FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of gabapentin enacarbil, more particularly, a novel process for the preparation of gabapentin benzyl ester, an intermediate utilized in the gabapentin enacarbil. It further relates to the novel intermediate cyclohexanediacetic acid monobenzyl ester monoamide.

BACKGROUND OF THE INVENTION:

1-{[(a-Isobutanoyloxyethoxy) carbonyl]aminomethyl}-l-cyclohexaneacetic acid (I), also known by gabapentin enacarbil, is a prodrug of the widely used anticonvulsant and analgesic agent gabapentin (II). This new prodrug has great significance as it provides predictable dose-proportional gabapentin exposure with high oral bioavailability. Studies on gabapentin enacarbil have shown that sustained-release gabapentin enacarbil formulation has improved efficacy over the pharmacokinetics of gabapentin. Gabapentin enacarbil has proved to be beneficial in treating the neurological symptoms associated with disorders such as restless legs syndrome.

Accordingly, there is an increased interest in preparing the GABA (y-aminobutyric acid) analogs, which are therapeutically superior to gabapentin. Gallop et al. first disclosed the compound (I) along with a variety of prodrugs of gabapentin and methods for making them.

US 4,024,175 discloses a process for the preparation of gabapentin starting from 1,1-cyclohexanediacetic acid (III), which is converted into the corresponding anhydride (IV), followed by the treatment with ammonia yielding 1,1-cyclohexanediacetic acid monoamide, which upon reaction with sodium hypochlorite gives gabapentin.

According to EP 1404324, the compound of formula (I) can be prepared by different methods. In accordance with one method described in that patent, as shown in Scheme 2 below, carboxylic acids can directly be coupled to the terminal amino group or hydroxyl group of gabapentin (II) in the presence of known coupling reagents such as carbodiimides, aminium salts, or phosphonium salts. The carboxyl group of gabapentin should be well protected before coupling and subsequent deprotection yields gabapentin enacarbil.

There are other methods described in said patent by which compound (I) can be obtained, either by reactions of carboxylic acid derivatives, such as acyl chlorides, symmetrical anhydrides or mixed anhydrides, with gabapentin in the presence of a base, for example hydroxide, tertiary amine etc., or by the addition reaction of an alcohol with an isocyanate, or via the carbonylation of gabapentin to an intermediate carbamic acid species which is captured by an in situ alkylation, or from the ketocarbamate derivative via Baeyer-Villiger type oxidation, or by the reaction of carbonic acid derivatives with gabapentin.

The synthesis starts with gabapentin containing a number of lactam based toxic impurities from the crude product mixture. The process using a p-nitrophenyl carbonate derivative as the acylating agent becomes unattractive due to toxicity concerns as the complete removal of liberated p-nitro phenol is rather difficult in large scale preparations.

In the most preferred convergent route opted from the previously reported sequences, gabapentin is suitably protected before coupling with the acyloxyalkoxycarbonyl moiety for building the gabapentin enacarbil. But the preparation of protected gabapentin precursors according to the reported literature is laborious and the starting material used for this purpose is also expensive. US 7,232,924 discloses a method for the preparation of protected gabapentin starting with gabapentin using thionyl chloride and an alkyl or arylalkyl alcohol as shown in Scheme 3 below. Although this process requires around 50 to 60 hours for completing the reaction, yields are low due to side reactions occuring at the amine group of gabapentin, resulting in the formation of byproducts and lactam type impurities.

According to the prior art methods, Hofmann degradation of 1,1-cyclohexanediacetic acid monoamide is performed in an aqueous medium to afford gabapentin as shown in Scheme 4 below.

There are methods reported in the art with regard to Hofmann degradation of 1,1-cyclohexanediacetic acid monoester monoamides using sodium hypochlorite and aqueous sodium hydroxide. However, when the benzyl ester is used as starting material the above conventional reaction conditions result in hydrolysis of the benzyl ester moiety by the free alkali, thus yielding gabapentin instead of the desired gabapentin benzyl ester.

In view of the above problems, there is a need to devise an industrially feasible and cost effective process for the preparation of gabapentin benzyl ester with minimum levels of gabapentin and without requiring extensive isolation procedures. The present invention provides a simple and expedient process in which the hydrolysis of benzyl ester is reduced to a minimum.

Object of the invention:

The object of the present invention is to provide a synthesis of gabapentin benzyl ester.

In a preferred embodiment, the present invention provides a synthesis of gabapentin benzyl ester without requiring much isolation effort.

In yet another preferred embodiment, the present invention provides a process for the preparation of gabapentin benzyl ester using a single solvent throughout the reaction sequence.

In particular, the present invention provides a process for the preparation of gabapentin benzyl ester via 1,1-cyclohexanediacetic acid monobenzyl ester monoamide,using sodium hypochlorite.

Summary of the invention:

The total reaction sequence is particularly preferably performed without changing the reaction solvent, and without isolation and purification of any intermediate.

Specifically there is provided a process for the synthesis of gabapentin benzyl ester hydrochloride (VII) starting from 1,1-cyclohexanediacetic acid (III), through the formation of the novel cyclohexanediacetic acid monobenzyl ester monoamide (VI). The total reaction is preferably performed without changing the reaction solvent, and without isolation and purification of any intermediate stages. The process comprises the following steps:

(a) Reacting 1,1-cyclohexanediacetic acid (III) with acetic anhydride, preferably in the presence of a suitable organic solvent,

(b) treating the product of step (a) with benzyl alcohol and pyridine, preferably in a suitable solvent,

(c) treating the product of step (b) with oxalyl chloride, preferably in a suitable solvent, followed by treating with aqueous ammonia,

(d) treating the product of step (c) with alkali hypohalite solution, followed by acidfication with hydrochloric acid, preferably in the presence of a suitable solvent,and

(e) isolating the gabapentin benzyl ester hydrochloride (VII).

More specifically, the synthesis of gabapentin benzyl ester hydrochloride (VII) starting from 1,1-cyclohexanediacetic acid through the formation of novel 1,1-cyclohexanediacetic acid monobenzyl ester monoamide (VI) comprises the following steps:

(a) Reacting 1,1-cyclohexanediacetic acid (III) with acetic anhydride in the presence of a suitable organic solvent and optionally isolating the 1,1-cyclohexanediacetic anhydride (IV),

(b) treating the anhydride (IV) with benzyl alcohol and pyridine in a suitable solvent and optionally isolating the 1,1-cyclohexanediacetic acid monobenzyl ester (V),

(c) reacting the monobenzyl ester (V) with oxalyl chloride in a suitable solvent followed by treating with aqueous ammonia and optionally isolating the 1,1-cyclohexanediacetic acid monobenzyl ester monoamide (VI),

(d) treating the monoamide (VI) with alkali hypohalite solution followed by acidification with hydrochloric acid in presence of a suitable solvent, and

(e) isolating the gabapentin benzyl ester hydrochloride (VII).

In another embodiment, there is provided a novel intermediate, 1,1-cyclohexanediacetic acid monobenzyl ester monoamide (VI).

Said 1,1-cyclohexanediacetic acid monobenzyl ester monoamide (VI) is a useful intermediate in the synthesis of gabapentin benzyl ester hydrochloride (VII) and gabapentin enacarbil.

In another preferred embodiment the process of the present invention includes the preparation of gabapentin enacarbil, which process comprises the steps of:

(a) Reacting 1,1-cyclohexanediacetic acid (III) with acetic anhydride, preferably in the presence of a suitable organic solvent, and optionally isolating the 1,1-cyclohexanediacetic anhydride (IV),

(b) treating the anhydride (IV) with benzyl alcohol and pyridine, preferably in a suitable solvent, and optionally isolating the 1,1-cyclohexanediacetic acid monobenzyl ester (V),

(c) reacting the monobenzyl ester (V) with oxalyl chloride, preferably in a suitable solvent, followed by treating with aqueous ammonia and optionally isolating the 1,1-cyclohexanediacetic acid monobenzyl ester monoamide (VI),

(d) treating the monoamide (VI) with alkali hypohalite solution, followed by acidification with hydrochloric acid, preferably in the presence of a suitable solvent,

(e) isolating the gabapentin benzyl ester as hydrochloride salt (VII), and, as additional steps,

(f) converting gabapentin benzyl ester to gabapentin enacarbil as per the reported processes, i.e., by (i) coupling the gabapentin benzyl ester (VII) with 1-carboxyoxyethyl isobutyrate in the presence of a coupling reagent to obtain the benzyl ester of gabapentin enacarbil, and (ii) cleaving the benzyl group to obtain gabapentin enacarbil.

Detailed description of the invention:

Thus in accordance with the present invention the starting material 1,1-cyclohexanediacetic acid (III) is prepared by the literature reported methods.

Dehydration of 1,1-cyclohexanediacetic acid (III) with acetic anhydride in the presence of a suitable organic solvent gives 1,1-cyclohexanediacetic anhydride (IV) and the organic solvent layer of (IV) can directly be used for next reaction nevertheless, the compound (IV) can be isolated.

The reaction of the anhydride (IV) with benzyl alcohol and pyridine, preferably in a suitable organic solvent, gives 1,1-cyclohexanediacetic acid monobenzyl ester (V) and the organic solvent layer of (V) can directly be used for next reaction. On the other hand, the compound (V) can be used in isolated form.

The reaction of the monobenzyl ester (V) with oxalyl chloride, preferably in a suitable organic solvent, followed by treating with aqueous ammonia gives 1,1-cyclohexanediacetic acid monobenzyl ester monoamide (VI), and the organic solvent layer of (VI) can either directly be used for the next reaction or can be isolated.

The obtained 1,1-cyclohexanediacetic acid monobenzyl ester monoamide (VI) was found to be novel and has been characterized by its melting point and 1H NMR data which has been elucidated in Figure 1. The suitable organic solvent in the foregoing preparation steps is preferably selected from halogenated hydrocarbons, such as dichloromethane or chlorobenzene, aliphatic hydrocarbons, such as hexanes or heptanes, aromatic hydrocarbons, such as toluene or xylenes, ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or 1,4-dioxane, and esters, such as ethyl acetate. The particularly preferred solvents are toluene and THF.

For the reaction of 1,1-cyclohexanediacetic acid monobenzyl ester monoamide (VI) with alkali hypohalite, the preferred alkali hypohalite is sodium hypochlorite solution and the reaction is preferably carried in a suitable organic solvent selected from those mentioned above for steps (a) to (c) and nitriles, such as acetonitrile or butyronitrile.

The particularly preferred solvents are toluene, acetonitrile and THF. The reaction is advantageously carried out at about -10°C to about +5°C, with the preferred range between about -5°C and about +5°C. After completion of the reaction the reaction mixture is advantageously quenched with a suitable reducing agent, such as sodium metabisulfite, to destroy excess hypohalite. Acidification of the reaction mixture to a pH of about 1.0 and preferably below 1.0 in the range of about 0.6 to about 0.8 is carried out with hydrochloric acid, for example a 1:1 mixture of concentrated hydrochloric acid and water.

For work-up, the reaction mixture is advantageously extracted with a suitable organic solvent, preferably with n-butanol. The n-butanol layer is distilled off completely and residual traces of solvent are advantageously removed by entrainment with a suitable entrainer such as ethyl acetate. The obtained crude solid is again dissolved in a suitable solvent such as ethyl acetate and the gabapentin benzyl ester hydrochloride (VII) allowed crystallizing on cooling. The precipitated hydrochloride is separated by conventional methods such as filtration or centrifugation and dried to constant weight.

The gabapentin benzyl ester as hydrochloride salt (VII) can be converted to gabapentin enacarbil as per the procedures reported in the literature, namely (i) coupling with 1-carboxyoxyethyl isobutyrate in the presence of a coupling reagent to obtain the benzyl ester of gabapentin enacarbil, and (ii) cleaving the benzyl group to obtain gabapentin enacarbil.

The present invention will now be defined in more detail by way of following examples, which are intended to be illustrative and not limiting.

Example 1: Synthesis of gabapentin benzyl ester

a. Preparation of 1,1-cyclohexanediacetic anhydride (IV)

1,1-Cyclohexanediacetic acid (100 g) and toluene (300 ml) were charged into a round bottomed flask at 20-25°C. Acetic anhydride (76.5 g) was added and the reaction mixture was heated to 95-100°C over a period of 3 h. After completion of the reaction the reaction mixture was cooled to 80°C. Toluene was distilled off to half of the initial volume of the reaction mixture under vacuum at 75-80°C. The residual mixture was cooled to 45°C and demineralized water (1500 ml) was added at 35-45°C. The mixture was cooled to 10°C and maintained for 1 h. The precipitated product was filtered, washed with demineralized water (200 ml) and diisopropyl ether (100 ml). The wet product was dried under vacuum at 35-40°C. Yield: 75 g

b. Preparation of 1,1-cyclohexanediacetic acid monobenzyl ester (V)

1,1-Cyclohexanediacetic anhydride (100 g) was dissolved in toluene (100 ml) and charged into a 4-neck round bottomed flask at 25-30°C. Benzyl alcohol (65.26 g) and pyridine (43.94 g) were added to the toluene solution at 25-30°C and the reaction mixture was heated at 95-100°C and maintained for about 15 h. The reaction completion was checked by HPLC. The reaction mixture was cooled 25-30°C and diluted with ethyl acetate (600 ml). The resulting mixture was washed with 1 N HC1 (2x500 ml) and saturated brine solution (2x500 ml) at 25-30°C. The organic layer was dried on sodium sulfate and the solvent was distilled off completely under vacuum at 50-55°C to obtain a thick residue. Residue wt: 150 g

c. Preparation of 1,1-cyclohexanediacetic acid monobenzyl ester monoamide (VI)

Crude 1,1-cyclohexanediacetic acid monobenzyl ester obtained in the preceding step (150 g) was dissolved in toluene (600 ml) and charged into a 4-neck 1 1 round bottomed flask at 25-30°C. Oxalyl chloride (180.5 g) was added slowly to the toluene solution over a period of 30-40 min at 25-30°C. The reaction mixture was stirred for 3 h at 25-30°C and 1 hr at 40-45°C. The reaction completion was monitored by TLC. Excess oxalyl chloride was distilled off under vacuum. One volume of toluene was added and distilled off at 40-45°C under vacuum to remove traces of oxalyl chloride. The residue was degassed at 50-55°C for 60 min. Toluene (150 ml) was added to the residue at 50°C and the resulting solution was cooled to 20-25°C.

In another reaction flask aqueous ammonia solution (900 ml) was charged at 25-30°C and cooled to 0-5°C. The above toluene solution was added at 0-5°C over a period of 30-45 min and maintained at 0-5°C for 1 hr. The reaction completion was checked by TLC. The precipitated product was filtered and the wet cake was washed with n-hexane (100 ml).The wet cake was dissolved in dichloromethane (500 ml) at 25-30°C and undissolved material was filtered off. The filtrate was distilled completely at 40°C to get a semi solid residue. n-Hexane (100 ml) was added to the semi-solid residue and distilled off completely under vacuum at 40°C to obtain a solid material. To the solid material n-hexane (100 ml) was added again at 40°C cooled the resulting mixture was cooled to 25-30°C. The precipitated product was filtered and washed with n-hexane (100 ml).The wet material was dried at 30-35°C under vacuum for 4-6 h to obtain 90 g of 1,1 -cyclohexanediacetic acid monobenzyl ester monoamide.

Melting point: 74-78°C

1HNMR(d6-DMSO): 5 7.37-7.25 (m, 5H), 7.18 (s, 1H), 6.72 (s, 1H), 5.04 (s, 2H),2.56 (s, 2H), 2.19 (s,2H), 1.30-1.39 (m,10H).

d. Preparation of gabapentin benzyl ester hydrochloride (VII)

1,1-Cyclohexanediacetic acid monobenzyl ester monoamide (100 g) was dissolved in toluene (500 ml) at 25-30°C in a 4-neck round bottomed flask at 25-30°C. The solution was cooled to -10 to -5°C and sodium hypochlorite (700.0 g) solution was added slowly over 30-45 min at -10°C to -5°C and maintained for 1 h at -10°C to -5°C. The temperature was slowly raised to 0°C and maintained for 2 h at 0-5°C. The reaction mixture was quenched with sodium metabisulfite solution (5 g in 20 ml of water) at 0-5°C. The temperature was slowly raised to 55-60°C. The reaction mixture was distilled out completely under vacuum at 55-60°C and cooled to 20-25°C. The pH of the residual mass was adjusted to 0.6-0.8 with 1:1 dil. aqueous HC1 at 20-25°C and stirred for 15 min at 20-25°C. The resulting mixture was extracted with n-butanol (2x300 ml) at 25-30°C. The n-butanol layer was separated and dried over sodium sulfate. n-Butanol was distilled out completely under vacuum at 55-60°C to obtain a semi-solid material. Ethyl acetate (100 ml) was added and distilled off completely under vacuum at 55-60°C to remove residual traces of n-butanol and to obtain a solid material. Ethyl acetate (600 ml) was added and the resulting mixture was cooled first to 25-30°C and then to 0-5°C and maintained at that temperature for 1 h. The precipitated product was filtered and washed with chilled ethyl acetate (100 ml). The wet material was dried under vacuum at 30-35°C to yield 80g of gabapentin benzyl ester hydrochloride with a purity of more than 99.6% by HPLC.

Example 2: Synthesis of gabapentin benzyl ester hydrochloride (VII) without isolating intermediates

1,1-Cyclohexanediacetic acid (100 g) and toluene (300 ml) were charged into a round bottomed flask at 20-25°C. Acetic anhydride (76.5 g) was added and the reaction mixture was heated to 95-100°C over a period of 3 h. After completion of the reaction, sodium bicarbonate solution was added and the toluene layer was separated and washed with water. Benzyl alcohol (60.0 g) was added to the toluene layer at 25-30°C and the resulting mixture was heated at 95-100°C and maintained at that temperature for about 15 h. The reaction completion was checked by HPLC. After the reaction completion the reaction mixture was washed with 1 N HC1 (2x300 ml) and saturated brine solution (2x300 ml) at 25-30°C. The toluene layer was dried on sodium sulfate and charged into a 500 ml 4-neck round bottomed flask at 25-30°C, followed by slow addition of oxalyl chloride (34.9 ml) over a period of 30-40 min at 25-30°C. The reaction mixture was stirred for another 3 h at 25-30°C and 1 h at 40-45°C. The reaction completion was monitored by TLC. Excess oxalyl chloride was distilled off under vacuum. One volume of toluene was added and distilled off at 40-45°C under vacuum.

The resulting mixture was cooled and slowly added to chilled aqueous ammonia (500 ml) at 5-10°C in a separate flask. The reaction mixture was maintained at that temperature for 1 h. Reaction completion was monitored by TLC. Toluene (500 ml) was added and the resulting mixture was stirred for 10 min at 25-30°C. The toluene layer was separated and charged into a 1

It 4-neck round bottomed flask at 25-30°C. The solution was cooled to -10 to -5°C, sodium hypochlorite (773.4 g) solution was added slowly over 30-45 min at -10°C to -5°C and the mixture was maintained at that temperature for 1 h. The temperature was slowly raised to 0°C and maintained for 2 h at 0-5 °C. The reaction mixture was quenched with sodium metabisulfite solution (5 g dissolved in 20 ml water) at 0-5°C. The temperature was then slowly raised to 55-60°C. The mixture was distilled out completely under vacuum at 55-60°C. The residue was cooled to 20-25°C and the pH was adjusted to 0.6-0.8 with 1:1 dil.aqueous HC1 at 20-25°C and stirred for 15 min at 20-25°C. The mixture was extracted with n-butanol (2x300 ml) at 25-30°C. The n-butanol layer was separated and dried over sodium sulfate. n-Butanol was distilled out completely under vacuum at 55-60°C to obtain a semi-solid material. Ethyl acetate (100 ml) was added and distilled out completely under vacuum at 55-60°C to remove residual traces of n-butanol and to obtain a solid material which was taken up in ethyl acetate (600 ml). The resulting mixture was cooled first to 25-30°C and then to 0-5°C and maintained at that temperature for 1 h. The precipitated product was filtered and washed with chilled ethyl acetate (100 ml). The wet material was dried under vacuum at 30-35°C to yield 86 g of gabapentin benzyl ester hydrochloride with a purity of more than 99.5% by HPLC.

We claim;

1.  A process for the production of gabapentin benzyl ester hydrochloride of formula
comprising the steps of;

(a) reacting 1,1-cyclohexanediacetic acid of formula
with acetic anhydride to obtain 1,1 -cyclohexanediacetic anhydride of formula

(b) treating the anhydride (IV) with benzyl alcohol and pyridine to obtain 1,1-
cyclohexanediacetic acid monobenzyl ester of formula

(c) reacting the monobenzyl ester (V) with oxalyl chloride followed by treating with aqueous ammonia to obtain 1,1-cyclohexanediacetic acid monobenzyl ester monoamide of formula

(d) treating the monoamide (VI) with alkali hypohalite solution followed by acidification with hydrochloric acid, and

(e) isolating the gabapentin benzyl ester hydrochloride (VII).

2. The process of claim 1, wherein at least one of steps (a) to (c) is conducted in an organic solvent selected from halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers and esters.

3. The process of claim 1 or 2, wherein step (d) is conducted in an organic solvent selected from selected from halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, nitriles, ethers and esters.

4. The process of claim 2 and 3, wherein steps (a) to (d) are conducted in the same organic solvent.

5. The process of any of claims 1 to 4, wherein at least one of the intermediates obtained in steps (a), (b)and (c) is not isolated or purified before subjecting it to the subsequent step.

6. The process of claim 5, wherein none of the intermediates obtained in steps (a),(b) and (c) is isolated or purified before subjecting it to the subsequent step.

7. The process of any of claims 1 to 6, further comprising the steps of

(i) coupling the gabapentin benzyl ester (VII) with 1-carboxyoxyethyl isobutyrate in the presence of a coupling reagent to obtain the benzyl ester of gabapentin enacarbil, and

(ii) cleaving the benzyl group to obtain gabapentin enacarbil of formula

8. 1,1-Cyclohexanediacetic acid monobenzyl ester monoamide of formula

9. The use of 1,1-cyclohexanediacetic acid monobenzyl ester monoamide as an intermediate in the synthesis of gabapentin enacarbil.