Novel process for the preparation of (6R)-6-(2-(n-(4-(2-(ethylamino) ethyl)benzyl)-n-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol or its pharmaceutically acceptable salts and intermediates thereof

Abstract

The present invention relates to a novel for the preparation of (6R) - 6 - (2 - (N - (4 - (2- (ethyl amino) ethyl) benzyl)- N- ethyl amino) – 4 – methoxy phenyl)- 5, 6, 7, 8 - tetra hydro naphthalen-2-ol of formula-1 or its pharmaceutically acceptable salts and intermediates thereof Formula-1.

Description

[0001] Novel process for the preparation of (6R)-6-(2-(N-(4-(2-(ethylamino) ethyl)benzyl)-N- ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol or its pharmaceutically acceptable salts and intermediates thereof

[0002] Related Applications:

[0003] This application claims the benefit of priority to Indian Patent Application Nos.

[0004] 202541004883, filed on Jan 21, 2025, the disclosures of all of which are incorporated by reference in their entirety.

[0005] Field of the invention:

[0006] The present invention provides a novel for the preparation of (6R)-6-(2-(N-(4-(2-(ethylamino) ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8 tetrahydronaphthalen-2-ol of formula- 1 or its pharmaceutically acceptable salts and intermediates thereof

[0007]

[0008] Formula- 1.

[0009] Background of the invention:

[0010] (6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)- 5, 6, 7, 8 tetrahydronaphthalen-2-ol of formula- 1 is generally known as Elacestrant. Its dihydrochloride salt i.e., Elacestrant dihydrochloride which is having the following structural formula- 1 a

[0011]

[0012] Formula- 1 a

[0013] and was approved in US under the brand name of ORSERDU™ for the treatment of postmenopausal women or adult men, with ER -positive, HER2-negative, ESRI -mutatedadvanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

[0014] US patent number US7612114B2 describes the process for the preparation of Elacestrant and its pharmaceutically acceptable salts. U.S patent publication number US2022162233A1 describes the process for the preparation of Elacestrant.

[0015] However, there is always a need exist for alternative preparative routes, which for example involves fewer steps, use reagents that are less expensive and / or easier to handle, consumes smaller amounts of reagents, provide a higher yield of product, have smaller and / or more ecofriendly waste products, and / or provide a higher purity of the final compound of Formula- 1. Hence the inventors of the present invention have developed improved process for the preparation of Elacestrant and its intermediate compounds.

[0016] Brief description of the invention:

[0017] An embodiment of the present invention provides a novel process for the preparation of Elacestrant of formula- 1 or its pharmaceutically acceptable salts and intermediates thereof.

[0018] Brief description of the drawings:

[0019] Figure-1: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline form-M of the compound of formula-4 la.

[0020] Figure-2: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline form of Elacestrant dihydrochloride obtained according to example- 17.

[0021] Figure-3: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline form of Elacestrant dihydrochloride obtained according to example- 18.

[0022] Figure-4: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline form of Elacestrant dihydrochloride obtained according to example- 19.

[0023] Detailed description of the invention:

[0024] As used herein the term “solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methyl cyclohexane, ethylbenzene, m-, o-, or p-xylene, or naphthalene 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, methyl t-butyl ether, diisopropyl ether, 1 ,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate 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, isobutyronitrile and the like; “alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoro ethanol, ethylene glycol, 1 ,2-propanediol (propylene 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 acetic acid, water or mixtures thereof.

[0025] As used herein the present invention the term “base” refers to inorganic bases like “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), potassium acetate or mixtures thereof.

[0026] As used herein the term “coupling agent” used in the present invention can be selected from but not limited to N,N'-dicyclohexylcarbodiimide, N,N"-diisopropyl carbodiimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1),N,N"-carbonyl diimidazole, l-[bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5-b] pyridinium 3-oxide hexafluorophosphate, 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate, IH-benzotriazolium-l-[bis(dimethylamino)methylene]-5-chloro-hexa fluorophosphate( 1 )-3-oxide, (benzotriazol- 1 -yloxy)tris(dimethylamino)phosphonium hexa fluorophosphate, benzotriazol- 1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 1-hydroxy-7-azatriazole, 1-hydroxy benzotriazole (HOBt), l-hydroxy-lH-l,2,3-triazole-4-carboxylate, O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, N-hydroxysuccinamide, N-hydroxysulfosuccinimide (Sulfo-NHS), ethyl cyanohydroxy iminoacetate (Oxyma), 7-Azabenzotriazol- 1 -yloxy)tripyrrolidinophosphonium hexafluoro phosphate, N,N,N',N'-Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate, alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, DPPA, thionyl chloride, pivaloyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), methane sulfonyl chloride and the like; optionally in combination with base or mixtures thereof.

[0027] As used herein the term “catalyst” used in the present invention refers to [1,1’-bis(diphenylphosphino) ferrocene] dichloro palladium (II) ([Pd(dppf)Ch]), [ 1, l’-bis(di-tert-butylphoshino) ferrocene] dichloro palladium(I) ([Pd(dtbpf)Ch]) tetrakis (triphenyl phosphine) palladium(O) (Pd(PPh3)4), bromo(tri-tert-butylphosphine) palladium(I) dimer ([Pd(p-Br)(t-Bu3P)]2), bis(tri-tert-butylphosphine)palladium(0) ([Pd(tBu3P)]2), palladium(II) acetate (Pd(OAc)2), palladium(II) chloride (PdCh), bis (benzonitrile)palladium(II) dichloride ([Pd(PhCN)2Ch]), bis(triphenylphosphine) palladium(II) dichloride ([Pd(PPh3)2Ch]), bis (acetonitrile)palladium(II) dichloride ([Pd(NCMe)2Ch]), bis[di-tert-butyl(4-dimethyl aminophenyl)phosphine] dichloro palladium(II) ([Pd(amphos)C12]), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine] palladium(O) (Pd(amphos)2), and allylpalladium(II) chloride dimer ([PdCl(C3H5)]2).

[0028] As used herein the term “alkylating agent” used in the present invention can be selected from but not limited to tri(Cl-C2 alkyl)oxonium salt, a (Cl-C2)alkylsulfate, a (Cl -C2)chloroformate, Triethyloxonium tetrafluoroborate (Et3O)BF4, Trimethyloxonium tetrafluoroborate (Me3O)BF4, Methyl trifluoromethanesulfonate (methyl triflate), methyl iodide, dimethyl sulfate, Ethyl chloroformate, diazomethane, ethyl iodide, isopropyl iodide,n-butyl iodide, Acetaldehyde.

[0029] As used herein the term “chiral resolving agent” or “chiral agent” or “chiral salt” used in the present invention refers to chiral acids such as S-(+) mandelic acid, R-(-) mandelic acid, L(+) -mandelic acid, acetyl mandelic acid, DL-mandelic acid, 2-chloromandelic acid, (-) -Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaric acid monohydrate, (+)-Dibenzoyl-D-tartaric acid, (+)-Dibenzoyl-D-tartaric acid monohydrate, L-(+)tartaric acid, D-(-)tartaric acid, (+)-di-p-toluoyltartaric acid, (-)-di-p-toluoyltartaric acid, (+)-dipara-tolyl-D-tartaric acid, (-)-dipara-tolyl-L-tartaric acid, (+)-di-para-tolyloxybenzoyl-D-tartaric acid, (-)-di-para-tolyloxybenzoyl-L-tartaric acid, (+)-di-para-methoxybenzoyl-D-tartaric acid, (-)-di-para-methoxybenzoyl-L-tartaric acid, D-di(p-anisoyl)tartaric acid, L-di(p-anisoyl)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, L(-)-pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, (-)-naproxen, (-t-)-naproxen, (lR)-(-)-camphor sulfonic acid, (lS)-(+)-camphor sulfonic acid, (lR)-(+)-bromocamphor-10-sulfonic acid, (lS)-(-)-bromocamphor-10-sulfonic acid, 3 -bromocamphor- 8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, 2-amino-7,7-dimethylbicyclo [2,2,1] heptan-1 -methylene sulfonic acid, 2-acrylamide-7,7-dimethylbicyclo [2,2,1] heptan-1 -methylene sulfonic acid; or chiral amino acid selected from but not limited to D-isomers and L-isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, ornithine, 4-aminobutyric acid, 2-amino isobutyric acid, 3-amino propionic acid, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, N-acetyl-leucine etc., and the like; or chiral amine is selected from (S)-l,2,3,4-tertahydronaphthalene- 1 amine, (R)- 1 ,2,3,4-tertahydronaphthalene- 1 amine, (R)-2-phenyl glycinol, (S)-2-phenyl glycinol and the like; or chiral bases such as (S)-phenylethyl amine, (S)-2-amino-3-methylbutane, (S)-4-Chloro-a-methylbenzylamine, (S)-(-)-N,a- Dimethylbenzylamine, (S)-(-)-N,N-Dimethyl- 1 phenylethylamine, (S)-(-)- 1 -(2- Naphthyl)ethylamine and the like.

[0030] As used herein the term “hydroxy protecting group” ‘Pi’ used in the present invention is selected from but not limited to the group consisting of methyloxy carbonyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trityl, formyl, propionyl, n-butyl, isobutyl, tert-butylcarboxycarbonyl, methoxy carbonyl, ethoxycarbonyl, tertbutoxycarbonyl, carbobenzyloxy (Cbz), benzoyl (Bz), benzyl (Bn), tosyl (Ts), methane sulphonyl (Ms), p-methoxybenzyl carbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), acetyl (Ac), carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl (PMP), trichloroethyl chloroformate, p-nitrobenzenesulfonyl (nosyl), pivaloyl (Piv), silyl ether protecting groups such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS) and triisopropylsilyl (TIPS) thereof.

[0031] As used herein the term “reducing agent” is used in is selected from but not limited to Metal hydride including but not limited to LiAltU, NaAltU, NaBPU, KBH4, mixture of NaBPU & acetic acid, mixture of NaBPU & trifluoroacetic acid, mixture of NaBPU & iodine, mixture of NaBPU & trimethylchlorosilane, mixture of NaBPU & magnesium chloride, mixture of NaBPU & calcium chloride, mixture of NaBPU & one of transition metal chlorides, mixture of sodium borohydride BF3. etherate, sodium cyanoborohydride, sodium triacetoxy borohydride, Aluminium hydride (AIH3), diisobutylaluminium hydride (DIBAL), Vitride {=Sodium bis(2-methoxyethoxy) aluminum hydride}, Lithium Tri-tert-butoxyaluminum Hydride, Tributyltin Hydride; boranes such as not limited to BH3-tetrahydrofuran, BfL-dimethyl sulfide; hydrazine; metal including but not limited to Na, Fe, Ni, Zn, Sn in presence of acidic medium; Na-liquid ammonia; Silanes including but not limited to tri(Cl-C6)alkylsilanes, tri(Cl-C6)alkylsilyl halides; catalytic hydrogenation in presence of transition metals catalysts including but not limited to Ni, Pd, Pt, Rh, Re, Ru and Ir, including their oxides, hydroxides, acetates and combinations optionally in presence of acids and the like.

[0032] As used herein the term “acid” in the present invention refers to inorganic acid and organic acid; inorganic acid is selected from but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hypo chlorous acid, hypo iodous acid, hypo bromous acid, hydrogen sulfide; organic acids is selected from but not limited to acetic acid, maleic acid, malic acid, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid, pivalic acid, formic acid, benzoic acid, methanoic acid and citric acid and like.

[0033] As used herein the term “pharmaceutically acceptable salts” or “salt” or “salts”include but are not limited to, hydrohalides like hydrochloride, hydrobromide and hydroiodide; nitrates; perchloric acid salts, sulfates or phosphates; lower-alkyl sulfonic acid salts such as methanesulfonate, or ethanesulfonate; arylsulfonic acid salts such as benzene sulfonate or p-toluenesulfoante; organic acid salts such as acteate, fumarate, succinate, citrate, oxalate or maleate; or 1,5-naphthalenedisulfonic acid salt, pivalic acid and the like.

[0034] The first embodiment of the present invention provides a novel process for the preparation of Elacestrant of formula- 1 or its pharmaceutically acceptable salt thereof comprising one or more of the following steps:

[0035] a) treating the compound of formula-34 with an acid to provide compound of formula-35, b) contacting the compound of formula-35 with a chiral resolving agent to form an enantiomerically enriched salt of formula-36 and optionally freeing the compound of formula-36 to provide compound of formula-37,

[0036] c) converting the compound of formula-36 or compound of formula-37 to compound of formula-39,

[0037] d) alkylating the compound of formula-39 in presence of an alkylating agent optionally in the presence of a reducing agent to provide compound of formula-40,

[0038] e) reacting the compound of formula-40 with ethyl amine in presence of a coupling agent to provide compound of formula-41,

[0039] f) reducing the compound of formula-41 in presence of a reducing agent in a solvent to provide compound of formula- 1 ,

[0040] g) optionally converting the compound of formula- 1 to its pharmaceutically acceptable salts.

[0041] The first aspect of the first embodiment, wherein the solvent in step-a) to g) is selected from ester solvents, ether solvents, hydrocarbon solvents, ketone solvents, alcoholic solvents, nitrile solvents, chloro solvents, water and / or mixtures thereof.

[0042] The second aspect of the first embodiment, wherein the acid used in step-a) is same as defined above and not a chiral acid; chiral resolving agent used in step-b) is same as defined above; alkylating agent used in step-d) is same as defined above; coupling agent used in step-e) is same as defined above; reducing agent used in step-d) and step-f) is same as definedabove; salt in step-g) are same as defined above.

[0043] The third aspect of the first embodiment, wherein the conversion of the compound of formula-36 or compound of formula-37 to compound of formula-39 in step-c) is carried out the reductive amination with the compound of formula-25.

[0044] The fourth aspect of the first embodiment, wherein the freeing the salt in step-b) can be carried out in presence of base which is same as defined above.

[0045] The fifth aspect of the first embodiment reductive amination can be carried out in presence of a reducing agent which is same as defined above.

[0046] The sixth aspect of the first embodiment, the different reaction steps of the process can be carried out using techniques known in the art by employing suitable conditions.

[0047] The first embodiment of the present invention is schematically represented in scheme- 1 as follows:

[0048]

[0049] Scheme- 1

[0050] The second embodiment of the present invention provides a process for the preparation of compound of formula-34 comprising one or more of the following steps: a) reacting the compound of formula-30 with compound of formula-22 in the presence of abase to provide compound of formula-33,

[0051] b) reduction followed by deprotecting the compound of formula-33 to provide the compound of formula-34.

[0052] The first aspect of the second embodiment, wherein the solvent in step-a) and step-b) is same as defined above; the base used in the step-a) is selected from inorganic bases, organic bases or mixture thereof; the reduction in step-b) can be carried out in presence of a reducing agent which is same as defined above; the deprotection can be carried out in presence of a deprotecting agent which is same as defined above.

[0053] The second aspect of the second embodiment, reduction and deprotection in step-b) can be carried out with a same reducing agent.

[0054] The third aspect of the second embodiment, the different reaction steps of the process can be carried out using techniques known in the art by employing suitable conditions.

[0055] The fourth aspect of the second embodiment, wherein the compound of formula-34 can be further converting to Elacestrant of formula- lor its pharmaceutically acceptable salts.

[0056] The second embodiment of the present invention is schematically represented in scheme-2 as follows:

[0057]

[0058] Formula-30 Formula-33 Formula-34

[0059] wherein P; is hydroxy protecting group;

[0060]

[0061] Scheme-2

[0062] Wherein X is a halogen, transition metal or boron-containing compound; X1is a halogen, transition metal-containing function or boron-containing function; X and X1are suitable for cross-coupling of compound of formula-30 with compound of formula-22; Pi is hydroxy protecting group.

[0063] The third embodiment of the present invention provides a process for the preparationof compound of formula-33a comprising one or more of the following steps:

[0064] a) reacting the compound of formula-30a with bis (neopentyl glycolato) diboron of formula- 29 in the presence of a coupling agent, optionally in the presence of a catalyst to provide compound of formula-30b,

[0065] b) reacting the compound of formula-30b with compound of formula-22a in the presence of a base to provide compound of formula-33a.

[0066] The first aspect of the third embodiment, wherein the solvent in step-a) and step-b) is same as defined above; the coupling agent and catalyst used in the step-a) are same as defined above; the base used in the step-b) is selected from inorganic bases, organic bases or mixture thereof.

[0067] The second aspect of the third embodiment, wherein the different reaction steps of the process can be carried out using techniques known in the art by employing suitable conditions.

[0068] The third aspect of the third embodiment, wherein the compound of formula-33a can be further converting to Elacestrant of formula- lor its pharmaceutically acceptable salts.

[0069] The third embodiment of the present invention specifically represented in scheme-3 as follows:

[0070]

[0071] The fourth embodiment of the present invention provides one or more novel intermediate compounds of Elacestrant selected from Formula-30b, Formula-35, Formula-39 and Formula-40. The said intermediates are used in the preparation of Elacestrant of formula-1.

[0072] In an aspect of the present invention, the compounds of Formula-29, Formula-30b and Formula-34 used in the present invention are synthesized from any of the known prior art processes.Fifth embodiment of the present invention provides the compound of formula-4 la

[0073]

[0074] Formula-4 la

[0075] The first aspect of the fifth embodiment, wherein the compound of formula-4 la obtained as a solid.

[0076] The second aspect of the fifth embodiment, wherein the compound of formula-4 la is an amorphous solid.

[0077] The third aspect of the fifth embodiment, wherein the compound of formula-4 la is a crystalline solid.

[0078] The fourth aspect of the fifth embodiment, wherein the compound of formula-4 la is a crystalline solid, herein after designated as crystalline form-M.

[0079] The fifth aspect of the fifth embodiment, wherein the crystalline form-M of compound of formula-4 la according to the fourth aspect having the PXRD peaks selected from about 5.6°, 7.2°, 8.4°, 8.8°, 9.5°, 11.3°, 13.6°, 14.2°, 14.9°, 15.8°, 16.4°, 16.8°, 18.1°, 18.7°, 19.4°, 20.7°, 21.0°, 21.5°, 22.0°, 23.5°, 25.0°, 25.8°, 28.6° and 29.5° 0.2° ± 26.

[0080] The sixth aspect of the fifth embodiment, wherein the crystalline form-M of compound of formula-4 la according to the fourth aspect is characterized by its PXRD pattern as substantially illustrated in figure- 1.

[0081] The seventh aspect of the fifth embodiment of the present invention, wherein the process for the preparation of the compound of formula-4 la comprises:

[0082] a) contacting the compound of formula-41 with a solvent,

[0083] b) treating the mixture obtained in step-a) with HC1 acid source,

[0084] c) isolating the compound of formula-4 la;

[0085] wherein the contacting the compound of formula-41 in a solvent in step-a) can be carried out by contacting compound of formula-41 with a solvent at a suitable temperature ranging from about 0°C to reflux temperature of the solvent or the mixture in step-a) can also be obtainedfrom the synthetic process in which the compound of formula-41 is prepared; wherein, 'contacting the compound of formula-41 with a solvent' means bringing the compound of formula-41 and the solvent into contact with each other, or obtaining the compound of formula-41 from the synthetic process in which it is prepared. This can be done by mixing the compound of formula-41 and solvent together or dissolving the compound of formula-41 in the solvent; the solvent used in step-a) is selected from alcohol solvent, ester solvent, nitrile solvent, ketone solvent, chloro solvent, ether solvent, water or mixture thereof; HC1 acid source in step-b) is IPA-HC1, methanolic HC1, concentrated HC1, dilute HC1, ethylacetate HC1, HC1 gas; isolating the compound of formula-41a in step-c) is involves the removal of solvent by suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, filtration, atmospheric distillation, agitated thin film drying (ATFD), melt extrusion, spray drying, cooling the mixture to lower temperatures followed by filtration by gravity or suction, or by any other suitable techniques known in the art.

[0086] Sixth embodiment of the present invention provides a crystalline form of Elacestrant dihydrochloride .

[0087] The first aspect of the sixth embodiment, wherein the crystalline form is having the PXRD peaks selected from about 5.9°, 6.2°, 8.1°, 9.7°, 11.3°, 12.4°, 13.3°, 13.6°, 15.4°, 17.3°, 18.2°, 18.6°, 21.0°, 21.7°, 22.2°, 22.9°, 23.8°, 24.9°, 26.1° and 29.7° 0.2° ± 26.

[0088] The second aspect of the sixth embodiment, wherein the crystalline form is characterized by its PXRD pattern as illustrated in figure-2 or figure-3 or figure-4.

[0089] The third aspect of the sixth embodiment of the present invention the process for the preparation of crystalline form of Elacestrant dihydrochloride of formula- la comprises: a) contacting the compound of formula- 1 a with a solvent,

[0090] b) isolating the compound of formula- 1 a;

[0091] wherein the contacting in a solvent in step-a) can be carried out by contacting compound of formula- la with a solvent at a suitable temperature ranging from about 0°C to reflux temperature of the solvent or the mixture in step-a) can also be obtained from the synthetic process in which the compound of formula- la is prepared; wherein, 'contacting thecompound of formula- la with a solvent' means bringing the compound of formula- la and the solvent into contact with each other, or obtaining the compound of formula- la from the synthetic process in which it is prepared. This can be done by mixing the compound of formula- 1 a and solvent together or dissolving the compound of formula- 1 a in the solvent; the solvent used in step-a) is selected from alcohol solvent, ester solvent, nitrile solvent, ketone solvent, chloro solvent, ether solvent, water or mixture thereof; isolating the compound of formula- la in step-c) is involves the removal of solvent by suitable techniques which includes but not limited to decantation, filtration, evaporation under reduced pressure, atmospheric distillation, agitated thin film drying, melt extrusion, spray drying, cooling the mixture to lower temperatures followed by filtration by gravity or suction, or by any other suitable techniques known in the art; optionally slurring the obtained compound.

[0092] The fourth aspect of the sixth embodiment of the present invention, wherein the crystalline form is used in the preparation of one or more crystalline forms of Elacestrant dihydrochloride known in the art, such as crystalline form-S of Elacestrant dihydrochloride and the like.

[0093] Seventh embodiment of the present invention provides Elacestr ant dihydrochloride is substantially free of one or more impurities selected from Des ethyl impurity, Aromatic impurity, Tetra hydro benzyl impurity, Alcohol impurity and Enantiomer impurity.

[0094] The first aspect of the seventh embodiment of the present invention wherein Elacestrant dihydrochloride is substantially free of one or more impurities selected from Des ethyl impurity, Aromatic impurity, Tetra hydro benzyl impurity, Alcohol impurity or Enantiomer impurity is obtained according to process described in the present invention.

[0095] The second aspect of seventh embodiment of the present invention wherein substantially pure Elacestrant dihydrochloride refers to one or more said impurities are less than about 0.15% or less than about 0.10% or less than about 0.09% or less than about 0.08% or less than about 0.07% or less than about 0.06% or less than about or 0.05% or less than about 0.04% or less than about 0.03% or less than about 0.02% or less than about 0.01% or less than about 0.005% or absent.

[0096] The third aspect of seventh embodiment of the present invention wherein thesubstantially pure Elacestrant or its pharmaceutically acceptable salts has a purity of greater than about 98%, preferably greater than about 99%, more preferably greater than about 99.5% measured by HPLC (High Performance Liquid Chromatography).

[0097] The fourth aspect of seventh embodiment, along with these impurities, the starting materials are well controlled as per ICH guidelines in the compound of formula- la.

[0098] The fifth aspect of the seventh embodiment, wherein the HPLC {High Pressure Liquid Chromatography} analytical method referred to herein is carried out using techniques known in the art by a person skilled in the art for the identification of impurities in Formula la.

[0099] The structures of impurities are of seventh embodiment of the present invention as shown below:

[0100]

[0101] An embodiment of the present invention provides pharmaceutical composition comprising Elacestrant dihydrochloride obtained according to the present invention and atleast one pharmaceutically acceptable excipient. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

[0102] Suitable pharmaceutically acceptable excipients are selected from but not limited to binders, diluents, disintegrants, surfactants and lubricants. Suitable binders that can be include polyvinylpyrolidone, copovidone, starches such as pregelatinized starch, cellulose derivatives such as hydroxypropylmethyl cellulose, ethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, gelatine, acacia, agar, alginic acid, carbomer, chitosan, dextrates, cyclodextrin, dextrin, glycerol dibehenate, guargum, hypromellose, maltodextrin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, sucrose, mixtures thereof; suitable diluents that can be include anhydrous lactose, lactose monohydrate, modified lactose, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, maize starch, pregelatinized starch, calcium carbonate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol starch, calcium lactate or mixtures thereof; suitable disintegrants that can be include magnesium aluminometa silicate (or magnesium aluminum silicate), starch, pregelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, alginic acid, carboxy methyl cellulose sodium, sodium alginate, calcium alginate and chitosan; suitable lubricants that can be include (but are not limited to) magnesium stearate, stearic acid, palmitic acid, talc, and aerosil. Suitable surfactants that can be include (but are not limited to) polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene-polyoxy-propylene copolymer and sodium lauryl sulphate; beta-cyclodextrin include (but are not limited to) sulfobutylalkyl ether-beta-cyclodextrin, betadex-sulfobutylether sodium, or hydroxypropyl -beta-cyclodextrin.

[0103] Elacestrant dihydrochloride 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 micronizationmay be performed before drying, or after the completion of drying of the product.

[0104] In another embodiment of the present invention provides a pharmaceutical composition comprising Elacestrant dihydrochloride prepared according to the present invention and one or more pharmaceutically acceptable carriers for the treatment of postmenopausal women or adult men, with ER -positive, HER2-negative, ESRI -mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

[0105] The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided for illustration only and hence should not be considered as limitation of the scope of the invention.

[0106] Examples:

[0107] Example-1: Preparation of 7-(benzyloxy)-3-(4-methoxy-2-nitrophenyl)-l,2-dihydro naphthalene of formula-33a

[0108] Bis(neopentyl glycolato)diboron of formula-29 (18.64 g) added to the mixture of 7-(Benzyloxy)-3-bromo-l,2-dihydronapthalene of formula-30a (20 g) and dimethoxyethane (140 ml) at 25-35°C. Potassium acetate (18.69 g) and bis(triphenylphosphine)palladium(II) dichloride (0.56 g) were added to the reaction mixture at 25-35°C and stirred at the same temperature. Heated the reaction mixture to 80-90°C and stirred at the same temperature. Cooled the reaction mixture to 15 -25 °C. Aqueous potassium bicarbonate solution (15 g of potassium bicarbonate in 60 ml water) and followed by 4-bromo-3-nitro-anisole of formula-22a (14.73 g) added to the above reaction mixture at 15-25°C. Heated the reaction mixture to 80-90°C and stirred at the same temperature. Cooled the mixture to 55-65°C, filtered the mixture through hyflow bed and washed with dimethoxyethane. Organic and aqueous layers were separated and distilled off the solvent completely from organic layer under reduced pressure and co-distilled with Methyl tertiary butyl ether. Methyl tertiary butyl ether (60 ml) added to the obtained compound at 25-35°C, cooled to 0-10°C and stirred at the same temperature. Filtered the solid, washed with Methyl tertiary butyl ether. Yield: 15.8 g Example-2: Preparation of 7-(benzyloxy)-3-(4-methoxy-2-nitrophenyl)-l,2-dihydro naphthalene of formula-33aPotassium acetate (93.42 g), Bis(neopentyl glycolato)diboron of formula-29 (93.17 g) and tetrakis (triphenyl phosphine) palladium(O) dichloride (1 g) were added to the mixture of 7-(Benzyloxy)-3-bromo-l,2-dihydronapthalene of formula-30a (100 g) and dimethoxyethane (700 ml) at 25-35 °C. Heated the reaction mixture to 80-90°C and stirred at the same temperature. Cooled the reaction mixture to 15-25°C. Aqueous potassium bicarbonate solution (75 g of potassium bicarbonate in 300 ml water) and followed by 4-bromo-3-nitro-anisole of formula-22a (73.61 g) added to the above reaction mixture at 15-25°C. Heated the reaction mixture to 80-90°C and stirred at the same temperature. Cooled the mixture to 55-65 °C, filtered the mixture through hyflow bed and washed with dimethoxy ethane. Organic and aqueous layers were separated and distilled off the solvent completely from organic layer under reduced pressure and co-distilled with methyl tertiary butyl ether. Methyl tertbutyl ether (6 ml) added to the obtained compound at 25-35°C, cooled to 0-10°C and stirred at the same temperature. Filtered the solid, washed with methyl tertiary butyl ether. Yield: 96.6 g Example-3: Preparation of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydro naphthalen-2-ol of formula-34

[0109] Hydrogen gas pressure applied to the mixture of 7-(benzyloxy)-3-(4-methoxy-2-nitrophenyl)-1 ,2-dihydronaphthalene of formula-33a (25 g), tetrahydrofuran (175 ml), palladium on carbon (2.5 g) and methanol (175 ml) under nitrogen atmosphere in auto clave at 25-35°C and stirred at the same temperature. Heated the reaction mixture to 35-45°C and stirred at the same temperature. Cooled the mixture to 5- 15 °C, filtered through hyflow bed and washed with a mixture of methanol and tetrahydrofuran. Distilled off the solvent completely from filtrate under reduced pressure and co-distilled with n-heptane. n-Heptane (75 ml) was added to obtained compound at 25-35°C, heated to 45-55°C and stirred at the same temperature. Cooled the mixture to 25-35°C and stirred at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get title compound. Yield: 15.8 g

[0110] Example-4: Preparation of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydro naphthalen-2-ol pivalate of formula-35a

[0111] Pivalic acid (11.37 g) was added to the solution of 6-(2-amino-4-methoxyphenyl)-5, 6,7,8-tetrahydro naphthalen-2-ol of formula-34 (25 g) in tetrahydrofuran (250 ml) at 25-35°C andstirred at the same temperature. Distilled off solvent completely from reaction mixture under reduced pressure to get the title compound as a solid.

[0112] Example-5: Preparation of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydro naphthalen-2-ol (2S,3S)-2,3-bis(benzoyloxy)succinate of formula-36a

[0113] Dissolved the compound of formula-35a obtained in example-4 in acetonitrile (325 ml) and dichloromethane (100 ml) at 35-45°C and stirred at the same temperature. Dibenzoyl-D-(+)-tartaric acid (16.62 g) was added to the above solution at 35-45°C and stirred at the same temperature. Heated the reaction mixture to 55-65°C and stirred at the same temperature. Cooled the mixture to 25-35°C and stirred at the same temperature. Filtered the solid, washed with mixture of acetonitrile and dichloromethane. To the obtained compound, acetonitrile added and followed by dichloromethane added at 25-35°C, heated to 55-65°C and stirred at the same temperature. Cooled the mixture to 25 -35 °C and stirred at the same temperature. Filtered the solid, washed with a mixture of acetonitrile and dichloromethane to get title compound. Yield: 12.6 g

[0114] Example-6: Preparation of (R)-2-(4-((ethyl(2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)acetic acid of formula-40

[0115] Distilled off the solvent from the mixture of (R)-6-(2-amino-4-methoxyphenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol of formula-37 (25 g) and tetrahydrofuran (250 ml). Tetrahydrofuran (500 ml) was added to the above obtained compound at 25-35°C and dried with sodium sulfate. 2-4-(formyl phenyl) acetic acid of formula-25 (18.28 g), n-heptane (175 ml) and dibenzoyl-D-(+)-tartaric acid (0.2 g) were added to above mixture at 25-35°C, heated to 55-65°C and stirred at the same temperature. Distilled off the solvent completely from the reaction mixture and co-distilled with mixture of tetrahydrofuran and n-heptane followed by n-heptane. n-Heptane is added to obtained compound and cooled to 25-35°C and stirred at the same temperature. Filtered the solid, washed with n- heptane. Sodium triacetoxy borohydride (88.50 g) and tetrahydrofuran (250 ml) were added to the above obtained compound at 25-35°C and heated to 55-65°C and stirred at the same temperature. Cooled the reaction mixture to 25-35°C, water was added and stirred at the same temperature. Separated the both organic layer and aqueous layers and aqueous layer extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Obtainedorganic layer was dried by using sodium sulfate and distilled off the solvent completely from organic layer and co-distilled with n-heptane to get the compound of formula -39. Acetaldehyde (88 ml) followed by sodium triacetoxyborohydride (49.17 g) were added to pre-cooled mixture of the above obtained compound in tetrahydrofuran (250 ml) at 0-10°C and stirred at the same temperature. Aqueous ammonia (50 ml) was slowly added to the reaction mixture at 0-10°C and stirred at the same temperature. Separated the both organic layer and aqueous layers and the aqueous layer extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from organic layer and co-distilled with n-hexane. The obtained compound is isolated with n-hexane and filtered the solid, washed with n- hexane and dried to get title compound. Yield: 41 g

[0116] Example-7: Preparation of the compound of formula-40

[0117] Mixture of acetaldehyde (45 ml) and Sodium triacetoxyborohydride (31.57 g) was added to pre-cooled mixture of tetrahydrofuran (150 ml) and the compound of formula-39 ( 15 g) at 0-10°C and stirred at the same temperature. Aqueous sodium hydroxide solution was slowly added to the above reaction mixture at 0-10°C, raised temperature to 25-35°C and stirred at the same temperature. Separated the both organic layer and aqueous layers and the aqueous layer extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium bicarbonate solution followed by aqueous sodium chloride solution. Distilled off the solvent completely from organic layer and co-distilled with n-hexane. The obtained compound is isolated with n- hexane and filtered the solid, washed with n- hexane and dried to get title compound. Yield: 14.8 g

[0118] Example-8: Preparation of 7-(benzyloxy)-3-(4-methoxy-2-nitrophenyl)-l,2-dihydro naphthalene of formula-33a

[0119] Bis(neopentyl glycolato)diboron of formula-29 (46.57 g) and tetrakis (triphenyl phosphine) palladium(O) (0.34 g) were added to the mixture of Potassium acetate (46.69 g), 7-(Benzyloxy)-3-bromo-l,2-dihydronapthalene of formula-30a (50 g) and dimethoxyethane (350 ml) at 25-35°C under nitrogen atmosphere and stirred at the same temperature. Heated the reaction mixture to 45-55°C and stirred at the same temperature. Further, heated the reaction mixture to 82-88°C and stirred at the same temperature. Cooled the reaction mixtureto 15-25°C. Aqueous potassium bicarbonate solution (37.47 g of potassium bicarbonate in 150 ml water) was slowly added and followed by l-bromo-4-methoxy-2-nitrobenzene of formula-22a (36.79 g) added to the above reaction mixture at 15-25°C. Heated the reaction mixture to 80-90°C and stirred at the same temperature. Cooled the mixture to 55-65°C, filtered the mixture through hyflow bed and washed with dimethoxyethane. Organic and aqueous layers were separated and distilled off the solvent completely from organic layer under reduced pressure and co-distilled with methyl tertiary butyl ether. The obtained compound was slurried in methyl tertiary butyl ether, followed by it with water and dried to get title compound. Yield: 55 g; Purity by HPLC: 99.58%.

[0120] Example-9: Preparation of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydro naphthalen-2-ol of formula-34

[0121] Hydrogen gas pressure applied to the mixture of 7-(benzyloxy)-3-(4-methoxy-2-nitrophenyl)-1 ,2-dihydronaphthalene of formula-33a (50 g), tetrahydrofuran (375 ml), methanol (350 ml) and 20% palladium hydroxide (0.5g) in auto clave at 25-35°C, heated the reaction mixture to 55-65°C and stirred at the same temperature. Cooled the mixture to 25-35°C, filtered through hyflow and washed with methanol and followed by tetrahydrofuran. Distilled off the solvent completely from filtrate under reduced pressure and co-distilled with isopropyl alcohol. Slurried the obtained compound isopropyl alcohol, filtered solid, washed with isopropyl alcohol and dried to get title compound. Yield: 26 g; Purity by HPLC: 95.74%.

[0122] Example-10: Preparation of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydro naphthalen-2-ol pivalate of formula-35a

[0123] Pivalic acid (68.25 g) was added to the solution of 6-(2-amino-4-methoxyphenyl)-5, 6,7,8-tetrahydro naphthalen-2-ol of formula-34 (150 g) in acetonitrile (750 ml) at 25-35°C and stirred at the same temperature. Raised temperature of the reaction mixture to 55-65°C and stirred at the same temperature. Distilled off solvent completely from reaction mixture under reduced pressure to get the title compound as a solid. Yield: 214 g

[0124] Example-11: Preparation of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydro naphthalen -2-ol of formula-37a

[0125] Dissolved the compound of formula-35a (214 g) obtained in example-10 in mixture of acetonitrile (1950 ml) and dichloromethane (600 ml) at 40-50°C. Dibenzoyl-D-(+)-tartaricacid (99.76 g) was added to the above solution at 40-50°C and stirred at the same temperature. Heated the mixture to 60-70°C and stirred at the same temperature. Slowly cooled the mixture to 15-25 °C and stirred at the same temperature. Filtered the solid, washed with dichloromethane (2 lots) and dried. Dissolved the obtained compound in mixture of acetonitrile (1950 ml) and dichloromethane (150 ml) at 60-70°C and stirred at the same temperature. Slowly cooled the mixture to 15-25 °C and stirred at the same temperature. Filtered the solid, washed with dichloromethane to compound of formula-36a. Methanol (450 ml) and water (1500 ml) were added to compound at 25-35°C and stirred at the same temperature. Cooled the mixture to 15 -25 °C and aqueous sodium bicarbonate solution was added to the mixture at 15-25°C, stirred at the same temperature. Filtered the solid, washed with water and dried to get title compound. Yield: 40.5 g

[0126] Example-12: Preparation of (R)-2-(4-(((2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)acetic acid of formula-39

[0127] 2-(4-formylphenyl)acetic acid of formula-25 (18.28 g) was added to the mixture of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol of formula-37 (25 g) and methanol (250 ml) at 25-30°C and stirred at same temperature. The reaction mixture was cooled to -5 to 5°C, sodium borohydride (8.7 g) added lot wise to the reaction mixture at under nitrogen atmosphere and stirred at same temperature. Acidified the reaction mixture with aqueous hydrochloric acid solution, raised the reaction mixture temperature to 25-35°C and stirred at same temperature. Filtered the solid, washed with mixture of methanol and water. The obtained compound was slurried in methanol, filtered and dried to get the titled compound. Yield: 30 g.

[0128] Example-13: Preparation of (R)-2-(4-((ethyl (2-(6-hydroxy-l,2,3,4-tetrahydro naphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)acetic acid of formula-40 Collected the pure acetaldehyde from the mixture of paraldehyde (75 ml), sulphuric acid (0.075 ml) Nicotinamide (0.0037 g) at 40-50°C. Triacetoxy sodium borohydrate (63.5 g) added in lot-wise to the pre-cooled solution of (R)-2-(4-(((2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)acetic acid of formula-39 (50 g) in tetrahydrofuran (500 ml) under nitrogen atmosphere at 0-10°C and stirred at the same temperature. To this reaction mixture, above obtained acetaldehyde added undernitrogen atmosphere at 0-10°C and stirred at the same temperature. Sodium bicarbonate added to it, followed by basified with aqueous sodium hydroxide solution and raised reaction mixture temperature to 25-30°C. Filtered the mixture washed with ethyl acetate and separated the layers. The aqueous layer was extracted with the mixture of ethyl acetate and tetrahydrofuran. Washed the organic layer with aqueous sodium chloride solution, distilled off the solvent from the organic layer and co distill with methanol. Added water to the obtained compound at 25-35°C and acidified with aqueous hydrochloric acid solution and stirred at same temperature. Filtered the solid, washed with water and dried to get the titled compound. Yield: 49 g.

[0129] Example-14: Preparation of (R)-N-ethyl-2-(4-((ethyl(2-(6-hydroxy-l,2,3,4-tetrahydro naphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)acetamide hydrochloride of formula-41a

[0130] N,N-diisopropylethylamine (38.2 ml) added to the solution of the compound of formula-40 (49 g) in tetrahydrofuran (490 ml) at 5-15°C. Added ethylamine solution (121.03 ml), hydroxybenzotriazole (7.35 g) to the reaction mixture followed by added EDC.HC1 lot wise. Raised reaction mixture temperature to 20-30°C and stirred at same temperature. Water added to the reaction mixture and separated the layers. The aqueous layer extracted with ethyl acetate. Combined the organic layers, washed with aqueous sodium bicarbonate solution. Water, followed by aqueous hydrochloric acid solution added to the organic layer. Separated the layers and the organic layer washed with aqueous sodium chloride solution. Distilled off the solvent, co-distilled with isopropanol. Added isopropanol (392 ml) to the obtained compound and followed by IPA.HC1 (49 ml) added. Heated the reaction mixture to 45-55°C and stirred at same temperature. Cooled to 25-35°C and stirred at same temperature, filtered the solid, washed with isopropanol. Obtained compound slurried in isopropanol, filtered the solid, washed with isopropanol and dried to get the titled compound.

[0131] Yield: 48 g. Purity by HPLC: 98.40%.

[0132] PXRD of the obtained compound is illustrated in figure- 1.

[0133] Example-15: Preparation of Elacestrant of formula-1

[0134] Converted the compound of formula-4 la (20 g) its free base by treated with aqueous sodium hydroxide in methyl tertiary butyl ether. Distilled off the solvent completely from organiclayer and co-distilled with tetrahydrofuran. Tetrahydrofuran added to the obtained compound of formula-41 and cooled to -5 to 5°C. Sodium borohydride (3.71 g) was added lot wise to above at -5 to 5 °C and stirred at the same temperature. Iodine solution (11.9 g of Iodine dissolved in 60 ml of tetrahydrofuran) was slowly added to the reaction mixture at 0-5 °C and stirred at the same temperature. Raised temperature to 25-35°C and stirred at the same temperature. Heated the reaction mixture to 60-70°C and stirred at the same temperature. Reaction mixture was cooled to 0-5 °C and hydrochloric acid followed by water were added to the above mixture at 0-5 °C and stirred at the same temperature. Partially distilled off the solvent from the mixture and cooled to 5- 15 °C and stirred at the same temperature. Filtered the solid and washed with water. Water and ethyl acetate were added to the above obtained solid at 25-35 °C and stirred at the same temperature. Aqueous sodium hydroxide solution was added to the mixture and separated the both layers. The aqueous layer extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium thiosulphate solution followed by aqueous sodium chloride solution. Distilled off the solvent completely from organic layer to get the title compound.

[0135] Example-16: Preparation of Elacestrant dihydrochloride of formula-la

[0136] Dissolved the Elacestrant obtained in example- 15 in the mixture of ethyl acetate and ethanol at 25-35°C. Ethanolic hydrochloride was added to above mixture at 25-35°C and stirred at the same temperature. Distilled off the solvent completely from the mixture.

[0137] Example-17: Preparation of Crystalline form of Elacestrant dihydrochloride of formula-la

[0138] Heated the mixture of the Elacestrant dihydrochloride of formula- la obtained in example- 16 ethyl acetate and ethanol to 45-55°C and stirred at the same temperature. Cooled the mixture to 25-35°C and stirred at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get title compound.

[0139] Yield: 17 g. PXRD of the obtained compound is illustrated in figure-2.

[0140] Example-18: Preparation of Elacestrant dihydrochloride of formula-la

[0141] The preparation of Elacestrant dihydrochloride of formula- la similar to the process described in above example using methanol and methanolic HC1 instead of ethanol and ethanolic hydrochloride. PXRD of the obtained compound is illustrated in figure-3.Example-19: Preparation of Crystalline form of Elacestrant dihydrochloride of formula-la

[0142] Dissolved the Elacestrant dihydrochloride of formula- la (850 g) in methanol (2550 ml) at 55-65°C. Cooled the solution to 25-35°C and stirred at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get title compound.

[0143] Yield: 719 g. Purity by HPLC: 99.55%.

[0144] PXRD of the obtained compound is illustrated in figure-4.

Claims

We Claims:

1. A process for the preparation of Elacestrant of formula- 1 or its pharmaceutically acceptable salt thereofcomprising one or more of the following steps:a) treating the compound of formula-34 with an acid to provide compound of formula-35,Formula-34 Formula-35 b) contacting the compound of formula-35 with a chiral resolving agent to form an enantiomerically enriched salt of formula-36 and optionally freeing the compound of formula-36 to provide compound of formula-37,c) converting the compound of formula-36 or compound of formula-37 to compound of formula-39,d) alkylating the compound of formula-39 in presence of an alkylating agent optionally inthe presence of a reducing agent to provide compound of formula-40,Formula-40e) reacting the compound of formula-40 with ethyl amine in presence of a coupling agent to provide compound of formula-41 or its salts, andFormula-41followed by reducing the compound of formula-41 in presence of a reducing agent in a solvent to provide compound of formula- 1 or its pharmaceutically acceptable salts.

2. The process according to claim 1, wherein the solvent in step-a) to e) is selected from ester solvents, ether solvents, hydrocarbon solvents, ketone solvents, alcoholic solvents, nitrile solvents, chloro solvents, water and / or mixtures thereof; acid used in step-a) is selected from organic or inorganic acid and not a chiral acid; chiral resolving agent used in step-b) is (+)-Dibenzoyl-D-tartaric acid; alkylating agent used in step-d) is acetaldehyde; coupling agent used in step-e) is oxalyl chloride; reducing agent used in step-d) and step- e) is sodium borohydride.

3. The process according to claim 1, wherein the conversion of the compound of formula-36 or compound of formula-37 to compound of formula-39 in step-c) is carried out the reductive amination with the compound of formula-25Formula-25freeing the salt in step-b) can be carried out in presence of base which is selected from inorganic bases, organic bases or mixture thereof; reductive amination can be carried out in presence of a reducing agent which is sodium borohydride.

4. A process for the preparation of compound of formula-33a comprisesFormula-33aa) reacting the compound of formula-30a with bis(neopentyl glycolato)diboron of formula-29 in the presence of a coupling agent, optionally in the presence of a catalyst to provide compound of formula-30b,b) reacting the compound of formula-30b with compound of formula-22a in the presence of a base to provide compound of formula-33aFormula- 22a.

5. The process according to claim 4, wherein the solvent in step-a) and step-b) is selected from ester solvents, ether solvents, hydrocarbon solvents, ketone solvents, alcoholic solvents, nitrile solvents, chloro solvents, water and / or mixtures thereof; the couplingagent and catalyst used in the step-a) is tetrakis (triphenyl phosphine) palladium(O); the base used in the step-b) is selected from inorganic bases, organic bases or mixture thereof.

6. The process according to claim 4, wherein the compound of formula-33a can be further converting to Elacestrant of formula- lor its pharmaceutically acceptable salts.

7. A compound of formula-35Formula-35.

8. The compound according to claim 7, wherein the compound of formula-35 is used in the preparation of Elacestrant of formula- lor its pharmaceutically acceptable salts.

9. The compound of formula-35 according to claim 7 is formula-35a10. A compound of formula-4 la11. The compound of formula-4 la according to claim 10, wherein the compound is obtainedas a solid.

12. The compound of formula-4 la according to claim 11, wherein the compound is an amorphous solid.

13. The compound of formula-4 la according to claim 11, wherein the compound is a crystalline solid.

14. The compound according to claim 10, wherein the compound of formula-41a is used in the preparation of Elacestrant of formula- lor its pharmaceutically acceptable salts.

15. A process for the preparation of the compound of formula-4 la comprises:a) contacting the compound of formula-41 with a solvent,b) treating the mixture obtained in step-a) with HC1 acid source,c) isolating the compound of formula-4 la.

16. The process according to claim 15, wherein the contacting the compound of formula-41 in a solvent in step-a) can be carried out by contacting compound of formula-41 with a solvent at a suitable temperature ranging from about 0°C to reflux temperature of the solvent or the mixture in step-a) can also be obtained from the synthetic process in which the compound of formula-41 is prepared; the solvent used in step-a) is selected from alcohol solvent, ester solvent, nitrile solvent, ketone solvent, chloro solvent, ether solvent, water or mixture thereof; HC1 acid source in step-b) is IPA-HC1, methanolic HC1, concentrated HC1, dilute HC1, ethylacetate HC1, HC1 gas; isolating the compound of formula-4 la in step-c) is involves the removal of solvent by suitable techniques such as decantation, evaporation under reduced pressure, filtration, atmospheric distillation, agitated thin film drying, melt extrusion, spray drying, cooling the mixture to lower temperatures followed by filtration by gravity or suction.

17. The pharmaceutically acceptable salts of Elacestrant of formula- 1 according to claim 1 is Elacestrant dihydrochloride of formula- laFormula- 1 a.

18. Elacestrant dihydrochloride of formula- laFormula- 1 a.is substantially free of one or more impurities selected fromTetra hydro benzyl impurity Alcohol impurity and19. The substantially pure Elacestrant dihydrochloride according to claim 18, wherein one ormore said impurities are less than about 0.15% or less than about 0.10% or less than about 0.09% or less than about 0.08% or less than about 0.07% or less than about 0.06% or less than about or 0.05% or less than about 0.04% or less than about 0.03% or less than about 0.02% or less than about 0.01% or less than about 0.005% or absent.

20. A method of using the Elacestrant dihydrochloride according to any of the preceding claims for the preparation of a pharmaceutical formulation.

21. A pharmaceutical composition comprising Elacestrant dihydrochloride of formula- la according any of the preceding claims and at least one pharmaceutically acceptable excipient.

22. A method of treating a mammal by administering a therapeutically effective amount of Elacestrant dihydrochloride of formula- la according to any of preceding claims for the treatment of postmenopausal women or adult men, with ER-positive, HER2-negative, ESRI -mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

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