WO2009047797A2

WO2009047797A2 - Process for the preparation of perhydroisoindole derivative

Info

Publication number: WO2009047797A2
Application number: PCT/IN2008/000645
Authority: WO
Inventors: Gurdeep Singh Sarin; Chidambaram Venkateswaran Srinivasan; Lalit Wadhwa
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2007-10-08
Filing date: 2008-10-07
Publication date: 2009-04-16
Also published as: WO2009047797A3

Abstract

The present invention relates to a novel, efficient and industrially advantageous process for preparing perhydroisoindole derivative, particularly (S)-mitiglinide of formula (I): and pharmaceutically acceptable salts thereof. Further, it relates to novel amide intermediates of formula (VI), including salts, solvates, hydrates, polymorphs, isomers and racemic mixtures thereof useful in the process of present invention. Formula (VI): wherein R is selected from straight chain or branched C 1-6 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl. The present invention also relates to amorphous form of mitiglinide calcium, its preparation and process for its conversion to crystalline mitiglinide calcium.

Description

PROCESS FOR THE PREPARATION OF PERHYDROISOINDOLE DERIVATIVE

FIELD OF THE INVENTION

The present invention relates to a novel and efficient process for preparing perhydroisoindole derivative. Particularly the present invention relates to an industrially advantageous process for the preparation of (S)-mitiglinide of formula I,

Formula I

and pharmaceutically acceptable salts thereof involving novel amide intermediate.

The present invention also relates to novel amorphous form of mitiglinide calcium and processes for the preparation thereof.

The present invention further relates to an amide impurity of (S)-mitiglinide and process of preparation thereof.

BACKGROUND OF THE INVENTION

Perhydroisoindole derivative, (S)-mitiglinide of formula I is a potassium channel antagonist for the treatment of type 2 diabetes mellitus and is chemically known as (5)-2-benzyl-3-(cis-hexahydro-2- isoindolinylcarbonyl) propionic acid.

Formula I

It has potent oral hypoglycemic activity and is structurally different from the sulphonylureas, although it stimulates calcium influx by binding to the sulphonylurea receptor on pancreatic β-cells and closing K⁺ _ATP channels. Perhydroisoindole derivatives including (S)-mitiglinide and salts thereof were first disclosed in US patent 5,202,335. This patent discloses preparation of (S)-mitiglinide by the reaction of (5)-3-benzyloxycarbonyl-4-phenylbutyric acid with cis-hexahydroisoindoline in the presence of N- methylmorpholine and isobutyl chloroformate followed by debenzylation with palladium on carbon in ethyl acetate to yield (5)-mitiglinide as viscous oil. (S)-Mitiglinide is isolated as its hemi calcium salt using calcium chloride in water which is further recrystallized with diisopropyl ether. Melting point of calcium salt of mitiglinide calcium dihydrate salt is herein reported as 179-185 ⁰C. (S)-Mitiglinide prepared by the above process is obtained in low yields. Further, the synthetic method described in the patent does not enable the desired regioselectivity. Extensive purification steps are required to obtain the desired compound, which makes the process unattractive from industrial point of view. US patent 6,133,454 discloses a process for the preparation of (S)-mitiglinide by reacting dimethyl succinate with benzaldehyde in methanolic medium, to yield a diacid which is converted to corresponding anhydride and is further reacted with the perhydroisoindole to yield 2-[(cis- perhydroisomdol^-ytycarbonylmethyl^-phenylacrylic acid which is then subjected to catalytic hydrogenation using the complex rhodium/(2S,4S)-N-butoxycarbonyl-4-diphenylphosphino-2-diphenyl- phosphino-methylpyrrolidine (Rh/(S,S) BPPM) as asymmetric hydrogenation catalyst, followed by conversion to pharmaceutically acceptable salt of (S)-mitiglinide. The above patent utilizes ruthenium complex which is expensive, carcinogenic and toxicity, hence not recommended for industrial scale. European patent publication no. EP 0967204 discloses the preparation of mitiglinide by deprotecting benzyl-(S)-2-benzyl-3-(cis-hexahydro-2-isoindolinyl-carbonyl) propionate and converting the same to calcium dihydrate salt in crystalline form using calcium chloride, water and ethanol. The crystals of calcium salt are further recrystallized using ethanol and water. But the patent is silent about the crystalline form of mitiglinide calcium.

It will be appreciated by those skilled in the art that perhydroisoindole derivative, (S)-mitiglinide of formula I contains a chiral centre and therefore exists as enantiomers. Optically active compounds have increasingly gained importance since the technologies to develop optically active compounds in high purity have considerably improved. Obtaining asymmetric molecules has traditionally involved resolving the desired molecule from a racemic mixture using a chiral reagent, which is not profitable as it increases the cost and processing time. Alternatively, desired enantiomer can be obtained by selective recrystallization of one enantiomer. However such a process is considered inefficient, in that product recovery is often low, purity is uncertain and more than 50% of the material is lost. Enantiomers can also be resolved chromatographically, although the large amount of solvent required for conventional batch chromatography is cost prohibitive and results in the preparation of relatively dilute products. Limited throughput volumes also often make batch chromatography impractical for large-scale production. Even so, it is a common experience for those skilled in the art to find chiral separation of certain chiral mixtures to be inefficient or ineffective, thereby resulting in the efforts towards development of newer methodologies for asymmetric synthesis.

It would be of significant advantage to obtain (.S)-mitiglinide by development of reaction conditions necessary for productive manufacture of the required (5)-enantiomer, substantially free of the unwanted (R)-enantiomer, in large quantities that meet acceptable pharmaceutical standards. It is the property of the solid compounds to exist in different polymorphic form. By the term polymorphs mean to include different physical forms, crystal forms, crystalline/liquid crystalline/non-crystalline (amorphous) forms. This has especially become very interesting after observing that many antibiotics, antibacterials, tranquilizers etc, exhibit polymorphism and some/one of the polymorphic forms of a given drug exhibit superior bio-availability and consequently show much higher activity compared to other polymorphs. It has also been disclosed that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form [Konne T., Chem. Pharm. Bull. 38, 2003 (1990)]. The solubility of a material is also influenced by its solid-state properties, and it has been suggested that the solubility of an amorphous compound is 10 to 1600 times higher than that of its most stable crystalline structures (Bruno C. Hancock and Michael Parks, 'What is the true solubility advantage for amorphous pharmaceuticals', Pharmaceutical Research 2000, Apr; 17(4):397-404). Thus it can be concluded that amorphous products are in general more soluble and often show improved absorption in humans.

Thus, there is a widely recognized need for developing a stable polymorph, which would further offer advantages over crystalline forms in terms of better dissolution and the availability profiles. Also none of the prior art references disclose amorphous form of mitiglinide calcium. Thus present invention provides amorphous form of mitiglinide calcium.

It is also required that the final API like mitiglinide whether in the amorphous form or crystalline form must be free from the other impurities including the unwanted enantiomer, these can be side product and by product of the reaction, degradation products and starting materials. Impurities in final API are undesirable and in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. Therefore impurities introduced during commercial manufacturing processes must be limited to very small amounts and are preferably substantially absent. These limits are less than about 0.15 percent by weight of each identified impurity and 0.10 % by weight of unidentified and/or uncharacterized impurities. After the manufacture of APIs, the purity of the products, such as (S)- mitiglinide calcium dihydrate is required before commercialization, and in the manufacture of formulated pharmaceuticals. Therefore, pharmaceutical active compounds must be either free from these impurities or contain the impurities in acceptable limits. There is also a need for the isolation, characterization and identification of the impurities and their use as reference markers and reference standard. Thus, the present invention meets the need in the art for a novel, efficient and industrially advantageous process for providing optically pure perhydroisoindole derivatives, particularly (iS)-mitiglinide, which is unique with respect to its simplicity, scalability and involves controlling the steps of the reaction so that predominantly the desired (S)-enantiomer is produced in high yields and purity. The present invention also provides substantially pure (S)-mitiglinide and salts thereof having novel amide impurity in acceptable limit or free from this impurity. OBJECT OF THE INVENTION

The principal object of the present invention is to provide a novel, efficient and industrially advantageous process for the preparation of perhydroisoindole derivatives, particularly (S)-mitiglinide and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a novel amide intermediate useful in the preparation of (S)-mitiglinide and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide amorphous form of mitiglinide calcium and process of preparation thereof.

Another object of the invention is to provide a process for the preparation of crystalline mitiglinide calcium.

Yet one another object of the present invention is to provide substantially pure (S)- mitiglinide or salts thereof having amide impurity in an amount of less than about 0.15 area percent as measured by high performance liquid chromatography.

Still another object of the present invention is to provide an amide impurity of (S)-mitiglinide and process of preparation thereof.

One more object of the present invention is to provide specifically an isolated (2S)-2-benzyl-Λ/-((lR)-l- benzyl-2-hydroxy-ethyl)-4-(hexahydro-isoindolin-2-yl)-4-oxo-butyramide as impurity of (S)-mitiglinide and process of preparation thereof.

SUMMARY OF THE INVENTION

The present invention relates to a novel and an industrially advantageous process for preparing perhydroisoindole derivative, particularly (S)-mitiglinide of formula I,

Formula I

and pharmaceutically acceptable salts thereof, which comprises a) reacting the compound of formula II,

CX ^FormulaI1 wherein R is selected from straight chain or branched C_/.C_ύ alkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl with an α-halo ester of formula III, ^_x T)R₁ Formula III

X T

wherein X is halo, preferably selected from chloro, bromo, iodo, and the like and

Ri is selected from straight chain or branched C_/.Cs alkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl in the presence of a suitable base in a suitable solvent to form oxazolidine ester derivative of formula

IV;

Formula IV

wherein R and R; are as defined above b)de-esterifying the compound of formula IV to form corresponding oxazolidine acid derivative of formula V;

Formula V

wherein R is as defined above c) condensing oxazolidine acid derivative of formula V with cis-hexahydroisoindoline in the presence of a suitable activating reagent and a base in an organic solvent; d) isolating amide intermediate of formula VI;

Formula VI

wherein R is as defined above e) optionally, recrystallizing the amide intermediate of formula VI using a suitable solvent; f) hydrolysing the amide intermediate of formula VI using a base in the presence of hydrogen peroxide in a solvent to form (S)-mitiglinide of formula I; and g) optionally, converting the same to its pharmaceutically acceptable salts thereof.

According to one another embodiment, the present invention provides a process for the preparation of (S)-mitiglinide pharmaceutically acceptable salts where (S)-mitiglinide is not isolated and the reaction mixture containing (S)-mitiglinide is directly converted to its pharmaceutically acceptable salts. According to another embodiment, the present invention provides a novel amide intermediate of formula VI including salts, solvates, hydrates, polymorphs, isomers and racemic mixtures thereof. According to one preferred embodiment, the present invention provides (2S)-2-benzyl-l-((4R)-4-benzyl- 2-oxo-oxazolidin-3-yl)-4-(hexahydro-isoindolin-2-yl)-butane-l,4-dione, an amide intermediate of formula Via including salts, solvates, hydrates, polymorphs, isomers and racemic mixtures thereof.

Formula Via

wherein R is as defined above

According to another embodiment, present invention provides crystalline form of amide intermediate of formula Via.

According to another embodiment, the present invention provides mitiglinide calcium in amorphous form.

According to another embodiment, the present invention provides a process for the preparation of amorphous mitiglinide calcium, comprises the step of a) dissolving mitiglinide calcium in a suitable solvent; b) admixing with an anti-solvent; and c) isolating the amorphous mitiglinide calcium.

According to one more embodiment, the present invention provides another process for the preparation of amorphous mitiglinide calcium, comprises the step of a) providing a solution of mitiglinide calcium in a suitable solvent; b) removing the solvent; and c) isolating the amorphous mitiglinide calcium.

According to another embodiment, the present invention provides a process for the preparation of amorphous mitiglinide calcium directly from mitiglinide of formula I, comprises the step of a) providing a solution of mitiglinide in an organic solvent; b) adding a suitable base to the solution; c) treating the resulting solution with a source of calcium ion; and d) isolating the amorphous mitiglinide calcium.

According to another embodiment, the present invention provides a process for the conversion of amorphous mitiglinide calcium into its crystalline form having XRD as shown in Figure 6, comprises: a) providing a solution of amorphous mitiglinide calcium in a suitable solvent; and b) stirring the solution for a time sufficient to convert in to crystalline form of mitiglinide calcium. According to yet another embodiment, the present invention provides a process for the preparation of crystalline mitiglinide calcium having XRD as shown in Figure 6, directly from mitiglinide. The process comprises the step of a) providing a solution of mitiglinide in a suitable solvent; b) optionally adding a suitable base to the solution; c) treating the resulting solution with a source of calcium ion; and d) isolating the crystalline mitiglinide calcium.

According to another embodiment, the present invention provides an amide impurity of formula VII.

Formula VII

wherein R is as defined above

According to another embodiment, the present invention provides a process for the preparation of novel amide impurity of formula VII, which comprises the step of a) providing the solution containing amide intermediate of formula VI; b) treating the above solution with suitable base; c) isolating the compound; and d) optionally, recrystallizing using a suitable solvent.

Preferably the present invention provides (2S)-2-benzyl-N-(( IR)-I -benzyl-2-hydroxy-ethyl)-4- (hexahydro-isoindolin-2-yl)-4-oxo-butyramide of formula Vila, an isolated impurity of (S)-mitiglinide.

Formula Vila

According to another preferred embodiment, the present invention provides a process for the preparation of amide impurity of formula Vila from amide intermediate of formula Via, a key intermediate in the preparation of (S)-mitiglinide.

According to another embodiment, the present invention provides substantially pure (S)- mitiglinide or salts thereof having less than about 0.15 area percent of an amide impurity of formula VII as measured by high performance liquid chromatography.

According to one another embodiment, the present invention provides a process for the preparation of substantially pure (S)-mitiglinide or salts thereof, comprises the steps of: (a)hydrolyzing the amide intermediate of formula VI with suitable base and hydrogen peroxide; (b) acidifying the reaction mixture with dilute acid;

(c) extracting the reaction mixture with water immiscible organic solvent; (d)optionally, isolating (S)-mitiglinide;

(e) treating reaction mixture or (S)-mitiglinide with a suitable base;

(f) optionally, recovering the substantially pure (S)-mitiglinide; and (g)converting the same to (S)-mitiglinide salt.

According to one preferred embodiment, the present invention provides a process for the preparation of substantially pure (S)-mitiglinide or salts thereof from amide intermediate of formula (2S)-2-benzyl-l-

((4R)-4-benzyl-2-oxo-oxazolidin-3 -yl)-4-(hexahydro-isoindolin-2-yl)-butane- 1 ,4-dione of formula Via.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure. 1 shows a powdered X-ray diffraction pattern of amide intermediate as isolated in example 5.

Figure. 2 shows an infrared absorption spectrum of amide intermediate as isolated in example 5.

Figure. 3 shows a typical chromatogram of the reaction mixture containing (S)-mitiglinide and amide impurity obtained by high performance liquid chromatography.

Figure. 4 shows a typical chromatogram of the pure amide impurity of formula Vila obtained by high performance liquid chromatography.

Figure.5 shows a powdered X-ray diffraction pattern of amorphous mitiglinide calcium.

Figure. 6 shows a powdered X-ray diffraction pattern of crystalline form of mitiglinide calcium.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "mitiglinide" refers to (S)-mitiglinide. As used herein the term "mitiglinide salts" refers to (S)-mitiglinide calcium, preferably (S)-mitiglinide calcium dihydrate. As used herein, the term "amide intermediate" includes salts, solvates, hydrates, polymorphs, isomers and racemic mixtures thereof. As used herein, unless the context requires otherwise, the amide impurity referred to in the application includes both the racemic mixture and the enantiomerically pure form. Thus, for example, 2- benzyl-N-(l-benzyl-2-hydroxy-ethyl)-4-(hexahydro-isoindolin-2-yl)-4-oxo-butyramide refers to either

(+)-2-benzyl-iV-( 1 -benzyl-2-hydroxy-ethyl)-4-(hexahydro-isoindolin-2-yl)-4-oxo-butyramide or (2 S)-2- benzyl-N-(( 1 R)- 1 -benzyl-2-hydroxy-ethyl)-4-(hexahydro-isoindolin-2-yl)-4-oxo-butyramide.

As used herein, the term "amide impurity" includes salts, solvates, hydrates, polymorphs, isomers and racemic mixtures thereof. As used herein, the term "isolated" refers to a compound that is at least 80%, preferably at least 90%, even more preferably at least 95% and most preferably at least 99% pure, as judged by high performance liquid chromatography or gas chromatography.

As used herein, the term "substantially pure" is used in reference to (S)-mitiglinide or salts containing less than about 0.15% area of amide impurity of formula VII by high performance liquid chromatography.

The present invention relates to a novel and industrially advantageous process for preparing perhydroisoindole derivatives, particularly (5)-mitiglinide of formula I and pharmaceutically acceptable salts thereof in high overall yield and high purity.

According to one embodiment, the present invention provides a process for the preparation of (S)- mitiglinide and pharmaceutically acceptable salts thereof by the reaction of compound of formula II with an α-halo ester of formula III in the presence of suitable base in a suitable solvent under conditions essential to produce the desired enantiomer of oxazolidine ester derivative of formula IV. Generally, the reaction is carried out at a temperature of about -110 to -50 ⁰C for few minutes to a few hours. Preferably the reaction is carried out at a temperature of -100 to -90 ⁰C for 1 to 6 hours, more preferably reaction is carried out till the completion of the reaction. The reaction completion is monitored by suitable chromatographic techniques such as high pressure liquid chromatography (HPLC) or thin layer chromatography (TLC). Solvents for carrying out the reaction include but are not limited to aliphatic or cyclic ethers, 1,2-dialkoxy alkanes and the like or mixtures thereof. Preferably the solvents can be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane and the like or mixture thereof. Base includes but not limited to alkali metal hydrides, carbonates, amides thereof or alkali metal hexamethyldisilazanes and the like. Preferably the base can be selected from sodium hexamethyldisilazane, lithium hexamethyldisilazane, potassium hexamethyldisilazane, lithium diisopropylamide, sodium hydride, potassium hydride and the like.

The oxazolidine ester derivative of formula IV so formed can be used as such in the next step or purified using suitable techniques such as crystallization, slurry wash and the like. The compound of formula IV can optionally be purified by using suitable organic solvent which includes, but not limited to straight chain or branched aliphatic alkanes, ethers, alcohols, esters, nitriles, aromatic solvents and the like or mixture thereof. Preferably, the solvent can be selected from n-pentane, n-hexane, n-heptane, diisopropyl ether, diethyl ether, methyl tert-butyl ether, methanol, ethanol, isopropyl alcohol, acetonitrile and the like or mixture thereof. Optionally, the compound can be recrystallized to achieve the desired purity of the compound. The oxazolidine ester derivative of formula IV is recrystallized to enhance the enantiomeric and chemical purity in excess of 97%, preferably up to about 99.7%, more preferably up to 99.9%. The oxazolidine ester derivative of formula IV can be de-esterified to form corresponding oxazolidine acid derivative of formula V by any methods known in art for the de-esterification. Specifically, the compound of formula IV can be de-esterified under acidic or basic conditions. Suitable de-esterifying reagent can be selected depending upon the nature of ester group that has to be removed. Suitable acids can be inorganic or organic acid. Inorganic acid includes, but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Organic acids include, but not limited to aliphatic or aromatic carboxylic acid such as acetic acid, trifluoroacetic acid, trichloroacetic acid, cumic acid and the like; or sulfonic acids such as para-toluenesulphonic acid, methanesulfonic acid, ethanesulfonic acid and the like. Suitable base can be inorganic base which includes, but not limited to alkali or alkaline metal hydroxides, alkali or alkaline metal carbonates/bicarbonates and the like. Preferably, the base can be selected from lithium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide and the like. Compound of formula IV (where R is benzyl or substituted benzyl) can be preferably hydrolyzed by using transition metal assisted hydrogenation. The hydrogenation can take place by employing the hydrogen gas pressure of about 0.5 to 6.0 kg; preferably 1 to 3 kg of hydrogen gas pressure is employed. The transition metal includes palladium with support (palladium on carbon) or without support, platinum with or without support and the like. The hydrolysis reaction is preferably conducted in the presence of an organic solvent which includes, but not limited to C₁-C₄ alcohols, halogenated solvents, aliphatic ethers, cyclic ether, alkoxy alkanes, esters and the like or mixture thereof. Preferably, the suitable solvent can be selected from ethyl acetate, methyl acetate, propyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, isopropyl ether, diethyl ether, methyl t-butyl ether, dibutyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane and the like. The reaction is generally carried out at a temperature of about 0-100 °C, preferably at 10-60 °C, more preferably at 15-30 °C till the completion of the reaction.

The compound of formula V can optionally be purified by the suitable technique such as recrystallization, slurry wash and the like. The organic solvent used for the purification includes, but not limited to straight chain or branched aliphatic alkanes, ethers, Ci-C₅ alcohols, halogenated solvents, esters, aromatic solvents and the like or mixtures thereof in any suitable proportions. The suitable solvent can be selected from n-pentane, n-hexane, n-heptane, n-octane, isopropyl ether, diethyl ether, methyl t- butyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, propylacetate, mixture of ethyl acetate and n-hexane, mixture of ethyl acetate and n-heptane and the like.

The oxazolidine acid derivative of formula V is further converted to novel amide intermediate of formula VI by involving the process of the conversion of compound of formula V to its reactive derivative followed by reaction with cis-hexahydroisoindoline under anhydrous reaction conditions which further forms an inventive part of the present invention.

Generally, the oxazolidine acid derivative of formula V can be converted to its reactive derivative, like acid halide, inorganic or organic acid anhydride, mixed acid anhydride, cyclic carboxy-anhydride, active amide or ester and the like, by reaction with a suitable activating reagent in presence of base. The activating reagent includes, but not limited to alkyl, allyl or aryl chloroformates such as isobutyl chloroformate, ethyl chlorofoπnate, methyl chloroformate, phenyl chlorofoπnate, benzyl chloroformate and the like; anhydride such as acetic anhydride, propionic anhydride and the like; mixed anhydride such as methyl ethyl anhydride and the like; phosphorous halides such as phosphorous trihalide, phosphorous pentahalide; thionyl halide such as thionyl chloride and the like; organic acid halide such as acetyl chloride, pivaloyl chloride and the like; Lewis acid such as boric acid, aluminium chloride, boron trifluoride, boron tribromide, titanium tetrachloride, titanium trichloride, ferric trichloride and the like. The reaction can be carried out in presence of dicyclohexylcarbodiimide as an activating compound. The base is selected from tertiary amines like triethyl amine, tripropyl amine, tri n-butyl amine, diisopropyl ethyl amine, iV-methyl morpholine and the like. Preferably triethyl amine or diisopropyl ethyl amine can be employed. The reaction is generally carried out in the presence of organic solvent. Organic solvent includes, but are not limited to aliphatic and cyclic ethers, alkoxy alkanes, halogenated solvents, nitriles and the like or mixture thereof. Preferably, the solvent can be selected from tetrahydrofuran, 2- methyltetrahydrofuran 1,2-dimethoxy ethane, 1,2-diethoxy ethane, dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile and the like.

The resulting reactive derivative can be isolated from the reaction mixture or in situ made to react with cis-hexahydroisoindoline to give intermediate of formula VI.

Preferably, the reaction mixture containing the resulting reactive derivative is made to react with cis- hexahydroisoindoline in an organic solvent as described above under anhydrous reaction conditions by maintaining temperature of the reaction medium at -60 to 60⁰C. Preferably, the reaction is carried out at a temperature of -20 to 20 ⁰C till the completion of the reaction. After aqueous work up and recovery of solvent, alcoholic solvent is added to the above reaction mixture at a temperature of 5 ⁰C to reflux temperature of solvent. Preferably solution is stirred at a temperature of about 0 to 15 ⁰C. Alcoholic solvent can be selected from methanol, ethanol and isopropanol, more preferably methanol is used. The amide intermediate is isolated from the reaction mixture by suitable techniques such as filtration and the like.

The amide intermediate of formula VI can be used as such in the preparation of (S)-mitiglinide or pharmaceutically acceptable salts thereof or further purified with suitable techniques such as crystallization, slurry wash and the like.

The amide intermediate of formula VI, if desired is optionally recrystallized with a suitable solvent. Suitable solvent for purification includes, but not limited to Ci-C₆ alcohols, Ci-C₈ esters, Ci-C₈ ethers, nitriles, or mixture thereof or mixture of water miscible organic solvent with water. Preferably, the solvent can be selected from methanol, ethanol, isopropanol, propanol and butanol, ethylacetate, acetonitrile, tetrahydrofuran, acetonitrile/ methanol, isopropyl alcohol/ methanol, acetonitrile/methanol/water and the like. The pure amide intermediate, if required, can be recrystallized further from the suitable solvent as described above to obtain the highly purified compound of desired purity. The amide intermediate obtained by the process described in the present invention is having chemical purity more than 95%, preferably more than 98.0%, more preferably 99.7%. Novel amide intermediate prepared using process of the present invention also is contemplated and characterized by ¹H Nuclear magnetic resonance spectroscopy (NMR), ¹³C Nuclear magnetic resonance spectroscopy (NMR), infra-red spectroscopy (IR), ultra violet spectroscopy (UV), mass spectra (MS). Additionally differential scanning calorimetry (DSC) and solid state X-ray diffraction (XRD) are carried out to identify its crystal form.

The amide intermediate of formula Via (wherein R is benzyl) is characterized by following data: 1H-NMR δ (CDCl₃, 400 MHz): 1.33-1.57 (8H, m, CH₂ at C₈, C₉, C₁₀ and C₁₁); 2.09-2.29 (2H, m, CH_at C₇, C₁₂); 2.34-2.87 (4H, m, CH₂ at C₃, C₁₄); 3.03-3.43 (6H, m, CH₂ at C₂₆, C₆, C₁₃); 3.90-4.07 (2H, m, CH₂ at C₂₄); 4.50-4.64 (2H, m, CH_at C₂, C₂₅); 7.22-7.34 (1OH, m, aromatic H).

¹³C-NMR δ (CDCl₃, 100 MHz): 22.59-22.80 (C-₉, ₁₀); 25.71-25.82 (C-₈, „); 35.92-36.49 (C₇, ,₂); 37.49- 37.54 (C₃); 37.58-37.61 (C₁₄); 38.37 (C₁₄); 40.84 -40.98 (C₂); 49.39-50.78 (C₆, ,₃); 55.59 (C₂₅); 65.83- 65.89 (C₂₄); 126.59 (C₁₈); 126.98 (C₃₀); 128.38 (C₁₇, ₁₉); 128.81 (C₂₉, ₃i); 129.26 (C₁₆, ₂₀); 129.50 (C₂₈, ₃₂); 136.15-136.18 (Ci₅); 138.29-138.33 (C₂₇); 152.96/153.0 (C₂₂); 169.82/169.86(C₄); 175.92/76.08(Ci). The amide intermediate of formula Via (wherein R is benzyl) is also characterized by X-ray diffractogram as shown in figure 1 and infra-red spectrum as shown in figure 2.

The amide intermediate of formula VI can be further converted to (5)-mitiglinide of formula I or pharmaceutically acceptable salts thereof and the process further forms an inventive part of the invention. Generally, the reaction is carried out by treating the solution of amide intermediate of formula VI with a suitable base and hydrogen peroxide followed by stirring at a temperature of -25 to 50⁰C for few minutes to few hours. The base employed in the reaction can be used as a solid or aqueous solution, preferably aqueous base is employed. The solution of amide intermediate of formula VI can be prepared by dissolving the amide intermediate of formula VI in a suitable water miscible solvent. Suitable solvent includes, but are not limited to Ci-C₄ alcohols, tetrahydrofuran, nitriles, alkoxyalkanes, diols, ketones and the like or mixture thereof. Preferably, the solvent can be selected from methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, ethanediol, 1,2 propandiol, 1,3 propandiol, tetrahydrofuran, acetonitrile, 1,2 dimethoxy ethane, 1,2 diethoxy ethane, acetone, ethyl methyl ketone, diethyl ketone and the like or mixture thereof. Suitable base includes but not limited to alkali metal hydroxides, carbonates or hydrates thereof. Preferably, the base can be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide monohydrate and the like. The reaction mixture is generally stirred at a temperature of -15 to 40⁰C for 24 hours. Preferably the reaction mixture is stirred at a temperature of -5 to 25 ⁰C till the completion of reaction. The reaction completion is monitored by suitable chromatographic techniques such as thin-layer chromatography (TLC) or high performance liquid chromatography (HPLC). After completion of reaction, the mixture is acidified with dilute acids followed by extraction with a suitable solvent. The pH of the solution varies from 1-6.5. The acids can be organic acid which include but not limited to carboxylic acids such as acetic acid, formic acid, propionic acid and the like; inorganic acid includes, but not limited to hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like; or sodium metabisulphite solution. Optionally, (S)-mitiglinide is isolated from the reaction mixture by suitable techniques known in art such as distillation of the solvent and the like. Solvent for the extraction include, but are not limited to straight chain or branched Ci-C₈ alkanes, C_4-Ci₀ aliphatic ethers, C_3-C₈ esters, halogenated solvents, aromatic or aliphatic hydrocarbons and the like or mixture thereof. Preferably, the solvent can be selected from dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, ethyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether and the like or mixtures thereof. More preferably the solvent can be selected from ethyl acetate or dichloromethane.

When high performance liquid chromatography analysis of crude (S)-mitiglinide obtained by the above process or the reaction mixture containing the mitiglinide is carried out, it is sometimes found that it shows the presence of an impurity in amounts of up to 4 area percent by high performance liquid chromatography. The high performance liquid chromatogram of reaction mixture containing the (S)- mitiglinide and impurity is shown in figure 3. Such analysis can also be performed by using thin layer chromatography.

However, further it is observed by the present inventors that the amount of hydrogen peroxide used in the reaction is highly critical for the complete removal of chiral auxiliary like (R)-benzyl oxazolidine-2-one. Thus, if the reaction is carried out using insufficient amount of hydrogen peroxide, the reaction does not go to completion. The completion of the reaction can be monitored by chromatographic techniques such as high performance liquid chromatography or thin layer chromatography. Under these conditions appreciable amount of that impurity is formed in addition to desired product, (S)-mitiglinide. In the absence of sufficient amount of hydrogen peroxide, the oxazolidin-2-one functionality undergoes ring- opening to generate that impurity in high amount instead of the selective cleavage of the oxazolidin-2- one functionality to generate mitiglinide. It is also observed that lower the amount of hydrogen peroxide used, higher is the percentage of formation of that by product impurity. This impurity is characterized as an amide impurity of general formula VII by various spectroscopic techniques like ¹H and ¹³C Nuclear magnetic resonance, Ultraviolet spectroscopy, Mass spectrometry, Infrared spectroscopy. The percentage of impurity present in (S)-mitiglinide or its salts is identified by chromatographic techniques like thin layer chromatography (TLC) or high pressure liquid chromatography (HPLC) preferably, by high pressure liquid chromatography.

The isolated amide impurity of formula Vila is characterized by following spectral data: 1H-NMR δ (CDC1₃):1.35-1.58 (8H, m, 4CH₂ at C_8-,,); 2.13-2.34 (3H, m, CH at C₇ & C₁₂ and OH ); 2.59-2.74 (2H, m, CH₂ at C₃); 2.79-2.81 (2H, m, CH₂ at C₁₄); 2.93-3.01 (2H, m, CH₂ at C₂₅); 3.14-3.84 (7H, m, CH₂ at C₆, C₁₃, C₂₃ and CH at C₂); 3.97-3.99 (IH, m, CH at C₂₂); 6.92-6.96 (IH, m, NH); 7.11- 7.27 (1OH, m, Aromatic H).

¹³C-NMR δ (CDCl₃): 22.65 (C₉,C,₀); 25.26-25.68 (C₈, C₁₁); 35.78-35.86 (C₇ or C_n); 36.39-36.67 (C₃); 37.33-37.40 (C₁₂ or C₇); 38.43-38.59 (Ci₄); 44.81-45.04 (C₂); 49.69-49.76 (C₂₅); 50.54-50.62 (C₆, C₁₃); 53.27/53.42 (C₂₂); 62.86/63.04 (C₂₃); 126.11/126.15 (C₁₈); 126.35-126.37 (C₂₉); 128.23(C₁₇, C₁₉); 128.26/ 128.34 (C₂₈, C₃₀); 129.01/129.03 (C₂₀, C₁₆); 129.25/129.28 (C₂₇/C₃0; 138.39 (C₁₅); 139.33/139.35 (C₂₆); 170.66 (C₄); 174.55/174.59 (C₁).

IR (KBr, cm^'1): 3629 (O-H stretch); 3306 (N-H stretch, amide); 3083, 3061, 3001 (C-H stretch); 2927, 2885, 2854 (C-H stretch); 1642 (C=O stretch, amide merged); 1625 (N-H bend); 1537 (C=C stretch, aromatic).

The isolated amide impurity of formula Vila is having melting point in range of 77 to 80⁰C. The isolated amide impurity of present invention may be present in more than one conformation as is interpreted from the displays of the two peaks in ¹³C-NMR spectra each at 139.33/139.35 (C₂₆); 170.66 (C₄); 174.55/174.59 (Ci) for the designated carbon atoms.

This amide impurity can be removed during the work up of the reaction mixture as is described in the present invention to give substantially pure (S)-mitiglinide or salts thereof.

According to another embodiment, the present invention provides a process for the removal of amide impurity of formula VII to provide substantially pure (S)-mitiglinide or salts thereof which further forms the inventive part of the invention.

Thus, the present invention provides substantially pure (S)-mitiglinide or salts thereof having less than 0.15% of amide impurity and a process for the preparation of substantially pure (S)-mitiglinide, by the hydrolysis of amide intermediate of formula VI. In a preferred embodiment, the present invention provide a process for the preparation of substantially pure (S)-mitiglinide or salts thereof by the hydrolysis of (2S)-2-benzyl-l-((4R)-4-benzyl-2-oxo- oxazolidin-3-yl)-4-(hexahydro-isoindolin-2-yl)-butane- 1 ,4-dione of formula Via.

Generally, the reaction is carried out by treating the solution of amide intermediate of formula VI (preferably Via) in a water miscible organic solvent using a suitable base and hydrogen peroxide followed by stirring at a temperature of -25 to 50 ⁰C. The base employed in the reaction can be solid or aqueous solution. Preferably, aqueous base is used. The solution of compound of formula III can be prepared by dissolving the compound of formula III in a water miscible organic solvent. Organic solvent and base employed for the reaction are same as described above in the hydrolysis reaction. After completion of the reaction, the mixture is acidified with dilute acid, followed by extraction with a suitable solvent. Acid employed and solvents for extraction are same as described above. Optionally, (S)- mitiglinide is isolated from the reaction mixture by suitable techniques known in art such as distillation of the solvent and the like.

The crude (S)-mitiglinide or the reaction mixture containing (S)-mitiglinide is treated with a suitable base or aqueous solution of base. Base can be an organic amine, which includes, but not limited to amine of general formula NR₁R₂R₃ wherein Ri, R2 and Rs can be independently selected from hydrogen, unsubstituted or monosubstituted or polysubstituted (Ci-Cβ)-alkyl; (C₁-C₃) cycloalkyl, alkenyl, alkynyl, alkaryl, aryl, arylalkyl, alkoxy, aryloxy, aminoalkyl or aminoaryl or a three to six membered heterocyclic ring with one or more hetero atom selected from nitrogen, oxygen or sulphur. Organic base may be selected from ammonia, 1,2-dimethylpropylamine, 3-(2-aminoethylamino)-propylamine, butylamine, amylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, dicyclohexylamine, N- methylcyclohexylamine, N,N'-diisopropylethylenediamine, N,N'-diethylene diamine, N-methyl-1,3- propanediamine, N-methylethylenediamine, NN,N'N'-tetramethyl-l,2-diaminoethane, N.NN'.N- tetramethyl-l-,4-diaminobutane, N,NN'N-tetramethyl-l,6-diamino hexane, 1,2-dipiperidinethane, dipiperidine methane, 2-amino-3,3-dimethylbutane, NN-dimethylcyclohexyl amine, neopentylamine, adamantylamine, N-methylcyclohexylamine, cyclobutylamine, N-isopropylccyclohexylamine, N₅N'- diethylcyclohexcylamine, cyclobutylamine and norborylamine etc. The reaction mixture is stirred for few minutes to few hours. Preferably, the reaction mixture is stirred for 15 to 30 minutes. It is optional to isolate the substantially pure (S)-mitiglinide from the reaction mixture by the suitable techniques. (S)- Mitiglinide can be converted insitu to its salts.

(5)-Mitiglinide, if isolated from the reaction mixture, can be optionally purified by giving acid-base treatment to the crude (S)-mitiglinide in the presence or absence of organic solvents. Alternatively, (S)- mitiglinide can be purified via the formation of benzyl ester of mitiglinide followed by debenzylation to give highly pure (5)-mitiglinide. The (5)-mitiglinide benzyl ester can be prepared by the reaction of (S)- mitiglinide with benzyl halide in the presence of a base or by the reaction with benzyl alcohol in the presence of acid or an activating reagent in presence of base. The activating reagent includes, but not limited to alkyl, allyl or aryl chloroformates like methyl chloroformate, ethyl chloroformate, isobutyl chloroformate; phenyl chloroformate, benzyl chloroformate; anhydride like acetic anhydride, propionic anhydride and mixed acid anhydride like methyl ethyl anhydride etc; phosphorous halides like phosphorous trihalide, phosphorous pentahalide; thionyl halide; organic acid halide like acetyl chloride, pivaloyl chloride; Lewis acid like boric acid, aluminium chloride, boron trifluoride, boron tribromide, titanium tetrachloride, titanium trichloride, ferric trichloride and activating compound like dicyclohexylcarbodiimide and the like. The base is selected from tertiary amines like triethylamine, tripropylamine, tri n-butylamine, diisopropyl ethylamine, N-methylmorpholine and the like. Preferably triethylamine or diisopropyl ethylamine can be employed. The mitiglinide benzyl ester is purified via recrystallization and then hydrolyzed or debenzylated with palladium-carbon under hydrogen gas pressure to give pure (5)-mitiglinide.

The (iS)-mitiglinide or the reaction mixture containing the (S)-mitiglinide is converted to (S)-mitiglinide pharmaceutically acceptable salts by the methods well known in art. Examples of such pharmaceutically acceptable salts includes alkaline metal salts such as sodium and potassium salt, alkaline earth metal salt such as calcium and magnesium salt and organic salt which is formed with organic amine such as ammonia, morpholine, piperidine and phenylalaninol or amino acids such as arginine. Preferably, the (5)-mitiglinide or reaction mixture containing (S)-mitiglinide is converted to (S)- mitiglinide calcium dihydrate salt using suitable source of calcium ion selected amongst, but not limited to calcium chloride, calcium acetate, calcium hydroxide and the like in the presence or absence of organic solvents. Preferably the reaction can be conducted in the presence of water. Base can be selected from ammonia, dimethyl amine, diethyl amine, dipropyl amine, morpholine and the like. According to one more embodiment, the present invention further provides a process for the preparation of crystalline form of mitiglinide calcium having XRD as shown in figure 6, from mitiglinide. Generally, the reaction is carried out by reacting mitiglinide with a source of calcium ion salt like calcium chloride or calcium acetate in the presence of suitable solvent, suitable solvent is selected from alcohols like methanol, ethanol, isopropyl alcohol; aliphatic ketones like acetone, diethyl ketone, ethyl methyl ketone; ethers like diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, methyl tetrahydrofuran; nitriles like acetonitrile; Cs-C₈ linear, branched and cyclic alkanes and the like in mixture thereof or mixture with water. The source of calcium ion employed is calcium salt such as calcium chloride or calcium acetate and the like. The calcium salt employed in the reaction can be used as a solid or solution of the salt in a suitable solvent selected from water or alcohol. The reaction can be conducted in the presence or absence of base. Bases include organic base selected from ammonia or inorganic base selected from metal hydroxide, metal carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide and the like. The crystalline mitiglinide calcium so obtained is optionally slurry washed with a suitable solvent selected from water or as described above Mitiglinide calcium isolated in any form can be converted to amorphous mitiglinide calcium. The present invention also provides a novel amorphous form of mitiglinide which forms an inventive part of the invention.

Amorphous form of mitiglinide calcium encompassed by the present invention may be characterized by at least one of techniques such as Karl Fisher or TGA, IR spectroscopy, X-Ray power diffraction (XRD), or differential scan calorimetry (DSC) techniques. Amorphous mitiglinide calcium is characterized by an X-Ray Powder Diffraction pattern, substantially as depicted in Figure 5. Amorphous mitiglinide calcium prepared by the processes of the present invention may be anhydrous or hydrous inclusive of solvates. The amorphous mitiglinide calcium is further characterized by infrared spectrum having peaks at about 3434, 3121, 3059, 3043, 3025, 3008, 2926, 2874, 2854, 1916, 1620, 1585, 1557, 1505, 1494, 1490, 1447, 1359, 1335, 1219, 1184, 1141, 1095, 1074, 1060, 1030, 939, 894 cm-¹.

The X-ray diffraction patterns of amorphous mitiglinide calcium are measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities. One of ordinary skill in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation, or other factors. All infrared measurements are made on Perkin Elmer Spectrum 100 spectrometer using KBr pellets having the characteristic absorption bands expressed in reciprocal centimeter.

According to another embodiment, the present invention provides a process for the preparation of amorphous mitiglinide calcium by employing solvent antisolvent system.

Generally, the process involves the dissolution of mitiglinide calcium in a suitable solvent. Suitable solvent includes, but not limited to halogenated solvents, esters, alkoxy alkanes and the like or mixture thereof. Preferably the solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, 1,2-dimethoxy ethane and the like or mixture thereof in any suitable proportions. A part of solvent is optionally distilled off to obtain a stirrable solution followed by cooling the solution to a temperature of about 10-20 °C.

The process further includes combining the solution with an antisolvent that is a poor solvent for mitiglinide calcium and which when mixed with a solution of mitiglinide calcium, causes it to precipitate. Antisolvent can be selected from, but not limited to aliphatic ethers, straight or branched C₅ to C₈ aliphatic alkanes, C₅ to C₈ cyclic aliphatic alkanes, aromatic solvents, halogenated solvents or mixture thereof in any suitable proportions. Preferably, the antisolvent is selected from diethyl ether, diisopropyl ether, methyl tertiary butyl ether, pentane, hexane, heptane, n-octane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, benzene, toluene, ortho xylene, para-xylene, meta-xylene, chlorobenzene, dichlorobenzene and the like or mixtures thereof in any proportion. The reaction mixture is further stirred for a period of about few minutes to half an hour to isolate amorphous mitiglinide calcium there from in high overall yield.

Amorphous mitiglinide calcium can be isolated by the methods well known in art such as filtration, centrifugation or decantation and the like. Typically, the product is isolated by filtration when any of the solvents within the scope of the process are used.

It has been found by the present inventors that if the above reaction mixture is stirred for a period of about more than 1 hour to about 24 hours, it results in the formation of crystalline form as depicted in Figure 2. Further the conversion of amorphous form into crystalline form is facilitated by high temperature. Higher the temperature, faster is the conversion of amorphous form into crystalline form. According to another embodiment, the present invention provides a process for the conversion of amorphous mitiglinide calcium into its crystalline form having XRD as shown in figure 6. Generally, the conversion is carried out by stirring amorphous mitiglinide calcium in a suitable solvent or solvent mixture for a time sufficient to convert to crystalline form of mitiglinide calcium. Preferably the reaction mixture is stirred for a period of about one hour to 24 hours. Further the conversion of amorphous form into crystalline form is facilitated by high temperature. Higher the temperature, faster is the conversion of amorphous form into crystalline form. The crystalline form of mitiglinide calcium is depicted in figure 6. Solvent can be selected from, but not limited to aliphatic ethers like diethyl ether, diisopropyl ether, methyl tertiary butyl ether; straight or branched C₅-C₈ aliphatic alkanes like pentane, , hexane, heptane, octane; Cs-C₈ cyclic aliphatic alkanes like cyclopentane, cyclohexane, cycloheptane, cyclooctane; aromatic solvents like benzene, toluene, ortho, meta and para xylenes; halogenated solvents like chlorobenzene, dichlorobenzene and the like or mixture thereof or mixture thereof with water or water miscible solvent like C₁-C₈ alcohol, C₃-C₈ ketones, acetonitrile, tetrahydrofuran, 1,2-dimethoxy ethane and the like in any suitable proportion. The crystalline mitiglinide calcium is then isolated from the reaction mixture by the suitable techniques such as filtration and the like. The crystalline mitiglinide calcium so obtained is optionally slurry washed with a suitable solvent selected from water or as described above.

According to another embodiment, the present invention provides another process for the preparation of amorphous mitiglinide calcium.

Generally, reaction is carried out by providing a solution of mitiglinide calcium in a suitable solvent selected from, but not limited to alcohols, cyclic ethers, ketones, esters, halogenated solvents or mixture thereof in any suitable proportions. Preferably, the solvent is selected from methanol, ethanol, tetrahydrofuran, acetone, dichloromethane, chloroform, ethyl acetate and the like or mixture thereof. If, the solution as in the case mentioned above is not clear, further purification steps, e.g. by filtering and/or adding of active charcoal may become necessary to obtain a clear solution. This is followed by the removal of the solvent and isolation of amorphous mitiglinide calcium from the reaction mixture by the processes well known in art. The solvent is preferably removed using, for example, devices like evaporator, rotary evaporator or drying technology such as, for example, vacuum drying, spray drying, freeze drying and the like.

According to yet another embodiment, the present invention provides a process for the preparation of amorphous mitiglinide calcium directly from mitiglinide of formula I.

Generally, the solution of mitiglinide is provided by the dissolving mitiglinide in an organic solvent and then treated with a suitable base. Organic solvent is selected from, but not limited to halogenated solvents, alcohols, ketones, cyclic ether, alkoxy alkanes or mixture thereof. Preferably the solvent is selected from methanol ethanol, acetone, tetrahydrofuran, chloroform, dichloromethane, 1,2- dichloroethane, diethoxymethane and the like. Base can be inorganic or organic base. Organic base includes but not limited to ammonia, tertiary amines such as diisopropylethylamine, triethyl amine and the like or solution thereof with solvent selected from water and alcohol. Inorganic base includes but not limited to metal hydroxides such as sodium hydroxide, potassium hydroxide and the like or solution thereof with solvent selected from water and alcohol. The reaction mixture is then treated with a source of calcium ion to form a solution, which can then optionally be filtered, washed with water to remove the unreacted calcium salt and dried over sodium sulfate. The source of calcium ion employed is calcium salt such as calcium chloride or calcium acetate and the like. The calcium salt employed in the reaction can be added as a solid or solution of the salt in a suitable solvent selected from water or alcohol. Thereafter, the amorphous mitiglinide calcium is isolated from the reaction mixture. Isolation of amorphous mitiglinide calcium can be performed via any of the following mentioned two processes. In the first process, the above solution containing mitiglinide calcium is subjected to removal of solvent and isolation of amorphous mitiglinide calcium from the reaction mixture by the processes well known in art. The solvent is preferably removed using, for example, devices like evaporator, rotary evaporator or drying technology such as, for example, vacuum drying, spray drying, freeze drying and the like. More preferably solvent is removed by evaporation and vacuum drying for a period of about 1 to 100 hours to obtain amorphous mitiglinide calcium.

In the second process, the organic solvent containing mitiglinide calcium is optionally concentrated to approximately 2 to 8 times of the amount of mitiglinide used and is mixed with an antisolvent. Antisolvent include, but not limited to non-polar water immiscible aliphatic ethers like diethyl ether, diisopropyl ether, methyl tertiary butyl ether; straight or branched C₅-C₈ aliphatic alkanes like pentane, hexane, heptane, octane; C₅-C₈ cyclic aliphatic alkanes like cyclopentane, cyclohexane, cycloheptane, cyclooctane; aromatic solvents like benzene, toluene, ortho xylene, para xylene, meta xylene; halogenated solvents like chlorobenzene, dichlorobenzene; or mixtures thereof in any suitable proportion to obtain amorphous mitiglinide calcium.

Amorphous, crystalline or crude (5)-mitiglinide calcium salt prepared by the above process is optionally purified to improve the purity of the desired pharmaceutical drug. Generally, the (ιS)-mitiglinide calcium dihydrate salt can be recrystallized using mixture of organic or inorganic solvents. Although similar processes for purification like column chromatography; acid-base treatment; conversion to another salt and reconversion to calcium salt; conversion to (S)-mitiglinide and reconversion to calcium salt etc. can be employed.

(S)-Mitiglinide and crystalline or amorphous (S)-mitiglinide salts prepared by the above process may have purity more than 95% area by high pressure liquid chromatography (HPLC), preferably more than 97% area by high performance liquid chromatography and more preferably more than 99.5% area by high performance liquid chromatography. The substantially pure (S)-mitiglinide or (S)-mitiglinide salts contains identified and unidentified impurities in the amount less than about 0.5 %, preferably less than about 0.2% by weight, more preferably free from the identified and unidentified impurities. In particular, (S)-mitiglinide or its salts obtained by the process described herein contains less than about 0.15% of amide impurity and preferably free from the amide impurity.

As is known in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and by identifying the parameters that influence the amount of impurities in the final product. Moreover, it is important that an impurity present in a product must be identified in any quality control process in order to ensure that the process complies with the required standards set down in the regulatory approval of that product prior to it being released for commercial sale. Therefore present invention provides impurity of formula VII of the mitiglinide and salts thereof.

According to another embodiment, the present invention provides a process for the preparation of novel amide impurity of formula VII by selective base assisted cleavage of amide intermediate of formula VI. According to a preferred embodiment, the present invention provides a process for the preparation of (2S)-2-benzyl-iV-((lR)-l-benzyl-2-hydroxy-ethyl)-4-(hexahydro-isoindol in -2-yl)-4-oxo-butyramide of formula Vila, an isolated impurity of (S)-mitiglinide by base assisted cleavage of (2S)-2-benzyl-l-((4R)- 4-benzyl-2-oxo-oxazolidin-3-yl)-4-(hexahydro-isoindolin-2-yl)-butane- 1 ,4-dione of formula Via. Generally, the process involves treating the solution of amide intermediate of formula VI (preferably Via) with a suitable base. The base employed in the reaction can be used as solid or aqueous solution; preferably aqueous solution of the base is employed. The solution of amide intermediate of formula VI can be prepared by dissolving the amide intermediate in a suitable solvent or can be obtained from the reaction mixture where amide intermediate is prepared. The suitable solvent for the dissolution includes, but are not limited to C2.C₄ nitriles, Ci-C₄ alcohols, tetrahydrofuran, alkoxy alkanes, diols , C_3-C₆ ketones and the like or mixture thereof. Preferably, the solvent can be selected from methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, ethanediol, 1,2 propandiol, 1,3 propandiol, tetrahydrofuran, acetonitrile, 1,2 dimethoxy ethane, 1,2 diethoxy ethane, acetone, ethyl methyl ketone, diethyl ketone and the like or mixture thereof. The dissolution of compound can be optionally performed by heating of the solution. Suitable bases include, but are not limited to alkali metal hydroxides, carbonates or hydrates thereof, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium or potassium carbonate and the like. Reaction can be carried out at a temperature of about 0⁰C to reflux temperature of solvent for few minute to few hours; preferably the reaction mixture is refluxed at a temperature of about 60 to 65⁰C for 6 hours. The reaction mixture is then extracted with water immiscible solvent followed by removal of solvent to give residue. Water immiscible solvents for the extraction include but not limited to C_3-C₈ alkyl esters, halogenated solvents, Cs-Ci₀ aliphatic ethers, aromatic solvents or mixture thereof. Preferably the solvent can be selected from toluene, xylene, dichloromethane and ethylacetate or mixture thereof. The above residue obtained is optionally crystallized from an alcoholic solvent to give a crystalline solid. Alcoholic solvents for crystallization can be selected from methanol, ethanol, isopropanol, n-propanol, n-butanol or isobutanol and the like or mixture thereof.

The amide impurity of (S)-mitiglinide or salts thereof prepared by the process of present invention is highly pure. Preferably it has purity not less than 95.0% by weight with respect to (S)-mitiglinide or salts thereof. Preferably, the amide impurity is isolated in about 99.3% purity by weight; more preferably, the amide impurity is isolated in about 99.7% purity by weight. Thus, the isolated amide impurity contains less than about 5%, preferably less than about 2%, and even more preferably less than about 1%, by weight, (S)- mitiglinide or salts thereof. The HPLC chromatogram of pure amide impurity is shown in Figure 4.

The starting material of formula II employed in the process of present invention can be procured from market or can be prepared by the processes well known in art. Specifically, the compound of formula II is prepared by the reaction of (7ξ)-4-benzyloxazolidin-2-one with 3-phenylpropionic acid or its reactive derivative like acid halide, inorganic or organic acid anhydride, mixed acid anhydride, cyclic carboxy- anhydride, active amide or ester and the like, preferably 3-phenyl propionic acid or 3-phenyl propionyl halide is used. The reaction is generally carried out in presence of a suitable base in a solvent at a temperature of -77 to 50 ⁰C, preferably till the completion of the reaction. The completion of the reaction is monitored by the high pressure liquid chromatography (HPLC) or by thin layer chromatography (TLC). Suitable base includes, but not limited to alkali metal alkyl amides, alkali metal hydrides, Ci-C₆ alkyl lithium, C_1-C₆ dialkyl lithium and the like. Preferably, the base is selected from sodium hydride, potassium hydride, lithium hydride, lithium di-isopropylamide and the like. Suitable solvent includes, but not limited to ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran and the like or halogenated solvent such as dichloromethane, chloroform, 1,2-dichloroethane; aromatic solvents like toluene, xylene; aliphatic ketones like acetone, diethyl ketone, methyl isobutyl ketone and the like or mixture thereof. The reaction can be carried out in the presence of dicyclohexylcarbodiamide in a suitable solvent as described above. The compound of formula II can be used as such or further purified by washing with a solvent selected from aliphatic alkanes such as n-hexane, n-heptane; C_1-C₄ alcohols; C_4-C_-8 ethers; C₃.C₇ esters; aliphatic nitriles and the like or mixture thereof in any suitable proportion. cis-Hexahydroisoindoline and compound of formula III used herein can be procured from market or can be prepared by the processes well known in the art.

The order and manner of combining the reactants in the reactions of the present invention are not important and may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further any of the reactants may be dissolved together as sub-groups and those solutions may be combined in any order.

The desired compound and intermediates prepared as such can be separated and purified by various means known per se such as, for example, concentration, conversion of liquid properties, transfer to another solvent and extraction with a solvent, recrystallization, chromatography and the like. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. EXAMPLES

Example 1: Preparation of (R) 4-benzyl-3-(3-phenylpropionv0-oxazolidin-2-one To a solution of (R)-4-benzyloxazolidin-2-one (50 g), 4-dimethylaminopyridine (4.85 g), 3-phenyl propionic acid (55.08 g) in dichloromethane (375 ml) under nitrogen atmosphere at 0-5 ⁰C, dicyclohexylcarbodiimide (975.65 g) was added. The temperature was slowly raised to 25-30 ⁰C and stirring was continued until no starting material was left as was confirmed by thin layer chromatography. Dicyclohexylurea formed during the reaction was filtered, washed with dichloromethane (200 ml) and the filtrate was washed with saturated solution of sodium bicarbonate (500 ml). The solution was dried over sodium sulphate and solvent was distilled off to obtained crude product which was purified from methanol (200 ml) at 10-15 °C and washed with methanol (50 ml) to obtain 81.0 g of the title compound. Example 2: Preparation of 3(5)-benzyl-4-(4-(J?)-benzyl-2-oxo-oxazolidin-3-yl)-4-oxo-butyrϊc acid tert-butyl ester

To a solution of (/?)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one (150 g) in anhydrous tetrahydrofuran (1.5 It) was added a solution of sodium hexamethyldisilazane (462 ml, 36-38% solution in tetrahydrofuran) with stirring at -85 to -95 ⁰C for 60 minutes. Tert-butyl bromo acetate (137.5 g) in tetrahydrofuran (300 ml) was added to reaction mass and then stirred to 60 minutes at -85 to -95 ⁰C. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ammonium chloride solution (10%, 2.0 It) and extracted with ethyl acetate (2x750 ml). The combined organic layer was washed with demineralized water (1x750 ml) and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain oily residue which was stirred with mixture of n-hexane (100 ml) and isopropyl alcohol (100 ml) at Oto -5 ⁰C, filtered and dried under vacuum to obtain 153.12 g of title compound having chemical purity 99.41%, chiral purity 99.91% by HPLC, [α]_D ²⁰: (-)97.52° (c = 1, CHCl₃) and M.P. : 117.1-118.2⁰C.

Example 3: Preparation of 3(5)-benzyl-4-(4(i?)-benzyl-2-oxo-oxazolidin-3-yl)-4-oxobutyric acid Trifluoroacetic acid (100 g) was added to a solution of 3(5)-benzyl-4-(4-(/?)-benzyl-2-oxo-oxazolidin-3- yl)-4-oxobutyric acid tert-butyl ester (100 g) in dichloromethane (700 ml) at 25 ⁰C and mixture was stirred further for about 12 hours ( when TLC indicated reaction to be complete). The reaction mixture was poured in to ammonium chloride solution (10%, 500 ml). The dichloromethane layer was separated and aqueous layer was extracted with dichloromethane (2 x 250 ml). The combined organic layer was dried over sodium sulphate and evaporated under reduced pressure to obtain title compound. The crude product was recrystallized from a mixture of ethyl acetate: n-hexane (1:4, 500 ml) to obtain 78.75g of the title compound having purity 99.56% by HPLC and M.P.: 145.9-146.4⁰C.

Example 4: Preparation of (2S)-2-benzyl-l-((4R)-4-benzyl-2-oxo-oxazolidin-3-vI)-4-(hexahydro- isoindolin-2-yl)-butane-l,4-dione

To a solution of 3(5)-benzyl-4-(4-(/?)-benzyl-2-oxo-oxazolidin-3-yl)-4-oxo-butyric acid (50 g) in anhydrous dichloromethane (1.25 It) was added triethylamine (50 ml) with stirring at -20 to -30 ⁰C and the stirred for 15 minutes. A solution of isobutylchloroformate (37.50g) in anhydrous dichloromethane (50 ml) was added at -20 to -30 ⁰C and stirred for 60 minutes. Thereafter, a solution of cis- hexahydroisoindoline (32.50 g) in anhydrous dichloromethane (50 ml) was slowly added by maintaining temperature -20 to -30⁰C. After the completion of the reaction (monitored by HPLC), the mixture was successively washed with 0.5N hydrochloric acid solution (500 ml), brine (300 ml) and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain 102.0 g of the title compound having purity 94.39% by HPLC.

Example 5: Purification of r2S)-2-benzyl-l-((4R)-4-benzyl-2-oxo-oxazolidin-3-yl)-4-(hexahydro- isoindolin-2-vD-butane-l,4-dione

To the crude (2S)-2-benzyl-l-((4R)-4-benzyl-2-oxo-oxazolidin-3-yl)-4-(hexahydro-isoindolin-2-yl)- butane- 1,4-dione (51.0 g) was added methanol (150 ml) and the mixture was stirred for 5 hours at 0 to 5 ⁰C. Solid that precipitated out was filtered, slurry washed with cold methanol (25 ml) and dried at 45 -50 ⁰C under vacuum to obtain 28.80 g of pure title compound as a crystalline solid having purity of 99.71% by HPLC and M. P.: 104.1-105.7⁰C.

Example 6: Preparation of calcium salt of (-SVmitiglinide. Step-1: Preparation of (-SVmitiglinide

(2S)-2-Benzyl- 1 -((4R)-4-benzyl-2-oxo-oxazolidin-3-yl)-4-(hexahydro-isoindolin-2-yl)-butane- 1 ,4-dione (28.0 g) was dissolved in tetrahydrofuran (196 ml) and a mixture of lithium hydroxide monohydrate (3.51 g) in demineralized water (56 ml) and hydrogen peroxide (40% solution, 5.5 ml) was added with stirring at 0 to 5 ⁰C over a period of 30 minutes. The reaction mixture was further stirred at 0 to 5 ⁰C till the completion of the reaction. After the completion of the reaction (monitored by TLC), the reaction was quenched with the addition of cooled sodium meta-bisulphate solution (25%, 168 ml) at 0 to 10 ⁰C. The reaction mixture was extracted with ethyl acetate (2x112 ml), the layers were separated and the aqueous layer was discarded. The HPLC analysis of the aqueous layer shows 0.77% of amide impurity. The ethyl acetate layer was then extracted with aqueous ammonia solution (4%, 2x40 ml). The layers were separated and the aqueous layer was further extracted with ethyl acetate (2x280 ml). Combined ethyl acetate layer was discarded. This aqueous layer (280 ml) was used as such in the next stage. The aqueous layer display purity 96.19 % by HPLC and amide impurity 0.04% by HPLC. Step-2: Preparation of calcium salt of dSVmitiglinide

To the above stirred solution of (S)-mitiglinide in water and ammonia(280 ml), methanol (168 ml) was added, followed by calcium chloride (4.48 g) dissolved in demineralized water (56 ml) at ambient temperature and the mixture was stirred for 2 hours. The resulting precipitate was filtered, successively slurry washed with water (3 x 140 ml) and acetone (2 x 70 ml) and dried at 45⁰C -50⁰C under vacuum to obtain 16.1 g of title compound having purity 99.67% by HPLC and amide impurity 0.01% by HPLC. The title product was re-precipitated from a mixture of methanol and water and dried to obtain pure title compound.

Example 7: Preparation of (.SVmitiglinide

To a solution of (2S)-2-benzyl-l-((4R)-4-benzyl-2-oxo-oxazolidin-3-yl)-4-(hexahydro-isoindolin-2-yl)- butane- 1,4-dione (50 g) in tetrahydrofuran (350 ml) was added a solution of lithium hydroxide monohydrate (8.65 g) in demineralized water (100 ml) and hydrogen peroxide (30% w/w, 40 ml) with stirring at 5 to 10 ⁰C over a period of 15 minutes. After the completion of reaction, sodium meta- bisulphate solution (40%, 500 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (2 x 250 ml). The organic layer was dried over sodium sulphate and evaporated under vacuum to obtain 45.5 g of title compound having 35 % of R-benzyl oxozolidin-2-one as impurity. Example 8: Purification of (.S)-mitiglinide

Aqueous ammonia solution (4%, 300 ml) was added to the crude (5)-mitiglinide (30 g) and stirred. The reaction mixture was washed with ethyl acetate (3 x 300 ml). Thereafter the reaction mixture was acidified to pH 1 to 2 with IN hydrochloric acid solution (250 ml) and extracted with ethyl acetate (2 x 150 ml). The layers were separated and ethyl acetate layer was washed with demineralized water (2 x 150 ml), dried over sodium sulphate and then evaporated under reduced pressure to obtain 16.2 g of pure (5)-mitiglinide having purity 95.55% by HPLC Example 9: Preparation of calcium salt of (S)-mitiglinide

To a solution of (<S)-mitiglinide (15 g) in water (150 ml) and aqueous ammonia solution (25%, 15 ml) at 25 to 30 ⁰C, a solution of calcium chloride (7.5 g) in demineralized water (37.5 ml) was added. The mixture was stirred for 1 hour to precipitate the calcium salt of (5)-mitiglinide dihydrate. The resulting precipitate was filtered, slurry washed with water (3 x 150ml) and dried at 45 to 50 ⁰C to obtain 13.25 g of the title compound having purity of 98.84% by HPLC. Example 10: Purification of calcium salt of (5)-mitiglinide

(iS)-mitiglinide calcium (10 g) was dissolved in dimethylformamide (100 ml). This is followed by the addition of demineralized water (500 ml) at 25 to 30 ⁰C. The mixture was stirred for 30 minutes. The precipitated solid was filtered, washed with water (10x 50ml) and dried at 45 to 50 ⁰C under vacuum to obtain 8g of pure title compound as a crystalline solid having purity of 99.62% by HPLC. Example 11: Preparation of amorphous mitiglinide calcium

Crystalline mitiglinide calcium (2.0 g) was dissolved in tetrahydrofuran (20 ml) and filtered to remove undissolved and suspended particles. The solvent was then evaporated under vacuum to obtain a powder which was then dried under vacuum at 40-60⁰C to obtain 1.70 g of the title compound. Example 12: Preparation of amorphous mitiglinide calcium

Crystalline mitiglinide calcium (2.0 g) was dissolved in dichloromethane (30 ml) and filtered to remove undissolved and suspended particles. The solvent was then evaporated under vacuum to obtain a powder which was then dried under vacuum at 40-60⁰C to obtain 1.64 g of the title compound. Example 13: Preparation of amorphous mitiglinide calcium

Mitiglinide (2.0 g) was dissolved in methanol (20 ml) and methanolic ammonia (5.0 ml) solution was added to it. The solution was stirred at 25-30 ⁰C and calcium chloride (1.5 g) dissolved in methanol was mixed with the solution of mitiglinide and ammonia in methanol and the solution was filtered to remove the suspended particles. The solvent was then evaporated under vacuum to obtain a powder which was then dried under vacuum at 40-60⁰C to obtain 1.9 g of the title compound. Example 14: Preparation of amorphous mitiglinide calcium

Mitiglinide (2.0 g) was dissolved in dichloromethane (20 ml) and aqueous ammonia (3.6 ml, 25 % solution) was added to it. The solution was stirred at 25-30⁰C and solid calcium chloride (1.5 g) was mixed with the solution of mitiglinide and ammonia in dichloromethane and the solution warmed at 30 - 35 ⁰C. The solution was washed with water (2 xlO ml) and the clear solution was dried over sodium sulfate, filtered and evaporated under vacuum and finally dried at under vacuum at 40-60 ⁰C to obtain 1.75 g of the title compound.

Example 15: Preparation of amorphous mitiglinide calcium

Crystalline mitiglinide calcium dihydrate (2.0 g) was dissolved in ethyl acetate (30 ml) and filtered to remove undissolved and suspended particles. Approimately. 60 % of the solvent was distilled off under vacuum to obtain a stirrable solution. The solution was then cooled to 15-2O⁰C, mixed with n-heptane (20 ml) and the mixture was stirred for 30 minutes. The resulting solid was filtered, washed with n-heptane and dried under vacuum at 45-60⁰C to yield 1.72 g of the title compound. Example 16: Preparation of amorphous mitiglinide calcium

Crystalline mitiglinide calcium (2.Og) was dissolved in dichloromethane (30 ml) and filtered to remove undissolved and suspended particles. Approximately 60 % of the solvent was distilled off under vacuum to obtain a stirrable solution. The solution was then cooled to 15-20⁰C and mixed with diisopropyl ether (20 ml). The mixture was stirred for 30 minutes and the resulting solid was filtered, washed with diisopropyl ether and dried under vacuum at 45-60⁰C to obtain 1.70 g of the title compound. Example 17: Preparation of amorphous mitiglinide calcium

Mitiglinide (2.0 g) was dissolved in dichloromethane (20 ml) and aqueous ammonia (3.6 ml, 25 % solution) solution was added to it. The solution was stirred at 25-30 ⁰C and mixed with solid calcium chloride (1.5 g) and the solution warmed at 30-35 ⁰C and stirred for 30 minutes. The solution was washed with water (2 x 10 ml) and the clear solution was dried over sodium sulfate, and filtered. Approximately 60% of the solvent was distilled off under vacuum and the resulting viscous oil was cooled to 10-15 ⁰C and mixed with diisopropyl ether (50 ml). The reaction mixture was stirred for 30-35 minutes and the resulting solid was filtered and dried at 40-60⁰C to obtain 1.75 g of the title compound. Example 18: Conversion of amorphous mitiglinide calcium into crystalline mitiglinide calcium A suspension of amorphous mitiglinide calcium in diisopropyl ether (30 ml) was stirred for 2 hours at 25- 30⁰C, filtered and dried under vacuum at 45-60⁰C to obtain crystalline form of mitiglinide calcium. Example 19: Preparation of crystalline mitiglinide calcium

To a solution of mitiglinide (2.5 g) in water (2.5 ml), aqueous ammonia solution (approx 25%, 4.0 ml) and acetonitrile (2.5 ml) at 10-15⁰C, calcium chloride (1.32 g) dissolved in demineralized water (15 ml) was added. The mixture was stirred for 2 hours. The resulting precipitate was filtered, slurry washed with water (3 x 25 ml) and acetone (2 x 5 ml) and dried at 45-50 ⁰C under vacuum to obtain 2.12 g of title compound having purity: 99.72 % by HPLC.

Example 20: Preparation of crystalline mitiglinide calcium

To a solution of mitiglinide (2.5 g) in water (2.5 ml), aqueous ammonia solution (approx 25%, 4.0 ml) and tetrahydrofuran (2.5 ml) at 10-15⁰C, calcium chloride (1.32 g) dissolved in demineralized water (15 ml) was added. The mixture was stirred for 2 hours. The resulting precipitate was filtered, slurry washed with water (3 x 25 ml) and acetone (2 x 5 ml) and dried at 45-50⁰C under vacuum to obtain 1.95 g of title compound having purity: 99.52 % by HPLC.

Example 21; Preparation of crystalline mitiglinide calcium

To a solution of mitiglinide (30.0 g) in water (300 ml), aqueous ammonia solution (approx 25%, 48 ml) and acetone (300 ml) at 10-15⁰C, calcium chloride (15.8 g) dissolved in demineralized water (180 ml) was added. The mixture was stirred for 2 hours. The resulting precipitate was filtered, slurry washed with water (3 x 300 ml) and acetone (2 x 60 ml) and dried at 45-50⁰C under vacuum to obtain 24.32 g of title compound having purity: 99.42 % by HPLC.

Example 22: Preparation of crystalline mitiglinide calcium

To a solution of mitiglinide (3.0 g) in water (30 ml), aqueous ammonia solution (approx 25%, 4.8 ml) and isopropyl alcohol (300 ml) at 10-15⁰C, calcium chloride (1.58 g) dissolved in demineralized water

(18 ml) was added. The mixture was stirred for 2 hours. The resulting precipitate was filtered, slurry washed with water (3 x 30 ml) and acetone (2 x 6 ml) and dried at 45-50⁰C under vacuum to obtain 1.92 g of title compound having purity: 99.65 % by HPLC.

Example 23: Preparation of (2S)-2-benzyWV-((lR)-l-benzyl-2-hydroxy-ethyl)-4-(hexahvdro- isoindolin-2-yl)-4-oxo-buryramide

To a solution of (2S)-2-benzyl-l-((4R)-4-benzyl-2-oxo-oxazolidin-3-yl)-4-(hexahydro-isoindolin-2-yl)- butane-l,4-dione (20.0 g) in tetrahydrofuran (140 ml), a solution of lithium hydroxide monohydrate

(3.43 g,) in demineralized water (40 ml) was added and the reaction mixture was refluxed for 4 hours till the completion of the reactions (monitored by thin layer chromatography). After the completion of the reaction, the reaction mixture was poured into demineralized water (100 ml) and extracted with ethyl acetate (2 x 80 ml). The combined organic layer was washed with water (80 ml) and dried over sodium sulphate. The solvent was evaporated under reduced pressure to give residue which was stirred in isopropyl alcohol at 0-5 ⁰C for 5 hours. The mixture was filtered and then dried at 40-45 ⁰C under vacuum to obtain 12.48 g of title compound having purity 99.77 % by HPLC. Melting point = 77 - 80⁰C.

Claims

WE CLAIM:

1) A process for preparing (S)-mitiglinide of formula I,

Formula I

or pharmaceutically acceptable salts thereof, comprising: a) reacting compound of formula II, Formula II

wherein R is selected from straight chain or branched Cj.Cβ alkyl, unsubstituted or substituted arγl, unsubstituted or substituted arylalkyl with an α-halo ester of formula III, χ^_OR, Formula III

wherein X is halo, preferably selected from chloro, bromo, iodo, and the like and Ri is selected from straight chain or branched Ci-C_t alkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl in the presence of a suitable base in a suitable solvent to form oxazolidine ester derivative of formula

IV;

Formula IV

wherein R and Ri are as defined above b) de-esterifying the compound of formula IV to form corresponding oxazolidine acid derivative of formula V;

Formula V

wherein R is as defined above c) condensing oxazolidine acid derivative of formula V with cis-hexahydroisoindoline in the presence of a suitable activating reagent and a base in an organic solvent; d) isolating amide intermediate of formula VI; Formula VI

wherein R is as defined above e) optionally, recrystallizing the amide intermediate of formula VI using suitable solvent; f) hydrolyzing the amide intermediate of formula VI using a base in the presence of hydrogen peroxide in a solvent to form (S)-mitiglinide of formula I; and g) optionally, converting the same to its pharmaceutically acceptable salts thereof.

2) The process according to claim 1 wherein in step a) solvent includes aliphatic or cyclic ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran; 1,2-dialkoxy alkanes such as 1,2-dimethoxy ethane, 1,2- diethoxy ethane or mixture thereof.

3) The process according to claim 1, wherein in step a) base includes alkali metal hydride, carbonates, amides thereof or alkali metal hexamethyldisilazane.

4) The process according to claim 3, base is selected from sodium hydride, potassium hydride, lithium diisopropylamide, sodium hexamethyldisilazane, lithium hexamethyldisilazane, potassium hexamethyldisilazane and the like.

5) The process according to claim 1, wherein in step b) is carried out in presence of reagent selected from organic or inorganic acid, base.

6) The process according to claim 5, organic acid includes aliphatic or aromatic carboxylic acids such as acetic acid, trifluoroacetic acid, trichloroacetic acid, cumic acid and the like; or sulfonic acids such as para-toluenesulphonic acid, methansulfonic acid, ethanesulfonic acid and the like.

7) The process according to claim 5, inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphonic acid and the like.

8) The process according to claim 5, base includes alkali or alkaline metal hydroxides, carbonates, bicarbonates thereof such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like.

9) The process according to claim 1, wherein in step b) the desertification is carried out by transition metal assisted hydrogenation.

10) The process according to claim 9, transition metal includes palladium, palladium on carbon and the like.

11) The process according to claim 1 wherein in step c) activating reagent includes alkyl, allyl or aryl chloroformates, such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, phenyl chloroformate, benzyl chloroformate and the like; anhydride such as acetic anhydride, propionic anhydride and the like; mixed anhydride such as methyl ethyl anhydride and the like; phosphorous halides such as phosphorous trihalide, phosphorous pentahalide and the like; thionyl halide such as thionyl chloride and the like; organic acid halide such as acetyl chloride, pivaloyl chloride and the like; Lewis acid such as boric acid, aluminium chloride, boron trifluoride, boron tribromide, titanium tetrachloride, titanium trichloride, ferric trichloride and the like; dicyclohexylcarbodiimide.

12) The process according to claim 1 wherein in step c) solvent includes ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran and the like; alkoxy alkanes such as 1,2-dimethoxyethane, 1,2- diethoxyethane and the like; halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform and the like; nitriles such as acetonitrile and the like or mixture thereof.

13) The process according to claim 1 wherein in step c) base includes tertiary amines like triethyl amine, tripropyl amine, tri n-butyl amine, diisopropyl ethyl amine, N-methyl morpholine and the like.

14) The process according to claim 1, wherein in step e) suitable solvent for crystallization of amide intermediate of formula VI includes C_1-C₆ alcohols such as methanol, ethanol, propanol, isopropanol, butanol; C_3-C₈ esters such as ethyl acetate; C_4-C₈ ethers such as tetrahydrofuran, 2- methyltetrahydrofuran; nitriles such as acetonitrile; and the like or mixture thereof or mixture of water miscible organic solvent with water and the like.

15) The process according to claim 1 wherein in step f) suitable base includes alkali metal hydroxides, carbonates or hydrates thereof such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide monohydrate and the like.

16) The process according to claim 1 wherein in step f) the organic solvent includes water miscible solvents selected from C_3-C₈ ethers such as tetrahydrofuran; nitrile such as acetonitrile; Ci-C₆ alcohol such as methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol; diols such as ethanediol, 1,2 propandiol, 1,3 propandiol; ketones such as acetone, ethyl methyl ketone, diethyl ketone; alkoxy alkanes such as 1,2 dimethoxy ethane, 1,2 diethoxy ethane; and the like or mixture thereof.

17) The process according to claim 1 wherein in step f) (S)-mitiglinide is not isolated, reaction mixture containing (S)-mitiglinide is used as such for conversion to (S)-mitiglinide pharmaceutically acceptable salts.

18) The process according to claim 1 wherein step in f) (S)-mitiglinide is isolated.

19) A compound of formula VI including salts, solvates, hydrates, polymorphs, isomers and racemic mixture thereof.

20) A compound of formula Via including salts, solvates, hydrates, polymorphs, isomers and racemic mixture thereof. Formula Via

wherein R is as defined above

21) A crystalline compound of formula Via, having X-ray diffraction pattern as depicted in figure 1.

22) Amorphous mitiglinide calcium.

23) A process for the preparation of amorphous mitiglinide calcium, the process comprising a) dissolving mitiglinide calcium in a suitable solvent; b) admixing an anti-solvent; and c) isolating the amorphous mitiglinide calcium.

24) The process according to claim 23, wherein in step a) suitable solvent include halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform; esters such as ethyl acetate; alkoxy alkanes such as 1,2-dimethoxy ethane; and the like or mixture thereof in any suitable proportions.

25) The process according to claim 23, wherein in step b) antisolvent include aliphatic ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether; straight or branched C₅ to C₈ aliphatic alkanes such as pentane, hexane, heptane, n-octane,; C₅ to C₈ cyclic aliphatic alkanes such as cyclopentane, cyclohexane, cycloheptane, cyclooctane; aromatic solvents such as benzene, toluene, ortho-xylene, para-xylene, meta-xylene; halogenated solvents such as chlorobenzene, dichlorobenzene; and the like or mixture thereof in any suitable proportions.

26) A process for the preparation of amorphous mitiglinide calcium, the process comprising a) providing a solution of mitiglinide calcium in a suitable solvent; b) removing the solvent; and c) isolating the amorphous mitiglinide calcium.

27) The process according to claim 26, wherein in step a) suitable solvent includes alcohols such as methanol, ethanol; cyclic ethers such as tetrahydrofuran; ketones such as acetone; halogenated solvents such as dichloromethane, chloroform; esters such as ethyl acetate; and the like or mixture thereof.

28) The process according to claim 26, wherein in step b) the solvent is removed by suitable techniques such as evaporation, drying, distillation and the like.

29) A process for the preparation of amorphous mitiglinide calcium directly from mitiglinide, comprising a) providing a solution of mitiglinide in an organic solvent; b) adding a suitable base to the solution; c) treating the resulting solution with a source of calcium ion; and d) isolating the amorphous mitiglinide calcium.

30) The process according to claim 29, wherein step a) organic solvent include halogenated solvents, such as chloroform, dichloromethane, 1,2-dichloroethane; alcohols such as methanol, ethanol, ketones, cyclic ether such as tetrahydrofuran, alkoxy alkanes such as diethoxyethane; and the like or mixture thereof.

31) The process according to claim 29, wherein in step b) base include organic base selected from ammonia, tertiary amines such as diisopropylethylamine, triethyl amine and the like or solution thereof with solvent selected from water and alcohol; or inorganic base selected from metal hydroxides such as sodium hydroxide, potassium hydroxide and the like or solution thereof with solvent selected from water and alcohol.

32) The process according to claim 29, wherein in step c) source of calcium ion include calcium salt selected from calcium chloride, calcium acetate and the like or solution thereof in a suitable solvent selected from water or alcohol.

33) The process according to claim 29, wherein isolation of the mitiglinide is carried out by removing the solvent.

34) The process according to claim 29, wherein isolation of the mitiglinide is carried out by concentrating the reaction mixture and; admixing an antisolvent.

35) The process according to claim 34, antisolvent include non-polar water immiscible aliphatic ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether; straight or branched Cs-C₈ aliphatic alkanes such as pentane, hexane, heptane, octane; C₅-C₈ cyclic aliphatic alkanes such as cyclopentane, cyclohexane, cycloheptane, cyclooctane; aromatic solvents such as benzene, toluene, ortho xylene, para xylene, meta xylene; halogenated solvents such as chlorobenzene, dichlorobenzene; and the like or mixtures thereof in any suitable proportion.

36) A process for the preparation conversion of amorphous mitiglinide calcium to crystalline mitiglinide calcium, comprising a) providing a solution of amorphous mitiglinide calcium in a suitable solvent; and b) stirring the solution for a time sufficient to convert in to crystalline form of mitiglinide calcium

37) The process according to claim 36, the solution is stirred for about 1 to 24 hours.

38) The process according to claim 36, suitable solvents include aliphatic ethers, straight or branched C₅- C₈ aliphatic alkanes, C₅-C₈ cyclic aliphatic alkanes, aromatic solvents, halogenated solvents and the like or mixture thereof or mixture thereof with water or water miscible solvent such as Cj-C₈ alcohol, C₃-C₈ ketones, acetonitrile, tetrahydrofuran, 1,2-dimethoxy ethane and the like in any suitable proportion.

39) The process according to claim 38, solvent is selected from diethyl ether, diisopropyl ether, methyl tertiary butyl ether, pentane, , hexane, heptane, octane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, benzene, toluene, ortho xylene, para xylene, meta xylene, chlorobenzene, dichlorobenzene and the like or mixture thereof.

40) A process for the preparation of crystalline mitiglinide calcium, directly from mitiglinide; comprising a) providing a solution of mitiglinide in a suitable solvent; b) optionally adding a suitable base to the solution; and c) treating the resulting solution with a source of calcium ion; and d) isolating the crystalline mitiglinide calcium.

41) The process according to claim 40, wherein in step a) suitable solvent is selected from alcohols such as methanol, ethanol, isopropyl alcohol; aliphatic ketones such as acetone, diethyl ketone, ethyl methyl ketone; ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, methyl tetrahydrofuran; nitriles such as acetonitrile; Cs-C₈ linear, branched and cyclic alkanes and the like or mixture thereof or mixture with water.

42) The process according to claim 40, wherein in step b) base include organic base selected from ammonia or inorganic base selected from metal hydroxide, metal carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide and the like.

43) The process according to claim 40, wherein in step c) source of calcium ion include calcium salt selected from calcium chloride, calcium acetate and the like or solution thereof in a suitable solvent selected from water or alcohol.

44) The process according to claim 40, wherein isolated crystalline mitiglinide calcium is optionally stirred in a suitable solvents selected from water, alcohols such as methanol, ethanol, isopropyl alcohol; aliphatic ketones such as acetone, diethyl ketone, ethyl methyl ketone; ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, methyl tetrahydrofuran; nitriles such as acetonitrile; Cs-C₈ linear, branched and cyclic alkanes and the like or mixture thereof.

45) A compound having formula VII including salts, solvates, hydrates, polymorphs, isomers and racemic mixtures thereof.

Formula VII

wherein R is as defined above 46) (2S)-2-Benzyl-N-(( 1 R)- 1 -benzyl-2-hydroxy-ethyl)-4-(hexahydro-isoindolin-2-yl)-4-oxo-butyramide of formula Vila including salts, solvates, hydrates, polymorphs, isomers and racemic mixtures thereof.

Formula Vila

47) Substantially pure (S)-mitiglinide or salts thereof having less than 0.15% of an amide impurity of formula VII.

48) A process for preparing substantially pure (S)-mitiglinide or salts thereof having less than 0.15% of impurity of formula VII, comprising: a) hydrolyzing the amide intermediate of formula VI; b) with suitable base and hydrogen peroxide; c) acidifying the reaction mixture with dilute acid; d) extracting the reaction mixture with water immiscible organic solvent; e) optionally, isolating crude (S)-mitiglinide; f) treating reaction mixture or (S)-mitiglinide with a suitable base; g) optionally, recovering the substantially pure (S)-mitiglinide; and h) converting the same to (S)-mitiglinide salt.

49) The process according to claim 48, wherein in step (a) suitable base include alkali metal hydroxides, carbonates or hydrates thereof such as lithium hydroxide monohydrate, sodium hydroxide or potassium hydroxide, sodium carbonate, potassium carbonate and the like.

50) The process according to claim 48, wherein in the step (b) acid is selected from organic and inorganic acid.

51) The process according to claim 50, organic acid includes carboxylic acid such as acetic acid, formic acid, propionic acid and the like; or sodium metabisulphite solution or inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.

52) The process according to claim 48, wherein in step (d) organic solvent used for extraction includes C_5- C₈ alkanes such as n-pentane, n-hexane, n-heptane, n-octane and the like; halogenated solvents such as dichloromethane, chloroform, 1,2 dichloroethane and the like; C_4-C₁₀ ethers such as diethyl ethers, isopropyl ether, methyl tertiarybutyl ether and the like; C_3-C₈ esters such as ethyl acetate, methyl acetate, ethyl propionate and the like; aliphatic or aromatic hydrocarbon such as toluene, 1,2- xylene, 1,4-xylene and the like; or mixtures thereof. 53) The process according to claim 48, wherein in step (e) suitable base includes amines of general formula NR₁R₂R₃ wherein Ri, R₂ andR^ can be independently selected from hydrogen, unsubstituted or monosubstituted or polysubstituted (Ci-Cβ)-alkyl; (Cι-Cs)cycloalkyl, alkenyl, aϊkynyl, alkaryl, aryl, arylalkyl, alkoxy, aryloxy, aminoalkyl or aminoaryl or a three to six membered heterocyclic ring with one or more hetero atom selected from nitrogen, oxygen or sulphur.

54) The process according to claim 53, suitable base is selected from ammonia, 1,2-dimethylpropylamine, 3-(2-aminoethylamino)-propylamine, butylamine, amylamine, cyclohexylamine, cycloheptylamine, dicyclohexylamine, N-methylcyclohexylamine, N,N'-diisopropylethylenediamine, NN- diethylenediamine, N-methyl-l,3-propanediamine, N-methylethylenediamine, NNN'N'-tetramethyl- 1,2-diaminoethane, NNN',N'-tetramethyl-l-,4-diaminobutane, 1,2-dipiperidinethane, 2-amino-3,3- dimethylbutane, NN-dimethylcyclohexylamine, neopentylamine, N-methylcyclohexylamine, N- isopropylccyclohexylamine, N,N'-diethylcyclohexcylamine, and the like.

55) The process according to claim 48, amide intermediate of formula VI is (2S)-2-benzyl-l-((4R)-4- benzyl-2-oxo-oxazolidin-3 -yl)-4-(hexahydro-isoindolin-2-yl)-butane- 1 ,4-dione.

56) A process for preparing compound of formula VII comprising: a) providing the solution of amide intermediate formula VI; b) treating the above solution with suitable base; c) isolating the compound; and d) optionally, recrystallizing using a suitable solvent.

57) The process according to claim 56, wherein in step (a) solvent includes C_2-C₄ nitriles such as acetonitrile and the like; C_1-C ₄ alcohol such as ethanol, isopropanol, n-propanol, butanol, isobutanol and the like; diols such as ethanediol, 1,2 propandiol and 1,3 propandiol and the like; tetrahydrofuran; alkoxyalkane such as 1,2 dimethoxy ethane, 1,2 diethoxy ethane and the like; C_3-C ₆ ketones such as acetone, methyl ethyl ketone, diethyl ketone and the like; or mixture thereof.

58) The process according to claim 56, wherein in step (b) suitable base includes alkali metal hydroxides, carbonates or hydrates thereof such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate and the like.

59) The process according to claim 56, wherein in step (d) the suitable solvent is alcoholic solvent such as methanol, ethanol, isopropanol, n-propanol, n-butanol or isobutanol or mixture thereof.

60) The process according to claim 56, wherein the (2S)-2-benzyl-N-(( IR)-I -benzyl-2-hydroxy-ethyl)-4- (hexahydro-isoindolin-2-yl)-4-oxo-butyramide of formula Vila is prepared from (2S)-2-benzyl-l- ((4R)-4-benzyl-2-oxo-oxazolidin-3-yl)-4-(hexa hydro-isoindolin-2-yl)-butane- 1 ,4-dione.