Process for the Preparation of Gabapentin

Abstract

The present invention relates to a process for the preparation of gabapentin and, more in particular, to a method of synthesis of 1,1-cyclohexane acetic acid monoamide, an intermediate used in the preparation of gabapentin, comprising the basic hydrolysis reaction of α,−-diaminocarbonyl-β,β-pentamethylene glutarimide.

Description

EXAMPLE 1

Synthesis of α,α′-diaminocarbonyl-β,β-pentamethylene glutarimide

A basic reducer was collected to a reactor A, then 16.0 kg of demineralised water were charged and subsequently, maintaining temperature below 60° C., 135.8 kg (74.0 l) of sulphuric acid (96% w/w) were added with a metering pump.

The loading line and the metering pump were washed with 1.6 kg of demineralised water.

The washings were added to the solution already contained in the reactor A.

The sulphuric acid solution was cooled to 25-30° C., then 12.5 kg of dry dinitryl were charged from a hatch.

A suspension was obtained, which was heated to about 60° C.

This temperature was maintained until obtaining a solution in about one hour and 12.5 kg of dry dinitryl were again added.

The suspension thus obtained was brought to about 60° C. and maintained at that temperature until dissolution in about 2 hours.

An additional 12.5 kg of dry dinitryl were then added.

The suspension thus obtained was brought and maintained to about 60° C.

After about four hours, the reaction check was carried out.

If the reaction check was within limits, the mixture was cooled to about 50° C.

In a reactor B, 102.0 kg of demineralised water were charged.

The water was heated to about 40-45° C., then, letting the temperature rise spontaneously to 50-55° C., the diamide solution contained in the reactor A was added in about 2-3 hours through a loading line.

A dense, but suitable for agitation solution was obtained.

In the reactor A were charged 11.1 kg of demineralised water and subsequently letting the temperature rise to 50-55° C., 11.1 kg (6.0 l) of sulphuric acid (96% w/w) were charged with anti-acid pump.

The solution was maintained for about 10 minutes at 50-55° C. and it was then added to the suspension formed in the reactor B through the loading line.

In the reactor A were charged 14.0 kg of demineralised water, which after about 10 minutes at 50-55° C. were added to the suspension present in the reactor B through the loading line.

The suspension in the reactor B was maintained at 50-55° C. for about 30 minutes, then it was cooled to 15-20° C. in about 1.5 hours.

After at least one hour at 15-20° C., several centrifuging operations were carried out, washing the panel multiple times with demineralised water.

Indicatively, a total of 180.0 kg of demineralised water were used for washings in the centrifuge.

The mother liquors were constituted by 50% sulphuric acid and were placed in plastic or metal drums, coated with anti-acid materials.

About 60.5 kg of humid product were obtained which, dried under vacuum at 50° C., yield about 55.5 kg of dry product.

¹H NMR (DMSO-d6): δ 1.34-1.88 (m, 10H), 4.00 (s, 2H), 7.20 (s, 2H, NH₂) and 7.85 (s, 2H, NH₂, 10.94 (s, 1H).

¹³C NMR (DMSO-d6): δ 20.55 (t, 2C), 25.29 (t, 1C), 31.06 (t, 2C), 38.22 (s, 1C), 54.16 (d, 2C), 168.83 (s, 2C), 170.50 (s, 2C).

MS (E.I. mode): m/z 250 (M-NH₃), 222 ((M—NH₃)—C═O), 122 ((M—NH₃)—NH₂COCHCONHCO).

I.R. (KBr): 3409, 3188 (NH stretch, 2937-2865 (C-H stretch of CH and CH₂), 1735, 1696, 1638 (C═O stretch), 1417, 1391, 1361 (C—H bend of CH and CH₂) cm⁻¹.

EXAMPLE 2

Synthesis of α, α′-dicarboxy-β,β-pentamethylene glutarimide di-sodium di-salt

In a reactor C, 170.8 kg (128.4 l) of electrolytic soda were charged under intercepted vacuum.

The loading line was washed with 1.5 kg of demineralised water which was loaded in reactor C.

The reactor was vented with nitrogen, an then it was connected to an acid reducer.

The electrolytic soda solution was cooled to about 0° C., then 90.0 kg of dry diamide were charged from the hatch.

The suspension was heated in about one hour to 55° C. and it was maintained at temperature until the solid was completely dissolved (about 10 minutes), then the solution was brought to about 105° C. in about four hours. The solution was maintained at temperature for about half an hour, then it was cooled to about 50° C.

EXAMPLE 3

Synthesis of pentamethylene glutarimide

The solution obtained as described in the previous example was transferred at 50° C. in a reactor D, then after weighing the solution about 37.9 kg (about 28.5 l) of solution of diacid sodium salt, corresponding to a portion of about 15% by weight of the reaction mixture, were charged in reactor C, whilst the rest of the solution was maintained at 50° C. in reactor D.

In reactor C were charged 70 kg of demineralised water letting temperature drop spontaucously, and subsequently 2.8 kg (2.4 l) of synthetic hydrochloric acid were charged by means of an anti-acid pump.

The loading line and the anti-acid pump were washed with 11.5 kg of demineralised water and the washings were added to the solution contained in reactor C.

The temperature inside reactor A was brought to about 95° C. and it was maintained until the transformation from diacid sodium salt solution to imide suspension.

Maintaining the temperature at about 95° C., about 215 kg (about 161.5 l) of diacid sodium salt solution, i.e. all of the solution left in reactor D, were charged in reactor C in about one hour.

Reactor D and the loading line were washed with 12.0 kg of demineralised water.

The washing was added to the reaction in reactor C.

Temperature was maintained for about two hours, whereupon the suspension was cooled to about 80° C.

EXAMPLE 4

Synthesis of 1,1-cyclohexane diacetic acid monoamide

25.7 kg (19.3 l) of electrolytic soda were charged in reactor C by means of metering pump.

The temperature was brought to about 95° C. and it was maintained until the complete dissolution of the solid, then the mixture was brought to reflux (101-105° C.).

Reflux was maintained for about six hours, then the reaction check was carried out

At the completion of the reaction, the solution was cooled to about 20° C. with precipitation of a solid white flocculate, then, at temperature 45.0 kg (57.3) of isopropanol were charged and subsequently in about one hour, maintaining temperature below 25° C., about 125 kg (107.7 l) of synthetic hydrochloric acid were charged until reaching a pH of 6.5±0.2, measured with pH meter.

Once the desired pH was reached, the suspension was heated to 35-40° C. and it was maintained at this temperature until dissolution of the solid.

At the completion of the dissolution, the solution was transferred into reactor E and subsequently 20 kg of demineralised water were charged in the reactor.

The washing was kept under stirring for 5-10 minutes, then it was transferred into reactor E.

The internal temperature of reactor E was regulated to about 35-40° C. then, maintaining temperature, 40 kg (34.5 l) of synthetic hydrochloric acid were added in about one hour until reaching a pH of 4.0-4.5, measured with paper.

The pH of the suspension was checked to be stable for at least 10-15 minutes, then the internal temperature of reactor E was brought to about 50° C. and it was maintained for about 30 minutes.

In about one and one half hours the suspension was cooled to about 15-20° C. and after about one hour several centrifuging operations were carried out. The panel was washed twice with a mixture formed by isopropanol and water.

In total, 23.6 kg (30 k) of isopropanol and 30 kg of demineralised water were used. After one washing with the alcoholic mixture, the panel was subjected to six washings with water.

In total, 270 kg of demineralised water were indicatively used.

78.0 kg of humid product were obtained, which after drying at about 50° C. under vacuum yield about 59.0 kg of the desired dry product.

EXAMPLE 5

Synthesis of 1-(aminomethyl)-cyclohexane acetic acid

The 1,1-cyclohexane diacetic acid monoamide thus obtained is transformed into gabapentin by known methods, e.g. by Hoffmann rearrangement, acidification, extraction, purification of an aqueous solution of gabapentin hydrochloride on a strong cationic ionic exchange resin followed by recrystallisation as described in the international patent application WO 02/34709 in the name of the same Applicant.

Claims

1) A process for the preparation of 1,1-cyclohexane diacetic acid monoamide which comprises the basic hydrolysis reaction of α,α′-diaminocarbonyl-β,β-pentamethylene glutarimide.

2) A process according to claim 1 wherein the basic hydrolysis reaction is carried out by reaction with a sodium hydroxide solution.

3) A process according to claim 1 which comprises the following steps: a) hydrolysis of α,α′-diaminocarbonyl-β,β-pentamethylene glutarimide to obtain α,α′-di-acid disodium salt;b) decarboxylation to obtain pentamethylene-glutarimide;c) hydrolysis of pentamethylene-glutarimide and precipitation of the product.

4) A process according to claim 3 wherein step a) is carried out by addition of α,α′-diaminocarbonyl-β,β-pentamethylene glutarimide to a sodium hydroxide solution and bringing to reflux.

5) A process according to claim 4 wherein the sodium hydroxide solution has a concentration around 30%.

6) A process according to claim 4 wherein the addition of α,α′-diaminocarbonyl-β,β-pentamethylene glutarimide is carried out at a temperature comprised between-5 and 5° C.

7) A process according to claim 4 wherein the sodium hydroxide/α,α′-diaminocarbonyl-β,β-pentamethylene glutarimide molar ratio is comprised between 3.5 and 4.

8) A process according to claim 3 wherein step b) is carried out by addition of a solution of hydrochloric acid at a portion of the solution obtained from step a), heating, formation of a suspension and addition of the remaining solution obtained from step a).

9) A process according to claim 8 wherein the heating of the reaction mixture takes place until a temperature of around 95° C. is reached.

10) A process according to claim 3 wherein step c) is carried out by addition of a sodium hydroxide solution, bringing to reflux and precipitating the product by addition of hydrochloric acid.

11) A process according to claim 10 wherein the sodium hydroxide solution has a concentration comprised between 10 and 30%.

12) A process according to claim 10 wherein the sodium hydroxide/α,α′-diaminocarbonyl-β,β-pentamethylene glutarimide molar ratio is comprised between 3.8 and 4.7.

13) A process according to claim 10 wherein the sodium hydroxide/α,α′-diaminocarbonyl-β,β-pentamethylene glutarimide molar ratio is around a value of 4.3.

14) A process according to claim 10 wherein the product precipitation is carried out in the presence of a precipitation co-solvent.

15) A process according to claim 14 wherein the precipitation co-solvent is isopropanol.

16) A process according to claim 1 further comprising the preparation of α,α′-diaminocarbonyl-β,β-pentamethylene glutarimide by hydrolysis of α,α′-dicyan-β,β-pentamethylene glutarimide with a solution of sulphuric acid.

17) A process according to claim 16 wherein the hydrolysis reaction is carried out at a temperature comprised between 25 and 70° C.

18) α,α′-diaminocarbonyl-β,β-pentamethylene glutarimide in solid form.

19) α,α′-diaminocarbonyl-β,β-pentamethylene glutarimide in solid form with a purity higher than 95%.

20) α,α′-dicarboxy-β,β-pentamethylene glutarimide disodium di-salt.

21) A process for the preparation of gabapentin which comprises the preparation of 1,1-cyclohexane diacetic acid monoamide by basic hydrolysis of α,α′-diaminocarbonyl-β,β-pentamethylene glutarimide.