INTERMEDIATES FIELD OF INVENTION

The invention relates to a process for resolution of racemic R (±) - 3- (carbamoylmethyl)-5-methylhexanoic acid I to obtain enantiomerically pure form of 3-(carbamoylmethyl)-5-methylhexanoic acid I and to the process for preparation of key intermediates for preparing racemic R (±) - 3- (carbamoylmethyl)-5-methylhexanoic acid I. Further, the invention relates to the process for preparation of enantiomerically pure (S)-3- (aminomethyl)-5-methylhexanoic acid from enantiomerically pure 3- (carbamoyimethyl)-5-methylhexanoic acid I

BACKGROUND OF INVENTION

R-(-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid is an important precursor for preparation of S-(-)-3-(Aminomethyl)-5-methyl-1 -hexanoic acid (Pregabalin),

S-(-)-3-(Aminomethyl)-5-methy ^' l-1 -hexanoic acid (Pregabalin), is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. Pregabalin is also called p-isobutyl-y-aminobutyric acid or isobutyl-GABA.

A process for the preparation of ~(-)-3-(Carbamoylmethyl)-5- methylhexanoic Acid has been reported in Organic Process Research & Development, 1997, 1 , 26-38. The process involves preparation of racemic 3-(Carbamoylmethyl)-5-methylhexanoic Acid, which was subsequently resolved using R-(+)-a-Phenylethylamine to obtain the required enantiomer. The present work describes an alternate process for the preparation of R- (-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid. The process is efficient, cost effective, and safe method for large scale synthesis that overcomes the limitations of above processes.

SUMMARY OF THE INVENTION

The invention provides a process for resolution of (±) - 3- (carbamoylmethyl)-5-methylhexanoic acid II to form R-(-)- 3- (carbamoylmethyl)-5-methylhexanoic acid of formula (I),

the said process comprises resolution of racemic mixture of compound of formula (II) with cinchona class of alkaloids or amines of formula (III) or

II

The cinchona class of alkaloids is selected from the group consisting of quinine, quinidine, cinchonine and cinchonidine. The amines used for the resolution are selected from compounds of formula (III) or (IV).

IV The solvent system used for resolution of (±) - 3-(carbamoylmethyl)-5- methylhexanoic acid II with cinchona alkaloids was water in combination with a water-miscible solvent selected from acetone, methanol, n- butanone or ethanol. The solvent system used for resolution of (±) - 3- (carbamoylmethyl)-5-methylhexanoic acid II with an aromatic amine mentioned above is chloroform-ethanol or terf-butyl methyl ether -ethanol. The invention also provides a process for preparing racemic (±) — 3- (carbamoylmethyl)-5-methylhexanoic acid II. Further, the invention provides methods for preparing 3-isobutylglutaric anhydride of formula (VIII) which is the key intermediate in the preparation of racemic (±) - 3-(carbamoylmethyl)-5-methylhexanoic acid II.

Furthermore, the invention provides a method for preparing enantiomerically pure (S)-3-(aminomethyl)-5-methylhexanoic acid from enantiomerically pure R- (-)- 3-(carbamoylmethyl)-5-methylhexanoic acid of formula (I)

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a process for resolution of (±) - 3- (carbamoylmethyl)-5-methylhexanoic acid (II) to form R-(-)- 3- carbamoylmethyl)-5-methylhexanoic acid of formula (I)

with cinchona class of alkaloids or amines of formula (III) or (IV). The cinchona class of alkaloid used for resolution is quinine, quinidine, cinchonine or cinchonidine. The amine used for resolution is selected from the formula (III) or (IV).

Ill

The solvent system used for resolution with cinchona alkaloid according to the invention is water in combination with a water-miscible solvent selected from acetone, methanol, n-butanone or ethanol. The solvent system used for resolution with amine is chioroform-ethanol or methyl tert- butylalcohol-ethanol. According to the invention the racemic (±) - 3-(carbamoylmethyl)-5- methylhexanoic acid (II) can also be prepared by a. reacting 3-isobutylglutaric anhydride of formula (VIII) with a racemic aromatic alcohol in the presence of a base and a solvent system to obtain, for example, (VSR, 3 SR)-1-(1 '- napthyl)ethyl-3-(carboxylomethyl)-5-methylhexanoate of formula (XII), b. converting the acid functional group of (VSR, 3 SR)-1-(V- napthyl)ethyl-3-(carboxylomethyl)-5-methylhexanoate of formula (XII) to an amide group to obtain compound of formula (XI)

which is hydrolysed under alkaline conditions in situ in the same pot to obtain racemic 3-(carbamoylmethyl)-5-methylhexanoic acid (II)

According to the invention a mixture of R and S isomers of 3- (carbamoylmethyl)-5-methylhexanoic acid is prepared by a. reacting anhydride compound of formula (VIII) with chiral alcohol in the presence of a base and a solvent system to obtain, for example, a mixture of (YR, 3S)-1-(1 '-napthyl)ethyl 3-(carboxylomethyl)-5-methylhexanoate of formula (VII) and

. (YR, 3f?)-1-(1'-napthyl)ethyl 3-(carboxylomethyl)-5- methylhexanoate of formula (Vila), b. Converting the acid functional group of the mixture of (YR, 3S)-1-(1'-napthyl)ethyl 3-(carboxylomethyl)-5- methylhexanoate of formula (VII) and (YR, 3R)-1-(T- napthyl)ethyl 3-(carboxylomethyl)-5-methylhexanoate of formula (Vila) to an amide group to obtain a mixture of formula (VI) and (Via) which

is hydrolysed under alkaline conditions in situ in the same pot to obtain mixture of R and S isomers 3-(carbamoylmethyl)-5- methylhexanoic acid.

According to the invention the intermediate anhydride compound of formula (VIII) is prepared by a. reacting diethylmalonate dimethylmalonate with isovaraldehyde in using catalytic amounts bases to obtain α, β - unsaturated compound of formula (XVI),

b. subjecting α, β - unsaturated compound of formula (XVI) to Micheal addition with diethylmalonate or dimethylmalonate to obtain 2-carbethoxy-3-(dicarbethxomethyl)-5-methylhexanoic acid of formula (XV),

c. treating 2-carbethoxy-3-(dicarbethxomethyl)-5-methylhexanoic acid of formula (XV) with aqueous hydrobromic acid or hydrochloric acid to obtain 3-isobutylglutaric acid of formula (XIV), and

d. treating the 3-isobutylglutaric acid of formula (XIV) with acetyl chloride or acetic anhydride to obtain the 3-isobutylglutaric anhydride of formula (VIII).

The invention also provides a process for preparing (S)-3-(aminomethyl)- 5-methylhexanoic acid from enantiomerically pure (S)-3- (carbamoylmethyl)-5-methylhexanoic acid of formula (I) under Hofmann rearrangement conditions wherein potassium hydroxide and potassium hypobromide were used to effect the rearrangement and acetic acid was used to hydrolyze the rearranged intermediate facilitating the precipitation of the desired compound from the reaction mixture.. In a further embodiment, the rearrangement was effected at temperature range 30 °C- 90 °C.

According to an embodiment of the invention, there is provided a process for preparing R-(-)- 3-(carbamoylmethyl)-5-methylhexanoic acid of formula (I):

I

wherein the said process comprises resolution of racemic mixture of compound of formula (II) with an aromatic amine of structure (III) or (IV). In a particular embodiment which may be mentioned, the aromatic amine 5 of structure (III) or (IV) used in resolution of the compound (II) was obtained by resolving its racemic mixture with tartaric acid. The advantage of using the amine of formula (III) or (IV) in the resolution of racemic compound of formula (II) is that the desired diastereomeric salt could easily be induced to precipitate from the reaction mixture. This facilitates Θ— theHsolation-oHhe-amidensf ^{^} ^^ purity. The process could be adopted on an industrial scale. In one embodiment, said resolution of the racemic amide was conducted in a dual solvent system, particularly, chloroform-ethanol at 60-65 °C. 5 According to another embodiment of the invention, there is provided a process for preparing ?-(-)- 3-(carbamoylmethyl)-5-methylhexanoic acid of formula (I):

I

wherein the said process comprises optical resolution of the racemic mixture of compound of formula (II) with a base selected from the cinchona class of alkaloids, particularly, quinine of formula (V).

In one embodiment, said resolution may be conducted in water containing a water miscible organic solvent at 80 °C - 90 °C. In one particular embodiment, said resolution was performed at 80 °C -90 °C using aqueous acetone as the solvent system. In another particular embodiment, aqueous methanol was used as the solvent system in conducting the resolution. The significant advantage of performing the resolution using quinine lies in the easy isolation of the product and the resolving base from the reaction mixture.

According to another embodiment of the invention, there is provided a process for preparing a mixture of R and S isomers of 3- (carbamoylmethyl)-5-methylhexanoic acid of formulae (I) and (la):

wherein the process comprises of alkaline hydrolysis of a mixture of formula (VI) and (Via).

In a further embodiment of the process, there is provided a process for preparing the said mixture of formulae (VI) and (Via), wherein the process comprises of converting the corresponding acid functional groups of a mixtu

In a further embodiment of the process, there is provided a process for preparing the said nixture of formulae (VII) and (Vila), wherein the process comprises of reacting the anhydride compound (VIII) with an enantiomerically pure aromatic alcohol.

In a further embodiment of the process, the said chiral alcohol was selected from one of the enantiomers of 1-napthylethyl alcohol having the formula (IX), (IXa) (

The meso cyclic anhydride of formula (VIII) reacted with one of the enantiomers of 1-napthylethyl alcohols of formula (IX) or (X), preferable (IX), at - 78 °C under the catalysis of a base to furnish the acid compound of formula (VII). The base used in the reaction was selected from 1 ,1 ,3,3- tetramethylguanidine, imidazole, DMAP, DABCO or the quinine derivatives of formula (XVII) or (XVIII).

The reaction was conducted in a solvent system selected from ferf-butyl methyl ether or dichloromethane.

The acid functional group of compound of formula (VII) was converted into an amide functional group in the subsequent step to furnish a compound of formula (VI). In this step, a solution of the acid compound of formula (VII) in acetone reacted with a suitable base, ethyl chloroformate and aqueous ammonia at a temperature range of 0 °C to - 30 °C to furnish the amide compound of formula (VI). The base was selected from triethylamine, pyridine, Htinig's base, preferably, triethylamine.

The hydrolysis of the amide compound of formula (VI) was performed using an aqueous solution of a suitable hydroxide selected from sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably, sodium hydroxide. For operational simplicity, the last two steps, namely the conversion of acid functional group to an amide group and the hydrolysis, were conducted in one step in the same pot without any loss of yield of the mixture constituting R and S isomers of 3-(carbamoylmethyl)-5- methylhexanoic acid of formulae (I) and (la):

According to another embodiment of the invention, the mixture constituting R and S isomers of 3-(carbamoylmethyl)-5-methylhexanoic acid of formulae (I) and (la) was resolved with cinchona class of alkaloids or amines of formula (Hi) or (IV) to form R-(-) 3-(carbamoylmethyl)-5- methylhexanoic acid of formulae (I).

According to another embodiment of the invention, there is provided a process for preparing racemic (±)-3-(carbamoylmethyl)-5-methylhexanoic acid of formula (II) wherein the process comprises of reacting the meso- anhydride of formula (VIII) with aqueous ammonia.

According to another embodiment of the invention, there is provided a process for preparing racemic (±)-3-(carbamoylmethyl)-5-methylhexanoic acid of formula (II) wherein the process comprises of alkaline hydrolysis of a compound of formula I).

In a further embodiment of the process, there is provided a process for preparing the said compound of formula (XI), wherein the process comprises of converting the acid functional group of compound of formula (XII) to an amide grou .

In a further embodiment of the process, there is provided a process for preparing the said compound of formula (XII), wherein the process comprises of reacting the anhydride compound (VIII) with a racemic aromatic alcohol, preferably, (±)-1-(1-napthyl)ethanol (XIII).

xiii

The meso cyclic anhydride of formula (IV) reacted with racemic (±) 1- napthylethyl alcohol of formula (XIII) at a temperature range of 0 °C to - 78 °C under the catalysis of a base to furnish the acid compound of formula (XII). The base used in the reaction was selected from 1 ,1 ,3,3- tetramethylguanidine, imidazole, DMAP, DABCO. The reaction was conducted in a solvent system selected from tert- butyl methyl ether or dichloromethane.

.

^he acid-funetionahgroup-of-eompound-of^orm

an amide functional group in the subsequent step to furnish a compound of formula (XI). In this step, a solution of the acid compound of formula (XII) in acetone reacted with a suitable base, ethyl chloroformate and aqueous ammonia at a temperature range of 0 °C to - 30 °C to furnish the amide compound of formula (XI). The base was selected from triethylamine, pyridine, Hunig's base, preferably, triethylamine.

The hydrolysis of the amide compound of formula (XI) was performed using an aqueous solution of a suitable hydroxide selected from sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably, sodium hydroxide. For operational simplicity, the last two steps, namely the conversion of the acid functional group to an amide group and the hydrolysis, were conducted in one step in the same pot without any loss of yield of the racemic compound of formula (II).

According to another aspect of the innovation, there is provided a process for preparing a compound of formula (XIV) wherein the process comprises hydrolysis C0 ₂ H C0 ₂ H

XIV

a tetraester compound of formula (XV) under acidic conditions.

XV

The tetraester compound represented by structure (XV) was treated with aqueou¥ ^{^} h7 robromic ^ — 90 °C to 120 °C to furnish the diacid compound of structure (XIV). The use of aqueous hydrobromic acid was preferable because its use in the hydrolysis gave a higher yield of the diacid compound (XIV).

According to another embodiment of the invention, there is provided a process for preparing the said tetraester compound of formula (XV) wherein the process comprises Michael addition of diethylmalonate or dimethylmalonate with a a, β-unsaturated compound of structure (XVI).

The process involved reacting diethylmalonate or dimethylmalonate with a a, β-unsaturated compound represented by structure (XVI) at 60 - 70 °C in the presence of a secondary, aliphatic amine. The secondary amines were selected from the class represented by formula

(CH ₃ CH ₂ CHn^NH where n= 1 , 2, 3 or 4. The use of a secondary amine such as di-n-propylamine or di-n-butylamine or di-n-pentylamine or di-n-hexylamine in the process led to higher yield of the tetraester di-n-hexylamine in the process led to higher yield of the tetraester compound (XV). The other advantage of using such an amine is that the amine could be recovered from the reaction mixture easily for reuse in subsequent batches.

Example: 1

2-Carbethoxy-5-methylhex-2-enoic Acid, Ethyl ester XVI

Diethylmalonate (69.7 g, 435,3 mmo!e) was added to isovaraldehyde (50 g, 580.5 mmole) at room temperature under an atmosphere of nitrogen. Pyridine (5 ml), Piperidine (1.5 ml) and acetic acid (2.5 ml) were added in succession to the reaction mixture at this temperature under an atmosphere of nitrogen. n-Hexane (100 ml) was then added and the reaction mixture was heated to reflux removing water azeotropically from the reaction mixture.

After two days at reflux, the reaction mixture was allowed to cool down to room temperature, diluted with n-hexane (100 ml) and washed with 10% aqueous hydrochloric acid (4 χ 100 ml). The organic layer was then washed with water (3 100 ml), brine (1 χ 100 ml), dried over sodium sulfate and concentrated to obtain the diester compound XVI; yield: 105 g, 80%.

The compound was carried over to the next stage without further purification.

Example: 2a

2-Carbethoxy-3-(dicarbethoxomethyl)-5-methylhexanoic Acid, Ethyl ester XV

XV

Diethylmalonate (175.6 g, 1 .096 mole) was added to the α, β - unsaturated diester compound XVI (250 g, 1.096 mole) at room temperature. The reaction mixture was cooled to 15 °C and di-n- propylamine (1 10.9 g, ^' 1 .096 mole) was added dropwise to it at this temperature. After completion of the addition, the reaction mixture was heated to 55 °C and maintained at this temperature overnight (approximately 16 h).

After completion of the reaction as indicated from TLC, the reaction mixture was poured onto crushed ice and extracted with n-hexane (4 ^χ 100 ml). The organic layer was washed with aqueous hydrochloric acid (3 ^χ 100 ml), water (3 ^χ 100 ml), brine (1 ^χ 100 ml), dried over sodium sulfate and concentrated to obtain the tetra ester compound XV; yield: 380 g. The crude material was carried over to the following step without further purification.

Example: 2b

2-Carbethoxy-3-(dicarbethoxomethyl)-5-methylhexanoic Acid, Ethyl ester XV

XV

Di-n-propylamine (5 ml) was added to a mixture of isovaraldehyde (35 g, 405.8 mmole) and diethylmalonate (50 g, 312 mmole) at room temperature. Sodium sulfate (40 g) was added to it. The reaction mixture was heated to 70 °C and maintained at this temperature for 21-24 h when the reaction was complete as indicated from TLC. Another batch of diethylmalonate (30 g) and di-n-propylamine (10 ml) were added to the reaction mixture at 70 °C. The mixture was maintained at this temperature for further 48-60 h when the reaction was complete as indicated from TLC. The reaction mixture was washed with water (4 ^χ 30 ml), dilute hydrochloric acid (4 ^χ 30 ml), water (4 ^χ 30 ml) and brine (4 ^χ 30 ml) to furnish 110 g crude material which was carried to the following step.

Example: 2c

2-Carbethoxy-3-(dicarbethoxomethyl)-5-methylhexanoic Acid, Ethyl ester XV

XV

Di-n-buylamine (5 ml) was added to a mixture of isovaraldehyde (35 g, 405.8 mmole) and diethylmalonate (50 g, 312 mmole) at room temperature. Sodium sulfate (40 g) was added to it. The reaction mixture was heated to 70 °C and maintained at this temperature for 21-24 h when the reaction was complete as indicated from TLC. Another batch of diethylmalonate (30 g) and di-n-butylamine (10 ml) were added to the reaction mixture at 70 °C. The mixture was maintained at this temperature for further 48-60 h when the reaction was complete as indicated from TLC. The reaction mixture was washed with water (4 ^χ 30 ml), dilute hydrochloric acid (4 ^χ 30 ml), water (4 30 ml) and brine (4 ^χ 30 ml) to furnish 110 g crude material which was carried to the following step. Example: 3a

3-lsobutylglutaric Acid XIV

Aqueous hydrochloric acid (12.07 litre) was added to the tetraester compound XIV (2.414 kg, 6.22 mole) at room temperature. The reaction mixture was heated to 100 °C and maintained at this temperature until the reaction was complete as indicated by TLC.

The reaction mixture was allowed to cool down to room temperature and extracted with hot toluene (5 χ 1500 ml). The extracts were combined and evaporated under reduced pressure to give the diacid compound XIV; yield: 880 g, 74%.. The crude material was carried over to the following stage without further purification.

Example: 3b

3-lsobutylglutaric Acid XIV

XIV

Aqueous hydrobromic acid (140 ml) was added to the tetraester compound XV (100 g, 257.7 mmole) and the reaction mixture was heated to 100 °C. After 24 h at this temperature, another batch of aqueous hydrobromic acid (140 ml) was added to it and the reaction mixture was maintained at this temperature for further 24 h when another batch of aqueous hydrobromic acid (140 ml) was again added to the mixture. After the addition of the third batch of aqueous hydrochloric acid (140 ml), the reaction mixture was maintained 100 °C for further 24 h when the reaction completed as indicated from TLC.

After allowing the reaction mixture to cool down to room temperature, it was poured into cold water, extracted with toluene (5 χ 80 ml), dried over sodium sulfate and concentrated under reduced pressure to give the diacid compound XIV; yield: 40 g, 82%.

Example: 4

3-lsobutylglutaric Anhydride

VIII

Acetyl chloride (140 ml) was added to the diacid compound XIV (35 g, 185.95 mmole) at room temperature under an atmosphere of nitrogen and the reaction mixture was stirred 5 minutes at this temperature. The mixture was then heated to 55 °C and was maintained at this temperature for 3 h when reaction was complete as indicated from TLC.

After distilling out acetyl chloride completely from the reaction mixture, the crude reaction mixture was distilled under vacuum to give the anhydride VIII; yield: 31 .6 g; 85%. Example: 5

(±)-3-(Carbamoylmethyl)-5-methylhexanoic Acid II

II An aqueous solution of ammonia (1.486 litre) was added to a solution of the anhydride VIII (667 g, 3.919 mole) in ferf-butyl methyl ether (901 ml) at 0 °C. The reaction mixture was allowed to warm to room temperature, and stirred at this temperature until the reaction was complete as indicated by TLC.

The aqueous layer was washed with terf-butyl methyl ether (3 ^χ 300 ml). The aqueous layer was cooled to 0 oC, acidified with dilute hydrochloric acid until the pH attained 2 and extracted with hot ethyl acetate (5 ^χ 300 ml). The extracts were combined and concentrated to give the amide II as a white solid; yield: 590 g, 80.4%.

A solution of (±)-1-(1-napthyl)ethanol XIII (20.2 g, 117.29 mmole) in tert- butyl methyl ether (50 ml) was added to a solution of the anhydride VIII (20 g, 117.50 mmole) in terf-butyl methyl ether (50 ml) at - 78 °C under an atmosphere of nitrogen. DABCO (3.2 g, 28.53 mmole) was added to it and the reaction mixture was maintained at this temperature for 2 h when the reaction was complete as indicated from the TLC.

An aqueous solution of citric acid was added to the reaction mixture and it was allowed to warm up to room temperature. The organic layer was washed with an aqueous solution of citric acid (3 ^χ 50 ml), water (3 * 50 ml) and brine (3 ^χ 50 ml), dried over sodium sulfate and concentrated to give the ester XII; yield 40 g, quantitative. The crude product was carried on to the following step without further purification.

This reaction was explored using different bases such as imidazole, DMAP and 1 ,1,3,3- Tetramethylguanidine. The reaction was also explored using halogenated solvents such as dichloromethane in place of terf-butyl methyl ether.

Example: 5b

(1 ' S R, 3 S -(1 ' -Napthy l)ethyl 3-(carboxylomethy l)-5- methylhexanoate XII

1 ,1 ,3,3- Tetramethylguanidine (3.4 g, 29.52 mmole) was added to a solution of the anhydride VIII (20 g, 117.50 mmole) in terf-butyl methyl ether (30 ml) at

- 78 °C under an atmosphere of nitrogen. A solution of (±)-1-(1- napthyl)ethanol XIII (20 g, 116.13 mmole) in terf-butyl methyl ether (70 ml) was added to it and the reaction mixture was stirred at this temperature until the reaction was complete as indicated from the TLC.

An aqueous solution of citric acid was added to the reaction mixture and it was allowed to warm up to room temperature. The organic layer was washed with an aqueous solution of citric acid (3 χ 50 ml) and brine (3 χ 50 ml), dried over sodium sulfate and concentrated to give the ester XII; yield 40.5 g, quantitative. The crude product was carried on to the following step without further purification.

Example: 6

(±)-3-(Carbamoylmethyl)-5-methylhexanoic Acid II

II

Triethylamine (20 ml) was added to a solution of the acid XII (41 g, 119.73 mmole) in acetone (205 ^' ml) at - 20 °C under an atmosphere of nitrogen. A solution of ethyl chloroformate (12.4 ml) in acetone (164 ml) was then added and the reaction mixture was maintained for 0.5 h to 1 h at this temperature. A solution of aqueous ammonia (120 ml) was added to the reaction mixture at - 20 °C and the reaction mixture was stirred for 2 h at this temperature when the reaction was complete as indicated from TLC. The reaction mixture was allowed to warm to room temperature and concentrated to furnish an oily residue. The crude residue was cooled to 0 °C, and an aqueous solution of sodium hydroxide was added at this temperature. The reaction mixture was stirred until the reaction was complete as indicated from the TLC.

The reaction mixture was washed with terf-butyl methyl ether (3 ^χ 50 ml). The aqueous layer was acidified with concentrated hydrochloric acid until the pH attained 1 , and extracted with ethyl acetate (5 * 50 ml). The organic layer was concentrated under reduced pressure to give the amide II; yield 13 g, 58%.

Example: 7

f?-(-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid 1- Phenylpropylamine enantiomer Salt

Enantiomerically enriched 1-Phenylpropylamine (17:8 g, 131.65 mmole), which was obtained from its racemic mixture by resolving said mixture with D-(-) tartaric acid, was added to a slurry of the amide II (30 g, 160.22 mmole) in a solvent mixture of chloroform (514.8 g) and ethanol (5.64 g) at 60-63 °C. After 15 minutes at this temperature, another batch of 1- Phenylpropylamine enantiomer (5.8 g, 42.896 mmole) was added to the mixture. The reaction mixture was maintained at this temperature for 30 minutes and allowed to cool down to room temperature. The precipitated salt was filtered and dried to give the diasteroisomeric salt; 21.5 g; HPLC purity: 85.99%.

The salt was further processed as described in the following experiment (Example: 8). Example: 8

1-Phenylpropylamine enantiomer (1.5 g, 11.09 mmole) was added to a slurry of the diasteremeric salt (21 g) in a solvent mixture of chloroform (360 g) and ethanol (5 ml) at 60-63 °C. After 30 minutes at this temperature, the reaction mixture was allowed to cool down to room temperature. The precipitated salt was filtered to furnish enantiomerically enriched diastereomeric salt of the amide I as a white solid; yield: 16.8 g; HPLC purity: 96.25%.

In order to increase the optical purity of the amide, the diastereoisomeric salt was crystallized in a manner described in the following examples (Example: 9a or 9b).

Example: 9a

A mixture of solvents of chloroform (286.5 g) and ethanol (3.1 g) was added to the diastereoisomeric salt (16.7 g) at room temperature and the reaction mixture was heated until it became homogenous. The reaction mixture was allowed to cool down to room temperature. The precipitated salt was filtered to furnish enantiomerically enriched diastereomeric salt of the amide I as a white solid; yield: 14.7 g; HPLC purity: 99.35%. Example: 9b

A mixture of solvents of methyl ferf-butylether and ethanol (14 ml) was added to the diastereoisomeric salt (1.2 g) at room temperature and the reaction mixture was heated until it became homogeneous. The reaction mixture was allowed to cool down to room temperature. The precipitated solid was filtered, washed with terf-butyl methyl ether and dried to furnish enantiomerically enriched diastereomeric salt of the amide I as a white solid; yield: 0.8 g; HPLC purity: 99.64%.

The enantiomerically enriched diastereomeric salt was broken down in a manner described in the following experiment (Experiment: 10) to give the desired enantiomerically pure amide as a solid. Example: 10

f?.(-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid

Aqueous ammonia (1 16 ml) was added to the diastereomeric salt (14.5 g) at room temperature and the mixture was heated to 80 °C . After 5 h at this temperature, the reaction mixture was allowed to cool down to room temperature and was extracted with dichloromethane (5 ^χ 50 ml). The aqueous layer was cooled to 0 °C, acidified with concentrated hydrochloric acid to pH 1 and extracted with hot ethyl acetate (5 ^χ 50 ml). The extracts were combined and concentrated under reduced pressure to give the enantiomerically enriched amide I as a white solid; yield: 8 g, 53%; HPLC purity: 99.39%.

Example: 11a

-(-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid Quinine Salt Aqueous acetone (795ml) was added to the amide II (53 g, 283.42 mmole) at room temperature and the reaction mixture was heated until it became homogenous. Quinine (91 .8 g, 283.42 mmole) was added to the mixture at 80 °C. After 15 minutes at this temperature, another batch of quinine (5.3 g, 28.34 mmole) was added to the reaction mixture and heating was continued until the mixture became homogenous. The reaction mixture was allowed to cool down to room temperature. The precipitated solid was filtered, dried and purified to furnish the diastereoisomeric salt of the amide I as a solid which was broken down to obtain enantiomerically enriched amide I; yield: 18 g; 67.9%; HPLC purity: 99.97%.

The salt was broken down following any of the procedures described in Example: 12a or 12b or 12c below to furnish enantiomerically pure amide I.

Example: 11 b

R-(-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid Quinine Salt A slurry of the amide II (5 g, 26.70 mmole) in aqueous methanol (75 ml) was heated until it became homogenous. Quinine (8.6 g, 26.73 mmole) was added to the reaction mixture and the heating was continued until a homogenous solution obtained. After 10 minutes of the solution becoming homogenous, another batch of quinine (0.86 g; 2,67. mmole) was added and the reaction mixture was heated until it became homogenous. The reaction mixture was then allowed to cool down to room temperature. The precipitated solid was filtered, washed with cold water and dried to give the diasteromeric salt of the amide I as a solid which was was broken down to obtain enantiomerically enriched amide I; yield: 1 .2 g; 48%; HPLC purity: 99.47%.

The salt was broken down following any of the procedures described in Example: 12a or 12b or 12c below to furnish enantiomerically pure amide I. Example: 12a

/?-(-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid

Aqueous ammonia (960 ml) was added to the diastereomeric salt of compound I (125 g) and the reaction mixture was heated to 80 °C. After 5 h at this temperature, the reaction mixture was allowed to cool down to room temperature and was extracted with dichloromethane (5 * 150 ml). The aqueous layer was cooled to 0 °C, acidified with concentrated hydrochloric acid to pH 1 and extracted with ethyl acetate (5 χ 100 ml). The extracts were combined and concentrated under reduced pressure to give the enantiomerically enriched amide I as a white solid; yield: 27.4 g.

Example: 12b

?-(-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid

An aqueous solution of sodium carbonate (9 g) was added to the diastereomeric salt (8 g) of compound I at room temperature. The reaction mixture was stirred overnight at this temperature and filtered. The filtrate was cooled with ice-water, acidified with dilute hydrochloric acid until the pH attained 1 and extracted with hot ethyl acetate (7 χ 20 ml). The extracts were combined and concentrated under reduced pressure to give the enantiomerically enriched amide I as a solid; yield: 1.6 g,

Example: 12c

f?-(-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid

An aqueous solution of sodium hydroxide (3.85 g) was added to the diastereomeric salt (9 g) of compound I at 0 °C. The reaction mixture was allowed to warm to room temperature, stirred at this temperature for 3 h and filtered. The filtrate was cooled with ice-water, acidified with dilute hydrochloric acid until the pH attained 1 and extracted with hot ethyl acetate (7 χ 20 ml). The extracts were combined and concentrated under reduced pressure to give the enantiomerically enriched amide I as a solid; yield: 1.2 g.. Example: 13a

(17?, 3S )-1-(1' -Napthyl)ethyl 3-(carboxylomethyl)-5- methylhexanoate VII and (1 'R, ZR )-1 -(1 ' -Napthyl)ethyl 3- (carboxylomethyl)-5- methylhexanoate Vila

Imidazole (0.02 g, 0.29 mmole) was added to a solution of the enantiomeric ( ?)- (+)-a-methyl-1 -napthalenemethanol IX (0.25 g, 1 .45 mmole) in terf-butyl methyl ether (2 ml) at - 78 °C under an atmosphere of nitrogen. A solution of the anhydride VIII (0.25 g, 1 .47 mmole) in terf-butyl methyl ether (1 ml) was added to it and the reaction mixture was stirred at this temperature until the reaction was complete as indicated from the TLC.

An aqueous solution of citric acid was added to the reaction mixture and it was allowed to warm up to room temperature. The organic layer was washed with an aqueous solution of citric acid (2 x 2 ml), water (3 x 2 ml) and brine (3 x 3 ml), dried over sodium sulfate and concentrated to furnish a diastereomeric mixture of esters VII and Vila; yield: 0.5 g, quantitative.

Example 13b:

(1 ?, 3S )-1 -(1 ' -Napthyl)ethyl 3-(carboxylomethyl)-5- methylhexanoate VII and (1 ?, ZR )-1 -(1 ' -Napthyl)ethyl 3- (carboxylomethyl)-5- methylhexanoate VII

A solution of the enantiomeric (R)- (+)-a-methyl-1 -napthalenemethanol IX (0.25 g, 1 .45 mmole) in terf-butyl methyl ether (2 ml) was added to the anhydride VIII (0.25 g, 1.47 mmole) at - 78 °C under an atmosphere of nitrogen. A solution of quinine benzoate XVII (0.6 g) in dichloromethane (0.5 ml) was added to it and the reaction mixture was stirred at this temperature until the reaction was complete as indicated from the TLC. An aqueous solution of citric acid was added to the reaction mixture and it was allowed to warm up to room temperature. The organic layer was washed with an aqueous solution of citric acid (3 2 ml), water (3 χ 2 ml) and brine (3 x 3 ml), dried over sodium sulfate and concentrated to furnish a diastereomeric mixture of esters VII and Vila; yield: 0.45 g, 80%.

Example: 14

f?-(-)-3-(carbamoylmethyl)-5-methylhexanoic Acid I

Triethylamine (0.38 g) was added to a solution of the acid XII (0.8 g, 2.0 mmole) in acetone (4 ml) at - 20 °C under an atmosphere of nitrogen. A solution of ethyl chloroformate (0.23 ml) in acetone (3.2 ml) was then added and the reaction mixture was maintained for 0.5 at this temperature. A solution of aqueous ammonia (2.4 ml) was added to the reaction mixture at - 20 °C and the reaction mixture was stirred for 2 h at this temperature when the reaction was complete as indicated from TLC.

The reaction mixture was allowed to warm to room temperature and concentrated to furnish an oily residue. The crude residue was cooled to 0 °C and an aqueous solution of sodium hydroxide was added at this temperature. The reaction mixture was stirred until the reaction was complete as indicated from the TLC.

The reaction mixture was washed with methyl terf-btutanol (3 5 ml). The aqueous layer was acidified with concentrated hydrochloric acid until the pH attained 1 , and extracted with ethyl acetate (5 χ 10 ml). The organic layer was concentrated under reduced pressure to give the amide I and la as a mixture of enantiomers; yield: 86 mg. The mixture was resolved in the manner described in experiments 7-1 0 1 1 -12 to obtain f?-(-)-3-(carbamoylmethyl)-5-methylhexanoic Acid I.

Example: 15a

(2'S, 3S )-1-(2' -Napthyl)ethyl 3-(carboxylomethyl)-5- methylhexanoate XIX and (2'S, 3R )-1-(2' -Napthyl)ethyl 3- (carboxylomethyl)-5-methylhexanoate XlXa

1 , 1 ,3,3- Tetramethylguanidine (0.084 g, 0.71 3 mmole) was added to a solution of (S)- (-)-methyl-2-napthalenemethanol Xa (0.5 g, 2.94 mmole) in terf-butyl methyl ether (5 ml) at - 78 °C under an atmosphere of nitrogen. A solution of the anhydride VIII (0.5 g, 2.94 mmole) in ferf-butyl methyl ether (2 ml) was added to it and the reaction mixture was stirred at this temperature until the reaction was complete as indicated from the TLC. An aqueous solution of citric acid was added to the reaction mixture and it was allowed to warm up to room temperature. The organic layer was washed with an aqueous solution of citric acid (3 x 2 ml), water (3 x 2 ml) and brine (3 χ 3 ml), dried over sodium sulfate and concentrated to furnish a diastereomeric mixture of esters XIX and XlXa; yield: 0.7 g, quantitative.

Example: 16

/?-(-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid I

Triethylamine (0.24 g) was added to a solution of the acid XII (0.7 g, 2.0 mmole) in. acetone (4 ml) at - 20 °C under an atmosphere of nitrogen. A solution of ethyl chloroformate (0.2 ml) in acetone (3 ml) was then added and the reaction mixture was maintained for 0:5 h to 1 h at this temperature. A solution of aqueous ammonia (2.1 ml) was added to the reaction mixture at - 20 °C and the reaction mixture was stirred for 2 h at this temperature when the reaction was complete as indicated from TLC.

The reaction mixture was allowed to warm to room temperature and concentrated to furnish an oily residue. The crude residue was cooled to 0 °C and an aqueous solution of sodium hydroxide was added at this temperature. The reaction mixture was stirred until the reaction was complete as indicated from the TLC.

The reaction mixture was washed with methyl te/f-btutanol (3 x 5 ml). The aqueous layer was acidified with concentrated hydrochloric acid until the pH attained 1 , and extracted with ethyl acetate (5 χ 10 ml). The organic layer was concentrated under reduced pressure to give the amide I and la as a mixture of enantiomers;; yield 0.2g.

The mixture was resolved in the manner described in experiments 7-10 or 11-12 to obtain R-(-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid I.

Example: 15b

(2'S, 3S )-1-(2' -Napthyl)eth l 3-(carboxylomethyl)-5- methylhexanoate XIX and (2'S, 3f? )-1-(2' -Napthyl)ethyl 3- (carboxylomethyl)-5- methylhexanoate XlXa

XIX XlXa Quinine benzoate XVII (0.3 g, 0.735 mmole) was added to a solution of (S)- (-)-a-methyl-2-napthalenemethanol Xa (0.5 g, 2.94 mmole) in dichloromethane (2.5 ml) at - 78 °C under an atmosphere of nitrogen. A solution of the anhydride VIII (0.5 g, 2.94 mmole) in dichloromethane (2 ml) was added to it and the reaction mixture was stirred at this temperature until the reaction was complete as indicated from the TLC.

An aqueous solution of citric acid was added to the reaction mixture and it was allowed to warm up to room temperature. The organic layer was washed with an aqueous solution of citric acid (3 x 2 ml), water (3 ^x 2 ml) and brine (3 * 3 ml), dried over sodium sulfate and concentrated to furnish a diastereomeric mixture of esters XIX and XlXa; yield: 0.7 g, quantitative.

Example : 17

(S)-3-(aminomethyl)-5-methylhexanoic acid

An aqueous solution of potassium hydroxide (50% W/V; 3.2 ml) was added to a cold solution of the amide I (5 g, 26.7 mmole) in water (4.6 ml) at 0 °C. After 30 minutes at this temperature, a cold solution of potassium hypobromide, prepared- by adding bromine (1.1 ml) to a cold aqueous solution of potassium hydroxide (7 g) in water (15 ml) at 0 °C, was added to the reaction mixture at 0 °C. After 10 minutes at this temperature, the reaction mixture was slowly heated to 80 °C. After 1 h 80 °C, acetic acid (5 ml) was added to the reaction mixture at this temperature and the mixture was heated to 90 °C.

After 30 minutes at 90 °C, the reaction mixture was allowed to cool down to room temperature and then was cooled at 0 °C for 1 h. The precipitated white solid was filtered, washed with cold water (20 ml) and filtered to give the racemic amino acid; 2.8 g, 66.6%.