FIELD OF THE INVENTION

The present invention relates to a simple and cost effective process for chiral resolution of racemic isovaline into their enantiomers with high enatiomeric excess using respective chiral resolving agent.

BACKGROUND OF THE INVENTION

Over the last two decades there is a great interest in the development of new synthetic methods for unnatural amino acids due to wide range of biological importance. In particular the a, a-disubstituted amino acids, members of modified amino acids have been the subject of considerable research interest in the last few years. Replacement of an a-hydrogen from the a-amino acids by an alkyl group affords a, a-disubstituted amino acids. 2-Amino-2-methylbutyric acid (Isovaline) is one of a, a-di substituted amino acids, an isomer of biologically important amino acid valine. Isovaline (Iva), a non proteogenic alpha-amino acid rarely found in Murchison meteorite as a racemic mixture in the biosphere, is structurally similar to the inhibitory neurotransmitters glycine and gamma-aminobutyric acid. Isovaline is used as anti-analgesic agent [Ernest Puil et. al. US 2010/0137438] without producing acute toxicity [MacLeod, B. A. et. al., Anesth. Analg. (2010) v. 1:110, p. 1206-1214]. Isovaline can act as enzyme inhibitors [L. H. Goodson et. al, J. Org. Chem. (1960) v. 25, p. 1920-1924]. D-Isovaline plays an important role in small peptides, peptaibols, microbial peptide antibiotics [G. Jung et. al., Berlin (1981), p.75-114], etc. For example Zervamicin IIB, a 16 membered peptide antibiotic contains D -Isovaline [W. H. Rimawi et. al., Russ. J. Bioorg. Chem.(2000) v.26, p.725-733]. In these peptides a, a-disubstituted amino acids play a crucial role to form trans-membrane helical ion channels. It is reported that methyl group at the a-position of a, a-disubstituted amino acids tend to induce 310 or a-helical conformations while incorporated into these peptides [K. H. Altmann et. al., Helv. Chim. Acta (1992) v.75, p.l 198-1210]. Isovaline is the precursor of potent immuno suppressant FR235222 [Weiqing Xie et. al., Org. Lett. (2005) v. 7, p. 2775-2777].
Due to wide range of biological and synthetic importance, various methods have been developed based on two strategies. One is asymmetric synthesis and the other one is resolution of the racemates. The following methods were reported using chiral auxiliary.

(i) Diasteroselcective alkylation of (lS,2R,4R)-10-dicyclohexylsulfamoylisobornyl-
2-cyanoester followed by hydrolysis and Curtius rearrangement [Carlos Cativiela et.
al., Tetrahedron:Asymm.(1993) v. 4, p. 1445-1448].

(ii) Double alkylation of (S)-(-)-t-butyl 2-tert-butyl-l,3-imidazolidin-4-one-l-
carboxylate [(S)-(-)-Boc-BMI] followed by hydrolysis [K. Nobel et. al., Tetrahedron
(1988) v. 44, p. 4793-4796].

(iii)Zrc situ double alkylation of (S)-t-butyl 2-tert-butyl-4-methoxy-2,5-
dihydroimidazole-1-carboxylate followed by hydrolysis [D. Seebach et. al., Eur. J. Org. Chem. (1998), p. 1337-1351].

(iv)Sulfinimine mediated asymmetric Strecker synthesis followed by hydrolysis [F.A.Davis et. al., J. Org. Chem. (2000) v. 65, p. 8704-8708].

(v) Alkylation of chiral oxazinone using organic bases such as BEMP or DBU [R.
Chinchilla et. al., TetrahedromAsymm. (1998) v. 9, p. 2769-2772].

(vi)Alkylation of chiral pyrazinone followed by degradation process [C. Najera et. al, Eur. J. Org. Chem. (2000) p. 2809-2820].

The following methods were reported via resolution of either appropriate hydantoin or suitably protected Isovaline using a resolving agent

(i) Resolution of 5-methyl-5-vinylhydantoin using brucine, hydrogenation followed by hydrolysis [H. Sobotka et. al., J. Am. Chem. Soc. (1932) v. 54, p. 4697-4702]

(ii)Resolution of 5-methyl-5-vinylhydantoin using L-menthyl ester, hydrogenation followed by hydrolysis [S. Terashima et. al., Chem. Pharm. Bull. (1965) v. 13, p. 1399-1407].

(iii) Resolution of 5-methyl-5-vinylhydantoin using sodium L-menthoxide, hydrogenation followed by hydrolysis, [N. Takamura et. al., Chem. Pharm. Bull.
(1967) v. 15, p. 1776-1784].

(iv) Resolution of N-Formyl-DL-Isovaline using brucine [S. Akabori et. al, Nippon Kagaku Zasshi (1952) v. 73, p. 112-115].

The asymmetric synthetic approach has some draw backs like multistep syntheis and use of expensive and commerically not easily accessible chiral auxiliaries. The alkylation reation involves moisture sensitive reactions, using phyrophoric reagents and cubersome isolation procedures. During the reaction, there is also a possiblity for the racemization and the stereochemical out come depends on some of the parameters like the reaction condition, solvent, reagent, and chiral auxiliary. Many times this approach is not suitable for large scale manufacturing for the above reasons. The resolution strategy is widely used today in the separation of racemic mixtures although the theoretical yield is only 50% as there is possiblity to convert the undesired isomer to the desired one via repeated racemization. Though, few resolution methods found in the literature for the synthesis of chiral isovaline, most of them reported to involve multi step synthesis including protection - deprotection strategies of the amino acid derivative. For example, chiral isovaline was made via the resolution of 5-methyl-5-vinylhydantoin using L-menthyl ester or sodium-L-menthoxide or brucine followed by hydrogenation and hydrolysis. Other method uses the resolution of protected isovaline namely, N-Formyl-DL-Isovaline using brucine. Also, no direct method reported so far for the resolution of racemic Isovaline. To overcome the limitations of the above methods, the inventors of the present invention developed a commercially feasible method for the preparation of both enantiomers of isovaline by direct resolution of racemic isovaline using an appropriate resolving agent in a reasonably good yield with high stereo selectivity (>98% ee).

SUMMARY OF THE INVENTION

Accordingly, the present invention a provides a process for the preparation of an optically pure or optically enriched enantiomers of a isovaline of formula (I) and (II) by resolution of mixture of enantiomers of isovaline in the organic solvent using a chiral resolving agent.

In another embodiment, the present invention provides a process for the preparation of an optically pure or optically enriched enantiomer of isovaline of formula (I)
said process comprising the steps of:

a) treating the mixture of enantiomers of isovaline (III) in an organic solvent, with a chiral
resolving agent to yield diastereomeric salt of isovaline;

b) separating the diastereomeric salt of D-isovaline and enriching its chiral purity by crystallization in an organic solvent;

c) treating the optically pure or optically enriched diastereomeric salt of D-isovaline with an acid followed by neutralization with a base to give a mixture of D-isovaline and an inorganic salt.

d) The D-Isovaline is finally freed from the inorganic salt by dissolving the D-isovaline selectively in a suitable organic organic solvent to give an optically pure or optically enriched D-isovaline having enantiomeric excess of greater than 98%

In another embodiment, the present invention also provides a process for preparation of an optically pure or optically enriched enantiomer of isovaline of formula (II) from the filtrate obtained during the separation of diastereomeric salt of D-isovaline, said process comprising the steps of:

a) isolating the mixture of enatiomers of isovaline in the ratio of ~ 7:3 of L and D-isovaline respectively from the filtrate obtained during the separation of diastereomeric salt of D-isovaline via acid followed by base treatment;

b) treating the above 7:3 mixture of L and D-isovaline in an organic solvent, with a chiral resolving agent to yield diastereomeric salt of L-isovaline,

c) separating the diastereomeric salt of L-isovaline and enriching its chiral purity by crystallization in an organic solvent;

d) treating the optically pure or optically enriched diastereomeric salt of L-isovaline with an acid followed by neutralization with a base to give a mixture of L-isovaline and an inorganic salt and

e) the L-Isovaline is finally freed from the inorganic salt by dissolving the L-isovaline selectively in a suitable organic organic solvent to give an optically pure or optically enriched L-isovaline having enantiomeric excess of greater than 98%

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the present invention provides a process for preparation of an optically pure or optically enriched enantiomer of isovaline of formula (I),
said process comprising the steps of:

a) treating the mixture of enantiomers of isovaline in an organic solvent, with a chiral resolving agent to yield diastereomeric salt of isovaline;

b) separating the diastereomeric salt of D-isovaline and enriching its chiral purity by crystallization in organic solvent;

c) converting the optically pure or optically enriched diastereomeric salt of D-isovaline to an optically pure or optically enriched D-isovaline having enantiomeric excess of greater than 98%.

In an embodiment, the present invention provides a process present invention also provides a process for preparation of an optically pure or optically enriched enantiomer of isovaline of formula (II)
from filtrate obtain during the separation of diastereomeric salt of D-isovaline, said process comprising the steps of:

a) isolating the mixture of enatiomers of isovaline in the ratio of ~ 7:3 of L and D-isovaline respectively from the filtrate obtained during the separation of diastereomeric salt of D-isovaline via acid followed by base treatment;

b) treating the above 7:3 mixture of L and D-isovaline in the organic solvent, with a chiral resolving agent to yield diastereomeric salt of L-isovaline,

c) separating the diastereomeric salt of L-isovaline and enriching its chiral purity by crystallization in organic solvent;

d) converting the optically enriched diastereomeric salt of L-isovaline to an optically pure or optically enriched L-isovaline having enantiomeric excess of greater than 98%.

In an embodiment, the present invention provides a process for preparation of an optically pure or optically enriched enantiomers of a isovaline of formula (I), said process comprising the steps of:

a) treating the mixture of enantiomers of isovaline (III) in an organic solvent, with a chiral resolving agent to yield diastereomeric salts of isovaline (la) and (Ha);

b) separating the diastereomeric salt of D-isovaline (la) and enriching its chiral purity by successive crystallations in an organic solvent

c) treating the optically pure or optically enriched diastereomeric salt of D-isovaline (la) with an acid followed by neutralization with a base to give a mixture of D-isovaline (I) and an inorganic salt and

d) the D-Isovaline (I) is finally freed from the inorganic salt by dissolving the D-isovaline selectively in a suitable organic organic solvent to give an optically pure or optically enriched D-isovaline having enantiomeric excess of greater than 98%

Scheme -1
In an embodiment, x is selected from chiral a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid such as 2,3-di-O-p-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid, and the like.

The chiral resolving agent according to the invention is selected from a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid such as 2,3-di-O-p-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid, and the like.

In an embodiment, the present invention also provides a process for the preparation of an optically pure or optically enriched enantiomer of isovaline of formula (II) from the filtrate obtained during the seperation of diastereomeric salt of D-isovaline, said process comprising the steps of:

a) Isolating the mixture of enatiomers of isovaline in the ratio of ~ 7:3 of L and D-isovaline respectively from the filtrate obtained during the separation of diastereomeric salt of D-isovaline via acid followed by base treatment;

b) treating the above 7:3 mixture of L and D-isovaline in the organic solvent, with an appropriate chiral resolving agent to yield diastereomeric salt of isovaline

c) separating the diastereomeric salt of L-isovaline (lib) and enriching its chiral purity by successive crystallations in organic solvent;

d) treating the optically pure or optically enriched diastereomeric salt of L-isovaline (lib) with an acid followed by neutralization with a base to give a mixture of L-isovaline (II) and an inorganic salt and

e) the L-Isovaline (II) is finally freed from the inorganic salt by dissolving the L-isovaline selectively in a suitable organic organic solvent to give an optically pure or optically enriched L-isovaline (II) having enantiomeric excess of greater than 98% The reaction is shown in the scheme- 2 given below :

Scheme -2
In an embodiment, y is selected from chiral a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid such as 2,3-di-0-/?-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid, and the like.

The chiral resolving agents according to the invention are selected from a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid such as 2,3-di-O-p-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid, and the like.

In another embodiment, the resolution is carried out in the presence of solvent selected from methanol, ethanol, propanol, butanol, water, THF, acetone, ethyl acetate, dichloromethane, DMF, DMSO, and the like or mixture thereof. The reaction is carried out at a temperature in the range from room temperature to reflux temperature.

In another embodiment, the enrichment of the chiral purity is carried out in the presence of solvent selected from methanol, ethanol, propanol, butanol, water, THF, acetone, ethyl acetate, dichloromethane, DMF, DMSO, and the like or mixture thereof. The reaction is carried out at a temperature in the range from room temperature to reflux temperature.

In another emobidment, the acid used for converting diastereomeric salt of D-isovaline is selected from sulphuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid and the like and base used for neutralization is selected from sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, sodium bicarbonate, potassium bicarbonate and the like.

In a preferred embodiment, the present invention provides a process for the preparation of an optically pure or optically enriched enantiomer of isovaline of formula (I), said process comprising the steps of:
a) dissolving (DL)-isovaline in the organic solvent and treating with a chiral resolving agent selected from a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid such as 2,3-di-0-/?-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid, and the like more preferably 2,3-di-O-p-toluoyl-D-tartaric acid (D-DPTTA) to yield diastereomeric salts of D and L isovaline; b) separating the diastereomeric salt of D-isovaline followed by enriching its chiral purity by crystallization in an organic solvent selected from methanol, ethanol, propanol, butanol, water, THF, acetone, ethyl acetate, dichloromethane, DMF, DMSO, and the like more preferably methanol, (c) treating the optically pure or optically enriched diastereomeric salt of D-isovaline with an acid selected from sulphuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid and the like more preferably sulfuric acid followed by neutralization with base selected from sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, sodium bicarbonate, potassium bicarbonate and the like to obtain a mixture of D-isovaline and an inorganic salt and d) the D-Isovaline is finally freed from the inorganic salt by dissolving the D-isovaline selectively in a suitable organic organic solvent to give an optically pure or optically enriched D-isovaline having enantiomeric excess of greater than 98%

In an another preferred embodiment, the present invention also provides a process for the preparation of an optically pure or optically enriched L-isovaline of formula (II) from the filtrate obtained during the separation of diastereomeric salt of D-isovaline, said process comprising the steps of:

a) Isolating the mixture of enatiomers of isovaline in the ratio of ~ 7:3 of L and D-isovaline respectively from the filtrate obtained during the separation of diastereomeric salt of D-isovaline via acid followed by base treatment;

b) treating the above 7:3 mixture of L and D-isovaline in the organic solvent, with chiral resolving agent selected from a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid such as 2,3-di-0-/?-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid, and the like, more preferably 2,3-di-0-/?-toluoyl-L-tartaric acid (L-DPTTA) to yield diastereomeric salts of isovaline;

c) separating the diastereomeric salt of L-isovaline (lib) and enriching its chiral purity by successive crystallations in an organic solvent selected from methanol, ethanol, propanol, butanol, water, THF, acetone, ethyl acetate, dichloromethane, DMF, DMSO, and the like more preferably methanol;

d) converting the optically pure or optically enriched diastereomeric salt of L-isovaline (lib) with an acid selected from sulphuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid and the like more preferably sulfuric acid followed by neutralization with base selected from sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, sodium bicarbonate, potassium bicarbonate and the like to give a mixture L-isovaline (II) and an inorganic salt; e) The L-Isovaline is finally freed from the inorganic salt by dissolving the L-isovaline selectively in a suitable organic organic solvent to give an optically pure or optically enriched L-isovaline (II) having enantiomeric excess of greater than 98%

In a preferred embodiment, dl-isovaline is reacted with 1 mole of 2,3-di-O-p-toluoyl-D-tartatic acid in methanol at reflux temperature for 4 h and crystallization of desired 89.2% e.e L-Isovaline.L-DPTTA salt is crystallized in the above manner to enrich its purity to 99.4%. Finally the L-Isovaline.L-DPTTA salt is acidified using inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and the like preferably sulfuric acid as its byproduct sulfate is not soluble in most of the organic solvents. L-Isovaline amine salt is neutralized using inorganic base such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, etc. Finally the L-isovaline is freed from inorganic salt by dissolving the L-isovaline selectively in a suitable solvent in which inorganic salt does not dissolve. The suitable solvent may be methanol, ethanol, propanol, butanol, water or combination of two or more than two solvents among them preferably methanol. The selective dissolution is made at room temperature to elevated temperature preferably 30 - 40° C. After the selective dissolution of L-isovaline and the resulting mixture is filtered through celite to remove inorganic salt. Concentration of filtrate at room temperature to elevated temperature preferably 45 - 50 ° C under reduced pressure to leave pure L-isovaline as shown in scheme -4 below :


In another embodiment, the present invention provides diastereomeric salt of D-isovaline of compound of formula (la)

wherein x is selected from chiral a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid.

In another embodiment, the present invention provides diastereomeric salt of L-isovaline of compound of formula (Ha)

wherein x is selected from chiral a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid.

In another embodiment, the present invention provides D-Isovaline.D-DPTTA salt of formula (la).

In an another embodiment, the present invention provides L-Isovaline.D-DPTTA salt of formula (Ha).

In an another embodiment, the present invention provides D-Isovaline.L-DPTTA salt of formula (lb).

In an another embodiment, the present invention provides L-Isovaline.L-DPTTA salt of formula (lib).

The key material, racemic isovaline was prepared from readily available commercial raw materials via 5-ethyl-5-methyl-hydantoin followed by hydrolysis and also the processes reported in the literature.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construe to limit the scope of the invention.
Example-1; Preparation of D-Isovaline

Step 1: Preparation of D-Isovaline. D-DPTTA salt
To a stirred suspended solution of 50g of DL-Isovaline in 350 ml of methanol was added 165. lg of D-DPTTA at room temperature. The reaction mixture was refluxed for 4 h during which the solution became clear and the reaction mass was cooled to room temperature. Approximately 90-100 ml of solvent was removed from the reaction mass at 40 ° C under vacuum. The resulting suspended reaction mass was stirred for 1 h at room temperature, filtered, washed with 50 ml of acetone and dried to afford 64g of the title product as white solid. The filtrate was used for the synthesis of L-Isovaline.

64G of the above D-Isovaline.D-DPTTA salt was crystallized to enrich the chiral purity as it dissolved in 256 ml of methanol at reflux temperature and then stirred at reflux temperature for 15 min. Approximately 180-190 ml (75% of solvent) of methanol was removed from the reaction mass at 40 ° C under vacuum. The resulting suspended reaction mass was stirred at room temperature for 20 min, filtered and washed with 50 ml

ExampIe-2: Preparation of L-Isovaline
Step 1: Preparation of L-Isovaline, L-DPTTA salt from Mother liquor The filtrate collected during the preparation of D-Isovaline.D-DPTTA salt was concentrated to yield lOOg of L-isovaline enriched D-DPTTA salt contains 72.7% of L-isovaline.D-DPTTA and 27.3% D-isovaline.D-DPTTA by HPLC. Water (1.5 L) was added and the resulting mass was cooled to 10 ° C. 50% Aq. sulfuric acid (24 ml) was added drop by drop at the same temperature followed by ethyl acetate (400 ml). The resulting mass was stirred for 45 min. at room temperature during which the reaction mass became clear and the layers were separated. The aqueous layer was washed with 100 ml of ethyl acetate. The combined ethyl acetate layer was concentrated separately to recover D-DPTTA. The aq. layer was neutralized with 5N aq. sodium hydroxide solution and the resulting mass was concentrated at 50 ° C under vacuum. Charged acetone (200 ml) and stirred for 30 min at room temperature. Filtered and dried under vacuum. The resulting dried solid was taken in methanol (400 ml) and stirred the suspended mass at room temperature for 45 min.

Filtered to remove sodium sulfate salt and concentrated the filtrate at 45 ° C under vacuum to yield 20g of DL-Isovaline contains major quantity (>70%) of L-isovaline.

To a stirred suspended solution of the above L enriched DL-Isovaline (20g, 0.17 mole) in methanol (140 ml) was added L-DPTTA (66g, 0.17 mole) at room temperature. The reaction mixture was refluxed for 4 h during which the solution became clear and the reaction mass was cooled to room temperature. Approximately 90 of solvent was removed from the reaction mass at 40 ° C under vacuum. The resulting suspended reaction mass was stirred for 1 h at room temperature, filtered, washed with acetone (20 ml) and dried to afford the title product (43 g) as a white solid with 89.2% of e.e by chiral HPLC.

43 G of the above L-Isovaline.L-DPTTA salt was crystallized to enrich its chiral purity as it was dissolved in methanol (172 ml) at reflux temperature and then stirred at reflux temperature for 15 min.

Approximately 110 ml of solvent was removed from the reaction mass at 40 ° C under vacuum. The resulting suspended reaction mass was stirred at room of acetone and dried. The obtained 45g of D-Iva.D-DPTTA salt was dissolved in 179 ml of methanol at reflux temperature and stirred the reaction mass at reflux temperature for 15 min. Approximately 125-135 ml (75% of solvent) of methanol was removed from the reaction mass at 40 ° C under vacuum. The resulting suspended reaction mass was stirred at room temperature for 20 min, filtered, washed with 50 ml of acetone and dried to yield 32g (29.7%) of title compound. M.p.: 186.4-188.6 °C.

'H-NMR (DMSO-4,): 5 0.82 (t, 3H, J= 7.43 Hz), 1.31 (s, 3H), 1.60-1.76 (m, 2H), 2.38 (s, 6H), 5.71 (s, 2H), 7.35 (d, 4H, J= 7.93 Hz), 7.87 (d, 4H, ./= 8.05 Hz). Chiral Purity by HPLC : 99.46 % e.e
Step 2: Preparation of D-Isovaline

A stirred solution of 32g of D-Isovaline.D-DPTTA in 320 ml of water was cooled to 10 ° C. 8 ml of 50% aq. sulfuric acid was added drop by drop at the same temperature and 256 ml of ethyl acetate was added.

The resulting mass was stirred for 45 min. at room temperature during which the reaction mass became clear and the layers were separated.

The aqueous layer was washed with 64 ml of ethyl acetate. The combined ethyl acetate layer was concentrated separately to recover D-DPTTA. The aqueous layer was neutralized with 5N aq. sodium hydroxide solution and the resulting mass was concentrated at 50 ° C under vacuum to remove water completely. The obtained solid was stirred with 100 ml of acetone for 30 min at room temperature, filtered and dried under vacuum. The resulting dried solid was taken in 100 ml of methanol and stirred the
suspended mass at room temperature for 45 min. Filtered to remove sodium sulfate salt and concentrated the filtrate at 45 ° C under vacuum to yield 7.39g (99%) of title product.

M.p.: >280 ° C.
Mass(m/z): 117.9(M+1)
H-NMR (DMSO-d6): 5 0.79 (t, 3H, J= 7.43 Hz), 1.18 (s, 3H), 1.45-1.54 (m, 1H), 1.58-
1.68 (m, 1H)
[a]D25 (c-5, H20): -10.48°
Chiral Purity by HPLC : 99.48 % e.e
Purity by HPLC : 99.2 %

diasteromeric salt (D-Isovaline.D-DPTTA) is initiated by seeding a 99% ee D-Isovaline.D-DPTTA. Then the enriched D-Isovaline.D-DPTTA salt is filtered at room temperature and its chiral purity is enriched from 82 to >99% via two successive crystallization in methanol. Finally D-Isovaline is isolated as a white solid with >99 % e.e from its D-DPTTA salt by acidification using inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and the like preferably sulfuric acid as its byproduct sulfate is not soluble in most of the organic solvents. D-Isovaline amine salt is neutralized using inorganic base such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, etc. The D-Isovaline is finally freed from inorganic salt by dissolving the D-isovaline selectively in a suitable solvent in which the resulting inorganic salt does not dissolve. The suitable solvent may be methanol, ethanol, propanol, butanol, water or combination of two or more than two solvents among them preferably methanol. The selective dissolution is made at room temperature to elevated temperature preferably 30 - 40° C. After the selective dissolution of D-isovaline and the resulting mixture is filtered through celite to remove inorganic salt. Concentration of the filtrate at room temperature to elevated temperature preferably 45 - 50 ° C under reduced pressure to leave D-isovaline. The reaction is shown in scheme -3 below :

Scheme -3
The filtrate containing a mixture of D&L-isovaline.D-DPTTA in the ratio of 3:7 is utilized to make L-isovaline using L-DPTTA. Thus the above mixture is acidified using inorganic acid and then neutralized using inorganic base to afford 3:7 mixture of D & L isovaline. This mixture is resolved using L-DPTTA in the same manner and the resulted temperature for 20 min, filtered and washed with acetone (20 ml) and dried. The obtained 34g of L-Isovaline.L-DPTTA salt was dissolved in 136 ml of methanol at reflux
temperature and stirred the reaction mass at reflux temperature for 15 min.

Approximately 85 ml of solvent was removed from the reaction mass at 40 ° C under vacuum. The resulting suspended reaction mass was stirred at room temperature for 20 min, filtered, washed with 20 ml of acetone and dried to yield 25 g (40 %) of pure L-Isovaline.L-DPTTA.
M.p.: 186.4-188.6 °C.

'H-NMR (DMSO-d6): 5 0.82 (t, 3H, J= 7.4 Hz), 1.30 (s, 3H), 1.60-1.80 (m, 2H), 2.37 (s,6H), 5.70 (s, 2H), 7.33 (d, 4H, J= 8.05 Hz), 7.86 (d, 4H, J= 8.17 Hz).

Chiral Purity by HPLC : 99.4 % e.e

Step 2: Preparation of L-Isovaline
A stirred solution of 25g of L-Isovaline.L-DPTTA in 250 ml of water was cooled to 10 ° C. 6.4 Ml of 50% aq. sulfuric acid was added drop by drop at the same temperature and 200 ml of ethyl acetate was added. The resulting mass was stirred for 45 min. at room temperature during which the reaction mass became clear and the layers were separated.

The aqueous layer was washed with 50 ml of ethyl acetate. The combined ethyl acetate layer was concentrated separately to recover L-DPTTA. The aq. layer was neutralized with 5N aq. sodium hydroxide solution and the resulting mass was concentrated at 50 ° C under vacuum. Charged 50 ml of acetone and stirred for 30 min at room temperature.

Filtered and dried under vacuum. The resulting dried solid was taken in 100 ml of methanol and stirred the suspended mass at room temperature for 45 min. Filtered to remove sodium sulfate salt and concentrated the filtrate at 45 ° C under vacuum to yield 5.7g (98%) of title product.
M.p.:>280°C.
Mass(m/z): 117.9(M+1)

JH-NMR (DMSO-4): 5 0.79 (t, 3H, J= 7.43 Hz), 1.18 (s, 3H), 1.45-1.54 (m, 1H), 1.58- 1.68 (m, 1H)
[a]D25 (c=5, H20): +10.48°
Chiral Purity by HPLC : 99.4 % e.e
Purity by HPLC : 99.0 %

Advantages of the invention
This process is more economic as both enantiomers of isovaline are isolated at high enantiomeric excess from racemic isovaline using respectively D and L- 2,3-Di-O-p-toluoyl tartaric acid and the resolving agents are recovered and recycled.

We claim :

1. A present invention provides a process for the preparation of an optically pure or optically enriched enantiomers of a isovaline of formula (I) and (II)

by resolution of mixture of enantiomers of isovaline in the organic solvent using a chiral resolving agent.

2. The process as claimed in claim 1, wherein the organic solvent is selected from methanol, ethanol, propanol, butanol, water, THF, acetone, DMF, DMSO, or mixture thereof.

3. The process as claimed in claim 1, wherein the chiral resolving agent is selected from a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid selected from 2,3-di-O-p-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid, and the like.

4. A process for preparation of an optically pure or optically enriched enantiomer of isovaline of formula (I),
said process comprising the steps of:

a) treating the mixture of enantiomers of isovaline in an organic solvent, with a chiral resolving agent to yield diastereomeric salt of isovaline;

b) separating the diastereomeric salt of D-isovaline and enriching its chiral purity by crystallization in organic solvent;

c) converting the optically pure or optically enriched diastereomeric salt of D-isovaline to an optically pure or optically enriched D-isovaline having enantiomeric excess of greater than 98%.

5. The process as claimed in claim 4, wherein the organic solvent is selected from methanol, ethanol, propanol, butanol, water, THF, acetone, DMF, DMSO, or mixture thereof.

6. The process as claimed in claim 4, wherein the chiral resolving agent is selected from a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid selected from 2,3-di-O-p-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid, and the like.

7. A process for preparation of an optically pure or optically enriched enantiomer of isovaline of formula (II)

from filtrate obtain during the separation of diastereomeric salt of D-isovaline, said process comprising the steps of:

a) isolating the mixture of enatiomers of isovaline in the ratio of ~ 7:3 of L and D-isovaline respectively from the filtrate obtained during the separation of diastereomeric salt of D-isovaline via acid followed by base treatment;

b) treating the above 7:3 mixture of L and D-isovaline in the organic solvent, with a chiral resolving agent to yield diastereomeric salt of L-isovaline,

c) separating the diastereomeric salt of L-isovaline and enriching its chiral purity by crystallization in organic solvent;

d) converting the optically enriched diastereomeric salt of L-isovaline to an optically pure or optically enriched L-isovaline having enantiomeric excess of greater than 98%.

8. The process as claimed in claim 7, wherein the organic solvent is selected from methanol, ethanol, propanol, butanol, water, THF, acetone, DMF, DMSO, or mixture thereof.

9. The process as claimed in claim 7 wherein the chiral resolving agent is selected from a-
methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid.

10. The process as claimed in claim 7, wherein the substituted chiral tartaric acid is selected from 2,3-di-O-p-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid, and the like.

11. The process as claimed in claim 7, wherein the diastereomeric salt of D-isovaline of compound of formula (lb)

wherein y is selected from chiral a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid selected from 2,3-di-O-p-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid.

12. The process as claimed in claim 7, wherein the diastereomeric salt of L-isovaline of
compound of formula (lib)

wherein y is selected from chiral a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid selected from 2,3-di-O-p-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid.

13. Diastereomeric salt of D-isovaline of compound of formula (la)

wherein x is selected from chiral a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid such as 2,3-di-O-p-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid, and the like.

14. Diastereomeric salt of L-isovaline of compound of formula (Ha)

wherein x is selected from chiral a-methylbenzyl amine, mandelic acid, tartaric acid and substituted tartaric acid selected from 2,3-di-O-p-toluoyl tartaric acid, 2,3-di-O-benzoyl tartaric acid, 2,3-di-O-pivaloyl tartaric, 2,3-di-O-benzyl tartaric acid.