HK1131968A - Process for preparing gabapentin - Google Patents

Description

Process for preparing gabapentin

The present invention relates to an improved process for the preparation of gabapentin (gabapentin).

U.S. Pat. nos. 4,024,175 and 4,087,544 disclose novel cyclic amino acids of formula a and pharmacologically compatible salts thereof:

wherein R is₁Is a hydrogen atom or a lower alkyl group, and n is 4, 5 or 6.

The compounds disclosed in the above U.S. patents are useful for treating certain brain diseases, for example, such compounds may be used to treat certain forms of epilepsy, faintness attacks (faintness attacks), hypokinesia, and craniocerebral trauma. In addition, such compounds cause an increase in brain function and are therefore effective in treating elderly patients. Of particular interest is 1- (aminomethyl) -cyclohexaneacetic acid (gabapentin).

Gamma-aminobutyric acid (GABA) is an inhibitory amino acid found in the Central Nervous System (CNS) of mammals. It has been reported that dysfunction of GABA neurotransmission in the CNS may contribute to or even lead to psychiatric and neurological diseases such as epilepsy, schizophrenia, Parkinson's disease, Huntington's chorea and dysautokinetic (Saletu B., et al, International Journal of Clinical Pharmacology, Therapy and toxicology.1986; 24: 362-. Gabapentin is designed as a GABA analog that traverses the blood-brain barrier. Gabapentin has been found to have antispasmodic (antisonvulsant) and antispasmodic (antispastic) activity and to be extremely toxic in humans.

Other methods and intermediates for making gabapentin are disclosed in U.S. Pat. nos. 5,132,451, 5,319,135, 5,362,833, 5,091,567, 5,068,413, 4,956,473, 4,958,044, 5,130,455, 5,095,148, 5,136,091, 5,149,870 and 5,693,845. Such processes require many steps and in some cases make uneconomical use of large amounts of reagents and hazardous solvents.

There is a need for an improved process for the more efficient large-scale preparation of gabapentin.

Disclosure of Invention

The present invention provides a one pot process for the preparation of 1- (aminomethyl) -cyclohexaneacetic acid or a pharmaceutically acceptable salt thereof, comprising the steps of:

hydrolyzing ethyl 1-cyanocyclohexaneacetate with potassium hydroxide, sodium hydroxide, or lithium hydroxide to form 1-cyanocyclohexaneacetate salt;

hydrogenating the 1-cyanocyclohexaneacetic acid salt in situ in the presence of a catalyst to form a 1- (aminomethyl) -cyclohexaneacetic acid salt; and

1- (aminomethyl) -cyclohexaneacetic acid is isolated.

In one embodiment of the invention, the method is carried out in an aqueous environment.

In one embodiment of the invention, after hydrolysis, the solution is washed with a water immiscible (water immiscible) solvent. Preferably, the water immiscible solvent is toluene or MTBE.

In one embodiment of the invention, the hydrolysis is carried out at a temperature of about 80 ℃ for about 3 hours.

The hydrolysis may also be carried out at room temperature.

In one embodiment of the invention, the hydrogenation reaction is carried out at about 30 ℃ for up to 20 hours. Preferably, the hydrogenation reaction is carried out for about 14 hours.

In one embodiment of the invention, the catalyst is Raney nickel (also known as "Raney nickel" or "Rn-Ni").

In another embodiment of the invention, the solution is filtered to remove the catalyst.

In another embodiment of the invention, the filtered-off catalyst is reused.

In one embodiment of the invention, the isolation of the product is accomplished by:

adding a weak acid; and

1- (aminomethyl) -cyclohexaneacetic acid is isolated.

Preferably, the weak acid is acetic acid.

In one embodiment of the invention, the solution is seeded with gabapentin after the acid is added.

Preferably, the method comprises the step of stirring the product at 0 to 10 ℃ for about 4 hours.

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

In one embodiment of the invention, the 1- (aminomethyl) -cyclohexaneacetic acid is recrystallized.

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

In another embodiment of the invention, the 1- (aminomethyl) -cyclohexaneacetic acid is dissolved in methanol and water; adding isopropanol; and the solution was distilled under vacuum.

In another embodiment of the invention, the product is washed with isopropanol and dried under vacuum.

The present invention also provides 1- (aminomethyl) -cyclohexaneacetic acid potassium salt compounds.

The invention also provides 1- (aminomethyl) -cyclohexaneacetic acid having a potassium acetate content of less than 0.01% by weight.

Detailed Description

We have developed an improved process for the preparation of 1- (aminomethyl) -cyclohexaneacetic acid. The process involves a one-pot reaction involving fewer unit operations than previous preparative methods. The reaction is carried out in water, thus giving an environmentally friendly process with high yields. This process is shown in the following equation 1:

reaction scheme 1

Compared with the methods for preparing gabapentin known in the prior art, the method has many advantages as follows:

without isolation of the intermediate product cyanic acid (1-cyanocyclohexaneacetic acid). This is a major advantage over prior art methods because the material is unstable and requires cryopreservation. The hydrogenation reaction is carried out in a purely aqueous environment, thereby reducing solvent costs and environmental burden. In addition, the raney nickel catalyst may be recovered at the end of the process and reused directly in subsequent processes.

The process has a doubled throughput relative to the processes known in the art for the preparation of gabapentin.

During the hydrolysis step (about 3 hours), ethyl 1-cyanocyclohexaneacetate along with potassium hydroxide was heated to an elevated temperature (about 80 ℃). This has been found to result in very reproducible hydrogenations and can provide a very efficient overall process. Reproducibility is a very important factor when gabapentin is prepared on a large factory scale. However, the process can also be carried out at room temperature.

Because the potassium cyanate is hydrogenated (relative to the free cyanate as used in other processes), at least 50% less raney nickel is used relative to other processes for the preparation of gabapentin. In some examples, about 60% less raney nickel may be used relative to other methods. This results in a safer process that is more environmentally friendly.

A major problem encountered with the prior art processes for the preparation of gabapentin is the production of impurities in the form of secondary amines. Typically, ammonia is added to suppress such impurities. The use of potassium salts in the process of the present invention appears to inhibit the formation of secondary amine impurities and, therefore, the addition of ammonia is not required to inhibit such impurities. This is a significant environmental advantage.

The absence of ammonia also appears to prevent nickel from being washed away by complexing with ammonia (leaching). Thus, the need for ion exchange resins to remove dissolved nickel after hydrogenation is eliminated, resulting in a significantly smoother batch process.

The process of the present invention provides an improved method for producing gabapentin that is substantially free of chloride ions. Chloride ions affect the stability of gabapentin drugs and increase the tendency to form lactams.

The process of the invention as a whole appears to be a more environmentally friendly process, since all reactions are carried out in water. The high reaction concentration maximizes energy consumption and minimizes waste treatment. Only one hydrocarbon (toluene) was used to extract the impurities. The toluene used can be completely recovered.

The present invention will be more clearly understood from the following examples.

EXAMPLE 1 preparation of 1- (aminomethyl) -cyclohexaneacetic acid

Ethyl 1-cyanocyclohexaneacetate (1) is prepared as described in US5693845, the entire contents of US5693845 are incorporated herein by reference.

Preparation of 1-cyano-cyclohexaneacetic acid ethyl ester (1)

148g (1mol) of 1-cyanocyclohexaneacetonitrile, 206mL of ethanol and 100mL of toluene were poured into a 1-liter pressure-resistant flask. The mixture was cooled to 5 ℃ and evacuated. Anhydrous hydrogen chloride (148g, 4.05mol) was added to the evacuated flask and the pressure was raised to 10 pounds per square inch gauge (psig) while the temperature was allowed to rise to 35 ℃. The temperature was maintained for 7 hours during which additional hydrogen oxide (25g, 0.68mol) was added to maintain the pressure at 5 pounds per square inch gauge (psig). At the end of the 7 hour period, excess hydrogen chloride and ethanol were removed by vacuum distillation while the mixture was maintained below 25 ℃. The resulting slurry was added with 200mL of toluene which was then removed by vacuum distillation. This procedure was repeated twice more with 150mL of toluene. After the final distillation, 150mL of toluene and 500mL of ice water were added, and the pH was adjusted to 4 with aqueous sodium hydroxide solution. After stirring for 18 hours, the mixture was filtered, the filtrate layers were separated, the aqueous layer was washed with 100mL of toluene, and the combined toluene layers were washed with 100mL of 1N aqueous sodium hydroxide solution and then twice with 50mL of water. The toluene solution was then dried by azeotropic distillation, and then the toluene was removed by vacuum distillation. The residual yellow oily substance (166g) was 91% ethyl 1-cyanocyclohexaneacetate. Further purification can be carried out by vacuum distillation, collecting the distillate at a temperature of from 0.2 to 0.3mmHg and from 85 ℃ to 95 ℃.

Preparation of 1- (aminomethyl) -cyclohexaneacetic acid

Ethyl 1-cyanocyclohexaneacetate (1) was mixed with 34% w/w KOH (1.05kg/kg1) over 1 hour. After the addition was complete, the batch was heated to about 80 ℃ and stirred for 3 hours. The solution was cooled to 20-25 ℃ and then washed with toluene (0.70kg/kg 1). After separation of the layers, the product-rich aqueous stream comprising the potassium 1-cyanocyclohexaneacetate salt (2) proceeds to the hydrogenation reaction process.

The potassium 1-cyanocyclohexanoate salt (2) is hydrogenated over a sponge nickel catalyst (12% active nickel loading relative to 1) at 3.5barg and 30 ℃ for 14-16 hours. The batch was cooled to ambient temperature and filtered to remove the catalyst. The catalyst bed was washed with water (0.4kg/kg1) and the solution was stored at 0-5 ℃. The catalyst bed was then washed with potassium hydroxide solution for reuse. This wash solution is disposed of and the Raney nickel is stored in a caustic solution.

The potassium 1- (aminomethyl) cyclohexaneacetate salt (3) solution (pH13-14) was heated to about 40 ℃ before adjusting the pH to 7.1 (isoelectric point) by adding 80% acetic acid (about 0.53kg/kg relative to 1). The 80% acetic acid addition rate was such that the temperature was maintained at <55 ℃. The batch was cooled to 40 ℃ and gabapentin was added to the batch to seed. The batch is then cooled to 0 ℃ and stirred for a minimum of 4 hours. The batch was separated and washed with Isopropanol (IPA) (1.56kg/kg 1). 1- (aminomethyl) -cyclohexaneacetic acid (4) moistened with IPA can be recrystallized using any of the crystallization steps described in examples 2 or 3. Yield: 68-73% of active ethyl 1-cyanocyclohexaneacetate.

Example 2 recrystallization of 1- (aminomethyl) -cyclohexaneacetic acid (4)

1- (aminomethyl) -cyclohexaneacetic acid (4) prepared as in example 1 was dissolved (about 65-67 ℃) in methanol (2.5 volumes) and water (about 0.6 volumes). A small portion of water was added until dissolution was complete. Preheated IPA (5.0 volumes) was added to the solution and the batch was cooled to 0 ℃ for isolation. The batch was washed with IPA (1.0 vol) and dried under vacuum at 50 ℃. And (3) recovering: 88-92%.

Example 3 recrystallization of 1- (aminomethyl) -cyclohexaneacetic acid (4)

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

Example 4 preparation of 1- (aminomethyl) -cyclohexaneacetic acid (4) using recovered Nickel catalyst

Ethyl 1-cyanocyclohexaneacetate (1) was mixed with 34% w/w KOH (1.05kg/kg1) over 1 hour. After the addition was complete, the batch was heated to about 80 ℃ and stirred for 3 hours. The solution was cooled to 20-25 ℃ and then washed with toluene (0.70kg/kg 1). After separation of the layers, the product-rich aqueous stream comprising the potassium 1-cyanocyclohexaneacetate salt (2) proceeds to the hydrogenation process.

1-cyanocyclohexaneacetic acid potassium salt (2) was hydrogenated at 3.5barg and 30 ℃ for 14-16 hours using the sponge nickel catalyst recovered from example 1 (12% active nickel loading relative to 1). The batch was cooled to ambient temperature and filtered to remove the catalyst. The catalyst bed was washed with water (0.4kg/kg1) and the solution was stored at 0-5 ℃.

The potassium 1- (aminomethyl) cyclohexaneacetate salt (3) solution (pH13-14) was heated to about 40 ℃ before adjusting the pH to 7.1 (isoelectric point) by adding 80% acetic acid (about 0.53kg/kg relative to 1). The 80% acetic acid addition rate was such that the temperature was maintained at <55 ℃. The batch was cooled to 40 ℃ and gabapentin was added to the batch to seed. The batch is then cooled to 0 ℃ and stirred for a minimum of 4 hours.

The batch was isolated and washed with Isopropanol (IPA) (1.56kg/kg 1). 1- (aminomethyl) -cyclohexaneacetic acid (4) moistened with IPA can be recrystallized using any of the crystallization steps described in examples 2 or 3. Yield: 68-73% of active ethyl 1-cyanocyclohexaneacetate.

The invention is not limited to the specific examples described above, which may vary in detail.

Claims (24)

1. A one-pot process for the preparation of 1- (aminomethyl) -cyclohexaneacetic acid or a pharmaceutically acceptable salt thereof comprising the steps of:

hydrolyzing ethyl 1-cyanocyclohexaneacetate with potassium hydroxide, sodium hydroxide, or lithium hydroxide to form 1-cyanocyclohexaneacetate salt;

hydrogenating the 1-cyanocyclohexaneacetic acid salt in situ in the presence of a catalyst to form a 1- (aminomethyl) -cyclohexaneacetic acid salt; and

1- (aminomethyl) -cyclohexaneacetic acid is isolated.

2. The method of claim 1, wherein the method is performed in an aqueous environment.

3. A process according to claim 1 or 2, wherein after hydrolysis the solution is washed with a water immiscible solvent.

4. The process of claim 3, wherein the water immiscible solvent is toluene or MTBE.

5. A process as claimed in any one of claims 1 to 4, wherein the hydrolysis is carried out at a temperature of about 80 ℃ for about 3 hours.

6. A process as claimed in any one of claims 1 to 4, wherein the hydrolysis is carried out at room temperature.

7. A process as claimed in any one of claims 1 to 6, wherein the hydrogenation is carried out at about 30 ℃ for up to 20 hours.

8. The process of claim 7 wherein the hydrogenation is carried out for about 14 hours.

9. The process of any of claims 1-8, wherein the catalyst is Raney nickel.

10. The process of any of claims 1-9, wherein the solution is filtered to remove the catalyst.

11. The process of claim 10, wherein the filtered catalyst is reused.

12. A process according to any one of claims 1 to 11 wherein the isolation of the product is achieved by:

adding weak acid: and

1- (aminomethyl) -cyclohexaneacetic acid is isolated.

13. The method according to claim 12, wherein the weak acid is acetic acid.

14. The process as claimed in claim 12 or 13, wherein after the addition of the acid, gabapentin is added to the solution as seed crystals.

15. A process according to any one of claims 12 to 14 including the step of stirring the product at 0 ℃ for about 4 hours.

16. A process as claimed in any one of claims 12 to 15, wherein the isolated 1- (aminomethyl) -cyclohexaneacetic acid is washed with an alcohol.

17. The process of claim 16, wherein the alcohol is isopropanol.

18. A process as claimed in any one of claims 1 to 17, wherein the 1- (aminomethyl) -cyclohexaneacetic acid is recrystallised.

19. The process of claim 18 wherein 1- (aminomethyl) -cyclohexaneacetic acid is dissolved in methanol and water.

20. The process of claim 18, wherein 1- (aminomethyl) -cyclohexaneacetic acid is dissolved in methanol and water; adding isopropanol; and the solution was distilled under vacuum.

21. A process according to claim 19 or 20, wherein the product is washed with isopropanol and dried under vacuum.

22. A method substantially as described herein with reference to the examples.

1- (aminomethyl) -cyclohexaneacetic acid potassium salt.

1- (aminomethyl) -cyclohexaneacetic acid containing less than 0.01% by weight of potassium acetate.