gabapentin production methods. In some cases, approximately 60% less Raney nickel is used compared to other methods. This provides a more environmentally friendly and safer method.

  The main problem encountered in current methods for producing gabapentin is the production of impurities in the form of secondary amines. Typically, ammonia is added to suppress these impurities. As in the process of the present invention, the use of potassium salts appears to inhibit the formation of secondary amine impurities, so there is no need to add ammonia to suppress such impurities, which is an important environment. Advantage.

  Since ammonia does not exist, nickel leaching due to complex formation with ammonia seems to be prevented. As a result, there is no need to remove solubilized nickel with an ion exchange resin after hydrogenation, resulting in a significantly streamlined batch process.

  The method of the present invention provides an improved method for producing gabapentin substantially free of chloride ions. Chloride ions affect the stability of gabapentin drug substance and facilitate lactam formation.

  Overall, the method of the present invention is a more environmentally friendly method because all reactions take place in water. High reaction concentration maximizes energy consumption and minimizes unnecessary processing. Only one hydrocarbon (toluene) is used in impurity extraction. The toluene used is completely recyclable.

  The invention will be more clearly understood by the following examples.

( Example 1: Production of 1- (aminomethyl) -cyclohexaneacetic acid )
1-Cyanocyclohexaneacetic acid ethyl ester (1) is prepared as described in US5693845. The entire contents of US5693845 are hereby incorporated by reference.

Preparation of ethyl 1-cyanocyclohexaneacetic acid (1) (or 1-cyanocyclohexaneacetic acid ethyl ester) A 1 L pressure flask is charged with 148 g (1 mol) of 1-cyanocyclohexaneacetonitrile, 206 mL ethanol and 100 mL toluene. The mixture is cooled to 5 ° C. and evacuated. Anhydrous hydrochloric acid (148 g, 4.05 mol) is added to the evacuated flask and the pressure is increased to 10 pounds per square inch gauge (psig) while the temperature is increased to 35 ° C. This temperature is maintained for 7 hours, during which time hydrochloric acid (25 g, 0.68 mol) is added over time to maintain a pressure of 5 pounds per square inch gauge (psig). At the end of the 7 hour period, excess hydrochloric acid and ethanol are removed by vacuum distillation and the mixture is maintained below 25 ° C. To the resulting slurry is added 200 mL of toluene, which is then removed by vacuum distillation. This procedure is repeated two more times with 150 mL of toluene. After the final distillation, 150 mL of toluene and 500 mL of ice water are added and the pH is adjusted to 4 using aqueous sodium hydroxide. After stirring for 18 hours, the mixture is filtered, the filter layer is separated, the aqueous layer is washed with 100 mL toluene, then with 100 Ml 1N aqueous sodium hydroxide solution, followed by 50 mL each of water. Wash twice. The toluene solution is then dried by azeotropic distillation followed by vacuum distillation to remove the toluene. The remaining yellow oil (166 g) is 91% ethyl 1-cyanocyclohexaneacetic acid. Further purification can be performed by vacuum distillation and the distillate can be collected at 85-95 ° C, 0.2-0.3 mmHg.

Preparation of 1- (aminomethyl) -cyclohexaneacetic acid 1-Cyanocyclohexaneacetic acid ethyl ester (1) is mixed with 34% w / w KOH (1.05 kg / kg 1) for 1 hour. Once complete, the batch is heated to about 80 ° C. and stirred for 3 hours. The solution is cooled to 20-25 ° C. and then washed with toluene (0.70 kg / kg 1). After separating the layers, the product-rich aqueous stream comprising 1-cyanocyclohexaneacetic acid potassium salt (2) is processed by proceeding to a hydrogenation reaction.

  1-Cyanocyclohexaneacetic acid potassium salt (2) is hydrogenated over a sponge nickel catalyst (as opposed to 1 containing 12% active nickel) at 3.5 barg and 30 ° C. for 14-16 hours. The batch is cooled to ambient temperature and filtered to remove the catalyst. The catalyst bed is washed with water (0.4 kg / kg 1) and the solution is stored at 0-5 ° C. The catalyst bed is then washed with potassium hydroxide solution in preparation for reuse. This wash is treated and Raney nickel is stored under caustic solution.

  1- (Aminomethyl) cyclohexaneacetic acid potassium salt (3) (pH 13-14) is heated to about 40 ° C., and then the pH is adjusted to 7 by addition of 80% acetic acid— (about 0.53 kg / kg 1). Adjust to 1 (isoelectric point). 80% acetic acid is added at such a rate as to maintain the temperature at <55 ° C. The batch is cooled to 40 ° C. and seeded by adding gabapentin to the batch. The batch is then cooled to 0 ° C. and stirred for a minimum of 4 hours. The batch is isolated and washed with isopropyl alcohol (IPA) (1.56 kg / kg 1). 1- (aminomethyl) -cyclohexaneacetic acid (4) moistened with IPA may be recrystallized using any of the crystallization steps described in Example 2 or 3. Yield from active 1-cyanocyclohexaneacetic acid ethyl ester = 68-73%.

( Example 2: Recrystallization of 1- (aminomethyl) -cyclohexaneacetic acid (4) )
1- (Aminomethyl) -cyclohexaneacetic acid (4) as prepared in Example 1 is dissolved in methanol (2.5 volumes) and water (about 0.6 volumes) (about 65-67 ° C.). . Water is added in small portions until it becomes a solution. Preheated IPA (5.0 vol) is added to the solution and the batch is cooled to 0 ° C. for isolation. The batch is washed with IPA (1.0 vol) and dried at 50 ° C. under vacuum. Yield: 88-92%.

( Example 3: Recrystallization of 1- (aminomethyl) -cyclohexaneacetic acid (4) )
1- (Aminomethyl) -cyclohexaneacetic acid (4) as prepared in Example 1 is dissolved in methanol (2.5 volumes) and water (about 0.6 volumes) (about 65-67 ° C.). . The solution is added to preheated IPA (5.0 volumes). The solution is then distilled to remove up to 70% of the volume of the batch. The batch is cooled to 0 ° C. for isolation. The batch is washed with IPA (1.0 vol) and dried at 50 ° C. under vacuum. Yield: 88-95%.

( Example 4: Production of 1- (aminomethyl) -cyclohexaneacetic acid (4) using regenerated nickel catalyst )
1-Cyanocyclohexaneacetic acid ethyl ester (1) is mixed with 34% w / w KOH (1.05 kg / kg 1) for 1 hour. Once complete, the batch is heated to about 80 ° C. and stirred for 3 hours. The solution is cooled to 20-25 ° C. and then washed with toluene (0.70 kg / kg 1). After separating the layers, the product-rich aqueous stream comprising 1-cyanocyclohexaneacetic acid potassium salt (2) is processed by proceeding to a hydrogenation reaction.

  1-Cyanocyclohexaneacetic acid potassium salt (2) was charged with hydrogen over a regenerated sponge nickel catalyst from Example 1 (as opposed to 1 containing 12% active nickel) at 3.5 barg and 30 ° C. for 14-16 hours. Append. The batch is cooled to ambient temperature and filtered to remove the catalyst. The catalyst bed is washed with water (0.4 kg / kg 1) and the solution is stored at 0-5 ° C.

  After 1- (aminomethyl) cyclohexaneacetic acid potassium salt (3) (pH 13-14) is heated to about 40 ° C., the pH is adjusted to 7. by adding 80% acetic acid (relative to about 0.53 kg / kg 1). Adjust to 1 (isoelectric point). 80% acetic acid is added at such a rate as to maintain the temperature at <55 ° C. The batch is cooled to 40 ° C. and seeded by adding gabapentin to the batch. The batch is then cooled to 0 ° C. and stirred for a minimum of 4 hours. The batch is isolated and washed with isopropyl alcohol (IPA) (1.56 kg / kg 1). 1- (Aminomethyl) -cyclohexaneacetic acid (4) moistened with IPA can be recrystallized using any of the crystallization steps described in Example 2 or 3. The yield from active 1-cyanocyclohexaneacetic acid ethyl ester is 68-73%.

  The present invention is not limited to the embodiments described above, and details may vary.

Claims (24)

A process for preparing 1- (aminomethyl) -cyclohexaneacetic acid or a pharmaceutically acceptable salt thereof in one pot, comprising:
Hydrolyzing 1-cyanocyclohexaneacetic acid ethyl ester with potassium hydroxide, sodium hydroxide or lithium hydroxide to form 1-cyanocyclohexaneacetic acid salt;
Hydrogenating 1-cyanocyclohexaneacetate in-situ in the presence of a catalyst to form 1- (aminomethyl) -cyclohexaneacetic acid;
Isolating 1- (aminomethyl) -cyclohexaneacetic acid;
Comprising the above method.   The method of claim 1, wherein the method is performed in an aqueous environment.   The method according to claim 1, wherein the solution is washed with a water-immiscible solvent after hydrolysis.   4. The method of claim 3, wherein the water immiscible solvent is toluene or MTBE.   The process according to any of claims 1 to 4, wherein the hydrolysis is carried out at a temperature of about 80 ° C for approximately 3 hours.   The method according to claim 1, wherein the hydrolysis is performed at room temperature.   The process according to any of claims 1 to 6, wherein the hydrogenation is carried out at approximately 30 ° C for up to 20 hours.   8. A process according to claim 7, wherein the hydrogenation is carried out for approximately 14 hours.   The method according to any one of claims 1 to 8, wherein the catalyst is Raney nickel.   The method according to any one of claims 1 to 9, wherein the solution is filtered to remove the catalyst.   11. A process according to claim 10, wherein the filtered catalyst is reused. Adding a weak acid; and
Isolating 1- (aminomethyl) -cyclohexaneacetic acid;
12. A process according to any of claims 1 to 11 wherein the product is isolated by   13. A process according to claim 12, wherein the weak acid is acetic acid.   14. A method according to claim 12 or 13, wherein gabapentin is seeded into the solution after the acid is added.   15. A process according to any of claims 12 to 14 comprising the step of stirring the product at 0 ° C for approximately 4 hours.   The process according to any of claims 12 to 15, wherein the isolated 1- (aminomethyl) -cyclohexaneacetic acid is washed with alcohol.   The method of claim 16, wherein the alcohol is isopropyl alcohol (IPA).   The method according to claim 1, wherein 1- (aminomethyl) -cyclohexaneacetic acid is recrystallized.   The method according to claim 18, wherein 1- (aminomethyl) -cyclohexaneacetic acid is dissolved in methanol and water.   19. The method of claim 18, wherein 1- (aminomethyl) -cyclohexaneacetic acid is dissolved in methanol and water, isopropyl alcohol is added, and the solution is distilled under vacuum.   21. A process according to claim 19 or 20, wherein the product is washed with isopropyl alcohol and dried under vacuum.   A method substantially as described above in connection with the examples.   1- (Aminomethyl) -cyclohexaneacetic acid potassium salt   1- (Aminomethyl) -cyclohexaneacetic acid containing less than 0.01% by weight of potassium acetate.