WO2021079380A1 - Improved process for the preparation of (2s)-n-{(1s)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)-amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-n-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide - Google Patents

Abstract

The present invention relates to improved process for the preparation of (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)-amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide and its pharmaceutically acceptable salts represented by the following structural formula. Formula-1 The present invention relates to novel intermediates useful in the preparation of Ivosidenib of formula-1 and novel process for the preparation of (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)-amino]-2­oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide. The present invention also relates to solid state forms of (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)-amino]-2­ oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide.

Description

Improved process for the preparation of (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluoro cyclobutyl)-amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5- oxopyrrolidine-2-carboxamide

Related Application:

This application claims the benefit of priority of our Indian patent application numbers 201941043015 filed on 23 October 2019 and 202041030704 18 July 2020 which is incorporated herein by reference.

Field of the Invention:

The present invention relates to improved process for the preparation of (2S)-N-{(1S)-1- (2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)-amino]-2-oxoethyl}-l-(4-cyanopyridin-2-yl)-N-(5- fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide.

Background of the Invention:

Ivosidenib is chemically known as (2S)-N- { ( 1 S)- 1 -(2-chlorophenyl)-2- [(3,3-difluoro cyclobutyl)-amino] -2-oxoethyl } - 1 -(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxo pyrrolidine-2-carboxamide represented by the following structural formula.

Ivosidenib is a small chiral molecule with two stereogenic centers. It has excellent permeability across Caco-2 cells and has therefore been classified as a BCS Class 2 compound.

Ivosidenib is approved by USFDA as tablet for oral administration for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase- 1 (IDH1) mutation as detected by an FDA-approved test.

(2S)-N- {(1S)-1 -(2-chlorophenyl-2-[(3 ,3-difluorocyclobutyl)-amino] -2-oxoethyl } - 1 -(4- cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide was disclosed in US9474779 B2. International PCT publication No. WO2015/138839 A1 discloses crystalline forms 1 and 2 of Ivosidenib.

Thus, there is a need for development of a process for the preparation of Ivosidenib, which is efficient, economical and feasible at commercial scale.

Brief description of the Invention:

The present invention relates to improved process for the preparation of Ivosidenib. The present invention also relates to solid state forms of Ivosidenib.

Brief description of Drawings:

Figure-1: Illustrates the PXRD pattern of amorphous form of Ivosidenib of formula- 1.

Figure-2: Illustrates the PXRD pattern of crystalline form-M of compound of formula-9. Figure-3: Illustrates the PXRD pattern of crystalline form-S of Ivosidenib of formula- 1. Figure-4: Illustrates the PXRD pattern of crystalline form-N of Ivosidenib of formula- 1.

Detailed description of the Invention:

The term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, n-pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N -methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone, acetyl acetone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1,2- ethoxy ethanol, diethylene glycol, 1,2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.

The “suitable base” as used in the present invention is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethylamine, methyl amine, ethylamine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1 ,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium diisopropylamide (LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine, diisopropylethylamine, N-methyl-2-pyrrolidone (NMP), N-methylmorpholine, N-ethylmorpholine, piperidine, 4-dimethylaminopyridine (DMAP), morpholine, pyridine, 2,6- lutidine, 2,4,6-collidine, imidazole, 1 -methyl imidazole, 1,2,4-triazole, 1 ,4-diazabicyclo[2.2.2] octane (DABCO) or mixtures thereof.

The “suitable acid” is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, paratoluenesulfonic acid, ethane- 1 ,2-disulfonic acid, camphorsulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid.

The term “enantiopure” as used herein means that a compound has an enantiomeric excess of at least 80%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99%.

The term “enantiopure” as used herein means that an enantiomer is present in a purity of at least 99% enantiomeric excess, preferably in a purity of 99.5-100% enantiomeric excess.

In the first embodiment, the present invention provides a process for the preparation of Ivosidenib compound of formula- 1

comprises one or more reaction steps of the following synthetic scheme.

Wherein “R” is selected from substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group and substituted or unsubstituted aralkyl group.

The term substituted or unsubstituted alkyl group refers to straight or branched chain hydrocarbon groups having 1-20 carbon atoms, preferably 1-7 carbon atoms. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl , octyl and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halo, hydroxy, cycloalkyl, alkoxy, alkenyl, alkynyl, alkylthio, alkylthiono, sulfonyl, nitro, cyano, alkoxycarbonyl, aryl, aralkoxy, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like.

The term unsubstituted and substituted aryl groups refers to phenyl or naphthyl groups, such as phenyl, naphthyl, tolyl, xylyl, mesityl, triisopropylphenyl, methoxyphenyl, chlorophenyl, and nitrophenyl and the like.

The compound of the formula-2 used in the present invention is synthesized from any of the known prior art processes.

In the second embodiment, the present invention provides a process for the preparation of Ivosidenib compound of formula- 1, which comprises: a) reacting compound of formula-2 with 2-bromoisonicotinonitrile in the presence of suitable palladium catalyst, suitable ligand, suitable base and in a suitable solvent to provide compound of formula-3,

b) converting compound of formula-3 to Ivosidenib compound of formula- 1.

In the process of the second embodiment, the suitable palladium catalyst used in step-a) is selected from PdCl₂, Pd₂(dba)₃, PdCl₂(PPh₃)₂, Pd(PPh₃)₄, Pd(OAc)₂ or [(cinnamyl)PdCl]₂ and the suitable ligands selected from phosphine such as triarylphosphine, trialkylphoshine; a bidentate diphosphine ligand (xantphos ligands) such as xantphos, t-butyl xantphos; Nixantphos ligands such as 4,6-bis(diphenylphosphino)phenoxazine; (oxydi-2, 1 -phenylene)bis(diphenylphosphine); 1 , 1'-bis(diphenylphosphino)ferrocene; or a bidentateamine ligand such as ethylenediamine, o- phenylenediamine, tetramethylethylenediamine, propane- 1 ,3-diamine and the suitable base is selected form inorganic base or organic base; and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof. In third embodiment, the present invention provides a process for the preparation of Ivosidenib compound of formula- 1, which comprises: a) converting the compound of formula-3 to (S)-l-(4-cyanopyridin-2-yl)-5-oxopyrrolidine- 2-carboxylic acid of formula-4 in the presence of suitable base and in a suitable solvent,

b) converting compound of formula-4 to Ivosidenib compound of formula- 1.

In the process of the third embodiment, the suitable base used in step-a) is selected form inorganic base or organic base; and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In the fourth embodiment, the present invention provides a process for the preparation of Ivosidenib compound of formula- 1, which comprises: a) reacting compound of formula-4 with S-fluoropyridine-3-amine in the presence of propanephosphonic anhydride or 2-bromo-l -ethyl pyridiniumtetrafluoroborate in a suitable base and in a suitable solvent to provide (S)- 1 -(4-cyanopyridin-2-yl)-N-(5- fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide of formula-5,

b) converting compound of formula-5 to Ivosidenib compound of formula- 1.

In the fifth embodiment, the present invention provides a process for the preparation of Ivosidenib compound of formula- 1, which comprises: a) reacting compound of formula-4 with 5-fluoropyridine-3-amine in the presence of suitable coupling agent in a suitable solvent to provide compound of formula-5, b) converting compound of formula-5 to Ivosidenib compound of formula- 1.

In the process of the fifth embodiment, the suitable coupling agent used in step-a) is selected from the suitable coupling agent is selected form Ν,Ν-carbonyldiimidazole (CDI); alkyl and aryl carbodiimides such as N,N-diisopropylcarbodiimide (DIC), N,N-dicyclohexyl carbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC- HC1), ditolylcarbodiimide optionally in combination with hydroxybenzotriazole or N -hydroxy succinimide (NHS) or N-hydroxysulfosuccinimide (Sulfo-NHS); carbonyl-di-1, 2, 4-triazole; alkyl and aryl halo formates such as ethyl chloroformate, phenyl chloroformate, benzyl chloroformate and the suitable base is selected form inorganic base or organic base and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar- aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In the sixth embodiment, the present invention provides a process for the preparation of Ivosidenib compound of formula- 1 comprising: a) reacting 2-bromo-2-(2-chlorophenyl)acetic acid of formula-6a with 3,3-difluorocyclo butanamine of formula-7 or its acid addition salt to provide 2-bromo-2-(2-chloro phenyl)- N-(3,3-difluorocyclobutyl)acetamide of formula-8a,

b) converting compound of formula-8a to Ivosidenib compound of formula- 1.

In the seventh embodiment, the present invention provides a process for the preparation of Ivosidenib compound of formula- 1, comprising: reacting a compound of formula- 11 with a compound of formula-5 to provide Ivosidenib compound of formula- 1 which schematically represented as below.

In an aspect of the seventh embodiment, compound of formula- 11 and compound of formula-5 are useful in the preparation of enantiopure Ivosidenib compound of formula- 1.

In an aspect of the seventh embodiment, provides Ivosidenib having chiral purity of about 99.90% ee; preferably of about 99.95% ee; more preferably of about 99.98% ee; most preferably of about 99.99% ee as measured by a chiral HPLC method.

In the eighth embodiment, the present invention provides a process for the preparation of enandopure Ivosidenib compound of formula- 1 which comprises: a) reacting (R)-2-bromo-2-(2-chlorophenyl)acetic acid of formula- 10 with 3,3-difluoro cyclobutanamine of formula-7 or its acid addition salts to provide (R)-2-bromo-2-(2- chlorophenyl)-N-(3,3-difluorocyclobutyl)acetamide of formula-11,

b) converting compound of formula- 11 to provide enantiopure Ivosidenib compound of formula- 1.

In the ninth embodiment, the present invention provides a process for the preparation of enandopure Ivosidenib compound of formula- 1, comprising: a) reacting (R)-2-(2-chlorophenyl)-2-hydroxyacetic acid of formula- 12 with 3,3-difluoro cyclobutanamine of formula-7 or its acid addition salts to provide (R)-2-(2-chloro phenyl)-N-(3,3-difluorocyclobutyl)-2-hydroxyacetainide of formula-13 which on bromination in the presence of a suitable brominating agent in a suitable solvent to provide (R)-2-bromo-2-(2-chlorophenyl)-N-(3 ,3-difluorocyclobutyl)acetamide of formula-11,

b) converting compound of formula- 11 to provide enantiopure Ivosidenib compound of formula- 1.

In tenth embodiment, the present invention provides novel intermediate compounds of Ivosidenib compound of formula- 1 represented by the following structural formulae.

wherein “X” is selected from leaving group such as halogen, substituted/unsubstituted alkyl/aryl sulfonyloxy. “R” is selected from substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group and substituted or unsubstituted aralkyl group. The above mentioned novel intermediate compounds are useful in the preparation of Ivosidenib of formula- 1.

In the eleventh embodiment, the present invention provides a process for the preparation of amorphous form of Ivosidenib of formula- 1, comprising: a) Dissolving compound of formula-9 in alcohol solvent, b) adding a suitable anti-solvent to the obtained solution of step-a), c) isolating amorphous form of Ivosidenib of formula- 1.

In the process of the eleventh embodiment, the suitable alcohol solvent used in step-a) is selected from selected from methanol, ethanol, propanol, isopropanol, butanol, 2-butanol and t- butanol.

In the process of the eleventh embodiment, optionally treating the solution containing compound of formula-9 and alcohol solvent with activated carbon and filtering the reaction mixture.

In the process of the eleventh embodiment, the suitable anti solvent used in step-b) is selected from hydrocarbon solvents, ester solvents, chloro solvents, ketone solvents, nitrile solvents, polar aprotic solvents, water or mixture thereof; preferably a mixture of DMSO and water.

In the process of the eleventh embodiment, isolating amorphous form of Ivosidenib compound of formula-1 is be carried out by any methods known in the art or can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In the twelfth embodiment, the present invention provides a process for the preparation of amorphous form of Ivosidenib of formula- 1, comprising: a) Dissolving compound of formula-9 in alcohol solvent; preferably n-butanol, b) adding an ester solvent, water or mixture to the mixture, c) adding hydrocarbon solvent to the mixture, d) isolating amorphous form of Ivosidenib of formula- 1. In the process of the twelfth embodiment, the suitable alcohol solvent used in step-a) is selected from selected from methanol, ethanol, propanol, isopropanol, butanol, 2-butanol and t- butanol.

In the process of the twelfth embodiment the hydrocarbon solvent used in step-c) is selected from n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like.

In the thirteenth embodiment, the present invention provides a process for the preparation of amorphous form of Ivosidenib of formula- 1, comprising: a) Dissolving Ivosidenib of formula- 1 in a suitable solvent; b) combining the solution of step-a) with anti-solvent and, c) isolating amorphous form of Ivosidenib of formula- 1.

In the process of the thirteenth embodiment, the suitable solvent used in step-a) is selected from alcohol solvent, ester solvent, nitrile solvents, ketone solvent, chloro solvent, ether solvent, polar aprotic solvent, water or mixture thereof;

In the process of the thirteenth embodiment, the suitable anti-solvent used in step-b) is selected from hydrocarbon solvents, water or mixture thereof;

In the first aspect of thirteenth embodiment, the present invention provides a process for the preparation of amorphous form of Ivosidenib of formula- 1, comprising: a) Dissolving Ivosidenib of formula- 1 in dimethylsulfoxide or dimethyl formamide, b) combining the solution of step-a) with water, c) isolating amorphous form of Ivosidenib of formula- 1.

In the second aspect of thirteenth embodiment, the present invention provides a process for the preparation of amorphous form of Ivosidenib of formula- 1, comprising: a) Dissolving Ivosidenib of formula- 1 in isobutyl acetate or isopropyl acetate, b) combining the solution of step-a) with n-hexane or n-heptane, c) isolating amorphous form of Ivosidenib of formula- 1.

In the third aspect of thirteenth embodiment, the present invention provides a process for the preparation of amorphous form of Ivosidenib of formula- 1, comprising: a) Dissolving Ivosidenib of formula- 1 in methyl tert-butyl ether, b) combining the solution of step-a) with n-hexane and, c) isolating amorphous form of Ivosidenib of formula- 1.

In the fourth aspect of thirteenth embodiment, the present invention provides a process for the preparation of amorphous form of Ivosidenib of formula- 1, comprising: a) Dissolving Ivosidenib of formula- 1 in methanol, b) combining the solution of step-a) with water, c) isolating amorphous form of Ivosidenib of formula- 1.

In an embodiment of the present invention the PXRD pattern of amorphous form of Ivosidenib compound of formula- 1 is depicted in figure- 1.

Ivosidenib and amorphous form of Ivosidenib obtained according to the present invention has purity of about 95%; preferably of at least about 97%; more preferably of at least about 98%; most preferably of at least about 99.9% as measured by HPLC.

Ivosidenib and amorphous form of Ivosidenib obtained according to the present invention has a chiral purity of about 95%; preferably of at least about 97%; more preferably of at least about 98%; most preferably of at least about 99.9% as measured by chiral HPLC.

In the fourteenth embodiment, the present invention provides a crystalline form-M of compound of formula-9, characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 9.8, 12.8, 16.6, 18.1 and 23.3 ± 0.2 degrees of 2-theta.

In the fifteenth embodiment, the present invention provides crystalline form-M of compound of formula-9 characterized by its X-powder diffraction (XRD) pattern as illustrated in figure-2.

In the sixteenth embodiment, the present invention provides a process for the preparation of crystalline form-M of compound of formula-9, comprising: a) Reacting 2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)-3-(5-fluoropyridin-3-yl)-4-oxo- 4-((S)-5-oxopyrrolidin-2-yl)butanamide

with 2-bromoisonicotinonitrile in the presence of Pd₂(dba)₃, Cs₂CO₃ and Xantphos in 1,4- dioxane, b) heating the reaction mixture to a suitable temperature, c) adding the mixture of water, ethyl acetate, L-cysteine and activated carbon to the reaction mixture, d) isolating crystalline form-M of compound of formula-9.

In the process of the sixteenth embodiment, the suitable temperature is ranging from 25 °C to the reflux temperature of the solvent used.

In the seventeenth embodiment, the present invention provides crystalline form-S of Ivosidenib of formula- 1, characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 8.2, 11.3, 14.0, 15.6 and 19.6 ± 0.2 degrees of 2-theta.

In the eighteenth embodiment, the present invention provides crystalline form-S of Ivosidenib of formula- 1 characterized by its X-powder diffraction (XRD) pattern as illustrated in figure-3.

In the nineteenth embodiment, the present invention provides a process for the preparation of crystalline form-S of Ivosidenib of formula- 1, comprising dissolving Ivosidenib of formula- 1 in a suitable solvent and isolating crystalline form-S of Ivosidenib of formula- 1.

In the process of the nineteenth embodiment, dissolving Ivosidenib compound of formula- 1 in a suitable solvent selected from alcohol solvents, ester solvents, ketone solvents, ether solvents, chloro solvents, nitrile solvents and water or mixtures thereof at a suitable temperature ranging from 30°C and above. Optionally, the solution may be filtered to make it particle free.

In the process of the nineteenth embodiment, isolating the crystalline form-S of Ivosidenib of formula- 1 is carried out by any methods known in the art or may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In an embodiment, the crystalline form-S of Ivosidenib of formula- 1 of the present invention is having purity of about 95%; preferably of at least about 97%; more preferably of at least about 98%; most preferably of at least about 99.9% as measured by HPLC.

In the twentieth embodiment, the present invention provides a crystalline form-N of Ivosidenib of formula- 1, characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 8.2, 10.9, 13.5, 13.9 and 22.3 ± 0.2 degrees of 2-theta.

The crystalline form-N of Ivosidenib of formula- 1 is further characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 8.6, 10.5, 11.2, 11.6, 13.5, 14.4, 16.8, 18.9, 20.22, 21.91 and 24.34 ± 0.2 degrees of 2-theta.

In the twenty-first embodiment, the present invention provides crystalline form-N of Ivosidenib of formula- 1 characterized by its X-powder diffraction (XRD) pattern as illustrated in figure-4.

In the twenty-second embodiment, the present invention provides a process for the preparation of crystalline form-N of Ivosidenib of formula- 1, comprises dissolving amorphous form of Ivosidenib compound of formula- 1 in diethyl ether and isolating crystalline form-N of Ivosidenib compound of formula- 1.

In an aspect, the crystalline form-N of Ivosidenib of formula- 1 of the present invention is having purity of about 95%; preferably of at least about 97%; more preferably of at least about 98%; most preferably of at least about 99.9% as measured by HPLC.

In the process of the twenty-second embodiment, dissolving Ivosidenib of formula- 1 in a suitable solvent selected from alcohol solvents, ester solvents, ketone solvents, ether solvents, chloro solvents, nitrile solvents and water or mixtures thereof at a suitable temperature ranging from 30°C and above. Optionally, the solution may be filtered to make it particle free.

In the process of the twenty-second embodiment, isolating the crystalline form-N of Ivosidenib of formula- 1 is carried out by any methods known in the art or may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In the process of the present invention, the amorphous or crystalline forms of Ivosidenib of formula- 1 produced according to the present invention is dried using suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressure at temperature of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperature. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In the twenty-third embodiment, the present invention provides a pharmaceutical composition comprising amorphous form of Ivosidenib of formula- 1 and one or more pharmaceutically acceptable excipients.

In the twenty-fourth embodiment, the present invention provides a pharmaceutical composition comprising crystalline form-S of Ivosidenib of formula- 1 and one or more pharmaceutically acceptable excipients.

In the twenty-fifth embodiment, the present invention provides a pharmaceutical composition comprising crystalline form-N of Ivosidenib compound of formula- 1 and one or more pharmaceutically acceptable excipients.

The excipient can be selected from one or more described in Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2006.

In yet another embodiment, pharmaceutical composition comprising amorphous form, crystalline form-S and form-N of Ivosidenib of formula- 1 and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.

In the twenty sixth embodiment, the present invention provides a process for the preparation of Ivosidenib of formula- 1.

comprising one or more reaction steps of the following synthetic scheme.

wherein “X” is selected from leaving group such as halogen such as fluoro, chloro, bromo or iodo, substituted/unsubstituted alkyl/aryl sulfonyloxy such as methane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate, nosyl and the like.

The compound of the S-fluoropyridin-3-amine, 2-bromoisonicotinonitrile, formula-2 and formula-7 used in the present invention are synthesized from any of the known prior art processes. In the twenty seventh embodiment, the present invention provides a process for the preparation of Ivosidenib of formula- 1, which comprises: c) reacting (S)-5-oxopyrrolidine-2-carboxylic acid of formula- 14 with 5-fluoropyridine-3- amine in the presence of coupling agent in a suitable solvent to provide (S)-N-(5- fluoropyridin-3-yl)-5-oxopyrrolidine-2-caiboxainide of formula- 15,

d) converting compound of formula- 15 to Ivosidenib of formula- 1.

In the process of the twenty seventh embodiment, the suitable coupling agent used in step-a) is selected from the suitable coupling agent is selected form N,N-carbonyldiimidazole (CDI); alkyl and aryl carbodiimides such as Ν,Ν-diisopropylcarbodiimide (DIC), N,N- dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HC1), ditolylcarbodiimide optionally in combination with hydroxybenzotriazole or N- hydroxy succinimide (NHS) or N-hydroxysulfosuccinimide (Sulfo-NHS); carbonyl-di-1, 2,4- triazole; alkyl and aryl halo formates such as ethyl chloroformate, phenyl chloroformate, benzyl chloroformate; boron-containing acids such as boric acid, boronic acids and the suitable base is selected form inorganic base or organic base and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In the twenty eighth embodiment, the present invention provides a process for the preparation of Ivosidenib of formula- 1, which comprises: a) Reacting (S)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide compound of formula- 15 with 2-bromoisonicotinonitrile in the presence of suitable palladium catalyst, suitable ligand, suitable base and in a suitable solvent to provide (S)-l-(4-cyanopyridin-2- yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-caiboxainide of formula-5,

b) converting compound of formula-5 to Ivosidenib of formula- 1.

In the process of the twenty eighth embodiment, the suitable palladium catalyst used in step-a) is selected from PdCl₂, Pd2(dba)3, PdCl₂(PPh₃)₂, Pd(PPh3)4, Pd(OAc)2 or [(cinnamyl)PdCl]2 and the suitable ligands selected from phosphine such as triarylphosphine, trialkylphoshine; a bidentatediphosphine ligand (xantphos ligands) such as xantphos, t-butyl xantphos; Nixantphos ligands such as 4,6-bis(diphenylphosphino)phenoxazine; (oxydi-2,1- phenylene)bis(diphenyl phosphine); 1 , 1'-bis(diphenylphosphino)ferrocene; or a bidentateamine ligand such as ethylene diamine, o-phenylenediamine, tetramethylethylenediamine, propane- 1,3- diamine and the suitable base is selected form inorganic base or organic base; and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In the process of the twenty ninth embodiment, the present invention provides a process for the preparation of Ivosidenib of formula- 1, which comprises a) reacting (S)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide compound of formula- 15 with 2-bromoisonicodnonitrile in the presence of N,N-dimethylethylene diamine, copper iodide and caesium carbonate and a suitable solvent to provide (S)-l-(4- cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide of formula-

5, b) converting compound of formula-5 to Ivosidenib of formula- 1.

In the thirtieth embodiment, the present invention provides a process for the preparation of Ivosidenib of formula- 1, which comprises: a) Reacting compound of formula-6 with 3,3-difluorocyclobutanamine of formula-7 or its acid addition salts to provide compound of formula-8,

wherein “X” is selected from leaving group such as halogen, substituted/unsubstituted alkyl/aryl sulfonyloxy. b) converting compound of formula-8 to Ivosidenib of formula- 1.

In the process of the thirtieth embodiment, the suitable base is selected from organic base or inorganic base and suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In the process of the thirtieth embodiment, the term suitable acid addition salts used in the present invention is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid and the like; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, para toluene sulfonic acid, ethane- 1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid and the like.

In the thirty first embodiment, the present invention provides a process for the preparation of Ivosidenib of formula- 1, which comprises reacting compound of formula-5 with compound of formula-8 to provide Ivosidenib of formula- 1 which schematically represented as below:

When X is bromo - Formula-8a X ii chloro - Formula-8b wherein “X” is selected from leaving group such as halogen, substituted/unsubstituted alkyl/aryl sulfonyloxy.

In the process of the thirty first embodiment, the suitable base is selected from organic base or inorganic base and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar- aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In an aspect of the thirty second embodiment, provides Ivosidenib having chiral purity of about 99.90% ee; preferably of about 99.95% ee; more preferably of about 99.98% ee; most preferably of about 99.99% ee as measured by a chiral HPLC method.

The thirty third embodiment of the present invention provides an improved process for the preparation of Ivosidenib of formula- 1, comprising: a) reacting compound of formula-5 with compound of formula- 13 in the presence of n- tributyl phosphate and diisopropylazodicarboxylate in dichloromethane to provide Ivosidenib of formula- 1.

b) optionally purifying to provide Ivosidenib of formula- 1. The thirty fourth embodiment of the present invention provides a process for the purification of Ivosidenib of formula- 1 by preparative HPLC.

Ivosidenib prepared according to the present invention is micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that are used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization is performed before drying, or after the completion of drying of the product.

In embodiment of the present invention, Ivosidenib obtained has a particle size distribution of D90 less than about 150 pm, or less than about 100 pm; or less than about 50 pm.

The present invention also encompasses pharmaceutical composition comprising Ivosidenib and its pharmaceutical acceptable salts one or more pharmaceutically acceptable excipients.

As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

P-XRD Method of Analysis: PXRD analyses of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A°.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of amorphous form of Ivosidenib

Ethanol (200.0 ml) was added to compound of formula-9 (20.0 gms) at 25-30°C. Heated the mixture to 80°C and stirred for 30 minutes. Filtered the mixture through hyflow bed and washed with ethanol. Distilled off solvent completely from the filtrate. Dimethylsulfoxide (30.0 ml) and water (100.0 ml) were added to the obtained compound at 25-30°C and stirred for 2 hours. Filtered the solid and dried to get the title compound. Yield: 12.0 gms.

Example-2: Preparation of amorphous form of Ivosidenib n-Butanol (200.0 ml) was added to compound of formula-9 (50.0 gms) at 25-30°C. Heated the mixture to 80-85°C and stirred for 30 minutes. Cooled the mixture to 25-30°C and stirred for 2 hours. Filtered the mixture, washed with n-butanol. Ethyl acetate (200.0 ml) and water (200.0 ml) were added to the obtained filtrate at 25-30°C and stirred for 15 minutes. Layers were separated. Organic layer is distilled off under reduced pressure. n-Heptane (150.0 ml) was added to the obtained compound at 25-30°C and stirred for 1 hour. Filtered the solid and dried to get the title compound. Yield: 30.0 gms.

Example-3: Preparation of amorphous form of Ivosidenib

Dimethylsulfoxide (2.0 ml) was added to Ivosidenib (1.0 gm) at 25-30°C and stirred for 10 minutes. Water (10.0 ml) was added to the mixture at 25-30°C and stirred for 2 hours. Filtered the precipitated solid and dried to get the title compound.

Yield: 0.75 gms; Purity by HPLC: 98.4%.

Example-4: Preparation of amorphous form of Ivosidenib

Dimethylformamide (2.0 ml) was added to Ivosidenib (1.0 gm) at 25-30°C and stirred for 10 minutes. Water (10.0 ml) was added to the mixture at 25-30°C and stirred for 3 hours. Filtered the precipitated solid and dried to get the title compound.

Yield: 0.85 gms; Purity by HPLC: 98.9%.

Example-5: Preparation of amorphous form of Ivosidenib

Isobutyl acetate (3.0 ml) was added to the Ivosidenib (1.0 gm) at 25-30°C and stirred for 10 minutes. Heated the mixture to 60-65°C and stirred for 10 minutes, n-hexane (15.0 ml) was added to the mixture at 60-65°C and stirred for 15 minutes. Cooled the mixture to 25-30°C and stirred for 2 hours. Filtered the precipitated solid and dried to get the title compound. Yield: 0.8 gms; Purity by HPLC: 98.6%.

Example-6: Preparation of amorphous form of Ivosidenib

Isopropyl acetate (3.0 ml) was added to the Ivosidenib (1.0 gm) at 25-30°C. Heated the mixture to 60°C and stirred for 10 minutes at the same temperature, n-heptane (15.0 ml) was added to the mixture at 60°C and stirred for 15 minutes. Cooled the mixture to 25-30°C and stirred for 2 hours. Filtered the solid and dried to get the title compound.

Yield: 0.8 gms; Purity by HPLC: 98.8%.

Example-7: Preparation of amorphous form of Ivosidenib

Methyl tert-butyl ether (3.0 ml) was added to Ivosidenib (1.0 gm) at 25-30°C. Heated the mixture to 60-65°C. N-hexane (15.0 ml) was slowly added to the reaction mixture at 60-65°C and stirred for 1 hour. Filtered the precipitated solid and dried to get the title compound. Yield: 0.8 gms; Purity by HPLC: 98.7%.

Example-8: Preparation of amorphous form of Ivosidenib

Methanol (2.0 ml) was added to Ivosidenib (1.0 gm) 25-30°C and stirred for 10 minutes. Water (12.0 ml) was added to the mixture at 25-30°C and stirred for 2 hours. Filtered the precipitated solid and dried to get the title compound.

Yield: 0.8 gms; Purity by HPLC: 98.3%.

Example-9: Preparation of crystalline form-M of compound of formula-9

1,4-Dioxane (500.0 ml) was added to 2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)-3- (5-fluoropyridin-3-yl)-4-oxo-4-((S)-5-oxopyrrolidin-2-yl)butanamide (50.0 gms) at 25-30°C. 2- Bromoisonicotinonitrile (22.74 gms), CS₂CO₃ (40.74 gms), xantphos (6.0 gms) and Pd₂(dba)₃ were added to the mixture at 25-30°C. Heated the mixture to 100°C and stirred for 2 hours. Cooled the mixture to 60-65°C. Water (1000.0 ml), ethyl acetate (500 ml), L-cysteine (2.50 gms) and activated carbon were added to the mixture at 60-65°C and stirred for 15 minutes. Filtered the mixture through hyflow bed and washed with ethyl acetate. Layers were separated and the aqueous layer was extracted with ethyl acetate. Distilled off the solvent from the organic layer completely under reduced pressure Methyl tert-butyl ether was added to the obtained compound at 25-30°C and stirred for 15 minutes. N-heptane was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Filtered the solid and dried to get the title compound. Yield: 55.0 gms.

The PXRD pattern of the obtained compound was illustrated in figure-2.

Example-10: Preparation of crystalline form-S of Ivosidenib

Isopropanol (4.0 ml) was added to Ivosidenib (1.0 gm) at 25-30°C. Heated the mixture to 60-65°C and stirred for 30 minutes. Cooled the mixture to 25-30°C and stirred for 1 hour. Filtered the precipitated solid and dried to get the title compound.

Yield: 0.55 gms. Purity by HPLC: 99.40%.

The PXRD pattern of the obtained compound was illustrated in figure-3.

Example-11: Preparation of crystalline form-N of Ivosidenib

Diethyl ether (126.0 ml) was added to amorphous form of Ivosidenib (21.0 gms) obtained in example-2 at 25-30°C. Heated the mixture to 35-40°C and stirred for 40-50 minutes. Filtered the solid and dried. Diethyl ether (95.0 ml) was added to the obtained compound at 25-30°C. Heated the mixture to 35-40°C and stirred for 50 minutes. Filtered the solid and dried to get the title compound. Yield: 13.0 gms; Purity by HPLC: 99.84%.

The PXRD pattern of the obtained compound was depicted in figure-4.

Example-12: Preparation of (S)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

A mixture of toluene (350.0 ml) and diphenyl ether (350.0 ml) were added to the 5- fluoropyridin-3-ainine (35.0 gms) at 25-30°C. (S)-5-oxopyrrolidine-2-carboxylic acid (80.0 gms) and boric acid (10.1 gms) were added to the mixture at 25-30°C and stirred for 15 minutes. Heated the mixture to 120-125°C and stirred for 36 hours. Distilled off the solvent completely from the mixture under vacuum and co-distilled with toluene. Cooled the obtained compound to 60-65°C. Methanol was added to it at 60-65°C. Cooled the mixture to 25-30°C. Neutral carbon was added to the mixture at 25-30°C. Filtered the mixture through hyflow bed and washed with methanol. Distilled off the solvent completely from the filtrate under vacuum. Isopropanol (70.0 ml) was added to the obtained compound at 25-30°C. Heated the mixture to 50-55°C and stirred for 2 hours. Cooled the mixture to 25-30°C. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 38.0 gms.

Example-13: Preparation of (S)-l-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxo pyrrolidine-2-carboxamide

Dioxane (350.0 ml) and 2-bromoisonicotinonitrile (29.28 gms) were added to (S)-N-(5- fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (35.0 gms) at 25-30°C under nitrogen atmosphere. Caesium carbonate (61.91 gms), Xantphos (2.31 gms) and Pd2(dba)3 (1.83 gms) were added to the mixture at 25-30°C and stirred for 20 minutes under nitrogen atmosphere. Heated the mixture to 60-65°C and stirred for 6 hours. Cooled the mixture to 25-30°C. Filtered the mixture through hyflow bed and washed with dioxane. Aqueous ammonium chloride solution was added to the mixture at 25-30°C. Distilled off the solvent completely from the mixture under vacuum. Ethyl acetate was added to the obtained compound at 25-30°C. Layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under vacuum. Ethyl acetate was added to the obtained compound at 25-30°C. Heated the mixture to 60-65°C and stirred for 2 hours. Cooled the mixture to 25-30°C. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 31.5 gms.

Example-14: Preparation of 2-chloro-2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl) acetamide

Tetrahydrofuran (400.0 ml) was added to 2-chloro-2-(2-chlorophenyl)acetic acid (40.0 gms) at 25-30°C under nitrogen atmosphere. Cooled the mixture to 0-5°C. Thionyl chloride (18.97 ml) was slowly added to the mixture at 0-5°C. Heated the mixture to 50-55°C and stirred for 90 minutes (Mixture-A). Tetrahydrofuran (400.0 ml) was added to 3,3-difluorocyclo butanamine hydrochloride (27.27 gms) at 25-30°C. Aqueous sodium carbonate solution was added to the mixture at 25-30°C. Cooled the mixture to 0-5°C (Mixture-B). Mixture-A was slowly added to the Mixture-B at 0-5°C and stirred for 2 hours. Water and ethyl acetate was added to the mixture at 0-5°C. Layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under vacuum. Cyclohexane was added to the obtained compound at 25-30°C and stirred for 2 hours. Filtered the solid, washed with cyclohexane and dried to get the title compound. Yield: 37.0 gms.

Example-15: Preparation of Ivosidenib

Dimethylformamide (300.0 ml) was added to (S)-l-(4-cyanopyridin-2-yl)-N-(5-fluoro pyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (30.0 gms) at 25-30°C. Cooled the mixture to 0- 5°C. Caesium carbonate (45.61 gms) was added to the mixture at 0-5°C and stirred for 45 minutes under nitrogen atmosphere. 2-Chloro-2-(2-chlorophenyl)-N-(3 ,3- difluorocyclobutyl)acetamide (27.40 gms), Toluene (84.0 ml) and Dimethylformamde (30.0 ml) was slowly added to the mixture at 0-5°C and stirred for 45 minutes. Heated the mixture to 25- 30°C and stirred for 24 hours. Aqueous ammonium chloride solution was added to the mixture at 25-30°C. Water and methyl tert-butyl ether were added to the mixture at 25-30°C and stirred for 45 minutes. Layers were separated and extracted the aqueous layer with methyl tert-butyl ether. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under vacuum and co-distilled with methyl tert-butyl ether. To the obtained compound, methyl tert-butyl ether was added at 25-30°C and stirred for 20 minutes. Mixture was slowly added to n-heptane at 25-30°C and stirred for 2 hours. Filtered the precipitated solid, washed with n-heptane and dried. n-Butanol was added to the obtained solid at 25-30°C. Heated the mixture to 70-75°C and stirred for 1 hour. Cooled the mixture to 25-30°C and stirred for 16 hours. Filtered the precipitated solid, washed with n-butanol. Ethyl acetate and water was added to the obtained solid at 25-30°C. Layers were separated and organic layer washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under vacuum and co-distilled with methyl tert-butyl ether. To the obtained compound, methyl tert-butyl ether was added at 25-30°C and stirred for 20 minutes. Mixture was slowly added to n-heptane at 25-30°C and stirred for 2 hours. Filtered the precipitated solid, washed with n-heptane and dried. Diethyl ether was added to the obtained solid at 25-30°C and stirred for 16 hours. Filtered the solid, washed with diethyl ether and dried. To the obtained compound, isopropanol was added at 25-30°C. Heated the mixture to 70-75°C and stirred for 1 hour. Activated carbon was added to the mixture at 70-75°C. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 8.5 gms.

Example-16: Preparation of crystalline Form-S of Ivosidenib

Isopropanol (32.0 ml) was added to Ivosidenib (8.0 gms) at 25-30°C. Heated the mixture to 70-75°C. Filtered the mixture through cloth, washed with isopropanol and stirred for 5 hours at 25-30°C. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 6.5 gms.

Example-17: Preparation of Ivosidenib

Dimethylformamide (300.0 ml) was added to (S)-l-(4-cyanopyridin-2-yl)-N-(5-fluoro pyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (30.0 gms) at 25-30°C. Cooled the mixture to 0- 5°C. Caesium carbonate (45.61 gms) was added to the mixture at 0-5°C and stirred for 45 minutes under nitrogen atmosphere. 2-chloro-2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl) acetamide (27.40 gms), Toluene (84.0 ml) and Dimethylformamde (30.0 ml) was slowly added to the mixture at 0-5°C and stirred for 45 minutes. Heated the mixture to 25-30°C and stirred for 24 hours. Aqueous ammonium chloride solution was added to the mixture at 25-30°C. Water and methyl tert-butyl ether were added to the mixture at 25-30°C and stirred for 45 minutes. Layers were separated and extracted the aqueous layer with methyl tert-butyl ether. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under vacuum and co-distilled with methyl tert-butyl ether. To the obtained compound, methyl tert-butyl ether was added at 25-30°C and stirred for 20 minutes. Mixture was slowly added to n-heptane at 25-30°C and stirred for 2 hours. Filtered the precipitated solid, washed with n-heptane and dried. The obtained compound was purified by using isopropanol to get the title compound. Yield: 19.3 gms; Purity by HPLC: 99.27%; Chiral Purity by HPLC: 99.8 % ee.

Example-18; Preparation of (S)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

Dichloromethane (500.0 ml) was added to 5-fluoropyridin-3-amine (25.0 gm) at 25-30°C. Hydroxybenzotriazole (2.97 gm) was added to the mixture at 25-30°C and stirred for 15 minutes. Ν,Ν'-Diisopropylcarbodiimide (45.11 ml) was slowly added to the mixture at 25-30°C and stirred for 15 minutes. Cooled the mixture to 0-5°C. (S)-5-oxopyrrolidine-2-carboxylic acid (34.56 gm) was added to the mixture at 0-5°C and stirred for 8 hours. Water was added to the mixture at 0- 5°C. Heated the mixture to 25-30°C and stirred for 30 minutes. Distilled the solvent completely under vacuum. Water was added to the obtained solid at 25-30°C and stirred for 90 minutes. Filtered the solid and washed with water. Methanol was added to the filtrate. Distilled off the solvent completely under vacuum and co-distilled with methanol. Methanol was added to the obtained solid. Heated the mixture to 60-65°C and stirred for 1 hour. Activated carbon was added to the mixture at 60-65°C and stirred for 20 minutes. Cooled the mixture to 25-30°C. Filtered the mixture through hyflow bed and washed with methanol. Distilled the filtrate completely under vacuum. Isopropanol and methyl tertiary butyl ether were added to the obtained solid at 25-30°C and stirred for 30 minutes. Heated the mixture to 65-70°C and stirred for 1 hour. Cooled the mixture to 25-30°C and stirred for 4 hours. Filtered the solid, washed with chilled isopropanol and methyl tertiary butyl ether and dried to get the title compound. Yield: 35.8 gms;

M.R: 179-180°C. Purity by HPLC: 99.67%; Chiral purity: 99.99%

Example-19; Preparation of (S)-l-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxo pyrrolidine-2-carboxamide

Toluene (600 ml) was added to Caesium carbonate (94.48 gm) at 25-30°C. Heated the mixture to 110-115°C azeotropically for 5 hours. Caesium carbonate was separated and 1,4- dioxane (600 ml) was added to it. (S)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (50.0 gm) was added to the mixture at 25-30°C. 2-Bromoisonicotinonitrile (40.26 gm), Xantphos (6.36 gm) and Pd2(dba)3 were added to the mixture at 25-30°C and stirred for 15 minutes. Heated the mixture to 65-70°C and stirred for 6 hours. Cooled the mixture to 25-30°C. Filtered the mixture through hyflow bed and washed with 1,4-dioxane. Ammonium chloride solution was added to the obtained solid at 25-30°C. Ethyl acetate was added to the mixture at 25-30°C. Layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers. Distilled off the organic layer. Ethyl acetate was added to the obtained solid at 25-30°C. Heated the mixture to 60-65°C and stirred for 2 hours. Cooled the mixture to 25-30°C. Filtered the solid, washed with chilled ethyl acetate and dried to get the title compound.

Yield: 52.5 gms; M.R: 152-158°C; Purity by HPLC: 98.04%; Chiral purity: 97.14%.

Example-20: Preparation of 2-chloro-2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl) acetamide

Methanol (300.0 ml) was added to methyl 2-bromo-2-(2-chlorophenyl)acetate (100.0 gm) at 25-30°C. Cooled the mixture to 15-20°C. Thionyl chloride (55.14 ml) was slowly added to the mixture at 15-20°C and stirred for 30 minutes. Heated the mixture to 65-70°C and stirred for 10 hours. Distilled off the solvent completely under vacuum and co-distil led with methanol. Acetic acid (160.0 ml) and hydrochloric acid (80.0 ml) were added to the obtained solid at 25-30°C. Heated the mixture to 90-95°C and stirred for 10 hours. Distilled off the solvent completely under vacuum and co-distilled with toluene. Tetrahydrofuran (165.0 ml) and dimethylformamide (0.50 ml) were added to the obtained solid at 25-30°C and stirred for 10 minutes. Cooled the mixture to 0-5°C. Oxalyl chloride (26.27 ml) was slowly added to the mixture at 0-5°C and stirred for 30 minutes. Heated the mixture to 25-30°C and stirred for 4 hours. Sodium carbonate (61.48 gm), water (66.0 ml), 3,3-difluorocyclobutanamine hydrochloride (33.0 ml) and 1,4-dioxane (165.0 ml) were slowly added to the mixture at 10-15°C and stirred for 2 hours. Water and ethyl acetate were added to the mixture at 25-30°C. Layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with sodium chloride solution. Distilled off the organic layer completely. Cyclohexane was added to the obtained solid at 25-30°C and stirred for 2 hours. Filtered the solid, washed with cyclohexane and dried to get the title compound. Yield: 57.0 gms; M.R: 95-100°C; Purity by HPLC: 97.97%.

Example-21: Preparation of Ivosidenib

Caesium carbonate (81.45 gms), sodium sulfate (7.10 gms) and toluene (600.0 ml) were charged into a clean and dry round bottom flask at 25-30°C. Heated the mixture to 110-115°C and stirred for 5 hours. A mixture of toluene and acetonitrile (1000.0 ml) were added to the obtained solid at 25-30°C. (S)-l-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2- carboxamide (50.0 gms) and tetra-n-butyl ammonium bromide (0.99 gms) were added to the mixture at 25-30°C and stirred for 2 hours. 2-Chloro-2-(2-chlorophenyl)-N-(3,3-difluorocyclo butyl)acetamide (44.11 gms) was slowly added to the mixture at 25-30°C and stirred for 36 hours. Cooled the mixture to 0-5°C. Ammonium chloride solution was slowly added to the mixture at 0-5°C and stirred for 15 minutes. Methyl tertiary butyl ether was added to the mixture at 0-5°C. Heated the mixture to 25-30°C. Layers were separated and the aqueous layer was extracted with methyl tertiary butyl ether. Combined the organic layers and washed with sodium chloride solution. Distilled off the organic layer and co-distilled with methyl tertiary butyl ether. To the obtained compound methyl tertiary butyl ether was added at 40-45°C and stirred for 30 minutes. Cooled the mixture to 25-30°C. n-Heptane was slowly added to the mixture at 25-30°C and stirred for 3 hours. Filtered the solid, washed with n-heptane and dried. N-Butanol was added to the obtained compound at 25-30°C. Heated the mixture to 70-75°C and stirred for 90 minutes. n-Heptane was added to the mixture at 70-75°C and stirred for 90 minutes. Cooled the mixture to 25-30°C and stirred for 3 hours. Filtered the solid, washed with a mixture of n-butanol and n- heptane and dried. Distilled the filtrate completely under vacuum and co-distilled with ethyl acetate. Isopropanol was added to the obtained residue at 25-30°C. Heated the mixture to 70- 75°C and stirred for 1 hour. Cooled the mixture to 25-30°C and stirred for 8 hours. Pet ether was added to the mixture at 25-30°C and stirred for 3 hours. Filtered the solid, washed with a mixture of isopropanol and pet ether. Isopropanol was added to the obtained solid at 25-30°C. Heated the mixture to 70-75°C and stirred for 1 hour. Cooled the mixture to 25-30°C and stirred for 8 hours. Filtered, the solid, washed with isopropanol and dried to get the title compound.

Yield: 17.0 gms; Purity by HPLC: 99.67%.

Example-22; Preparation of (S)-ethyl-5-oxopyrrolidine-2-carboxylate

Ethanol (300.0 ml) was added to (S)-5-oxopyrrolidine-2-carboxylic acid (150.0 gms) at 25-30°C. Cooled the mixture to 0-5°C. Thionyl chloride (101.44 ml) was slowly added to the mixture at 0-5°C and stirred for 4 hours. Distilled the solvent completely under vacuum. Sodium bicarbonate solution was added to the obtained solid at 0-5°C. Dichloromethane was added to the mixture at 0-5°C. Layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with sodium chloride solution. Distilled off the organic layer completely under vacuum to get the title compound.

Yield: 132.0 gms (Residue); Purity by HPLC: >95%.

Example-23; Preparation of (S)-ethyl-l-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2- carboxylate

Dioxane (1560.0 ml) was added to (S)-ethyl-5-oxopyrrolidine-2-carboxylate (130.0 gms) at 25-30°C. 2-Bromoisonicodnonitrile (151.89 gms), Caesium carbonate (540.86 gms) and 1,2- dimethylethylenediamine (26.89 ml) were added to the mixture at 25-30°C. Nitrogen expelling was applied to the mixture at 25-30°C and stirred for 20 minutes. Heated the mixture to 70-75°C and stirred for 8 hours. Cooled the mixture to 25-30°C. Filtered the mixture through hyflow bed and washed with dioxane. Distilled the solvent completely. The obtained compound was purified by using ethyl acetate and cyclohexane to get the title compound.

Yield: 140.0 gms; Purity by HPLC: 98.50%.

Example-24; Preparation of (S)-l-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-carboxylic add

Dioxane (840.0 ml) was added to (S)-ethyl-l-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2- carboxylate (210.0 gms) at 25-30°C. Cooled the mixture to 0-5°C. Lithium hydroxide solution was slowly added to the mixture at 0-5°C and stirred for 4 hours. Toluene (1050.0 ml) was added to the mixture at 0-5°C. Layers were separated. Aqueous hydrochloride solution was slowly added to the aqueous layer and washed with ethyl acetate. Combined the organic layers and washed with water and sodium chloride solution. Distilled off the organic layer completely. The obtained compound was purified by using methanol and dichloromethane to get the title compound. Yield: 94.0 gms; Purity by HPLC: 97.50%.

Example-25; Preparation of (S)-l-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxo pyrrolidine-2-carboxamide

A mixture of (S)-l-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-carboxylic acid (90.0 gms), 5-fluoropyridin-3-amine (131.16 gms), acetonitrile (1800.0 ml) and ethyl acetate (900.0 ml) were added into a round bottom flask at 25-30°C. Cooled the mixture to 0-5°C. Pyridine (107.56 ml) was added to the mixture at 0-5°C and stirred for 15 minutes. Propylphosphonic anhydride (496.08 ml) was slowly added to the mixture at 0-5°C and stirred for 16 hours. Sodium bicarbonate solution was slowly added to the mixture at 0-5°C. Layers were separated and the aqueous layer was extracted with ethyl acetate at 25-30°C. Combined the organic layers and washed with water and sodium chloride solution. Distilled off the organic layer completely. The obtained compound was purified by using methanol and dichloromethane to get the title compound. Yield: 64.0 gms; Purity by HPLC: 98.40%.

Example-26; Preparation of (R)-2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)-2-hydroxy acetamide

A mixture of (R)-2-(2-chlorophenyl)-2-hydroxyacetic acid (50.0 gms), trimethyl borate (46.55 ml) and acetonitrile (500.0 ml) were added into a round bottom flask at 25-30°C. Heated the mixture to 60-65°C and stirred for 90 minutes (Mixture-A). A mixture of 3,3- Difluorocyclobutanamine hydrochloride (38.76 gms), DIPEA (70.93 ml) and acetonitrile (250.0 ml) were added into a round bottom flask at 25-30°C and stirred for 45 minutes (Mixture-B). Mixture-B was added to the mixture-A at 60-65°C and stirred for 45 minutes. Heated the mixture to 80-85°C and stirred for 16 hours. Distilled the solvent completely under vacuum. Water and ethyl acetate were added to the obtained solid at 25-30°C. Layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with sodium chloride solution. Distilled off the organic layer completely. The obtained compound was purified by using ethyl acetate and cyclohexane to get the title compound.

Yield: 53.0 gms; Purity by HPLC: 98.80%.

Example-27; Preparation of (R)-2-chloro-2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl) acetamide

Dimethylformamide (500.0 ml) was added to (R)-2-(2-chlorophenyl)-N-(3,3- difluorocyclobutyl)-2-hydroxyacetamide (50.0 gms) at 25-30°C. Cooled the mixture to 0-5°C. Triethylamine (75.36 ml) was added to the mixture at 0-5°C and stirred for 15 minutes. Thionyl chloride (39.41 ml) was slowly added to the mixture at 0-5°C and stirred for 10 hours. Water (500.0 ml) was added to the mixture at 0-5°C. Heated the mixture to 25-30°C. Methyl tert-butyl ether (500.0 ml) was added to the mixture at 25-30°C. Layers were separated and the aqueous layer was extracted with MTBE. Combined the organic layers and washed with sodium chloride solution. Distilled off the organic layer completely. The obtained compound was purified by using ethyl acetate and cyclohexane to get the title compound.

Yield: 53.34 gms; Purity by HPLC: 99.15%.

Example-28; Preparation of Ivosidenib Dimethylfonnamide (300.0 ml) was added to (S)-l-(4-cyanopyridin-2-yl)-N-(5-fluoro pyridin-3-yl)-5oxopyrrolidine-2-carboxamide (30.0 gms) at 25-30°C. Cooled the mixture to 0- 5°C. Caesium carbonate (45.61 gms) was added to the mixture at 0-5°C and stirred for 45 minutes (Mixture-A). Toluene (84.0 ml) and dimethylfonnamide (30.0 ml) was added to (R)-2- chloro-2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl) acetamide (32.35 gms) (Mixture-B). Mixture-B was slowly added to the mixture- A at 0-5°C and stirred for 15 minutes. Heated the mixture to 25-30°C and stirred for 24 hours. Ammonium chloride solution was added to the mixture at 25-30°C. Water (1350.0 ml) and methyl tertiary butyl ether (300.0 ml) were added to the mixture at 25-30°C and stirred for 45 minutes. Layers were separated and the aqueous layer was extracted with methyl tertiary butyl ether. Combined the organic layers and washed with sodium chloride solution. Distilled off the organic layer completely under vacuum and co- distilled with methyl tertiary butyl ether. To the obtained compound, methyl tertiary butyl ether was added at 25-30°C and stirred for 20 minutes. N-Heptane was slowly added to the mixture at 25-30°C and stirred for 2 hours. Filtered the solid, washed with n-heptane and dried. n-Butanol was added to the obtained compound at 25-30°C. Heated the mixture to 70-75°C and stirred for 1 hour. Cooled the mixture to 25-30°C and stirred for 16 hours. Filtered the precipitated solid and washed with n-butanol. Ethyl acetate and water were added to the obtained solid at 25-30°C. Layers were separated and organic layer washed with sodium chloride solution. Distilled off the organic layer completely under vacuum and co-distilled with methyl tert-butyl ether. To the obtained compound, methyl tert-butyl ether was added at 25-30°C and stirred for 20 minutes. N- Heptane was slowly added to the mixture at 25-30°C and stirred for 2 hours. Filtered the precipitated solid, washed with n-heptane and dried. Diethyl ether was added to the obtained compound at 25-30°C and stirred for 16 hours. Filtered the solid, washed with diethyl ether and dried. Isopropanol was added to the obtained compound at 25-30°C. Heated the mixture to 70- 75°C and stirred for 1 hour. Activated carbon was added to the mixture at 70-75°C. Filtered the mixture through filter aid and washed with isopropanol at 70-75°C. Cooled the mixture to 25- 30°C and stirred for 16 hours. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 8.5 gms; Purity by HPLC: 98.84%.

Example-29; Purification of Ivosidenib

Isopropanol (24.0 ml) was added to Ivosidenib (8.0 gms) at 25-30°C. Heated the mixture to 70-75°C. Filtered the mixture through cloth, washed with isopropanol and stirred for 3 hours. Filtered the solid, washed with isopropanol and dried to get the title compound.

Yield: 6.5 gms; Purity by HPLC: 99.59%.

Example-30: Preparation of Ivosidenib

A mixture of (S)-l-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5oxopyrrolidine-2- carboxamide (10.0 gms), (R)-2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)-2-hydroxy acetamide (25.64 gms) and dichloromethane (50.0 ml) were added into a round bottom flask at 25-30°C and stirred for 15 minutes (Mixture- A). Diisopropylazodicaiboxylate (18.43 ml) and dichloromethane (50.0 ml) were added into another round bottom flask at 25-30°C. Cooled the mixture to 0-5°C. Tri n-butyl phosphine (18.82 gms) was slowly added to the mixture at 0-5°C and stirred for 15 minutes. Heated the mixture to 25-30°C and stirred for 30 minutes (Mixture-B). Mixture-B was slowly added to the mixture-A at 25-30°C and stirred for 5 hours. Water was added to the mixture at 25-30°C. Layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with sodium chloride solution. Distilled off the organic layer completely. The obtained compound was purified by using ethyl acetate and cyclohexane to get the title compound. Yield: 6.3 gms; Purity by HPLC: 99.85%.

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Claims

We Claim:

1. A process for the preparation of Ivosidenib of formula- 1,

which comprises reacting compound of formula- 5 with compound of formula-8 to provide Ivosidenib of formula- 1.

wherein “X” is selected from leaving group such as halogen, substituted/unsubstituted alkyl/aryl sulfonyloxy.

2. The process as claimed in claim 1 wherein, a process for the preparation of Ivosidenib compound of formula- 1, comprises reacting compound of formula-5 with formula-8 in the presence of a base in a solvent to provide Ivosidenib of formula- 1.

3. The process as claimed in claim 2 wherein, the base is organic base or inorganic base and solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

4. The process as claimed in claim 1 wherein, a process for the preparation of Ivosidenib of formula- 1, comprising; a) reacting (S)-5-oxopyrrolidine-2-carboxylic acid of formula- 14 with 5-fluoropyridine-3- amine in the presence of coupling agent in a base in a solvent to provide (S)-N-(5- fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide of formula-15, b) reacting (S)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide of formula-15 with 2-bromoisonicotinonitrile in the presence of palladium catalyst, a ligand, a base and in a solvent to provide (S)-l-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxo pyrrolidine-2-carboxamide of formula-5, c) converting compound of formula-5 to Ivosidenib of formula- 1. d) optinally purifying Ivosidenib of formula- 1.

5. The process as claimed in claim 4 wherein, the coupling agent used in step-a) is selected from the suitable coupling agent is selected form Ν,Ν-carbonyldiimidazole (CDI); alkyl and aryl carbodiimides such as Ν,Ν-diisopropylcarbodiimide (DIC), N,N-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HC1), ditolyl carbodiimide optionally in combination with hydroxybenzotriazole or N-hydroxy succinimide (NHS) or N-hydroxysulfosuccinimide (Sulfo-NHS); carbonyl-di-l,2,4-triazole; alkyl and aryl halo formates such as ethyl chloroformate, phenyl chloroformate, benzyl chloroformate; boron-containing acids such as boric acid, boronic acids and the suitable base is selected form inorganic base or organic base; the palladium catalyst used in step-b) is selected from PdCl₂, Pd₂(dba)₃, PdCl₂(PPh₃)₂, Pd(PPh₃)₄, Pd(OAc)₂ or [(cinnamyl)PdCl]₂ and the suitable ligands selected from phosphine such as triarylphosphine, trialkylphoshine; a bidentatediphosphine ligand (xantphos ligands) such as xantphos, t-butyl xantphos; Nixantphos ligands such as 4,6-bis(diphenylphosphino) phenoxazine; (oxydi-2, 1 -phenyl ene)bis(diphenylphosphine); 1 , 1 '-bis(diphenylphosphino) ferrocene; or a bidentateamine ligand such as ethylenediamine, o-phenylenediamine, tetra methylethylenediamine, propane-1, 3-diamine and the suitable base is selected form inorganic base or organic base; the solvent used in step-a) to step-d) is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

6. The process as claimed in claim 1 wherein, a process for the preparation of Ivosidenib of formula- 1, comprising: a) reacting compound of formula-6 with 3,3-difluorocyclobutanamine of formula-7 or its acid addition salts to provide compound of formula-8,

wherein “X” is selected from leaving group such as halogen, substituted/unsubstituted alkyl/aryl sulfonyloxy. b) converting compound of formula-8 to Ivosidenib of formula- 1.

7. The process as claimed in claim 6 wherein, the base is selected from organic base or inorganic base and solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

8. The process as claimed in claim 1 wherein, a process for the preparation of Ivosidenib of formula- 1, which comprises a) reacting (S)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide compound of formula- 15 with 2-bromoisonicotinonitrile in the presence of N,N-dimethylethylenedi amine, copper iodide and caesium carbonate and a solvent to provide (S)-l-(4-cyano pyridm-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide of formula-5, b) converting compound of formula-5 to Ivosidenib of formula- 1.

9. A process for the preparation of Ivosidenib of formula- 1, which comprises a) reacting compound of formula-5 with compound of formula-8b to provide Ivosidenib of formula- 1.

b) optionally purifying Ivosidenib compound of formula- 1.

10. A process for the preparation of Ivosidenib of formula- 1 comprises: reacting a compound of formula- 11 with a compound of formula-5 to provide Ivosidenib of formula- 1.

11. The process as claimed in claim 10, wherein reacting compound of formula- 11 with compound of formula-5 in the presence of a base in the presence or absence of phase transfer catalyst in a solvent to provide Ivosidenib of formula- 1.

12. The process as claimed in claim 11 wherein the base is selected from organic base or inorganic base and phase transfer catalyst is selected from tetra alkyl/aryl ammonium halides such as tetra butyl ammonium bromide (TBAB), tetrapropyl ammonium bromide, tributyl benzylammonium bromide, tetraoctylammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide and ethyl triphenylphosphonium bromide in a solvent selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

13. The process as claimed in claim 10 wherein, a process for the preparation of Ivosidenib of formula-1, which comprises: a) reacting compound of formula-4 with 5-fluoropyridine-3 -amine in the presence of propanephosphonic anhydride or 2-bromo-l-ethylpyridiniumtetrafluoroborate or a coupling agent in a base and in a solvent to provide (S)-l-(4-cyanopyridin-2-yl)-N-(5- fluoro pyridin-3-yl)-5-oxopyrrolidine-2-carboxamide of formula-5, b) converting compound of formula-5 to Ivosidenib compound of formula- 1.

14. The process as claimed in claim 13 wherein, the coupling agent used in step-a) is selected from the suitable coupling agent is selected form Ν,Ν-carbonyldiimidazole (CDI); alkyl and aryl carbodiimides such as Ν,Ν-diisopropylcarbodiimide (DIC), N,N-dicyclohexyl carbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (EDC-HC1), ditolylcarbodiimide optionally in combination with hydroxybenzotriazole or N-hydroxy succinimide (NHS) or N-hydroxysulfosuccinimide (Sulfo-NHS); carbonyl-di-1, 2, 4-triazole; alkyl and aryl halo formates such as ethyl chloroformate, phenyl chloroformate, benzyl chloroformate and the suitable base is selected form inorganic base or organic base and the solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

15. The process as claimed in claim 10, wherein a process for the preparation of enantiopure Ivosidenib compound of formula- 1, comprising: a) reacting (R)-2-(2-chlorophenyl)-2-hydroxyacetic acid of formula-12 with 3,3-difluoro cyclobutanamine of formula-7 or its acid addition salts to provide (R)-2-(2-chloro phenyl)-N-(3,3-difluorocyclobutyl)-2-hydroxyacetamide of formula-13 which on bromination in the presence of a brominating agent in a solvent to provide (R)-2-bromo- 2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)acetamide of formula-11,

b) converting compound of formula- 11 to provide enantiopure Ivosidenib compound of formula- 1.

16. A process for the preparation of amorphous form of Ivosidenib compound of formula- 1, comprising: a) Dissolving Ivosidenib of formula- 1 in dimethylsulfoxide or dimethylformamide or isobutyl acetate or isopropyl acetate or methyl tert-butyl ether, or methanol, b) combining the solution of step-a) with water or n-hexane or n-heptane and, c) isolating amorphous form of Ivosidenib compound of formula- 1.

17. A crystalline form-M of compound of formula-9, characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 9.8, 12.8, 16.6, 18.1 and 23.3 ± 0.2 degrees of 2-theta.

18. Crystalline form-M of compound of formula-9 as claimed in claim 17 is further characterized by its X-powder diffraction (XRD) pattern as illustrated in figure-2.

19. A process for the preparation of crystalline form-M of compound of formula-9 as claimed in claim 17, comprising: a) Reacting 2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)-3-(5-fluoropyridin-3-yl)-4-oxo- 4-((S)-5-oxopyrrolidin-2-yl)butanamide

with 2-bromoisonicotinonitrile in the presence of Pd2(dba)3, CS2CO3 and Xantphos in 1,4- dioxane, b) heating the reaction mixture to a temperature, c) adding the mixture of water, ethyl acetate, L-cysteine and activated carbon to the reaction mixture, d) isolating crystalline form-M of compound of formula-9.

20. The process as claimed in claim 19 wherein, in step-b) the temperature is ranging from 25°C to the reflux temperature of the solvent used.

21. A crystalline form-S of Ivosidenib of formula- 1, characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 8.2, 11.3, 14.0, 15.6 and 19.6 ± 0.2 degrees of 2-theta.

22. Crystalline form-S of Ivosidenib of formula-1 as claimed in claim 21 is further characterized by its X-powder diffraction (XRD) pattern as illustrated in figure-3.

23. A process for the preparation of crystalline form-S of Ivosidenib of formula-1 as claimed in claim 21, comprising, dissolving Ivosidenib of formula- 1 in isopropanol and isolating crystalline form-S of Ivosidenib of formula- 1.

24. The process as claimed in claim 23 wherein, dissolving Ivosidenib of formula- 1 in isopropanol at a temperature ranging from 30°C and above and the solution may be filtered to make it particle free.

25. A crystalline form-N of Ivosidenib of formula-1, characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 8.2, 10.9, 13.5, 13.9 and 22.3 ± 0.2 degrees of 2-theta.

26. Crystalline form-N of Ivosidenib of formula- 1 as claimed in claim 25 is further characterized by its X-powder diffraction (XRD) pattern as illustrated in figure-4.

27. A process for the preparation of crystalline form-N of Ivosidenib of formula- 1 as claimed in claim 25 which comprises, dissolving amorphous form of Ivosidenib of formula- 1 in diethyl ether and isolating crystalline form-N of Ivosidenib of formula- 1.

28. The process as claimed in claims 23 and 28 wherein, isolating the crystalline form-S and form-N of Ivosidenib of formula- 1 is carried out by decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, and optionally washing with a solvent

29. Compounds having the following structural formulae.

30. An improved process for the preparation of Ivosidenib of formula- 1, comprising: a) reacting compound of formula-5 with compound of formula-13 in the presence of n- tributyl phosphate and diisopropylazodicarboxylate in dichloromethane to provide Ivosidenib of formula- 1.

b) optionally purifying to provide Ivosidenib of formula- 1.

31. Compounds as claimed in claim 29 are useful for the preparation of Ivosidenib of formula- 1.

32. Ivosidenib obtained according to claims 1, 9, 10 and 30 is useful for the preparation of pharmaceutical composition.

33. A pharmaceutical composition comprising Ivosidenib according to claim 30 and its pharmaceutically acceptable excipients.

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