WO2009047797A2 - Procédé de préparation d'un dérivé du perhydroisoindole - Google Patents

Procédé de préparation d'un dérivé du perhydroisoindole Download PDF

Info

Publication number
WO2009047797A2
WO2009047797A2 PCT/IN2008/000645 IN2008000645W WO2009047797A2 WO 2009047797 A2 WO2009047797 A2 WO 2009047797A2 IN 2008000645 W IN2008000645 W IN 2008000645W WO 2009047797 A2 WO2009047797 A2 WO 2009047797A2
Authority
WO
WIPO (PCT)
Prior art keywords
mitiglinide
process according
formula
acid
calcium
Prior art date
Application number
PCT/IN2008/000645
Other languages
English (en)
Other versions
WO2009047797A3 (fr
Inventor
Gurdeep Singh Sarin
Chidambaram Venkateswaran Srinivasan
Lalit Wadhwa
Original Assignee
Ind-Swift Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ind-Swift Laboratories Limited filed Critical Ind-Swift Laboratories Limited
Publication of WO2009047797A2 publication Critical patent/WO2009047797A2/fr
Publication of WO2009047797A3 publication Critical patent/WO2009047797A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • desired enantiomer can be obtained by selective recrystallization of one enantiomer.
  • 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.
  • 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).
  • amorphous products are in general more soluble and often show improved absorption in humans.
  • 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.
  • 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.
  • 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- ⁇ /-((lR)-l- benzyl-2-hydroxy-ethyl)-4-(hexahydro-isoindolin-2-yl)-4-oxo-butyramide as impurity of (S)-mitiglinide and process of preparation thereof.
  • the present invention relates to a novel and an industrially advantageous process for preparing perhydroisoindole derivative, particularly (S)-mitiglinide of formula I,
  • 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
  • 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.
  • the present invention provides a novel amide intermediate of formula VI including salts, solvates, hydrates, polymorphs, isomers and racemic mixtures thereof.
  • 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.
  • present invention provides crystalline form of amide intermediate of formula Via.
  • the present invention provides mitiglinide calcium in amorphous form.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides an amide impurity of formula VII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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;
  • 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-
  • 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.
  • the term "mitiglinide” refers to (S)-mitiglinide.
  • the term “mitiglinide salts” refers to (S)-mitiglinide calcium, preferably (S)-mitiglinide calcium dihydrate.
  • the term “amide intermediate” includes salts, solvates, hydrates, polymorphs, isomers and racemic mixtures thereof.
  • the amide impurity referred to in the application includes both the racemic mixture and the enantiomerically pure form.
  • 2- benzyl-N-(l-benzyl-2-hydroxy-ethyl)-4-(hexahydro-isoindolin-2-yl)-4-oxo-butyramide refers to either
  • amide impurity includes salts, solvates, hydrates, polymorphs, isomers and racemic mixtures thereof.
  • 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.
  • 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.
  • 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 ⁇ -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.
  • the reaction is carried out at a temperature of about -110 to -50 0 C for few minutes to a few hours.
  • the reaction is carried out at a temperature of -100 to -90 0 C for 1 to 6 hours, more preferably reaction is carried out till the completion of the reaction.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 C 1 -C 4 alcohols, halogenated solvents, aliphatic ethers, cyclic ether, alkoxy alkanes, esters and the like or mixture thereof.
  • 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-C 5 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.
  • 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 chlorofo ⁇ nate, methyl chloroformate, phenyl chlorofo ⁇ nate, 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.
  • 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.
  • 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.
  • 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 60 0 C.
  • the reaction is carried out at a temperature of -20 to 20 0 C till the completion of the reaction.
  • alcoholic solvent is added to the above reaction mixture at a temperature of 5 0 C to reflux temperature of solvent.
  • solution is stirred at a temperature of about 0 to 15 0 C.
  • 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.
  • Suitable solvent for purification includes, but not limited to Ci-C 6 alcohols, Ci-C 8 esters, Ci-C 8 ethers, nitriles, or mixture thereof or mixture of water miscible organic solvent with water.
  • 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 1 H Nuclear magnetic resonance spectroscopy (NMR), 13 C 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 ⁇ (CDCl 3 , 400 MHz): 1.33-1.57 (8H, m, CH 2 at C 8 , C 9 , C 10 and C 11 ); 2.09-2.29 (2H, m, CH_at C 7 , C 12 ); 2.34-2.87 (4H, m, CH 2 at C 3 , C 14 ); 3.03-3.43 (6H, m, CH 2 at C 26 , C 6 , C 13 ); 3.90-4.07 (2H, m, CH 2 at C 24 ); 4.50-4.64 (2H, m, CH_at C 2 , C 25 ); 7.22-7.34 (1OH, m, aromatic H).
  • 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.
  • 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 50 0 C 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-C 4 alcohols, tetrahydrofuran, nitriles, alkoxyalkanes, diols, ketones and the like or mixture thereof.
  • 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.
  • 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 40 0 C for 24 hours.
  • the reaction mixture is stirred at a temperature of -5 to 25 0 C 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).
  • TLC thin-layer chromatography
  • HPLC high performance liquid chromatography
  • 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.
  • (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-C 8 alkanes, C 4- Ci 0 aliphatic ethers, C 3- C 8 esters, halogenated solvents, aromatic or aliphatic hydrocarbons and the like or mixture thereof.
  • 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.
  • 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.
  • 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.
  • 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 1 H and 13 C 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 ⁇ (CDC1 3 ):1.35-1.58 (8H, m, 4CH 2 at C 8- ,,); 2.13-2.34 (3H, m, CH at C 7 & C 12 and OH ); 2.59-2.74 (2H, m, CH 2 at C 3 ); 2.79-2.81 (2H, m, CH 2 at C 14 ); 2.93-3.01 (2H, m, CH 2 at C 25 ); 3.14-3.84 (7H, m, CH 2 at C 6 , C 13 , C 23 and CH at C 2 ); 3.97-3.99 (IH, m, CH at C 22 ); 6.92-6.96 (IH, m, NH); 7.11- 7.27 (1OH, m, Aromatic H).
  • the isolated amide impurity of formula Vila is having melting point in range of 77 to 80 0 C.
  • 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 13 C-NMR spectra each at 139.33/139.35 (C 26 ); 170.66 (C 4 ); 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.
  • 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.
  • 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.
  • 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.
  • 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 0 C.
  • the base employed in the reaction can be solid or aqueous solution.
  • 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.
  • 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.
  • (S)- mitiglinide is isolated from the reaction mixture by suitable techniques known in art such as distillation of the solvent and the like.
  • Base can be an organic amine, which includes, but not limited to amine of general formula NR 1 R 2 R 3 wherein Ri, R2 and Rs can be independently selected from hydrogen, unsubstituted or monosubstituted or polysubstituted (Ci-C ⁇ )-alkyl; (C 1 -C 3 ) 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.
  • Ri, R2 and Rs can be independently selected from hydrogen, unsubstituted or monosubstituted or polysubstituted (Ci-C ⁇ )-alkyl; (C 1 -C 3 ) cycloalkyl, alkenyl, alkynyl, alkaryl, aryl, arylalkyl,
  • 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,
  • 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.
  • (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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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-C 8 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 .
  • 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.
  • PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities.
  • All infrared measurements are made on Perkin Elmer Spectrum 100 spectrometer using KBr pellets having the characteristic absorption bands expressed in reciprocal centimeter.
  • the present invention provides a process for the preparation of amorphous mitiglinide calcium by employing solvent antisolvent system.
  • 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.
  • 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 C 5 to C 8 aliphatic alkanes, C 5 to C 8 cyclic aliphatic alkanes, aromatic solvents, halogenated solvents or mixture thereof in any suitable proportions.
  • 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.
  • 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.
  • 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 C 5 -C 8 aliphatic alkanes like pentane, , hexane, heptane, octane; Cs-C 8 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 C 1 -C 8 alcohol, C 3 -C 8 ketones, acetonitrile, tetrahydrofuran, 1,2-dimethoxy ethane and the like in any
  • the present invention provides another process for the preparation of amorphous mitiglinide calcium.
  • 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.
  • a suitable solvent selected from, but not limited to alcohols, cyclic ethers, ketones, esters, halogenated solvents or mixture thereof in any suitable proportions.
  • the solvent is selected from methanol, ethanol, tetrahydrofuran, acetone, dichloromethane, chloroform, ethyl acetate and the like or mixture thereof.
  • further purification steps e.g. by filtering and/or adding of active charcoal may become necessary to obtain a clear solution.
  • 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.
  • the present invention provides a process for the preparation of amorphous mitiglinide calcium directly from mitiglinide of formula I.
  • 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.
  • 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.
  • 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.
  • 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 C 5 -C 8 aliphatic alkanes like pentane, hexane, heptane, octane; C 5 -C 8 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, crystalline or crude (5)-mitiglinide calcium salt prepared by the above process is optionally purified to improve the purity of the desired pharmaceutical drug.
  • the ( ⁇ S)-mitiglinide calcium dihydrate salt can be recrystallized using mixture of organic or inorganic solvents.
  • (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.
  • HPLC high pressure 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.
  • (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.
  • 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.
  • 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.
  • 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.C 4 nitriles, Ci-C 4 alcohols, tetrahydrofuran, alkoxy alkanes, diols , C 3- C 6 ketones and the like or mixture thereof.
  • 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 0 0 C to reflux temperature of solvent for few minute to few hours; preferably the reaction mixture is refluxed at a temperature of about 60 to 65 0 C 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- C 8 alkyl esters, halogenated solvents, Cs-Ci 0 aliphatic ethers, aromatic solvents or mixture thereof.
  • 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.
  • 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.
  • 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.
  • the compound of formula II is prepared by the reaction of (7 ⁇ )-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 0 C, preferably till the completion of the reaction.
  • Suitable base includes, but not limited to alkali metal alkyl amides, alkali metal hydrides, Ci-C 6 alkyl lithium, C 1- C 6 dialkyl lithium and the like.
  • 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- C 4 alcohols; C 4- C -8 ethers; C 3 .C 7 esters; aliphatic nitriles and the like or mixture thereof in any suitable proportion.
  • a solvent selected from aliphatic alkanes such as n-hexane, n-heptane; C 1- C 4 alcohols; C 4- C -8 ethers; C 3 .C 7 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.
  • 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 0 C, dicyclohexylcarbodiimide (975.65 g) was added. The temperature was slowly raised to 25-30 0 C and stirring was continued until no starting material was left as was confirmed by thin layer chromatography.
  • 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.
  • 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 0 C 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).
  • Example 6 Preparation of calcium salt of (-SVmitiglinide.
  • Step-1 Preparation of (-SVmitiglinide
  • the reaction was quenched with the addition of cooled sodium meta-bisulphate solution (25%, 168 ml) at 0 to 10 0 C.
  • 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.
  • 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).
  • 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 0 C 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 40-60 0 C 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 25-30 0 C 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 0 C. 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 0 C to obtain 1.75 g of the title compound.
  • 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 15-2O 0 C, 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 45-60 0 C 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 15-20 0 C 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 45-60 0 C 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 0 C and mixed with solid calcium chloride (1.5 g) and the solution warmed at 30-35 0 C 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 0 C and mixed with diisopropyl ether (50 ml).
  • 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- 30 0 C, filtered and dried under vacuum at 45-60 0 C to obtain crystalline form of mitiglinide calcium.
  • Example 19 Preparation of crystalline mitiglinide calcium

Abstract

La présente invention concerne un nouveau procédé, efficace et industriellement avantageux de préparation d'un dérivé du perhydroisoindole, en particulier le (S)-mitiglinide de formule (I) : et des sels pharmaceutiquement acceptables de ceux-ci. En outre, l'invention concerne de nouveaux intermédiaires amides de formule (VI), y compris les sels, les solvates, les hydrates, les polymorphes, les isomères et les mélanges racémiques de ceux-ci utiles dans le procédé de la présente invention. Formule (VI) : R étant choisi parmi une chaîne alkyle en C1 à C6 linéaire ou ramifiée, un aryle non substitué ou substitué, un arylalkyle non substitué ou substitué. La présente invention concerne également la forme amorphe du mitiglinide de calcium, sa préparation et un procédé pour sa conversion en mitiglinide de calcium cristallin.
PCT/IN2008/000645 2007-10-08 2008-10-07 Procédé de préparation d'un dérivé du perhydroisoindole WO2009047797A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IN2096/DEL/2007 2007-10-08
IN2096DE2007 2007-10-08
IN2765/DEL/2007 2007-12-28
IN2765DE2007 2007-12-28
IN2031/DEL/2008 2008-08-27
IN2031DE2008 2008-08-27

Publications (2)

Publication Number Publication Date
WO2009047797A2 true WO2009047797A2 (fr) 2009-04-16
WO2009047797A3 WO2009047797A3 (fr) 2011-05-26

Family

ID=40549714

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000645 WO2009047797A2 (fr) 2007-10-08 2008-10-07 Procédé de préparation d'un dérivé du perhydroisoindole

Country Status (1)

Country Link
WO (1) WO2009047797A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102898348A (zh) * 2012-06-27 2013-01-30 迪沙药业集团有限公司 一种米格列奈钙的制备方法
CN103450069A (zh) * 2013-06-24 2013-12-18 山西大同大学 一种米格列奈钙的制备方法
CN103724253A (zh) * 2013-12-11 2014-04-16 苑振亭 一种米格列奈钙的制备方法
CN109425666A (zh) * 2017-08-28 2019-03-05 广东东阳光药业有限公司 一种酰氯衍生物的lc-ms分析方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0507534A1 (fr) * 1991-03-30 1992-10-07 Kissei Pharmaceutical Co., Ltd. Dérivés de l'acide succinique
EP0967204A1 (fr) * 1997-01-29 1999-12-29 Kissei Pharmaceutical Co. Ltd. Procede de production de derives d'acide benzylsuccinique
US6133454A (en) * 1997-07-03 2000-10-17 Adir Et Compagnie Method for preparing a substituted perhydroisoindole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0507534A1 (fr) * 1991-03-30 1992-10-07 Kissei Pharmaceutical Co., Ltd. Dérivés de l'acide succinique
EP0967204A1 (fr) * 1997-01-29 1999-12-29 Kissei Pharmaceutical Co. Ltd. Procede de production de derives d'acide benzylsuccinique
US6133454A (en) * 1997-07-03 2000-10-17 Adir Et Compagnie Method for preparing a substituted perhydroisoindole

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102898348A (zh) * 2012-06-27 2013-01-30 迪沙药业集团有限公司 一种米格列奈钙的制备方法
CN102898348B (zh) * 2012-06-27 2015-09-02 迪沙药业集团有限公司 一种米格列奈钙的制备方法
CN103450069A (zh) * 2013-06-24 2013-12-18 山西大同大学 一种米格列奈钙的制备方法
CN103724253A (zh) * 2013-12-11 2014-04-16 苑振亭 一种米格列奈钙的制备方法
CN103724253B (zh) * 2013-12-11 2016-06-15 苑振亭 一种米格列奈钙的制备方法
CN109425666A (zh) * 2017-08-28 2019-03-05 广东东阳光药业有限公司 一种酰氯衍生物的lc-ms分析方法

Also Published As

Publication number Publication date
WO2009047797A3 (fr) 2011-05-26

Similar Documents

Publication Publication Date Title
US8946477B2 (en) Solid forms of an N-(phenylmethyl) propanamide derivative and processes of preparation
NO336765B1 (no) Fremgangsmåte for fremstilling av (R)-2-acetamido-N-benzyl-3-metoksypropionamid (lacosamid).
KR101540435B1 (ko) 발리올아민의 입체선택적 합성
JP2008239629A (ja) 新規なベンラファクシン塩酸塩多型形状、ならびにその調製方法
WO2014020555A2 (fr) Procédé amélioré de préparation d'étexilate-mésylate de dabigatran
US20080167477A1 (en) Novel polymorphic forms of carvedilol dihydrogen phosphate and process for preparing the same
US20210323920A1 (en) Method of preparing 5r-[(benzyloxy) amino] piperidine-2s-carboxylic acid or a derivative thereof
US11760723B2 (en) Method of preparing a DON prodrug from L-pyroglutamic acid
WO2009047797A2 (fr) Procédé de préparation d'un dérivé du perhydroisoindole
KR20100022081A (ko) 결정성 로티고틴 염기 및 이의 제조 방법
US9771317B2 (en) Process for preparing lacosamide and related compounds
US20180339964A1 (en) The process of preparing indoline compounds and a novel indolinesalt
NZ547354A (en) A process for resolving, optionally substituted, mandelic acids by salt formation with a chiral base cyclic amide
US8278484B2 (en) Process for preparing a benzoylbenzeneacetamide derivative
WO2008096373A2 (fr) Procédé de synthèse de polymorphes de natéglinide extrêmement pure
KR100743617B1 (ko) 고광학순도를 갖는 키랄 3-히드록시 피롤리딘 및 그유도체를 제조하는 방법
EP2032581B1 (fr) Composés enrichis en énantiomères et procédé
AU2005209382B2 (en) Method for producing a 2-(ethoxymethyl)tropane derivative
JP5569397B2 (ja) ２−ヒドロキシメチルモルホリン塩の製造方法
US20050239837A1 (en) Process for production of highly pure donepezil hydrochloride
Lysenko et al. A convenient procedure for preparation of 1-(1-aminoalkyl)-1-cyclopropanols from N-benzyl α-amino acid esters
WO2013054273A2 (fr) Procédé pour la préparation d'agomélatine
JPH09143127A (ja) ニトロトルエン誘導体およびその製造方法
JPS58164573A (ja) １−（４−クロロベンゾイル）−５−メトキシ−２−メチル−３−インド−ルアセトキシ酢酸類の製法
WO2013080095A1 (fr) Procédé de préparation d'agomélatine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08836822

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08836822

Country of ref document: EP

Kind code of ref document: A2