Improved process for the preparation of 4-amino-n-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinecarboxamide and its salts

Abstract

Improved process for the preparation of 4-amino-N-[(1S)-1-(4- chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4- piperidinecarboxamide and its salts. The present invention relates to an improved process for the preparation of 4-amino-N- [(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4- piperidinecarboxamide, which is referred to as Capivasertib and represented by the following structural formulae, Formula-1 The present invention also relates to a solid state forms of Capivasertib of formula-1 and process for its preparation.

Description

[0001] Improved process for the preparation of 4-amino-N-r(lS)-l-(4-chlorophenyl)-3- hvdroxypropyll-l-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-4-piperidinecarboxamide and its salts

[0002] Related Application:

[0003] This application claims the benefit of priority of our Indian patent application number 202441038242 filed on 15 May 2024, 202441075185 filed on 04 October 2024, 202541001178 filed on 06 January 2025 and 202541023143 filed on 15 March 2025, which are incorporated herein by reference.

[0004] Field of the Invention:

[0005] The present invention relates to an improved process for the preparation of 4-amino- N-[(lS)-l-(4-chlorophenyl)-3-hydroxypropyl]-l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4- piperidinecarboxamide, which is referred to as Capivasertib and represented by the following structural formulae,

[0006] The present invention also relates to a solid state forms of Capivasertib of formula- 1 and process for its preparation.

[0007] Background of the Invention:

[0008] Capivasertib is a first-in-class, potent, adenosine triphosphate (ATP) -competitive inhibitor of all three AKT isoforms of serine / threonine kinase AKT (AKT1, AKT2 and AKT3) and inhibits phosphorylation of downstream AKT substrates. Capivasertib is approved by United States Federal Drug Administration (USFDA) as TRUQAP tablet for oral administration is indicated in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA / AKTl / PTEN-alterations as detected by an FDA-approved test following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.

[0009] U.S patent US8101623 B2 discloses Capivasertib or a pharmaceutically acceptable salt. This patent discloses process for the preparation of Capivasertib.

[0010] U.S patent US9487525 B2 discloses crystalline Form B of Capivasertib and semicrystalline Forms A and C of Capivasertib.

[0011] Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and / or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.

[0012] Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.

[0013] Brief description of the Invention: The present invention relates to an improved process for the preparation of Capivasertib of formula- 1.

[0014] The present invention also relates to solid state forms of Capivasertib and process for its preparation.

[0015] Brief description of Drawings:

[0016] Figure-1: Illustrates the PXRD pattern of crystalline Form-M of Capivasertib.

[0017] Figure-2: Illustrates the PXRD pattern of crystalline Form-S of Capivasertib.

[0018] Figure-3: Illustrates the PXRD pattern of crystalline Form-M of Capivasertib fumarate. Figure-4: Illustrates the PXRD pattern of crystalline Form-M 1 of Capivasertib tartrate.

[0019] Figure-5: Illustrates the PXRD pattern of crystalline Form-M2 of Capivasertib methanesulfonate.

[0020] Figure-6: Illustrates the PXRD pattern of crystalline Form-M3 of Capivasertib p- toluenesulfonate .

[0021] Figure-7: Illustrates the PXRD pattern of solid dispersion of Capivasertib with povidone - K30.

[0022] Figure-8: Illustrates the PXRD pattern of solid dispersion of Capivasertib with HPMC-AS. Figure-9: Illustrates the PXRD pattern of solid dispersion of Capivasertib with HPMC-E5. Figure-10: Illustrates the PXRD pattern of solid dispersion of Capivasertib with HPMC- phthalate.

[0023] Detailed description of the Invention:

[0024] As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, 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, 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, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyro nitrile 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-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol, monoethyl ether, cyclohexanol, benzyl alcohol or glycerol and the like; “polar solvents” such as water or mixtures thereof.

[0025] As used herein, the term “solid dispersion” refers to dispersion of drug in a solid matrix where the matrix is either a small molecule or polymer. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two or more components (polymer and API) form a homogeneous one -phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.

[0026] As used herein, the term “excipient” refers to play a significant role in stabilizing solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs.

[0027] In the present application, solid dispersion and premix are used interchangeably to describe solid states disclosed herein.

[0028] 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; triethyl amine, methyl amine, ethylamine, 1,8-diaza bicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiiso propylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N- methylmorpholine, N-ethylmorpholine, piperidine, dimethylamino pyridine, 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.

[0029] 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 substituted or unsubstituted “alkenyl group” refers to straight or branched chain hydrocarbon groups ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the like. The term substituted or unsubstituted "aryl" refers to monovalent or divalent aromatic groups respectively including 5 and 6 membered monocyclic aromatic groups that contain zero to four heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of monocyclic aryl groups include, without limitation, phenyl, pyrrolyl, pyranyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyradazinyl, pyrimidinyl, and the like. The aryl groups also include bicyclic groups, tricyclic groups etc including fused 5 and 6 membered rings described above. Examples of multicyclic aryl groups include, without limitation, naphthyl, biphenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl. The term substituted or unsubstituted “arylalkyl" such as p-methoxy benzyl, p-nitrobenzyl, benzyl, p- bromo benzyl and the like.

[0030] The “suitable acid” used in the present invention is selected from inorganic acids such as hydrochloric acid, hydrobromie acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, malic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0031] The “amino protecting group” as used in the present invention is selected from benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), p-methoxybenzylethers (PMB), methyloxycarbonyl, acetoxy carbonyl, propoxycarbonyl, tert-butyloxycarbonyl (Boc), acetyl, propanoyl, iso-butyryl, tert-butyryl, t-butylacetyl, pivaloyl, benzoyl, trimethylsilyl, ter- butyldimethylsilyl, methanesulphonyl, ptolylsulphonyl, 2-nitrophenylsulfenyl; urethane; nitroso, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(4- trifluoromethylphenylsufony)ethoxycarbonyl, 1 -adamantyloxycarbonyl, 2- adamantyloxycarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, benzyl, vinyl, cyclohexyloxycarbonyl, l,l-dimethyl-2,2,2-trichloroethoxy carbonyl, 2-chloroethyl, 2- phenysulfonylethyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, Nz,NZ- dimethylhydrazinyl, methoxymethyl, tert-butoxymethyl, benxyloxymethyl, 2- tetrahydropyranyl, allyl, 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, 1- (ethoxy)ethyl, triphenylmethyl, diphenylmethyl, hydroxylmethyl and diethoxymethyl.

[0032] As used herein the term “deprotection” can be carried out in presence of a suitable “deprotection agent” is selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, formic acid, Lewis acid, substituted / unsubstituted alkyl / aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, pyridinium p-toluene sulfonic acid, trifluromethane sulfonic acid optionally in combination with alcohols and "hydrogen fluoride (HF) sources" such as ammonium fluoride, tetrabutyl ammonium fluoride, pyridine-HF, Et3N-3HF etc; metal catalysts in presence of hydrogen source and the like;

[0033] The term “enantiopure” as used herein in the present invention 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%.

[0034] The term “enantiopure” as used herein in the present invention means that an enantiomer is present with a purity of at least 99% enantiomeric excess, preferably in a purity of 99.5-100% enantiomeric excess.

[0035] In the first embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1, comprising one or more reaction steps of the following synthetic scheme.

[0036] For mula-6b; Formula-5a; Formula-4

[0037] X=C1 & Pg=Boc Formula-3 R=Et & Pg = Boc Formula-4b; Formula-3b; Pg = Boc

[0038] R=Et & Pg = Boc

[0039] Formula-2b; Pg = Boc wherein “R” is selected from substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl and substituted or unsubstituted arylalkyl, “Pg” is selected from amino protecting group and “X” is a halogen such as chloro, bromo or iodo.

[0040] In the first aspect of the first embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1, comprising one or more reaction steps of the following synthetic scheme.

[0041] In the second embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1, comprising one or more reaction steps of the following synthetic scheme.

[0042] Fonnula-9

[0043] Deprotecti on

[0044] Capivasertib

[0045] Formula- 1 wherein “Ri” is selected from Ci-6 straight or branched alkyl group, “R” and “Pg” as defined above.

[0046] In the first aspect of the second embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1 , comprising one or more reaction steps of the following synthetic scheme. In the third embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1, comprising one or more reaction steps of the following synthetic scheme. wherein “R2” is selected from C2-6 straight or branched alkyl group, R and “Pg” as defined above.

[0047] In the fourth embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1, comprising one or more reaction steps of the following synthetic scheme.

[0048] wherein “R” and “Pg” as defined above.

[0049] In the fifth embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1, which comprises: a) reacting the compound of formula- 17 or an acid with compound of formula- 18 in the presence of suitable base in a suitable solvent to provide compound of formula- 19; and

[0050]

[0051] Formula-19 b) converting the compound of formula- 19 to Capivasertib of formula- 1.

[0052] In the process of the fifth embodiment, wherein the suitable solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar-aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof; the suitable base used in step-a) is selected from inorganic base or organic base.

[0053] In the sixth embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1, which comprises: a) converting the compound of formula- 19 to compound of formula-20; and

[0054] Formula- 19 Formula-20 b) converting the compound of formula-20 to Capivasertib of formula- 1.

[0055] In the seventh embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1, which comprises: a) converting the compound of formula-20 to compound of formula-3 in the presence of suitable amino protecting group in a suitable solvent; and

[0056] Formula-20 Formula-3 wherein Pg is selected from suitable amino protecting group. b) converting the compound of formula-3 to Capivasertib of formula- 1.

[0057] In the process of the seventh embodiment, wherein the suitable solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar- aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof; the suitable amino protecting group used in step-a) is defined above.

[0058] In the eighth embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1, which comprises: a) reacting the compound of formula-3 with compound of formula-7 to provide compound of formula-2; and wherein Pg is selected from suitable amino protecting group. b) deprotecting the compound of formula-2 to provide Capivasertib of formula- 1.

[0059] In the ninth embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1, which comprises: a) converting the compound of formula-20 to compound of formula- 13 in the presence of suitable amino protecting group in a suitable solvent; and

[0060] Formula-20 Formula- 13 wherein Pg is selected from suitable amino protecting group, with the proviso that the amino protecting group is not tert-butyloxycarbonyl (Boc). b) converting the compound of formula- 13 to Capivasertib of formula- 1.

[0061] In the process of the ninth embodiment, wherein the suitable solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar-aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof; the suitable amino protecting group used in step-a) is defined above.

[0062] In the tenth embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1, which comprises: a) reacting the compound of formula- 13 with compound of formula-7 to provide compound of formula- 15; and

[0063] Formula-13 Formula-7 Formula-15 wherein Pg is selected from suitable amino protecting group, with the proviso that the amino protecting group is not tert-butyloxycarbonyl (Boc). b) deprotecting the compound of formula- 15 to provide Capivasertib of formula- 1.

[0064] In the eleventh embodiment, the present invention provides a crystalline form of Capivasertib of formula- 1 , hereinafter designated as crystalline Form-M.

[0065] In the first aspect of the eleventh embodiment, wherein the crystalline Form-M of Capivasertib of formula- 1, is characterized by its X-ray powder diffraction (PXRD) pattern having 2 theta values at about 13.8, 20.8 and 26.5 ± 0.2 degrees.

[0066] In the second aspect of the eleventh embodiment, wherein the crystalline Form-M of Capivasertib of formula- 1, is characterized by its X-ray powder diffraction (PXRD) pattern having 2 theta values at about 9.2, 13.8, 15.4, 15.7, 16.0, 17.4, 18.6, 18.8, 19.5, 20.7, 20.8, 21.7, 22.5, 23.0, 24.4, 24.5, 25.5, 26.5, 26.8 and 28.9 ± 0.2 degrees.

[0067] In the third aspect of the eleventh embodiment, wherein the crystalline Form-M of Capivasertib of formula- 1, is characterized by the X-ray powder diffraction (PXRD) pattern as illustrated in Figure- 1.

[0068] In the twelfth embodiment, the present invention provides a process for the preparation of crystalline Form-M of Capivasertib of formula- 1, which comprises: a) contacting or suspending Capivasertib in a suitable solvent; and b) isolating crystalline Form-M of Capivasertib.

[0069] In the process of the twelfth embodiment, wherein the suitable solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar- aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof.

[0070] In the first aspect of the twelfth embodiment, the present invention provides a process for the preparation of crystalline Form-M of Capivasertib of formula- 1, which comprises: a) contacting or suspending Capivasertib in a mixture of suitable ether solvent and water; and b) isolating crystalline Form-M of Capivasertib.

[0071] In the second aspect of the twelfth embodiment, the present invention provides a process for the preparation of crystalline Form-M of Capivasertib of formula- 1, which comprises: a) contacting or suspending Capivasertib in a mixture of methyl tertiary butyl ether and water; and b) isolating crystalline Form-M of Capivasertib.

[0072] In the thirteenth embodiment, the present invention provides a crystalline form of Capivasertib of formula- 1, hereinafter designated as crystalline Form-S.

[0073] In the first aspect of thirteenth embodiment, wherein the crystalline Form-S of Capivasertib of formula- 1, is characterized by its X-ray powder diffraction (PXRD) pattern having 2 theta values at about 13.9, 17.9 and 18.6 ± 0.2 degrees.

[0074] In the second aspect of the thirteenth embodiment, wherein the crystalline Form-S of

[0075] Capivasertib of formula- 1, is characterized by its X-ray powder diffraction (PXRD) pattern having 2 theta values at about 3.0, 9.1, 13.9, 15.3, 15.6, 15.9, 16.5, 17.2, 17.9, 18.6, 19.8, 20.6, 21.5, 22.8, 23.9, 24.6, 25.3, 26.5, 26.7, 27.7 and 29.0 ± 0.2 degrees.

[0076] In the third aspect of the thirteenth embodiment, wherein the crystalline Form-S of Capivasertib of formula- 1, is characterized by the X-ray powder diffraction (PXRD) pattern as illustrated in Figure-2.

[0077] In the fourteenth embodiment, the present invention provides a process for the preparation of crystalline Form-S of Capivasertib of formula- 1, which comprises: a) contacting or suspending Capivasertib in a suitable solvent; and b) isolating crystalline Form-S of Capivasertib.

[0078] In the process of the fourteenth embodiment, wherein the suitable solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar- aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof.

[0079] In the first aspect of the fourteenth embodiment, the present invention provides a process for the preparation of crystalline Form-S of Capivasertib of formula- 1, which comprises: a) contacting or suspending Capivasertib in a suitable ether solvent; and b) isolating crystalline Form-S of Capivasertib.

[0080] In the first aspect of the fourteenth embodiment, adding water to the mixture obtained in step-a) and isolating the crystalline Form-S of Capivasertib.

[0081] In the process of fourteenth embodiment, the suitable ether solvent used in step-a) is selected from dimethoxy methane, 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, methyl tertiary butyl ether, diisopropyl ether, 1 ,2-dimethoxy ethane and the like.

[0082] In the fifteenth embodiment, the present invention provides a crystalline form of Capivasertib fumarate.

[0083] In the sixteenth embodiment, the present invention provides a crystalline Form-M of Capivasertib fumarate, characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-3.

[0084] In the seventeenth embodiment, the present invention provides a process for the preparation of crystalline Form-M of Capivasertib fumarate, which comprises: a) contacting Capivasertib with fumaric acid in a suitable solvent; and b) isolating crystalline Form-M of Capivasertib fumarate.

[0085] In the process of the seventeenth embodiment, wherein the suitable solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar-aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof.

[0086] In the first aspect of the seventeenth embodiment, the present invention provides a process for the preparation of crystalline Form-M of Capivasertib fumarate, which comprises: a) contacting Capivasertib with fumaric acid in a ketone solvent; and b) isolating crystalline Form-M of Capivasertib fumarate.

[0087] In the second aspect of the seventeenth embodiment, the present invention provides a process for the preparation of crystalline Form-M of Capivasertib fumarate, which comprises: a) contacting Capivasertib with fumaric acid in acetone; and b) isolating crystalline Form-M of Capivasertib fumarate.

[0088] In the eighteenth embodiment, the present invention provides a crystalline form of Capivasertib tartrate.

[0089] In the nineteenth embodiment, the present invention provides a crystalline Form-M 1 of Capivasertib tartrate, characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-4.

[0090] In the twentieth embodiment, the present invention provides a process for the preparation of crystalline Form-Mi of Capivasertib tartrate, which comprises: a) contacting Capivasertib with tartaric acid in a suitable solvent; and b) isolating crystalline Form-Mi of Capivasertib tartrate.

[0091] In the process of the twentieth embodiment, wherein the suitable solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar- aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof.

[0092] In the first aspect of the twentieth embodiment, the present invention provides a process for the preparation of crystalline Form-Mi of Capivasertib tartrate, which comprises: a) contacting Capivasertib with tartaric acid in a ketone solvent; and b) isolating crystalline Form-Mi of Capivasertib tartrate.

[0093] In the second aspect of the twentieth embodiment, the present invention provides a process for the preparation of crystalline Form-Mi of Capivasertib tartrate, which comprises: a) contacting Capivasertib with tartaric acid in acetone; and b) isolating crystalline Form-Mi of Capivasertib tartrate.

[0094] In the twenty-first embodiment, the present invention provides a crystalline form of Capivasertib methanesulfonate.

[0095] In the twenty-second embodiment, the present invention provides a crystalline Form- M2 of Capivasertib methanesulfonate, characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-5.

[0096] In the twenty-third embodiment, the present invention provides a process for the preparation of crystalline Form-M2 of Capivasertib methanesulfonate, which comprises: a) contacting Capivasertib with methanesulfonic acid in a suitable solvent; and b) isolating crystalline Form-M2 of Capivasertib methanesulfonate.

[0097] In the process of the twenty-third embodiment, wherein the suitable solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar-aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof. In the first aspect of the twenty-third embodiment, the present invention provides a process for the preparation of crystalline Form-M2 of Capivasertib methanesulfonate, which comprises: a) contacting Capivasertib with methanesulfonic acid in a ketone solvent; and b) isolating crystalline Form-M2 of Capivasertib methanesulfonate.

[0098] In the second aspect of the twenty-third embodiment, the present invention provides a process for the preparation of crystalline Form-M2 of Capivasertib methanesulfonate, which comprises: a) contacting Capivasertib with methanesulfonic acid in methyl isobutyl ketone; and b) isolating crystalline Form-M2 of Capivasertib methanesulfonate.

[0099] In the second aspect of the twenty-third embodiment, adding methyl isobutyl ketone to Capivasertib and heating the mixture to 40-45°C, then adding methanesulfonic acid.

[0100] In the twenty-fourth embodiment, the present invention provides a crystalline form of Capivasertib p-toluenesulfonate.

[0101] In the twenty-fifth embodiment, the present invention provides a crystalline Form-M3 of Capivasertib p-toluenesulfonate, characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-6.

[0102] In the twenty-sixth embodiment, the present invention provides a process for the preparation of crystalline Form-M3 of Capivasertib p-toluenesulfonate, which comprises: a) contacting Capivasertib with p-toluenesulfonic acid in a suitable solvent; and b) isolating crystalline Form-M3 of Capivasertib p-toluenesulfonate.

[0103] In the first aspect of the twenty-sixth embodiment, the present invention provides a process for the preparation of crystalline Form-M3 of Capivasertib p-toluenesulfonate, which comprises: a) contacting Capivasertib with p-toluenesulfonic acid in a ketone solvent; and b) isolating crystalline Form-M3 of Capivasertib p-toluenesulfonate. In the second aspect of the twenty-sixth embodiment, the present invention provides a process for the preparation of crystalline Form-M3 of Capivasertib p-toluenesulfonate, which comprises: a) contacting Capivasertib with p-toluenesulfonic acid in methyl isobutyl ketone; and b) isolating crystalline Form-M3 of Capivasertib p-toluenesulfonate.

[0104] In the twenty-seventh embodiment, the present invention provides a solid dispersion of Capivasertib with one or more pharmaceutically acceptable excipients.

[0105] In the twenty- seventh embodiment, the suitable pharmaceutically acceptable excipient is selected from but not limited to syloid, polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120 may be used), co-povidone, crospolyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), cros-copovidone, Eudragit, polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethylcellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropylmethyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose-E5 (HPMC-E5), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropylmethylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a-, P-, y-cyclodextrins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.

[0106] In the twenty-eighth embodiment, the present invention provides a process for the preparation of solid dispersion of Capivasertib with one or more pharmaceutically acceptable excipients, which comprises: a) providing a solution comprising Capivasertib and at least one pharmaceutically acceptable excipient; and b) isolating the solid dispersion of Capivasertib.

[0107] In the process of the twenty-eighth embodiment, providing a solution of Capivasertib and at least one pharmaceutically acceptable excipient in step-a) comprises dissolving Capivasertib and at least one pharmaceutically acceptable excipient in a suitable solvent at a suitable temperature of about 25 °C and above. Optionally, the solution can be filtered to make it particle free.

[0108] In the process of twenty-eighth embodiment, the suitable solvent used in step-a) is selected from alcohol solvent and chloro solvent or mixture thereof.

[0109] In the process of twenty-eighth embodiment, the suitable pharmaceutically acceptable excipient used in step-a) is same as defined in the thirteenth embodiment.

[0110] In the first aspect of the twenty-eighth embodiment, the present invention provides a process for the preparation of solid dispersion of Capivasertib with povidone-K30, which comprises: a) providing a solution comprising Capivasertib and povidone-K30; and b) isolating the solid dispersion of Capivasertib with povidone-K30.

[0111] In the process of the first aspect of twenty-eighth embodiment, providing a solution of Capivasertib and povidone-K30 in step-a) comprises dissolving Capivasertib and povidone - K30 in methanol at a suitable temperature of about 25 °C and above. Optionally, the solution can be filtered to make it particle free. In the second aspect of the twenty-eighth embodiment, the present invention provides a process for the preparation of solid dispersion of Capivasertib with HPMC-AS, which comprises: a) providing a solution comprising Capivasertib and HPMC-AS; and b) isolating the solid dispersion of Capivasertib with HPMC-AS.

[0112] In the process of the second aspect of twenty-eighth embodiment, providing a solution of Capivasertib and HPMC-AS in step-a) comprises dissolving Capivasertib and HPMC-AS in methanol at a suitable temperature of about 25 °C and above. Optionally, the solution can be filtered to make it particle free.

[0113] In the third aspect of the twenty-eighth embodiment, the present invention provides a process for the preparation of solid dispersion of Capivasertib with HPMC-E5, which comprises: a) providing a solution comprising Capivasertib and HPMC-E5; and b) isolating the solid dispersion of Capivasertib with HPMC-E5.

[0114] In the process of the third aspect of twenty-eighth embodiment, providing a solution of Capivasertib and HPMC-E5 in step-a) comprises dissolving Capivasertib and HPMC-E5 in a mixture of methanol and dichloromethane at a suitable temperature of about 25 °C and above. Optionally, the solution can be filtered to make it particle free.

[0115] In the fourth aspect of the twenty-eighth embodiment, the present invention provides a process for the preparation of solid dispersion of Capivasertib with HPMC- phthalate, which comprises: a) providing a solution comprising Capivasertib and HPMC- phthalate; and b) isolating the solid dispersion of Capivasertib with HPMC- phthalate.

[0116] In the process of the fourth aspect of twenty-eighth embodiment, providing a solution of Capivasertib and HPMC- phthalate in step-a) comprises dissolving Capivasertib and HPMC- phthalate in a mixture of methanol and dichloromethane at a suitable temperature of about 25 °C and above. Optionally, the solution can be filtered to make it particle free.

[0117] In another embodiment, the ratio of Capivasertib and pharmaceutically acceptable excipient present in the ranging from about 0.5 : 99.5 to about 99.5 : 0.5. Preferably, the ratio is about 50 : 50.

[0118] In the twenty-ninth embodiment, the present invention provides novel intermediate compounds represented by the following structural formulae.

[0119] Formula-9 Formula- 11 Formula- 14 and wherein “R”, “Ri”, “R2” and “Pg” as defined above.

[0120] The above mentioned novel intermediate compounds are useful in the preparation of

[0121] Capivasertib of formula- 1.

[0122] In the thirtieth embodiment, the present invention provides a process for the preparation of Capivasertib of formula- 1 ,

[0123] which comprises converting a compounds selected from the group comprises one of formula- 19, formula-3 and formula-2 to Capivasertib of formula- 1. wherein Pg is selected from amino protecting group.

[0124] In the thirty- first embodiment, Capivasertib of formula- 1 obtained according to the present invention has a particle size distribution of D90 is less than about 150 pm, preferably less than about 100 pm, more preferably less than about 50 pm.

[0125] In the process of the present invention, isolating involves removal of solvent is carrying out by suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction mixture or by any other suitable techniques known in the art. In the process of the present invention, drying crystalline forms or solid dispersion of Capivasertib by a 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 pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. 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.

[0126] In an aspect of the present invention, provides Capivasertib 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 chiral HPLC method.

[0127] In an embodiment, Capivasertib obtained according to the present invention is enantiopure.

[0128] The compounds of formulae 5, 6, 7, 8, 10, 17 and 18 used in the present invention are synthesized from any of the known prior art processes.

[0129] Capivasertib of formula- 1 obtained according to the present invention can be purified using a suitable solvent selected form alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof.

[0130] Crystalline forms or solid dispersion of Capivasertib prepared according to the present invention can be further 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 may be used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.

[0131] In the present invention, pharmaceutically acceptable excipient used for the preparation of solid dispersion can be amorphous, crystalline or any other physical form.

[0132] In the process of the present invention the resulting, solid dispersion of Capivasertib can be amorphous, crystalline or a mixture thereof. In yet another embodiment, pharmaceutical composition comprising crystalline forms or solid dispersion of Capivasertib and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.

[0133] As used herein, the term "pharmaceutical compositions" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

[0134] The process of the present invention can be represented schematically as follows:

[0135] Formula- 17a: Formula- 19 Formula-20

[0136] H

[0137] P-XRD Method of Analysis: PXRD analysis of compounds of the present invention was carried out by using BRUKER / D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.037min.

[0138] PSD method of Analysis: Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 3000 instrument.

[0139] The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation of the scope of the invention.

[0140] Examples:

[0141] Example-1: Preparation of tert-butyl 2,4-dioxo-l,3,8-triazaspiro|4.5]decane-8- carboxylate.

[0142] Ethanol (250.0 ml) was added to N-Boc-4-piperidone (50.0 gm) at 25-30°C. Water (250.0 ml) and acetone cyanohydrin (32.03 gm) were added to the mixture at 25-30°C and stirred for 10 minutes. Ammonium carbonate (72.34 gm) was added to the mixture at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 80-85°C and stirred for 3 hours. Cooled the mixture to 10-15°C. Water (250.0 ml) was added to the mixture at 10-15°C and stirred for 1 hour. Filtered the solid and washed with water. Water (250.0 ml) was added to the obtained compound at 25-30°C and stirred for 1 hour. Filtered the solid, washed with water and dried to get the title compound. Yield: 54.2 gm.

[0143] Example-2: Preparation of 1, 3, 8-triazaspiro[4.5]decane-2, 4-dione hydrochloride of Formaula-17a.

[0144] 1,4-Dioxane (270.0 ml) was added to tert-butyl 2,4-dioxo-l,3,8- triazaspiro[4.5]decane-8-carboxylate (54.0 mg) at 25-30°C. Cooled the mixture to 0-5°C. A mixture of hydrochloric acid (97.2 ml) and water (97.2 ml) was slowly added to the mixture at 0-5°C. Raised the temperature of the mixture to 25-30°C and stirred for 2 hours. Distilled off the solvent completely from the mixture under vacuum at below 50°C and co-distilled with ethyl acetate. Ethyl acetate (270.0 ml) was added to the obtained compound at 25-30°C and stirred for 1 hour. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 37.1 gm. Example-3: Preparation of compound of formula-19.

[0145] Acetonitrile (299.0 ml) was added to compound of formula- 17a (36.96 gm) at 25- 30°C. Aqueous sodium carbonate solution was added to the mixture at 25-30°C and stirred for 15 minutes. Compound of formula-18 (23.0 gm) was added to the mixture at 25-30°C. Raised the temperature of the mixture to 90-95°C and stirred for 8 hours. Distilled off the solvent completely from the mixture at below 90°C. Water (115.0 ml) was added to the obtained compound at 25-30°C. Cooled the mixture to 0-5°C and stirred for 1 hour. Filtered the solid and washed with water. Methyl tert-butyl ether (69.0 ml) was added to the mixture at 25-30°C and stirred for 1 hour. Filtered the solid, washed with methyl tert-butyl ether and dried to get the title compound. Yield: 35.5 gm.

[0146] Example-4: Preparation of compound of formula-20.

[0147] A mixture of water (1200.0 ml) and barium hydroxide (165.30 gm) was added to the compound of formula-19 (30.0 gm) at 25-30°C and stirred for 15 minutes. Raised the temperature of the mixture to 120-125°C and stirred for 16 hours. Cooled the mixture to 25- 30°C. Aqueous sulfuric acid was slowly added to the mixture at 25-30°C and stirred for 1 hour. Heated the mixture to 100-105°C and stirred for 1 hour. Cooled the mixture to 25-30°C and stirred for 1 hour. Filtered the mixture and washed with water. Distilled off the solvent completely from the mixture at below 60°C. Aqueous ammonia solution was added to the obtained compound at 25-30°C and stirred for 1 hour. Filtered the solid, washed with water and dried to get the title compound. Yield: 22.1 gm.

[0148] Example-5: Preparation of compound of formula-3b.

[0149] Dichloromethane (380.0 ml) was added to compound of formula-20 (38.0 gm) at 25- 30°C. Triethylamine (162.12 ml) was added to the mixture at 25-30°C. Boc anhydride (200.42 ml) was slowly added to the mixture at 25-30°C. 4-Dimethylaminopyridine (0.17 gm) was added to the mixture at 25-30°C and stirred for 11 hours. Water (190.0 ml) was added to the mixture at 25-30°C and stirred for 15 minutes. Layers were separated. Distilled off the solvent completely from the organic layer under vacuum at below 45°C and co-distilled with n- heptane. n-Heptane (380.0 ml) was added to the obtained compound at 25-30°C and stirred for 20 minutes. Filtered the solid, washed with n-heptane and dried to get the title compound.

[0150] Yield: 65.0 gm.

[0151] Example-6: Preparation of compound of formula-2b.

[0152] Dimethylacetamide (100.0 ml) was added to compound of formula-3b (24.9 gm) at 25-30°C. Compound of formula-7 (10.0 gm) and N,N-diisopropylethylamine (41.8 gm) were added to the mixture at 25-30°C. 2-(lH-Benzotriazole-l-yl)-l,l,3,3-tetramethylaminium tetrafluoroborate (TBTU) (18.32 gm) was added to the mixture at 25-30°C and stirred for 20 hours. Water (100.0 ml) was added dropwise to the mixture at 25-30°C and stirred for 1 hour. Dichloromethane (100.0 ml) was added to the mixture at 25-30°C and stirred for 15 minutes. Layers were separated. Dichloromethane (50.0 ml) was added to the aqueous layer at 25-30°C and stirred for 15 minutes. Layers were separated. Combined the total organic layers. Water (50.0 ml) was added to the organic layer at 25-30°C and stirred for 15 minutes. Layers were separated. Dried the organic layer with sodium sulfate. Distilled off the solvent completely from the organic layer under vacuum at below 45°C and co-distilled with isopropanol under vacuum at below 50°C to get the title compound. Yield: 26.5 gm.

[0153] Example-7: Preparation of Capivasertib of formula-1.

[0154] Isopropanol (250.0 ml) was added to compound of formula-2b (25.0 gm) at 25-30°C. A mixture of hydrochloride (25.0 ml) and water (250.0 ml) was added to the mixture at 25- 30°C. Heated the mixture to 60-65°C and stirred for 4 hours. Cooled the mixture to 0-5°C. Water (125.0 ml) was added to the mixture at 0-5°C. Aqueous sodium hydroxide solution was added to the mixture at 0-5°C. Ethyl acetate (250.0 ml) was added to the mixture at 0-5°C. Raised the temperature of the mixture to 25-30°C and stirred for 20 minutes. Layers were separated. Water (250.0 ml) was added to the organic layer at 25-30°C. A mixture of hydrochloride and water was added to the mixture at 25-30°C and stirred for 15 minutes. Layers were separated and aqueous layer washed with ethyl acetate. Ethyl acetate (50.0 ml) was added to the aqueous layer at 25-30°C. Cooled the mixture to 0-5°C. Aqueous sodium hydroxide solution was added to the mixture at 0-5°C. Ethyl acetate (250.0 ml) was added to the mixture at 0-5°C. Raised the temperature of the mixture to 25-30°C and stirred for 20 minutes. Layers were separated and organic layer washed with sodium chloride. Dried the organic layer with sodium sulfate. Distilled off the solvent completely from the organic layer under vacuum at below 45°C. Methyl tertiary butyl ether (250.0 ml) was added to the obtained at 25-30°C and stirred for 9 hours. Filtered the solid, washed with methyl tertiary butyl ether and dried to get the title compound. Yield: 12.8 gm.

[0155] Example-8: Purification of Capivasertib of formula-1.

[0156] Isopropyl acetate (50.0 ml) was added to Capivasertib of formula- 1 (10.0 gm) at 25- 30°C and stirred for 5 minutes. Methanol (50.0 ml) was slowly added to the mixture at 25- 30°C and stirred for 30 minutes. Carbon was added to the mixture at 25-30°C and stirred for 15 minutes. Filtered the mixture through hyflo bed. n-Heptane (200.0 ml) was added to filtrate at 25-30°C and stirred for 13 hours. Cooled the mixture to 0-5°C and stirred for 8 hours. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 5.1 gm.

[0157] Example-9: Preparation of crystalline Form-M of Capivasertib.

[0158] A mixture of methyl tertiary butyl ether (80.0 ml) and water (10.0 ml) was added to Capivasertib (2.0 gm) at 25-30°C and stirred for 1 hour. Filtered the solid under vacuum and dried to get the title compound. Yield: 1.695 gm.

[0159] The PXRD pattern of the obtained compound is illustrated in figure- 1.

[0160] Example-10: Preparation of crystalline Form-S of Capivasertib.

[0161] Methyl tertiary butyl ether (80.0 ml) was added to Capivasertib (2.0 gm) at 25-30°C. Water (10.0 ml) was added to the mixture at 25-30°C and stirred for 1 hour. Filtered the solid under vacuum and dried to get the title compound. Yield: 1.527 gm.

[0162] The PXRD pattern of the obtained compound is illustrated in figure-2.

[0163] Example- 11: Preparation of crystalline Form-M of Capivasertib fumarate.

[0164] Acetone (15.0 ml) was added to Capivasertib (200.0 mg) and fumaric acid (60.0 mg) at 25-30°C. Heated the mixture to 40-45°C and stirred for 2 hours. Cooled the mixture to 25- 30°C. Filtered the solid under vacuum and dried to get the title compound. Yield: 165.0 mg. The PXRD pattern of the obtained compound is illustrated in figure-3. Example-12: Preparation of crystalline Form-Mi of Capivasertib tartrate.

[0165] Acetone (20.0 ml) was added to Capivasertib (200.0 mg) and tartaric acid (75.0 mg) at 25-30°C and stirred for 20 minutes. Heated the mixture to 40-45°C and stirred for 2 hours. Cooled the mixture to 25-30°C. Filtered the solid under vacuum and dried to get the title compound. Yield: 170.0 mg.

[0166] The PXRD pattern of the obtained compound is illustrated in figure-4.

[0167] Example-13: Preparation of crystalline Form-M2 of Capivasertib methanesulfonate.

[0168] Methyl isobutyl ketone (10.0 ml) was added to Capivasertib at 25-30°C. Heated the mixture to 40-45°C. Methanesulfonic acid (50.0 ml) was added to the mixture at 40-45°C and stirred for 2 hours. Cooled the mixture to 25-30°C. Filtered the solid under vacuum and dried to get the title compound. Yield: 275.0 mg.

[0169] The PXRD pattern of the obtained compound is illustrated in figure-5.

[0170] Example-14: Preparation of crystalline Form-M3 of Capivasertib p-toluenesulfonate.

[0171] Methyl isobutyl ketone (20.0 ml) was added to Capivasertib (300.0 mg) and p- toluenesulfonic acid (130.0 mg) at 25-30°C. Heated the mixture to 40-45°C and stirred for 2 hours. Cooled the mixture to 25-30°C. Filtered the solid under vacuum and dried to get the title compound. Yield: 290.0 mg.

[0172] The PXRD pattern of the obtained compound is illustrated in figure-6.

[0173] Example-15: Preparation of solid dispersion of Capivasertib with povidone-K30.

[0174] Capivasertib (200.0 mg) and Povidone-K30 (200.0 mg) were dissolved in methanol (10.0 ml) at 25-30°C and stirred for 15 minutes. Filtered the mixture to make it particle free. Distilled off the solvent completely from the filtrate under vacuum at below 45°C to get the title compound. Yield: 325.0 mg.

[0175] The PXRD pattern of the obtained compound is illustrated in figure-7.

[0176] Example-16: Preparation of solid dispersion of Capivasertib with HPMC-AS.

[0177] Capivasertib (200.0 mg) and HPMC-AS (200.0 mg) were dissolved in methanol (25.0 ml) at 25-30°C and stirred for 15 minutes. Heated the mixture to 50-55°C and stirred for 30 minutes. Filtered the mixture to make it particle free. Distilled off the solvent completely from the filtrate under vacuum at below 45°C to get the title compound. Yield: 330.0 mg.

[0178] The PXRD pattern of the obtained compound is illustrated in figure-8.

[0179] Example-17: Preparation of solid dispersion of Capivasertib with HPMC-E5.

[0180] Capivasertib (200.0 mg) and HPMC-E5 (200.0 mg) were dissolved in a mixture of methanol (10.0 ml) and dichloromethane (5.0 ml) at 25-30°C and stirred for 10 minutes. Filtered the mixture to make it particle free. Distilled off the solvent completely from the filtrate under vacuum at below 45°C to get the title compound. Yield: 310.0 mg.

[0181] The PXRD pattern of the obtained compound is illustrated in figure-9.

[0182] Example-18: Preparation of solid dispersion of Capivasertib with HPMC-phthalate.

[0183] Capivasertib (200.0 mg) and HPMC-phthalate (200.0 mg) were dissolved in a mixture of methanol (10.0 ml) and dichloromethane (10.0 ml) at 25-30°C and stirred for 20 minutes. Filtered the mixture to make it particle free. Distilled off the solvent completely from the filtrate under vacuum at below 45°C to get the title compound. Yield: 320.0 mg.

[0184] The PXRD pattern of the obtained compound is illustrated in figure- 10.

Claims

We Claim:

1. A process for the preparation of Capivasertib of formula- 1 ,which comprises converting a compounds selected from the group comprises one of formula- 19, formula-3 and formula-2 to Capivasertib of formula- 1.wherein Pg is selected from amino protecting group.

2. The process as claimed in claim 1 wherein, the amino protecting group is selected from benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), p -methoxybenzylethers (PMB), methyloxycarbonyl, acetoxy carbonyl, propoxycarbonyl, tert-butyloxycarbonyl (Boc), acetyl, propanoyl, iso-butyryl, tert-butyryl, t-butylacetyl, pivaloyl, benzoyl, trimethylsilyl, ter-butyldimethylsilyl, methanesulphonyl, ptolylsulphonyl, 2- nitrophenylsulfenyl; urethane; nitroso, 2,2,2-trichloroethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, 2-(4-trifluoromethylphenylsufony)ethoxycarbonyl, 1 - adamantyloxycarbonyl, 2-adamantyloxycarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, benzyl, vinyl, cyclohexyloxycarbonyl, 1 , 1 -dimethyl-2,2,2-trichloroethoxy carbonyl, 2- chloroethyl, 2-phenysulfonylethyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, Nz,NZ-dimethylhydrazinyl, methoxymethyl, tert-butoxymethyl, benxyloxymethyl, 2-tetrahydropyranyl, allyl, 2-(trimethylsilyl)ethoxymethyl, N- pivaloyloxymethyl, l-(ethoxy)ethyl, triphenylmethyl, diphenylmethyl, hydroxylmethyl and diethoxymethyl; the solvent is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar-aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof.

3. A process for the preparation of Capivasertib of formula- 1 , which comprises: a) reacting the compound of formula- 17 or an acid with compound of formula- 18 in the presence of base in a solvent to provide compound of formula- 19.Formula-19 wherein acid is selected from inorganic acids such as hydrochloric acid, hydrobromie acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, malic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like. b) converting the compound of formula- 19 to Capivasertib of formula- 1.

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

5. A process for the preparation of Capivasertib of formula- 1 , which comprises:a) converting the compound of formula- 19 to compound of formula-20.Formula- 19 Formula-20 b) converting the compound of formula-20 to Capivasertib of formula- 1.

6. A process for the preparation of Capivasertib of formula- 1 , which comprises: a) converting the compound of formula-20 to compound of formula-3 in the presence of amino protecting group in a solvent.Formula-20 Formula-3 wherein Pg is selected from amino protecting group. b) converting the compound of formula-3 to Capivasertib of formula- 1.

7. A process for the preparation of Capivasertib of formula- 1 , which comprises; a) reacting the compound of formula-3 with compound of formula-7 to provide compound of formula-2; andwherein Pg is selected from amino protecting group. b) deprotecting the compound of formula-2 to provide Capivasertib of formula- 1.wherein Pg is selected from amino protecting group.

9. A crystalline Form-M of Capivasertib of formula- 1.

10. A crystalline Form-M of Capivasertib of formula- 1, is characterized by its X-ray powder diffraction (PXRD) pattern having 2 theta values at about 13.8, 20.8 and 26.5 ± 0.2 degrees.

11. A process for the preparation of crystalline Form-M of Capivasertib of formula- 1 , which comprises: a) contacting or suspending Capivasertib in a solvent; and b) isolating crystalline Form-M of Capivasertib.

12. The process as claimed in claim 11 wherein, the solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar-aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof.

13. A crystalline Form-S of Capivasertib of formula- 1.

14. A crystalline Form-S of Capivasertib of formula- 1, is characterized by its X-ray powder diffraction (PXRD) pattern having 2 theta values at about 13.9, 17.9 and 18.6 ± 0.2 degrees.

15. A process for the preparation of crystalline Form-S of Capivasertib of formula- 1, which comprises: a) contacting or suspending Capivasertib in a solvent; and b) isolating crystalline Form-S of Capivasertib.

16. The process as claimed in claim 15 wherein, the solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar-aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof.

17. The process as claimed in claim 15 wherein, a process for the preparation of crystalline Form-S of Capivasertib of formula- 1, which comprises: a) contacting or suspending Capivasertib in an ether solvent; and b) isolating crystalline Form-S of Capivasertib.

18. The process as claimed in clam 17 wherein, adding water to the mixture obtained in step- a) and isolating the crystalline Form-S of Capivasertib.

19. The process as claimed in claim 17 wherein, the ether solvent used in step-a) is selected from dimethoxy methane, 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, methyl tertiary butyl ether, diisopropyl ether, 1 ,2-dimethoxy ethane and the like.

20. A crystalline Form-M of Capivasertib fumarate21. A crystalline Form-M of Capivasertib fumarate, characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-3.

22. A process for the preparation of crystalline Form-M of Capivasertib fumarate, which comprises: a) contacting Capivasertib with fumaric acid in a solvent; and b) isolating crystalline Form-M of Capivasertib fumarate.

23. The process as claimed in claim 22 wherein, the solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar-aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof.

24. A crystalline form of Capivasertib tartrate.

25. A crystalline Form-M 1 of Capivasertib tartrate, characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-4.

26. A process for the preparation of crystalline Form-M 1 of Capivasertib tartrate, which comprises: a) contacting Capivasertib with tartaric acid in a solvent; and b) isolating crystalline Form-M 1 of Capivasertib tartrate.

27. The process as claimed in claim 26 wherein, the solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar-aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof.

28. A crystalline form of Capivasertib methanesulfonate.

29. A crystalline Form-M2 of Capivasertib methanesulfonate, characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-5.

30. A process for the preparation of crystalline Form-M2 of Capivasertib methanesulfonate, which comprises: a) contacting Capivasertib with methanesulfonic acid in a solvent; and b) isolating crystalline Form-M2 of Capivasertib methanesulfonate.

31. The process as claimed in claim 30 wherein, the solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar-aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof.

32. A crystalline form of Capivasertib p-toluenesulfonate.

33. A crystalline Form-M3 of Capivasertib p-toluenesulfonate, characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-6.

34. A process for the preparation of crystalline Form-M3 of Capivasertib p-toluenesulfonate, which comprises: a) contacting Capivasertib with p-toluenesulfonic acid in a solvent; and b) isolating crystalline Form-M3 of Capivasertib p-toluenesulfonate.

35. The process as claimed in claim 34 wherein, the solvent used in step a) is selected from alcohol solvent, ester solvent, hydrocarbon solvent, nitrile solvent, polar-aprotic solvent, ketone solvent, ether solvent, chloro solvent, and water or mixture thereof.

36. A solid dispersion of Capivasertib with one or more pharmaceutically acceptable excipients.

37. The solid dispersion as claimed in claim 36 wherein, the pharmaceutically acceptable excipient is selected from but not limited to syloid, polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120 may be used), copovidone, crospolyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), cros-copovidone, Eudragit, polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethylcellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropylmethyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose-E5 (HPMC-E5), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropylmethylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a-, P-, y-cyclodextrins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.

38. A process for the preparation of solid dispersion of Capivasertib with one or more pharmaceutically acceptable excipients, which comprises: a) providing a solution comprising Capivasertib and at least one pharmaceutically acceptable excipient; and b) isolating the solid dispersion of Capivasertib.

39. The process as claimed in claim 38 wherein, providing a solution of Capivasertib and at least one pharmaceutically acceptable excipient in step-a) comprises dissolving Capivasertib and at least one pharmaceutically acceptable excipient in a solvent at a temperature of about 25°C and above.

40. The process as claimed in claims 38 to 39 wherein, the solvent used in step-a) is selected from alcohol solvent and chloro solvent or mixture thereof.

41. The process as claimed in claim 38 wherein, the pharmaceutically acceptable excipient used in step-a) is same as defined in claim 37.

42. Capivasertib having a particle size distribution of D90 is less than 150 pm, preferably less than 100 pm, more preferably less than 50 pm.

43. Capivasertib having a purity of about 99.9% by chiral HPLC.

44. The crystalline forms or solid dispersion of Capivasertib according to any of the preceding claims are useful for the preparation of pharmaceutical composition.

45. A pharmaceutical composition comprising Capivasertib according to any of the preceding claims and one or more pharmaceutically acceptable excipients.

46. The use of Capivasertib according to any of preceding claims for the preparation of a medicament for breast cancer, prostate cancer or gastric cancer.

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