Novel process for the preparation of elacestrant and its intermediates thereof

Abstract

The invention provides processes for preparing elacestrant or its pharmaceutically acceptable salts, including sequences comprising borylation, condensation, reduction, catalytic hydrogenation, chiral-acid resolution, base treatment, alkoxylation, and deprotection, with optional in situ operations and purification to yield elacestrant free base. It further discloses novel intermediates (e.g., compounds of formulae V, VI, VII, VIII, IX / IX', XI, XII, XIII, XIV, XV, and XVI), methods for their preparation, and their use in synthesizing elacestrant. Also described are purification methods in which an acid addition salt of elacestrant is formed and subsequently basified to isolate purified elacestrant free base.

Description

[0001] NOVEL PROCESS FOR THE PREPARATION OF ELACESTRANT AND ITS INTERMEDIATES THEREOF PRIORITY:

[0002] This application claims the benefit under Indian Provisional Application No(s).

[0003] 202441087415 fded on Nov 13, 2024 entitled “NOVEL PROCESS FOR THE PREPARATION OF ELACESTRANT AND ITS INTERMEDIATES THEREOF” and 202441087416 filed on Nov 13, 2024 entitled “NOVEL PROCESS FOR THE PREPARATION OF ELACESTRANT AND ITS INTERMEDIATES THEREOF” the content of each of which are incorporated by reference herein.

[0004] FIELD OF INVENTION:

[0005] The present invention relates to processes for preparing elacestrant and its intermediates, and to methods for purifying elacestrant free base of formula I.

[0006] BACKGROUND OF THE INVENTION:

[0007] Elacestrant dihydrochloride, the active ingredient, is an estrogen receptor (ER) antagonist and is used in the treatment of patients with postmenopausal & breast cancer. It is chemically known as (6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol dihydrochloride, having structural formula as represented by formula la.

[0008]

[0009] Formula la

[0010] Elacestrant was discovered by Eisai Co., Ltd. Radius Health, Inc. has an exclusive right and license from Eisai to research, develop, manufacture, and commercialize elacestrant worldwide. It is marketed in USA and Europe under the trade name ORSERDU® in the form of tablets having strengths 345mg and 86mg. Elacestrant is an estrogen receptor antagonist that binds to estrogen receptor-alpha (ERa). Elacestrant and process for its preparation was first disclosed in U.S. Patent no. 7,612,114, which is schematically depicted in the following scheme:

[0011]

[0012] The said process involves optical resolution of compound of formula (1) is performed by using chiral HPLC. Chiral HPLC is capital-intensive, solvent-consumptive, and throughput-limited, rendering it unsuitable for large-scale synthesis and commercial manufacture.

[0013] There remains a need for an alternative process that avoids preparative chiral chromatography, uses inexpensive and easy-to-handle reagents and common industrial solvents, reduces solvent consumption, and affords higher isolated yield and purity.

[0014] Accordingly, an objective of the present invention is to provide a cost-effective, environmentally friendlier, and commercially viable process for preparing elacestrant or a pharmaceutically acceptable salt thereof, suitable for robust scale-up to large-batch operations.

[0015] OBJECTIVES OF THE INVENTION:

[0016] It is an object of the present invention to overcome the shortcomings of the prior art.

[0017] It is an object of the present invention to provide a novel process for the preparation of elacestrant or a pharmaceutically acceptable salt thereof.

[0018] It is another object of the present invention to provide novel intermediate compounds and process for the preparation thereof. It is another object of the present invention to provide use of novel intermediate compounds in the preparation of elacestrant or a pharmaceutically acceptable salt thereof.

[0019] It is yet another object of the present invention to provide a process for the purification of elacestrant free base compound.

[0020] SUMMARY OF THE INVENTION:

[0021] According to one aspect, the invention provides a novel process for the preparation of elacestrant or a pharmaceutically acceptable salt thereof, which comprises:

[0022] a) reacting a compound of formula II with a borylation reagent to obtain a compound of formula III;

[0023]

[0024] b) condensing the compound of formula III with a compound of formula IV to obtain a compound of formula V ;

[0025]

[0026] c) reducing the compound of formula V with a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula VI;

[0027]

[0028] d) catalytic hydrogenation of the compound of formula VI with a suitable hydrogenation catalyst in the presence of a suitable solvent to obtain a compound of formula VII;

[0029]

[0030] alternatively, catalytic hydrogenation of the compound of formula V with a suitable hydrogenation catalyst in the presence of a suitable solvent to obtain a compound of formula VII;

[0031] "

[0032]

[0033] e) contacting the compound of formula VII with a chiral acid in the presence of a suitable solvent to obtain a compound of formula VIII;

[0034]

[0035] f) treating the compound of formula VIII with a base in the presence of a suitable solvent to obtain a compound of formula IX;

[0036]

[0037] g) condensing the compound of formula VIII or compound of formula IX with a compound of formula X to obtain a compound of formula XI (in-situ)',

[0038]

[0039] h) reducing the compound of formula XI (in-situ) with a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XII;

[0040]

[0041] i) alkoxylation of the compound of formula XII with a suitable alkoxylating agent to obtain a compound of formula XIII;

[0042]

[0043] j) deprotecting the compound of formula XIII with a suitable deprotecting agent in the presence of a suitable solvent to obtain elacestrant or a pharmaceutically acceptable salt thereof; and

[0044]

[0045] k) optionally, purifying elacestrant or a pharmaceutically acceptable salt thereof in a suitable solvent.

[0046] According to another aspect, the invention provides a novel process for the preparation of elacestrant or a pharmaceutically acceptable salt thereof, which comprises:

[0047] a) condensing a compound of formula VIII or a compound of formula IX with a compound of formula X to obtain a compound of formula XI (in-situ);

[0048]

[0049] b) reducing the compound of formula XI (in-situ) with a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XII;

[0050]

[0051] c) alkoxylation of the compound of formula XII with a suitable alkoxylating agent to obtain a compound of formula XIII;

[0052]

[0053] d) deprotecting the compound of formula XIII with a suitable deprotecting agent in the presence of a suitable solvent to obtain elacestrant or a pharmaceutically acceptable salt thereof; and

[0054]

[0055] e) optionally, purifying elacestrant or a pharmaceutically acceptable salt thereof in a suitable solvent.

[0056] According to another aspect, the invention provides a novel process for the preparation of compound of formula IX, which comprises:

[0057] a) catalytic hydrogenation of a compound of formula VI with a suitable hydrogenating catalyst in the presence of a suitable solvent to obtain a compound of formula VII;

[0058]

[0059] b) contacting the compound of formula VII with a chiral acid in the presence of a suitable solvent to obtain a compound of formula VIII; and

[0060]

[0061] c) treating the compound of formula VIII with a base in the presence of a suitable solvent to obtain a compound of formula IX;

[0062]

[0063] alternatively, asymmetric hydrogenation of the compound of formula VI to obtain a compound of formula IX.

[0064]

[0065] According to yet another aspect, the invention provides a novel compound of formula VIII or compound of formula IX, used in the preparation of elacestrant or a pharmaceutically acceptable salt thereof.

[0066] According to another aspect, the invention provides a novel process for the preparation of elacestrant or a pharmaceutically acceptable salt thereof, which comprises:

[0067] a) reductive amination of a compound of formula IX with acetaldehyde or with corresponding acetal and a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XIV ;

[0068]

[0069] b) condensing the compound of formula XIV with a compound of formula X to obtain a compound of formula XII; and

[0070]

[0071] c) converting the compound of formula XII into elacestrant or a pharmaceutically acceptable salt thereof.

[0072] According to another aspect, the invention provides a novel process for the preparation of elacestrant or a pharmaceutically acceptable salt thereof, which comprises: a) reducing a compound of formula X with a suitable reducing agent in presence of a suitable solvent to obtain a compound of formula XV ;

[0073]

[0074] b) halogenating the compound of formula XV with a suitable halogenating agent to obtain a compound of formula XVI;

[0075]

[0076] c) condensing the compound of formula XVI with a compound of formula XIV to obtain a compound of formula XII; and

[0077]

[0078] d) converting the compound of formula XII into elacestrant or a pharmaceutically acceptable salt thereof.

[0079] According to another aspect, the invention provides a novel process for the preparation of compound of formula XIX, which comprises:

[0080] alkoxylating compound of formula IX or a compound of formula IX’ with a suitable alkoxylating agent to obtain a compound of formula XIX.

[0081]

[0082] According to yet another aspect, the invention provides a novel process for the preparation of compound of formula XIX, and use in the preparation of elacestrant or a pharmaceutically acceptable salt thereof. According to another aspect, the invention provides a novel process for the preparation of elacestrant or a pharmaceutically acceptable salt thereof, which comprises:

[0083] a) alkoxylation of a compound of formula IX or a compound of formula IX’ with a suitable alkoxylating agent to obtain a compound of formula XIX;

[0084]

[0085] b) reductive amination of the compound of formula XIX with acetaldehyde or with corresponding acetal and a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XXVI, followed by condensing with a compound of formula XVI in the presence of a base in a suitable solvent to provide a compound of formula XIII;

[0086]

[0087] alternatively;

[0088] condensing the compound of formula XIX with a compound of formula X to obtain a compound of formula XI (in-situ)', followed by reduction with a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XIII; and

[0089]

[0090] c) converting the compound of formula XIII into elacestrant or a pharmaceutically acceptable salt thereof.

[0091] According to another aspect, the invention provides process for purifying elacestrant free base, comprising:

[0092] a) deprotecting a compound of formula XIII with a suitable deprotecting agent in the presence of a suitable solvent to obtain an acid addition salt of elacestrant; b) treating the acid addition salt of elacestrant with a suitable base; or treating the step-a) reaction mass with a base; and

[0093] c) isolating elacestrant in purified free base form.

[0094] According to another aspect, the invention provides novel intermediate

[0095]

[0096] wherein Pg, Pg’ and Pg” are independently hydrogen or a protecting group; X is halogen; Lg is a leaving group.

[0097] According to yet another aspect, the invention provides use of novel intermediate compounds of formulae V, VI, VII, VIII, IX, IX’ , XI, XII, XIV, XV & XVI, in the preparation of elacestrant or a pharmaceutically acceptable salt thereof.

[0098] According to another aspect, the invention provides a process for the purification of elacestrant free base. DETAILED DESCRIPTION:

[0099] The following description is provided to assist in a comprehensive understanding of exemplary embodiments of the invention. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary.

[0100] Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness.

[0101] The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustration purposes only and not for the purpose of limiting the scope of the invention as defined by the appended claims and their equivalents.

[0102] It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0103] Features that are described and / or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and / or in combination with or instead of the features of the other embodiments.

[0104] It should be emphasized that the term “comprises / comprising” when used in this specification is taken to specify the presence of stated features, steps or components but does not preclude the presence or addition of one or more other features, steps, components or groups thereof.

[0105] The term “suitable solvent” used in the present invention is selected from the group comprising of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons; wherein alcohol is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; ester is selected from the group consisting of ethyl acetate (EtOAc), isopropyl acetate (IP Ac) and the like; ketone is selected from the group consisting of acetone, methyl isobutyl ketone, and the like; ether is selected from the group consisting of tetrahydrofuran (THF), methyl tert-butyl ether, diisopropyl ether, 1,2-dimethoxyethane, 1,4-dioxane and the like; halogenated solvent is selected from the group consisting of dichloromethane (DCM), chloroform, and the like; hydrocarbons is selected from the group consisting of toluene, xylene, and the like; nitrile is selected from the group consisting of acetonitrile (ACN), propionitrile and the like; amide is selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethyl acetamide and the like; sulfoxide such as dimethyl sulfoxide; sulfone and the like; or mixtures thereof.

[0106] The term “base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, and the like; “alkali metal carbonates” such sodium carbonate, potassium carbonate, and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, and the like, potassium acetate, sodium acetate, dipotassium phosphate, tripotassium phosphate, disodium phosphate, trisodium phosphate, ammonia and organic bases such as triethylamine, l,8-diazabicycle[5.4.0]undec7-ene (DBU), lithiumdiisopropylamine (LDA), isopropyl amine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl amino pyridine (DMAP) and the like; “organosilicons” such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like, or mixtures thereof, and the like. The term “chiral acid” used in the present invention is selected from the group comprising of S-(+)mandelic acid, R-(-)mandelic acid, L(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (lR)-(-)-camphor sulfonic acid, (lS)-(+)-camphor sulfonic acid, (1R)-(+)-bromocamphor- 10- sulfonic acid, (lS)-(-)-bromocamphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid (L-DBTA), (-)-Dibenzoyl-L-tartaric acid monohydrate, (+)-Dibenzoyl-D-tartaric acid (D-DBTA), (+)-Dibenzoyl-D-tartaric acid monohydrate, (+)-dipara-tolyl-D-tartaric acid (D-DTTA), (-)-dipara-tolyl-L-tartaric acid (L-DTTA), L(-)-pyro glutamic acid, L(+)-pyro glutamic acid, (-)-lactic acid and the like.

[0107] The term “salt” used in the present invention refers to acid addition salts selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as acetic acid, maleic acid, malic acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; and the like.

[0108] The term “hydrogenation catalyst” is selected from but not limited to Ni, Pd, Pt, Rh, Re, Ru and Ir, including their oxides, hydroxides, acetates and combinations thereof. For example, Raney nickel, palladium catalyst such as Pd / C, Pd(OH)2 / C, palladium acetate, Pd / SrCCh, Pd / AFCh. Pd / MgO, Pd / CaCCh, Pd / BaSCU, PdO, PdCb, Rh / C, Ru / C, Re / C, Pt / C, platinum oxide, platinum black, PtCh, Rh / C, RuOi. and the like.

[0109] The term “protecting group (Pg, Pg’ and Pg”)” is selected from but not limited to hydrogen, tert-Butyloxycarbonyl (Boc), benzyl, 4-methoxybenzyl, 3,4-dimethoxy benzyl, p-methoxyphenyl, acetyl, propionyl, butyryl, phenylacetyl, toluyl, phenoxyacetyl, benzoyl, tosyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-iodo ethoxycarbonyl, carbobenzyl, 4-methoxybenzyloxycarbonyl, (Fluoren-9-ylmethoxy)carbonyl (Fmoc), 4-methoxy-2,3,6-trimethylbenzenesulphonyl, benzyl carbamate, acetamide, phthalimide, benzylamine and p-toluenesolfonamide, alkyl trifluoroacetyl such as methyl trifluoroacetyl, ethyl trifluoroacetyl, isopropyl trifluoroacetyl, vinyl trifluoroacetyl and the like.

[0110] The term “leaving group (Lg)” is selected from but not limited to halides such as chloride, bromide, iodine and the like; mesyl, tosyl, nosyl and triflyl and the like.

[0111] The term “deprotecting 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, 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 (such as Pd, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb) in presence of hydrogen source and the like.

[0112] The term “chiral ligand” used in the present invention refers to phosphine ligands selected from but not limited to trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, tricyclohexylphosphine, trimethylphosphite, triethylphosphite, tripropylphosphite, triisopropylphosphite, tributylphosphite, triphenylphosphine, tri-tert-butylphosphine, XPhos, t-BuXphos, tricyclohexylphosphite, 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (BINAP), 1,2-bis- (dimethylphosphino)ethane, l,2-bis(diethylphosphino)ethane, 1,2-bis(dipropylphos-phino)ethane, 1 ,2-bis(diisopropylphosphino)ethane, 1,2-bis(dibutylphosphino)ethane, l,2-bis(dicyclohexylphosphino)ethane, 1 ,3-bis(dicyclohexylphosphino)propane, l,3-bis(diiso-propylphosphino)propane, 1,4-bis(diisopropylphosphino)butane, 2,4-bis-(dicyclohexylphosphino)pentane, 2-Dicyclohexylphosphino-2,6'-dimethoxybiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, and 2-dicyclohexylphosphino-2', 4',6'-triisopropylbiphenyl, methyl 3a- Acetyloxy- 12a-(biphenyl-2,2-diyl)phosphite-5P-cholan-24-oate and like.

[0113] The term “borylation reagent” is selected from but not limited to trialkyl borate, pinacol borane, catecholborane, bis (neopentyl glycolato) diboron, bis(pinacolato)diboron (B Pim), bis (hexylene glycolato) diboron or bis(catecholato)diboron, tetrahydroxy di boron and other suitable borylation reagent known in the art can be used.

[0114] The term “catalyst” is selected from but not limited to PdCh, Pd(OAc)2, Pd(PPh3)4, PdCl2(CH3CN)2, PdCl2(PPh3)2, Pd(dppf)Cl2, Pd2(dba)3, Pd(dba)2, Pd(PCy3)2, [(Allyl)PdCl]2, and [PdCl(crotyl)]2, copper (I) catalyst, (IPr)PdCl(r|2-N,C-Ci2H7NMe2), Ni(PPh3)4, and other suitable catalyst known in the art can be used.

[0115] The term “ligand” is selected from but not limited to BINAP, Xantphos, triphenylphosphine, tributylphosphine, XPhos, t-BuXphos, SPhos, Johnphos, Xantphos, BNMO and other suitable ligand known in the art can be used.

[0116] The term "reducing agent" is selected from Fe, Fe in acidic media like NH4CI or HC1 or acetic acid, Sn in acidic media like HC1, Zn, Zn in acidic media like HC1 or NH4CI or acetic acid, sodium borohydride with catalytic N1CI2.6H2O or COCI2.6H2O, diborane, sodium aluminium hydride, hydrazine hydrate, sodium dithionate, sodium sulfide, ammonium sulfide, sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride and sodium triethylborohydride, hydrogenation catalysts such as nickel, Raney nickel, rhodium, Pd-C combined with borohydrides , cyclohexene , acidic media like formic acid, H3PO2 etc., Raney cobalt, Raney iron, lithium aluminum hydride, sodium amalgam, platinum oxide, Pt-C, boranetetrahydrofuran complex and the like in combination with hydrogen, DIBAL-H, lithium aluminium hydride, vitride, sodium borohydride / aluminium chloride or borane / aluminium chloride, sodium borohydride / iodine; and "sulfur derivatives" like sodium sulfite, sodium sulfide, sodium dithionate, sodium metabisulfite and the like.

[0117] The term “halogenating agent” is selected from but not limited to, HX, CX4, CuX2, ZnX2, SOCI2, SO2CI2, COCI2, X2, C(=O)(OC13)2, t-BuOCl, NaOCl, chloramine-T, N-halosuccinimides, methane sulfonyl chloride, POX3, PX3, PX5 or metal halides; wherein X is Cl, Br, I or F.

[0118] In one embodiment, the invention provides a novel process for the preparation of elacestrant of formula I or a pharmaceutically acceptable salt thereof, which comprises:

[0119] a) reacting a compound of formula II with a borylation reagent to obtain a compound of formula III; wherein Pg is a hydrogen or a protecting group; X is a halogen; R is a borane group;

[0120]

[0121] b) condensing the compound of formula III with a compound of formula IV to obtain a compound of formula V; wherein Pg, X and R, are as defined above; Lg is a leaving group;

[0122]

[0123] c) reducing the compound of formula V with a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula VI; wherein Pg and Lg are as defined above;

[0124]

[0125] d) catalytic hydrogenation of the compound of formula VI with a suitable hydrogenation catalyst in the presence of a suitable solvent to obtain a compound of formula VII; wherein Pg and Lg are as defined above;

[0126]

[0127] alternatively,

[0128] catalytic hydrogenation of the compound of formula V with a suitable hydrogenation catalyst in the presence of a suitable solvent to obtain a compound of formula VII; wherein Pg and Lg are as defined above;

[0129]

[0130] e) contacting the compound of formula VII with a chiral acid in the presence of a suitable solvent to obtain a compound of formula VIII; wherein Lg is as defined above;

[0131]

[0132] f) treating the compound of formula VIII with a base in the presence of a suitable solvent to obtain a compound of formula IX; wherein Lg is as defined above;

[0133]

[0134] g) condensing the compound of formula VIII or compound of formula IX with a compound of formula X to obtain a compound of formula XI (in-situ); wherein Pg’ is hydrogen or protecting group and Lg is as defined above;

[0135]

[0136] h) reducing the compound of formula XI (in-situ) with a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XII; wherein Pg’ and Lg are as defined above;

[0137]

[0138] i) alkoxylating the compound of formula XII with a suitable alkoxylating agent to obtain a compound of formula XIII; wherein Pg’ and Lg are as defined above;

[0139]

[0140] j) deprotecting the compound of formula XIII with a suitable deprotecting agent in the presence of a suitable solvent to obtain elacestrant or a pharmaceutically acceptable salt thereof; when Pg’ is a protecting group; and

[0141]

[0142] k) optionally, purifying the elacestrant or a pharmaceutically acceptable salt thereof in a suitable solvent or a mixture of solvents.

[0143] In an embodiment, the starting compound of formula II is commercially available or may be prepared by methods known in the art.

[0144] The step a) of above process involves reaction of the compound of formula II with a borylation reagent in the presence of a base and a catalyst in a suitable solvent under appropriate reaction conditions to obtain a compound of formula III; wherein Pg is a hydrogen or a protecting group; X is a halogen; R is a borane group.

[0145] The intermediate compound of formula III obtained in step a) may be used in- situ without isolation or, optionally, isolated prior to subsequent transformations.

[0146] The step b) of above process involves condensation of the compound of formula III with a compound of formula IV in the presence of a base and a suitable solvent under appropriate reaction conditions to obtain a compound of formula V ; wherein Pg, X and R, are as defined above; Lg is a leaving group. The step c) of above process involves reduction of the compound of formula V with a suitable reducing agent in the presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula VI; wherein Pg and Lg are as defined above.

[0147] The step d) of above process involves catalytic hydrogenation of the compound of formula VI with a suitable hydrogenation catalyst in the presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula VII; alternatively,

[0148] catalytic hydrogenation of compound of formula V with a suitable hydrogenation catalyst in the presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula VII; wherein Pg and Lg are as defined above.

[0149] The step e) of above process involves contacting the compound of formula VII with a chiral acid in presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula VIII; wherein Lg is as defined above.

[0150] The step f) of above process involves treating the compound of formula VIII with a base in presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula IX; wherein Lg is as defined above.

[0151] The step g) of above process involves condensation of the compound of formula VIII or compound of formula IX with a compound of formula X under appropriate reaction conditions to obtain a compound of formula XI (in-situ); wherein Pg’ is a hydrogen or a protecting group and Lg is as defined above.

[0152] The step h) of above process involves reduction of the compound of formula XI (in-situ) with a suitable reducing agent in the presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula XII; wherein Pg’ and Lg are as defined above. The step i) of above process involves alkoxylation of the compound of formula XII with an alkoxylating agent to obtain a compound of formula XIII; wherein Pg’ and Lg are as defined above; wherein the alkoxylation can be carried out under alkoxylation reaction conditions known in the art, for example, methanol can be used as an alkoxylating agent.

[0153] The step i) alkoxylation reaction can be carried out in the presence of a base, catalyst and a ligand in a suitable solvent under appropriate reaction conditions.

[0154] The step j) of above process involves deprotection of the compound of formula XIII with a suitable deprotecting agent in the presence of a suitable solvent under appropriate reaction conditions to obtain elacestrant or a pharmaceutically acceptable salt thereof; when Pg’ is a protecting group.

[0155] The step k) of above process involves purifying elacestrant or a pharmaceutically acceptable salt thereof in a suitable solvent or mixture thereof; wherein the suitable solvent is as defined above and preferably, selected from but not limited to methanol, n-propanol, dichloromethane, acetonitrile, water and the like.

[0156] In an embodiment, the borylation reagent, base, catalyst and a suitable solvent used in step a) is selected from, but not limited to, bis(pinacolato)diboron, potassium acetate, bis(triphenylphosphine)palladium(II) dichloride and 1,2-dimethoxyethane; the base and a suitable solvent used in step b) is selected from, but not limited to, potassium bicarbonate and water; the reducing agent and a suitable solvent used in step c) is selected from, but not limited to, iron in ammonium chloride, methanol and water; the suitable hydrogenation catalyst and suitable solvent used in step d) is selected from, but not limited to, palladium on alumina or palladium on carbon, ethyl acetate and THF; the chiral acid and suitable solvent used in step e) are selected from, but not limited to, (+)-2,3-dibenzoyl-D-tartaric acid, acetonitrile and dichloromethane; the base and suitable solvent used in step f) are selected from, but not limited to, potassium bicarbonate, methanol and water; the reducing agent and suitable solvent used in step h) are selected from, but not limited to, sodium triacetoxyborohydride, tetrahydrofuran and dichloromethane; the base, catalyst, ligand, and suitable solvent used in step i) are selected from, but not limited to, sodium tert-butoxide, Pd2(dba)3 or Cui, t-BuXPhos or BNMO and 1,4-di oxane; and the deprotecting agent and suitable solvent used in step j) are selected from, but not limited to, hydrochloric acid, methanol, ethanol, isopropyl alcohol, n-propanol, ethyl acetate, and the like..

[0157] In an embodiment, steps a) to k) are performed at a suitable temperature of about -100 °C to about 150 °C for a time sufficient to achieve reaction completion.

[0158] In another embodiment, the invention provides a novel process for the preparation of elacestrant or a pharmaceutically acceptable salt thereof, which comprises:

[0159] a) condensing a compound of formula VIII or a compound of formula IX with a compound of formula X to obtain a compound of formula XI (in-situ); wherein Pg’ is a hydrogen or a protecting group; Lg is a leaving group;

[0160]

[0161] b) reducing the compound of formula XI (in-situ) with a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XII; wherein Pg’ and Lg are as defined above;

[0162]

[0163] c) alkoxylating the compound of formula XII with a suitable alkoxylating agent to obtain a compound of formula XIII; wherein Pg’ and Lg are as defined above;

[0164]

[0165] d) deprotecting the compound of formula XIII with a suitable deprotecting agent in the presence of a suitable solvent to obtain elacestrant or a pharmaceutically acceptable salt thereof; when Pg’ is a protecting group; and

[0166]

[0167] e) optionally, purifying elacestrant or a pharmaceutically acceptable salt thereof in a suitable solvent.

[0168] In an embodiment, the starting compounds of formula IX and X may be prepared by the processes described herein.

[0169] The step a) of above process involves condensation of the compound of formula VIII or compound of formula IX with a compound of formula X under appropriate reaction conditions to obtain a compound of formula XI (in-situ); wherein Pg’ is a hydrogen or a protecting group; Lg is a leaving group.

[0170] The step b) of above process involves reduction of the compound of formula XI (in-situ) with a suitable reducing agent in the presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula XII; wherein Pg’ and Lg are as defined above.

[0171] The step c) of above process involves alkoxylation of the compound of formula XII with an alkoxylating agent to obtain a compound of formula XIII; wherein Pg’ and Lg are as defined above; wherein the alkoxylation can be carried out under alkoxylation reaction conditions known in the art, for example, methanol can be used as the alkoxylating agent. The step c) alkoxylation reaction can be carried out in the presence of a base, catalyst and a ligand in a suitable solvent under appropriate reaction conditions.

[0172] The step d) of above process involves deprotection of the compound of formula XIII with suitable deprotecting agent in the presence of a suitable solvent under appropriate reaction conditions to obtain elacestrant or a pharmaceutically acceptable salt thereof; when Pg’ is a protecting group.

[0173] The step e) of above process involves purification of elacestrant or a pharmaceutically acceptable salt thereof in a suitable solvent or mixture thereof; wherein the suitable solvent is as defined above and preferably, selected from but not limited to methanol, dichloromethane, acetonitrile, water and the like.

[0174] In an embodiment, the suitable reducing agent and suitable solvent used in step b) are selected from, but not limited to, sodium triacetoxyborohydride, tetrahydrofuran and dichloromethane; the base, catalyst, ligand, and suitable solvent used in step c) are selected from, but not limited to, sodium tert-butoxide, Pd2(dba)3 or Cui, t-BuXPhos or BNMO and 1,4-di oxane; and the deprotecting agent and suitable solvent used in step d) are selected from, but not limited to, hydrochloric acid, methanol, ethanol, isopropyl alcohol, ethyl acetate, and the like.

[0175] In an embodiment, steps a) to e) are performed at a suitable temperature of about -100 °C to about 150 °C for a time sufficient to achieve reaction completion.

[0176] In another embodiment, the invention provides a novel process for the preparation of compound of formula IX, which comprises:

[0177] a) catalytic hydrogenation of a compound of formula VI with a suitable hydrogenating catalyst in the presence of a suitable solvent to obtain a compound of formula VII; wherein Pg is a hydrogen or a protecting agent; Lg is a leaving

[0178]

[0179] b) contacting the compound of formula VII with a chiral acid in the presence of a suitable solvent to obtain a compound of formula VIII; wherein Lg is as defined above;

[0180]

[0181] c) treating the compound of formula VIII with a base in the presence of a suitable solvent to obtain a compound of formula IX; wherein Lg is as defined above;

[0182]

[0183] alternatively,

[0184] asymmetric hydrogenation of the compound of formula VI to obtain a compound of formula IX; wherein Pg is a hydrogen or a protecting agent; Lg is a leaving group.

[0185]

[0186] In an embodiment, the starting compound of formula VI may be prepared by the processes described herein.

[0187] The step a) of above process involves catalytic hydrogenation of the compound of formula VI with a suitable hydrogenating catalyst in the presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula VII; wherein Pg is a hydrogen or a protecting agent; Lg is a leaving group.

[0188] The step b) of above process involves contacting the compound of formula VII with a chiral acid in presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula VIII; wherein Lg is as defined above. The step c) of above process involves treating the compound of formula VIII with a base in presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula IX; wherein Lg is as defined above;

[0189] Alternatively, asymmetric hydrogenation of the compound of formula VI to obtain a compound of formula IX; wherein Pg is a hydrogen or a protecting agent; Lg is a leaving group.

[0190] The asymmetric hydrogenation can be carried out in the presence of a chiral-metal complex is selected from, but not limited to, (S)-(-)-[(l,5-cyclooctadien-7-(2-phenyl-6,7-dihydro-5H-[l]pyridin)-di-(tert-butyl)phosphiniteiridium(I)]tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, (R,R)-l,2-bis[(2-methoxyphenyl)(phenyl phosphino)]ethane, (S,S)-l,2-Ethanediylbis[(2-methoxyphenyl)phenylphosphine], (S)-(-)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline, (R)-(+)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline, bis(l,5-cyclooctadiene) diiridium(I) dichloride, (ethane- l,2-diyl)bis [(2-methoxyphenyl)(phenyl)phosphane], and the like; preferably (S)-(-)-[( 1 ,5-cyclooctadien-7-(2-phenyl-6,7-dihydro-5H-[l]pyridin)-di-(tert-butyl)phosphiniteiridium(I)]tetrakis[3,5-bis(trifluoromethyl) phenyl]borate and the suitable solvent is selected from, but not limited to, dichloromethane under appropriate reaction conditions.

[0191] In an embodiment, the suitable hydrogenation catalyst and suitable solvent used in step a) are selected from, but not limited to, palladium on alumina or palladium on carbon, ethyl acetate and THF; the chiral acid and suitable solvent used in step b) are selected from, but not limited to, (+)-2,3-dibenzoyl-D-tartaric acid, acetonitrile and dichloromethane; and the base and suitable solvent used in step c) are selected from, but not limited to, potassium bicarbonate, methanol and water.

[0192] In an embodiment, steps a) to c) are performed at a suitable temperature of about -100 °C to about 150 °C for a time sufficient to achieve reaction completion. In yet another embodiment, the invention provides a novel compound of formula VIII or compound of formula IX, used in the preparation of elacestrant or a pharmaceutically acceptable salt thereof.

[0193] In another embodiment, the present invention provides a novel process for the preparation of elacestrant or a pharmaceutically acceptable salt thereof, which comprises:

[0194] a) reductive amination of a compound of formula IX with acetaldehyde or with corresponding acetal and a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XIV; wherein Lg is a leaving group;

[0195]

[0196] b) condensing the compound of formula XIV with a compound of formula X to obtain a compound of formula XII; wherein Pg’ is a hydrogen or a protecting group; Lg is as defined above; and

[0197]

[0198] c) converting the compound of formula XII into elacestrant or a pharmaceutically acceptable salt thereof; wherein Pg’ and Lg are as defined above.

[0199] In an embodiment, the starting compound of formula VI may be prepared by the processes described herein.

[0200] The step a) of above process involves reaction of the compound of formula IX with acetaldehyde or with corresponding acetal and a suitable reducing agent in the presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula XIV; wherein Lg is a leaving group.

[0201] The step b) of above process involves condensation of the compound of formula XIV with a compound of formula X, and then reducing the resulting product with a reducing agent and a suitable solvent under appropriate reaction conditions to obtain a compound of formula XII; wherein Pg’ is a hydrogen or a protecting group; Lg is as defined above.

[0202] In an embodiment, step c) comprises converting the compound of formula XII into elacestrant or a pharmaceutically acceptable salt thereof by the process described in steps i) and j) of the first embodiment; wherein Pg’ and Lg are as defined above.

[0203] In an embodiment, the reducing agent and suitable solvent used in step a) are selected from, but not limited to, sodium borohydride, methanol and dichloromethane; and the reducing agent and suitable solvent used in step b) are selected from, but not limited to, sodium triacetoxyborohydride, dichloromethane and 1,2-di chloroethane.

[0204] In an embodiment, steps a) to c) are performed at a suitable temperature of about -100 °C to about 150 °C for a time sufficient to achieve reaction completion.

[0205] In another embodiment, the present invention provides a novel process for the preparation of elacestrant or a pharmaceutically acceptable salt thereof, which comprises:

[0206] a) reducing a compound of formula X with a suitable reducing agent in presence of a suitable solvent to obtain a compound of formula XV; wherein Pg’ is a hydrogen or a protecting group;

[0207]

[0208] b) halogenating the compound of formula XV with a suitable halogenating agent to obtain a compound of formula XVI; wherein X is halogen and Pg’ is as defined above;

[0209]

[0210] c) condensing the compound of formula XVI with a compound of formula XIV to obtain a compound of formula XII; wherein Pg’ is as defined above; Lg is a leaving group; and

[0211]

[0212] d) converting the compound of formula XII into elacestrant or a pharmaceutically acceptable salt thereof; wherein Pg’ and Lg are as defined above.

[0213] In one embodiment, the starting compound of formula X may be prepared by the processes described herein.

[0214] The step a) of above process involves reduction of the compound of formula X with a suitable reducing agent in the presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula XV ; wherein Pg’ is a hydrogen or a protecting group.

[0215] The intermediate compound of formula XV obtained in step a) may be used in situ or, optionally, isolated.

[0216] The step b) of above process involves halogenation of the compound of formula XV with a suitable halogenating agent to obtain a compound of formula XVI; wherein X is halogen and Pg’ is as defined above;

[0217] The step b) halogenation reaction can be carried out in the presence of a ligand under appropriate reaction conditions.

[0218] The step c) of above process involves condensation of the compound of formula XVI with a compound of formula XIV in the presence of a base and a suitable solvent under appropriate reaction conditions to obtain a compound of formula XII; wherein Pg’ is as defined above; Lg is a leaving group. The step d) of above process involves the conversion of compound of formula XII into elacestrant or a pharmaceutically acceptable salt thereof can be carried out by the process described in steps i) and j) of the first embodiment.

[0219] In an embodiment, the reducing agent and suitable solvent used in step a) are selected from, but not limited to, sodium borohydride and methanol; the halogenating agent and ligand used in step b) are selected from, but not limited to, carbon tetrabromide (CBr4) and triphenylphosphine; and the base and suitable solvent used in step c) are selected from, but not limited to, triethylamine and toluene.

[0220] In an embodiment, steps a) to d) are performed at a suitable temperature of about -100 °C to about 150 °C for a time sufficient to achieve reaction completion.

[0221] In another embodiment, the invention provides a novel process for the preparation of compound of formula XIX, which comprises:

[0222] alkoxylating compound of formula IX or a compound of formula IX’ with a suitable alkoxylating agent to obtain a compound of formula XIX; wherein Pg” is a hydrogen or a protecting group; Lg is a leaving group.

[0223]

[0224] The above process involves alkoxylation of the compound of formula IX or IX’ with a alkoxylating agent to obtain a compound of formula XIX; wherein Pg” is a hydrogen or a protecting group; Lg is a leaving group; wherein the alkoxylation can be carried out under alkoxylation reaction conditions known in the art, for example, methanol can be used as an alkoxylating agent.

[0225] The alkoxylation reaction can be carried out in the presence of a base, catalyst and a ligand in a suitable solvent under appropriate reaction conditions.

[0226] The base, catalyst, ligand and a suitable solvent used is selected from but not limited to sodium tert-butoxide, Pd2(dba)3, t-BuXphos and 1,4-dioxane. In yet another embodiment of the present invention provides a novel process for the preparation of a compound of formula XIX, and use in the preparation of elacestrant or a pharmaceutically acceptable salt thereof.

[0227] In another embodiment, the invention provides a novel process for the preparation of elacestrant or a pharmaceutically acceptable salt thereof, which comprises:

[0228] a) alkoxylation of a compound of formula IX or a compound of formula IX’ with a suitable alkoxylating agent to obtain a compound of formula XIX; wherein Pg” is a hydrogen or a protecting group; Lg is a leaving group;

[0229]

[0230] b) reductive amination of the compound of formula XIX with acetaldehyde or with corresponding acetal and a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XXVI, followed by condensing with a compound of formula XVI in the presence of a base in a suitable solvent to obtain a compound of formula XIII; wherein Pg’ & Pg” is a hydrogen or a protecting group; and X is halogen;

[0231]

[0232] alternatively;

[0233] condensing the compound of formula XIX with a compound of formula X to obtain a compound of formula XI (in-situ); followed by reduction with a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XIII; wherein Pg’ & Pg” is a hydrogen or a protecting group; and

[0234]

[0235] c) converting the compound of formula XIII into elacestrant or a pharmaceutically acceptable salt thereof.

[0236] The step a) of above process involves alkoxylation of the compound of formula IX or IX’ with a suitable alkoxylating agent to obtain a compound of formula XIX; wherein Pg” is a hydrogen or a protecting group; Lg is a leaving group; the alkoxylation may be carried out according to the process described in the foregoing embodiment of the present invention.

[0237] The step b) of above process involves reaction of the compound of formula XIX with acetaldehyde or with corresponding acetal and a suitable reducing agent in the presence of a suitable solvent under appropriate reaction conditions to obtain a compound of formula XXVI; followed by with a compound of formula XVI in the presence of a base and a suitable solvent under appropriate reaction conditions to obtain a compound of formula XIII; wherein Pg’ and Pg” is a hydrogen or a protecting group; X is halogen.

[0238] In an embodiment, the suitable reducing agent, base, and suitable solvent are selected from, but not limited to, sodium borohydride, triethylamine, and methanol, dichloromethane, or toluene.

[0239] alternatively;

[0240] The step b) of above process involves condensation of the compound of formula XIX with a compound of formula X to obtain a compound of formula XI (in-situ); followed by reducing with a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XIII; wherein Pg’ & Pg’ ’ is a hydrogen or a protecting group.

[0241] In an embodiment, the suitable reducing agent and suitable solvent used are selected from, but not limited to, sodium triacetoxyborohydride, THF and toluene.

[0242] In an embodiment, the step c) of above process involves conversion of the compound of formula XIII into elacestrant or a pharmaceutically acceptable salt thereof by the process described in step j) of the first embodiment. In an embodiment, steps a) to c) are performed at a suitable temperature of about -100 °C to about 150 °C for a time sufficient to achieve reaction completion.

[0243] In another embodiment, the invention provides novel intermediate

[0244]

[0245] wherein Pg, Pg’ and Pg” are independently hydrogen or a protecting group; X is halogen; Lg is a leaving group.

[0246] In yet another embodiment, the invention provides use of novel intermediate compounds of formulae V, VI, VII, VIII, IX, IX’, XI, XII, XIV, XV & XVI, in the preparation of elacestrant or a pharmaceutically acceptable salt thereof.

[0247] In another embodiment, the invention provides a process for the preparation of elacestrant or a pharmaceutically acceptable salt thereof, which comprises treating elacestrant with a suitable acid is selected from, but not limited to, inorganic acids, organic acids, chiral acids or chiral amino acid and the like in a suitable solvent is selected from but not limited to alcohols, esters or mixture thereof.

[0248] In another embodiment, the invention provides a process for the purification of elacestrant free base compound of formula I, which comprises: a) deprotecting a compound of formula XIII with a suitable deprotecting agent in the presence of a suitable solvent to obtain acid addition salt of elacestrant; b) treating the acid addition salt of elacestrant with a suitable base; or treating the step-a) reaction mass with a base; and

[0249] c) isolating elacestrant in purified free base form.

[0250] In an embodiment, the deprotecting agent and suitable solvent used in step a) are selected from, but not limited to, hydrochloric acid and methanol, ethanol, 1 -propanol, isopropyl alcohol, and the like; the base used in step b) is selected from, but not limited to, sodium bicarbonate, potassium bicarbonate, and the like; optionally, the elacestrant free base obtained in step b) is treated with a solvent selected from, but not limited to, alcohols, halogenated solvents, nitriles, and water, or mixtures thereof, preferably methanol, dichloromethane, acetonitrile and water, or mixtures thereof; isolation of elacestrant in step c) is carried out by methods known in the art, for example, filtration followed by drying.

[0251] EXAMPLES:

[0252] The process details of the invention are provided in the examples given below, which

[0253] are provided by way of illustration only and therefore should not be construed to limit

[0254] the scope of the invention.

[0255] Example-1: Preparation of 7-(benzyloxy)-3-(4-chloro-2-nitrophenyl)-l,2-dihydronaphthalene :

[0256] To a stirred solution of 7-(benzyloxy)-3-bromo-l,2-dihydronaphthalene (400 g) in 1,2-dimethoxyethane (7 V), bis(pinacolato)diboron (1.3 eq.), potassium acetate (3.1 eq.) were added at RT under N2 atmosphere. Degassed the reaction mass for 20 to 30 min under N2 gas and bis(triphenylphosphine)palladium(II)dichloride (0.01 eq.) was added. The reaction mass was heated to 75 to 85 °C and stirred for 3 to 4 h. The reaction mass was cooled to 25 to 35°C, and aq. potassium bicarbonate solution (potassium bicarbonate (300 g) in water (3 V)) followed by l-bromo-4-chloro-2- nitrobenzene (1.0 eq.) were added at same temperature. The reaction mass was heated to 75 to 85°C and stirred for 14 to 16 h under N2 atmosphere. After completion of the reaction, the reaction mass was cooled to 50 to 55°C, then filtered the reaction mass on Hyflo bed and washed the solid with 1,2-dimethoxyethane (2 V). The layers were separated at 50 to 55°C, organic layer was cooled to 25 to 35°C, water (9 V) was added and stirred at 25 to 35°C for 2 to 3 h. The obtained solid was filtered, washed with water (I V) and suck dry for 1 to 2 h. The wet solid was dissolved in DCM (10 V) at 25 to 35°C, activated carbon (20 g) was added, stirred for 15 to 20 min, then filtered the reaction mass and washed with DCM (2 V). The filtrate was distilled off up to 1 V under vacuum at below 45°C. Then strip off with IPA (0.5 V). IPA (5 V) was added to residue at 40 to 45°C, heated the reaction mass to 70 to 80°C and stirred for 1 to 2 h. The reaction mass was cooled to 20 to 25°C and stirred for 6 to 8 h, at same temperature. The solid was filtered, washed with IPA (I V) and dried to get the title compound.

[0257] Yield: 397.8 g

[0258] Example-2: Preparation of 2-(6-(benzyloxy)-3,4-dihydronaphthalen-2-yl)-5-chloroaniline:

[0259] To a stirred solution of 7-(benzyloxy)-3-(4-chloro-2-nitrophenyl)-l,2-dihydronaphthalene (350 g) in methanol (10 V) and water (2 V) solution, Iron powder (8 eq.) and ammonium chloride (4 eq.) were added at 25 to 35°C. The reaction mass was heated to 60 to 65°C and stirred for 20 to 24 h. After completion of the reaction, the reaction mass was filtered and washed with dichloromethane (3 x 5 V) and distilled off solvent completely under vacuum at below 45°C. The reaction mass was cooled to 25 to 35°C, the compound was extracted with dichloromethane (4 V) and combined organic layer was washed with 5% aq. sodium chloride (5 V) solution followed by distilled off the organic layer up to 1 to 2 V at below 45°C under vacuum and strip off the residue with methanol (2 x 2 V) up to 1 to 2 V at below 45°C under vacuum. Dichloromethane (2 V) and methanol (8 V) were added to residue at 40 to 45°C and stirred for 1 to 2 h. The reaction mass was cooled to 20 to 25°C and stirred for 1 to 2 h at same temperature. The solid was filtered, washed with methanol (I V) and dried to get the title compound. Yield: 284.4 g

[0260] Example-3: Preparation of 6-(2-amino-4-chlorophenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol:

[0261] A stirred solution of 2-(6-(benzyloxy)-3,4-dihydro naphthalen-2-yl)-5-chloroaniline (280 g) in tetrahydrofuran (7 V), ethyl acetate (13 V), diphenyl sulfide (0.002 t) and 5% dry palladium alumina (0.05 t) were added at 25 to 35°C under nitrogen. The reaction mixture was agitated under 8 to 10 kg of H2 pressure at 20 to 25°C. After completion of the reaction, hydrogen gas was removed and purge the reaction mass with N2 gas at 25 to 35°C, then filtered the reaction mass and washed with EtOAc (3 V). The filtrate was distilled off up to 1 to 2 V under vacuum at below 50°C and strip off the mass with acetic acid (1 V). Acetic acid (5 V) and aqs hydrobromic acid (2.3 V) were added to residue at 40 to 45°C, heated the reaction mass to 60 to 70°C and stirred for 1 to 2 h. The reaction mass was cooled to 20 to 30°C, then water (5 V) and dichloromethane (5 V) were added and stirred for 2 to 3 hours at same temperature. The solid was filtered and washed with water (2 V). Isopropyl acetate (2 V) was added to wet solid and heated to 45 to 55°C and stirred for 10 to 20 min. Then cooled to 20 to 30°C and stirred for 2-4 hours at same temperature and filtered the solid and washed the solid with isopropyl acetate (0.5 V). Water (10 V) was added to wet solid and added the 10% aq. sodium carbonate solution up to adjust pH 9.0 to 10.5 at 25 to 35°C and compound extracted with MTBE (2 x 5 V). Then combined organic layer washed with water (5 V) and 10% aq. Sodium chloride solution (5 V). Then distilled the organic layer up to 1 to 2 V at below 50°C under vacuum then strip-off with toluene (1 V). Toluene (3 V) was added to crude solid mass at 50 to 55°C, stirred for 1 to 2 hours. Then cooled to 10 to 20°C and stirred for 3 to 4 hours at same temperature. The solid was filtered, washed with toluene (0.5 V) and dried to get the title compound.

[0262] Yield: 169.4 g

[0263] Alternative preparation: To a stirred solution of 7-(benzyloxy)-3-(4-chloro-2-nitrophenyl)-l,2-dihydronaphthalene (10 g) in methanol (10 V) and water (5 V) solution, Iron powder (6 eq.) and ammonium chloride (6 eq.) were added at 25 to 35°C. The reaction mass was heated to 65 to 70°C and stirred for 12 to 14 h. After completion of the reaction, the reaction mass was filtered and washed with ethyl acetate (3 V) and distilled off the solvent completely under vacuum at below 45°C. The reaction mass was cooled to 25 to 35°C, the compound was extracted with EtOAc (2 x 5 V) and combined organic layer was washed with 5% aq. sodium chloride (5 V) solution. The organic layer was purged with N2 gas followed by 10% Pd / C (0.5 g) was added at 25 to 35°C. The reaction mixture was agitated under 4 to 6 kg of H2 pressure at 25 to 35°C. After completion of the reaction, hydrogen gas was removed and purge the reaction mass with N2 gas at 25 to 35°C, then filtered the reaction mass and washed with EtOAc (3 V). The filtrate was distilled off up to 0.5 V under vacuum at below 45°C. Then strip off the mass with IPA (1 V). IPA (5 V) was added to residue at 40 to 45°C, heated the reaction mass to 70 to 80°C and stirred for 1 to 2 h. The reaction mass was cooled to 10 to 15°C and stirred for 1 to 2 hours at same temperature. The solid was filtered, washed with IPA (I V) and dried to get the title compound. Yield: 4.9 g

[0264] Alternative preparation: To a stirred solution of 7-(benzyloxy)-3-(4-chloro-2-nitrophenyl)-l,2-dihydronaphthalene (10 g) in Ethyl acetate (10 V) solution was purged with N2 gas followed by 10% Pd / C (0.5 g) was added at 25 to 35°C. The reaction mixture was agitated under 4 to 6 kg of H2 pressure for 12 to 16 h at 25 to 35°C. After completion of the reaction, hydrogen gas was removed and purge the reaction mass with N2 gas at 25 to 35°C, then filtered the reaction mass and washed with EtOAc (3 V). The filtrate was distilled off up to 0.5 V under vacuum at below 45°C. Then strip off solid residue with IPA (1 V). IPA (5 V) was added to residue at 40 to 45°C, heated the reaction mass to 70 to 80°C and stirred for 1 to 2 h. The reaction mass was cooled to 10 to 15°C and stirred for 1 to 2 h, at same temperature. The solid was filtered, washed with IPA (I V) and dried to get the title compound. Yield: 4.74 g Example-4: Preparation of (+)-DBTA salt of (R)-6-(2-amino-4-chlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol:

[0265] To a stirred solution of 6-(2-amino-4-chlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (150 g) in acetonitrile (2 V), (+)-2, 3 -dibenzo yl-D-tartaric acid [(+)-DBTA] (1.5 eq.) in acetonitrile (2 V) was added at 60 to 70°C and stirred for 10 to 20 min, then cooled to 30 to 40°C, dichloromethane (12 V) was added and stirred for 1 to 2 hours. Seed (R)-6-(2-amino-4-chlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (+)-DBTA (0.0041) to the reaction mass at 20 to 30°C, stirred for 30 to 40 min, then dichloromethane (4 V) was added, stirred for 2 to 3 hours, cooled to 5 to 10°C and stirred for 2 to 3 hours at same temperature. The solid obtained was filtered and washed with dichloromethane (2 V) to obtain wet solid. Toluene (9.24 V) and acetonitrile (1.76 V) were added to the above wet solid at 25 to 35°C, heated to 60 to 70°C and stirred for 15 to 20 min at same temperature. The reaction mass was cooled to 20 to 30°C, stirred for 1 to 2 hours, further cooled to 10 to 15 °C and stirred for 3 to 4 hours. The solid obtained was filtered, washed with toluene (2 V) and dried to get the title compound. Yield: 131.6 g

[0266] Example-5: Preparation of (R)-6-(2-amino-4-chlorophenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol:

[0267] To a stirred solution of (+)-DBTA salt of (R)-6-(2-amino-4-chlorophenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol (130 g) in water (15 V) and methanol (3 V), 25% aq. KHCO3 (10 V) solution was added at 20 to 25°C, stirred for 2 to 3 h, at same temperature. The obtained solid was filtered, washed with water (4 V). The wet solid was slurred with mixture of water (4 V) and n-Heptane (4 V), then filtered the reaction mass and dried to get the title compound. Yield: 53.49 g

[0268] Example-6: Preparation of tert-butyl (R)-(4-(((5-chloro-2-(6-hydroxy-l, 2,3,4-tetrahydronaphthalen-2-yl)phenyl)(ethyl)amino)methyl)phenethyl)(ethyl) Carbamate (Lot wise):

[0269] To a stirred solution of (R)-6-(2-amino-4-chlorophenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol (30 g) in toluene (15 V), tert-butyl ethyl(4-formylphenethyl)carbamate (1.0 eq.) and (+)-2,3-dibenzoyl-D-tartaric acid [(+)- DBTA] (0.15 g) were added at 25 to 35°C. The reaction mass was heated to reflux temperature and stirred for 12 to 16 h, water was removed through azeotropic distillation at same temperature. The reaction mass was cooled to 50 to 60°C and distilled off the solvent up to 0.5 V under vacuum. Strip off residual solvent with THF (1 V). The reaction mass was cooled to 20 to 30°C, THF (20 V) and sodium triacetoxyborohydride (4.5 eq.) were added under N2 atmosphere at same temperature. The reaction mass was heated to 55 to 60°C and stirred for 6 h, at same temperature. Sodium triacetoxyborohydride (4.5 eq.) was added at 55 to 60°C and stirred at same temperature. After completion of reaction, the reaction mass was cooled to 25 to 35°C, water (10 V) and ethyl acetate (7 V) were added, stirred for 10 min and further cooled to 10 to 15°C. pH of the mass was adjusted to pH 7 to 9 using 20% aq. NaOH solution and stirred for 10 min. The reaction mass was warmed 25 to 35°C and separated the aqueous layer and organic layer. The aq. layer was extracted with ethyl acetate (5 V). The combined organic layer was washed with 10% aq. sodium chloride (3 V) solution. Neutral activated carbon (3 g) was added to the organic layer, stirred for 20 min at 25 to 35°C, then filtered the reaction mass on Hyflo bed and washed with ethyl acetate (1 V). Distilled off ethyl acetate under vacuum at below 45°C. The crude compound was purified by column chromatography to get the title compound. Yield: 43.9 g

[0270] Alternative preparation (Single lot): To a stirred solution of (R)-6-(2-amino-4-chlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (30 g) in toluene (15 V), tert-butyl ethyl(4-formylphenethyl)carbamate (1.0 eq.) and (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA] (0.12 g) were added at 25 to 35°C. The reaction mass was heated to reflux temperature and stirred for 12 to 16 h, water was removed through azeotropic distillation at same temperature, the reaction mass was cooled to 50 to 60°C and distilled off the solvent up to 0.5 V under vacuum. Strip off the solvent traces with THF (1 V). The reaction mass was cooled to 20 to 30°C, THF (20 V) and sodium triacetoxyborohydride (7 eq.) were added under N2 atmosphere at same temperature. The reaction mass was heated to 55 to 60°C and stirred at same temperature. After completion of reaction, the reaction mass was cooled to 25 to 35°C, water (10 V) and ethyl acetate (7 V) were added, stirred for 10 min and further cooled to 10 to 15°C. pH of the mass was adjusted to 7 to 9 using 20% aq. NaOH solution. The mass was stirred for 10 min. The reaction mass was warmed to 25 to 35°C and separated the aqueous layer and organic layer. The compound was extracted with ethyl acetate (5 V) from aq. layer. The combined organic layer was washed with 10% aq. sodium chloride (3 V) solution. Neutral activated carbon (3 g) was added to the organic layer, stirred for 20 min at 25 to 35°C, then filtered the reaction mass on Hyflo bed and washed with ethyl acetate (1 V). Distilled off ethyl acetate under vacuum at below 45°C. The crude compound was purified by column chromatography to get the title compound.

[0271] Yield: 43.9 g

[0272] Example-7: Preparation of tert-butyl (R)-ethyl(4-((ethyl(2-(6-hydroxy-l, 2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl) carbamate:

[0273] To a stirred solution of Pd2(dba)3 (0.01 eq.) in 1,4-dioxane (12 V), t-BuXphos (0.04 eq.), sodium tert-butoxide (1.4 eq.) were added and degassed the reaction mass through N2 gas bubbling for 20 to 30 min at 25 to 35°C. tert-butyl (R)-(4-(((5-chloro-2-(6-hydroxy- 1,2,3, 4-tetrahydronaphthalen-2-yl)phenyl)(ethyl)amino)methyl)phenethyl) (ethyl)carbamate (30 g) and methanol (5 eq.) were added under N2 atmosphere at same temperature. The reaction mass was heated to 55 to 65°C and stirred for 14 to 16 h, at same temperature. After completion of reaction, the reaction mass was cooled to 20°C to 30°C and quenched with water (10 V). The compound was extracted with ethyl acetate (2 x 5 V) and combined organic layer was washed with 10% aq. sodium chloride (5 V) solution. The organic layer was distilled off completely to get the title compound and it was used for next reaction without further purification. Yield: 29.76 g

[0274] Alternative preparation: To a stirred solution of tert-butyl (R)-(4-(((5-chloro-2-(6-hydroxy- 1,2,3, 4-tetrahydronaphthalen-2-l)phenyl)(ethyl)amino)methyl)phenethyl) (ethyl)carbamate (1 g) in 1,4-dioxane (10 V), Cui (0.25 eq.), NaOtBu (1.5 eq.), methanol (10 eq.) and N,N'-bis(naphthalen- l-ylmethyl)oxalamide (BNMO) ligand (0.25 eq.) were added at 25 to 35°C under N2 atmosphere. The reaction mass was heated to 75 to 80°C and stirred for 20 to 24 h, at same temperature. The reaction mass was cooled to 25 to 35°C, acidified with 2N HC1, then diluted with ethyl acetate and washed with brine. The organic layer was separated, distilled off completely and the crude compound was purified by silica gel flash chromatography to get the title compound. Yield: 1 g

[0275] Example-8: Preparation of tert-butyl (4-bromophenethyl)(ethyl)carbamate:

[0276] A stirred solution of 4-bromophenethyl methanesulfonate (100 g) and aq. ethylamine (5 V) in ethanol was heated to 60 to 70°C and stirred for 4 to 5 h. After completion of reaction, distilled off the solvent under vacuum at below 45°C. The reaction mass was cooled to 20 to 30°C, 5% aq. citric acid solution (5 V), DCM (5 V) were added at 25 to 30°C. The mass was stirred for 10 min at same temperature. The layers were separated and aq. Layer was washed with DCM (3 V). The aqueous layer was cooled to below 20°C and adjusted the pH to >11 using 20% aq. sodium hydroxide solution. The reaction mass was warmed to 25 to 30°C, di-tert-butyl dicarbonate (1 eq.) was added and stirred for 1 to 2 h, at same temperature. After completion of reaction, settled the reaction mass for 10 min and the organic layer was separated and washed with water (3 V), 10% aq. sodium chloride (3 V) solution. The organic layer was distilled off under vacuum at below 70°C to get the title compound. Yield: 94.03 g

[0277] Example-9: Preparation of tert-butyl ethyl(4-formylphenethyl)carbamate: A solution of tert-butyl (4-bromophenethyl)(ethyl)carbamate (90 g) in THF (10 V) was cooled to -70 to -75°C.To the reaction mass, n-BuLi (2.0 eq.) solution was added over a period of 30 min and stirred for 1 to 2 h. DMF (2.2 eq.) was added dropwise to the reaction mass and stirred for 2 to 3 h. After completion of reaction, the reaction mass was quenched with 10% aq. ammonium chloride (0.5 V) solution at -75 to 25°C. The reaction mass was warmed to RT (If required), 10% aq. ammonium chloride (4 V) was added and the compound was extracted with MTBE (2x 4 V). Combined the organic layers and washed with 10% aq. sodium chloride (3 V) solution. The organic layer was distilled off under vacuum at below 45°C. The residue was cooled to 25 to 35°C, DMF (5 V) and 50% sodium bisulfite (3 V) solution were added, stirred for 20 min at same temperature. The impurities were removed by using 10% ethyl acetate in hexane medium (4 x 5 V). 20% aq. sodium hydroxide (2 V) solution was added to aq.layer and the compound was extracted with MTBE (3 x 3 V). Combined MTBE layers were washed with water (5 V) and 10% aq. sodium chloride (5 V) solution. The solvent was distilled off completely and degassed for 30 to 40 min under vacuum at below 50°C to get the title compound. Yield: 53.2 g

[0278] Example-10: Preparation of (R)-6-(4-chloro-2-(ethylamino)phenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol:

[0279] To a stirred solution of (R)-6-(2-amino-4-chlorophenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol (30 g) in DCM (9 V) and Methanol (I V) solution, acetaldehyde (1.3 eq.) were added at RT under N2 atmosphere. The reaction mass was cooled to 0 to 5°C, sodium borohydride (1 eq.) was added lot- wise over a period of 10 to 20 min at same temperature. The reaction mass was warmed to RT, stirred for 14 to 16 h, at same temperature. After completion of reaction, the reaction mass was quenched with ammonium chloride (10 V) and DCM (10 V) was added to the mass. The layers were separated, organic layer was washed with water (5 V) and 10% aq. sodium chloride (5 V) solution. The organic layer was distilled off completely to get the title compound and it was used in the next reaction without further purification. Yield: 33.07 g

[0280] Example-11: Preparation of tert-butyl (R)-(4-(((5-chloro-2-(6-hydroxy-l, 2,3,4-tetrahydronaphthalen-2-yl)phenyl)(ethyl)amino)methyl) phenethyl) (ethyl) carbamate:

[0281] To a stirred solution of (R)-6-(4-chloro-2-(ethylamino)phenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol (33.07 g) in DCM (10 V), tert-butyl ethyl(4-formylphenethyl)carbamate (1.0 eq.) and sodium triacetoxyborohydride (1.5 eq.) were added at 0 to 5°C under N2 atmosphere. The reaction mass was warmed to RT, stirred for 6 to 8 h, at same temperature. After completion of reaction, the reaction mass was quenched with ammonium chloride (10 V). The layers were separated, organic layer was washed with water (5 V) and 10% aq. sodium chloride (5 V) solution.

[0282] The organic layer was distilled off completely and the crude compound was purified by column chromatography to get the title compound. Yield: 49.3 g

[0283] Alternative preparation: To a stirred solution of (R)-6-(2-amino-4-chlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (10 g) in DCM (9 V) and methanol (1 V) solution acetaldehyde (1.3 eq.) were added at RT under N2 atmosphere. The reaction mass was cooled to 0 to 5°C, lot wise addition of sodium borohydride ( 1 eq.) over a period of 10 to 20 min. The reaction mass was warmed to RT, stirred 14 to 16 h, at same temperature. After completion of reaction, distilled off solvent, then 1,2-dichloroethane (10 V), tert-butyl ethyl(4-formylphenethyl)carbamate (1 eq.) and sodium triacetoxyborohydride (1.5 eq.) were added at 0 to 5°C under N2 atmosphere. The reaction mass was warmed to RT, stirred for 6 to 8 h, at same temperature. After completion of reaction, the reaction mass was quenched with ammonium chloride (10 V) and DCM (10 V). The layers separated, organic layer was washed with water (5 V) and 10% aq. sodium chloride (5 V) solution.

[0284] The organic layer was distilled off completely and the crude compound was purified by column chromatography to get the title compound. Yield: 13.3 g

[0285] Example-12: Preparation of (R)-6-(2-amino-4-chlorophenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol:

[0286] To a stirred solution of 2-(6-(benzyloxy)-3,4-dihydronaphthalen-2-yl)-5-chloroaniline (2 g) in DCM (10 V) was purged with N2 gas, (S)-(-)-[(l,5-cyclooctadien-7-(2-phenyl-6,7-dihydro-5H-[l]pyridin)-di-(tert-butyl)pho sphiniteiridium(I) ] tetrakis [3 , 5 -bis (trifluoromethyl)phenyl] borate (0.02 g) was added at 25 to 35°C. The reaction mixture was heated to 55 to 60°C, and agitated under 4 to 6 kg of H2 pressure for 12 to 16 h, at same temperature. After completion of the reaction, hydrogen gas was removed and purge the reaction mass with N2 gas at 25 to 35°C, then filtered the reaction mass and washed with DCM (3 V). The filtrate was distilled off up to 0.5 V under vacuum at below 45°C. Then strip off solid residue with IPA (1 V). IPA (5 V) was added to residue at 40 to 45°C, heated the reaction mass to 70 to 80°C and stirred for 1 to 2 h. The reaction mass was cooled to 10 to 15 °C and stirred for 1 to 2 h, at same temperature. The solid was filtered, washed with IPA (I V) and dried to get the title compound. Yield: 1.13 g

[0287] Example-13: Preparation of tert-butyl (4-(bromomethyl)phenethyl)(ethyl) carbamate:

[0288] To a stirred solution of tert-butyl ethyl(4-formylphenethyl) carbamate (50 g) in methanol (10 V) and lot wise addition of sodium borohydride (1.1 eq.) at 0 to 5°C over a period of 10 to 20 min under N2 atmosphere, stirred for 1 to 2 h, at same temperature to obtain the solid mass (in-situ). Water (5 V) was added at 0 to 25°C, and acetic acid was added to reaction mass up to pH 7 to 9. The compound was extracted with DCM (2 x 4 V). Combined organic layer was washed with 10% aq. sodium chloride (3 V) solution. To this organic layer were added the CBr4 (1.1 eq.) and PPhs (1.2 eq.) at room temperature under nitrogen atmosphere and the reaction mass was stirred for 2 to 4 h, at same temperature. After completion of the reaction, 5% aq. sodium bicarbonate (5 V) solution was added, stirred for 10 min and the organic layer was separated. The organic layer was washed with 5% aq. sodium chloride (5 V) solution. The organic layer was distilled off and crude compound was purified by column chromatography to get the title compound. Yield: 43.19 g

[0289] Example-14: Preparation of tert-butyl (R)-(4-(((5-chloro-2-(6-hydroxy-l, 2,3,4-tetrahydronaphthalen-2-yl)phenyl)(ethyl)amino)methyl)phenethyl)(ethyl) carbamate:

[0290] To a stirred solution of (R)-6-(4-chloro-2-(ethylamino)phenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol (30 g) in Toluene (6 V) were added the Triethyl amine (1.5 eq.) and tert-butyl (4-(bromomethyl) phenethyl)(ethyl)carbamate (1 eq.) at room temperature under N2 atmosphere. Then heated the reaction mass to reflux temperature and stirred for 4 to 6 h, at same temperature. After completion of reaction, cooled the reaction mass to room temperature and added the water (10 V) and the reaction mass was stirred for 10 min. The layers were separated and organic layer was washed with 10% aq. sodium chloride (5 V) solution. The organic layer was distilled off and crude compound was purified by using column chromatography to get the title compound. Yield: 47.58 g

[0291] Example-15: Preparation of Elacestrant dihydrochloride:

[0292] To a stirred solution of tert-butyl (R)-ethyl(4-((ethyl(2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (25 g) in ethyl acetate (I V) and ethanol (2 V) at 25 to 35°C, 4M ethanolic HC1 (5 V) solution was added and stirred for 10 to 12 h, at same temperature. After completion of reaction, filtered the reaction mass, washed the solid with ethanol (2 V). Methanol (4 V) was added to wet solid at 25 to 35°C, the reaction mass was heated to reflux temperature, and then ethanol (6 V) was added, stirred for 30 min at same temperature. The reaction mass was cooled to RT, stirred for 6 to 8 h, at same temperature. The solid was filtered, washed with ethanol (I V) and dried to get the title compound.

[0293] Yield: 15.45 g

[0294] Example-16: Preparation of (R)-6-(2-amino-4-methoxyphenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol:

[0295] To a stirred solution of Pdi(dba)3 (0.01 eq.) in 1,4-dioxane (12 V), t-BuXphos (0.04 eq.), sodium tert-butoxide (1.4 eq.) were added and degassed the reaction mass through N2 gas bubbling for 20 to 30 min at 25 to 35°C. (R)-6-(2-amino-4-chlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (30 g) and methanol (8 eq.) were added at 25 to 35°C under N2 atmosphere. The reaction mass was heated to 60 to 70°C and stirred for 14 to 16 h, at same temperature. After completion of reaction, the reaction mass was cooled to 20°C to 30°C and quenched with water (10 V). The compound was extracted with ethyl acetate (2 x 5 V) and combined organic layer was washed with 10% aq. sodium chloride (5 V) solution. The organic layer was distilled off completely to obtain the crude compound. The crude compound was purified by isopropanol (5 V) to get the title compound. Yield: 10.3 g Example-17: Preparation of (R)-6-(2-(ethylamino)-4-methoxyphenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol:

[0296] To a stirred solution of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (30 g) in DCM (9 V) and methanol (I V) solution, acetaldehyde (1.3 eq.) were added at RT under N2 atmosphere. The reaction mass was cooled to 0 to 5°C, lot wise addition of sodium borohydride ( 1 eq.) over a period of 10 to 20 min at same temperature. The reaction mass was warmed to RT, stirred for 14 to 16 h, at same temperature. After completion of reaction, the reaction mass was quenched with ammonium chloride (10 V) and DCM (10 V). The layers separated, organic layer was washed with water (5 V) and 10% aq. sodium chloride (5 V) solution. The organic layer was distilled off completely to get the title compound and it was used for next reaction without further purification. Yield: 33.12 g

[0297] Example-18: Preparation of tert-butyl (R)-ethyl(4-((ethyl(2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl) amino) methyl) phenethyl) carbamate:

[0298] To a stirred solution of (R)-6-(2-amino-4-methoxyphenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol (30 g) in toluene (15 V), tert-butyl ethyl(4-formylphenethyl)carbamate (1.0 eq.) and (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA] (0.12 g) were added at 25 to 35°C. The reaction mass was heated to reflux temperature and stirred for 12 to 16 h, water was removed through azeotropic distillation at same temperature to obtain the solid (in-situ), the reaction mass was cooled to 50 to 60°C and distilled off up to 0.5 V under vacuum at below 45°C. Then strip off solid residue with THF (1 V). The reaction mass was cooled to 20 to 30°C, THF (20 V) and sodium triacetoxyborohydride (7 eq.) was added under N2 atmosphere at same temperature. The reaction mass was heated to 55 to 60°C and stirred for 14 to 16 h, at same temperature. After completion of reaction, the reaction mass was cooled to 25 to 35°C, water (10 V) and ethyl acetate (7 V) were added, stirred for 10 min and further cooled to 10 to 15°C, 20% aq. NaOH solution was added up to pH 7 to 9 and stirred for 10 min. Then warmed the reaction mass to 25 to 35°C and separated the aqueous layer and organic layer. The compound was extracted with ethyl acetate (5 V) from aq. layer. The combined organic layer was washed with 10% aq. sodium chloride (3 V) solution. Neutral activated carbon (3 g) was added to the organic layer, stirred for 20 min at 25 to 35°C, then filtered the reaction mass on Hyflo bed and washed with ethyl acetate (1 V). Distilled off ethyl acetate under vacuum at below 45°C to get the title compound and it was used for next reaction without further purification.

[0299] Yield: 62.23 g

[0300] Alternative preparation: To a stirred solution of (R)-6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (33.12 g) in Toluene (6 V) were added the Triethyl amine (1.5 eq.) and tert-butyl (4-(bromomethyl) phenethyl)(ethyl)carbamate (1 eq.) at room temperature under N2 atmosphere. Then heated the reaction mass to reflux temperature and stirred for 4 to 6 h, at same temperature. After completion of reaction, cooled the reaction mass to room temperature and added the water (10 V) and the reaction mass was stirred for 10 min. The layers were separated and organic layer was washed with 10% aq. sodium chloride (5 V) solution. The organic layer was distilled off and crude compound was purified by using column chromatography to get the title compound. Yield: 37.34 g

[0301] Example-19: Preparation of Elacestrant dihydrochloride:

[0302] To a stirred solution of tert-butyl (R)-ethyl(4-((ethyl(2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl)carbamate (62.23 g) in ethyl acetate (1 V) and ethanol (2 V) solution at 25 to 35°C, 2M ethanolic HC1 (5 V) solution was added and stirred for 10 to 12 h, at same temperature. After completion of reaction, filtered the reaction mass, washed the solid with ethanol (2 V). Methanol (4 V) was added to wet solid at 25 to 35°C, the reaction mass was heated to reflux temperature, and then ethanol (6 V) was added, stirred for 30 min at same temperature. The reaction mass was cooled to RT, stirred for 6 to 8 h, at same temperature. The solid was filtered, washed with ethanol (I V) and dried to get the title compound. Yield: 41.4 g Example-20: Preparation of tert-butyl (R)-(4-(((5-chloro-2-(6-hydroxy-l, 2,3,4-tetrahydronaphthalen-2-yl)phenyl)(ethyl)amino)methyl)phenethyl)(ethyl) carbamate:

[0303] To a clean and dry RB flask, tetrahydrofuran (400 mL) was added at 20 to 30°C, stirred for 5 to 10 min, cooled to -90 to -70°C, then 2.5 M n-BuLi in n-hexane solution (158.4 mL), tert-butyl (4-bromophenethyl)(ethyl)carbamate (100 g) in tetrahydrofuran (100 mL) and dimethylformamide (31.2 g) were added to the reaction mass and stirred for 2 to 3 hours at same temperature. After completion of the reaction, aq. ammonium chloride solution (50 g of ammonium chloride in 500 mL of water) at -90 to -30°C, then 4V of aq. ammonium chloride solution added at -30 to 5°C and settled for 10 to 15 min at 5 to 30°C. The aqueous and organic layers were separated, toluene (500 mL) was added to the aqueous layer, stirred for 10 to 15 min and settled for 10 to 15 min at 5 to 30°C. The aqueous and organic layers were separated, distilled the organic layer and strip off the crude residue with n-heptane (100 mL) under vacuum at below 55°C. The reaction mass was cooled to 20 to 30°C, methanol (200 mL) was added and stirred for 10 to 15 min, then 50% aq. sodium bisulfite solution (200 g of sodium bisulfite in 400 mL of water) and stirred for 3 to 4 hours at same temperature. Water (100 mL) was added to the reaction mass at 20 to 30°C, stirred for 5 to 10 min, then n-heptane (500 mL) was added, stirred for 10 to 20 min and settled for 10 to 15 min at same temperature. The aqueous and organic layers were separated, 20% aq. sodium carbonate solution (240 g of sodium carbonate in 1200 mL of water) was added to adjust the pH 8.0 to 11.5 at 20 to 30°C. Toluene (500 mL) was added to the reaction mass at 20 to 30°C, stirred for 10 to 20 min and settled for 10 to 15 min at same temperature. The aqueous and organic layers were separated, toluene (500 mL) was added to the aqueous layer at 20 to 30°C, stirred for 10 to 20 min and settled for 10 to 15 min at same temperature. The aqueous and organic layers were separated, water (300 mL) was added to the organic layer at 20 to 30°C, stirred for 10 to 20 min and settled for 10 to 15 min at same temperature. The aqueous and organic layers were separated, 10% aq. sodium chloride solution (30 g of sodium chloride in 300 mL of water) was added to the organic layer at 20 to 30°C, stirred for 10 to 20 min and settled for 10 to 15 min at same temperature. The aqueous and organic layers were separated, distilled the organic layer completely, degas the reaction mass for an hour and strip off the residue with dichloromethane (50 mL) under vacuum at below 55°C. The reaction mass was cooled to 20 to 30°C, dichloromethane (2000 mL) was added, stirred for 10 to 15 min, then (R)-6-(2-amino-4-chlorophenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol (+)-2,3-dibenzoyl-D-tartaric acid (169.4 g) was added to the reaction mass, heated to reflux temperature for 3 to 5 hours. The reaction mass was cooled to 20 to 30°C, sodium triacetoxyborohydride (101.99 g) was added, stirred for 1 to 2 hours, 10% aq. sodium carbonate solution (100 g sodium carbonate in 1000 mL of water) was added to adjust the pH 8.0 to 10.0 and settled for 10 to 20 min at same temperature. The aqueous and organic layers were separated, water (850 mL) was added to the organic layer at 20 to 30°C, stirred for 10 to 20 min and settled for 10 to 20 min at same temperature. The aqueous and organic layers were separated, 10% aq. sodium chloride solution (85 g of sodium chloride in 850 mL of water) at 20 to 30°C, stirred for 10 to 20 min and settled for 10 to 20 min at same temperature. The aqueous and organic layers were separated, heat the organic layer to reflux temperature for 2 to 3 hours. The reaction mass cooled to 5 to 10°C, acetic acid (16.1 g), sodium triacetoxyborohydride (142.02 g) and acetaldehyde (59.07 g) were added and stirred for 1 to 2 hours at same temperature. 10% aq. sodium carbonate solution (170 g sodium carbonate in 1700 mL of water) was added to the reaction mass to adjust the pH 8.0 to 10.0 at 5 to 10°C, heated to 20 to 30°C, stirred for 10 to 20 min and settled for 10 to 20 min at same temperature. The aqueous and organic layers were separated, water (850 mL) was added to the organic layer at 20 to 30°C, stirred for 10 to 20 min and settled for 10 to 20 min at same temperature. The aqueous and organic layers were separated, 10% aq. sodium chloride solution (85 g of sodium chloride in 850 mL of water) at 20 to 30°C, stirred for 10 to 20 min and settled for 10 to 20 min at same temperature. The aqueous and organic layers were separated, distilled the organic layer completely, degas the reaction mass under vacuum at below 45°C. The reaction mass cooled to 25 to 35°C, n-heptane (1700 mL) and dichloromethane (85 mL) were added, heated to 60 to 70°C, stirred for an hour, then cooled to 20 to 30°C, stirred for 1 to 2 hours, heated to 60 to 70°C, stirred for an hours, again cooled to 20 to 30°C and stirred for 3 to 4 hours at same temperature. The reaction mass was filtered, washed with n-heptane and suck dry to obtain wet material. To the above wet material, n-heptane (1700 mL) and dichloromethane (85 mL) were added at 20 to 30°C, heated to 60 to 70°C, stirred for an hour, then cooled to 20 to 30°C and stirred for 3 to 4 hours at same temperature. The reaction mass was filtered, washed with n-heptane, suck dry and dried under vacuum at 25 to 35°C to get the title compound. Yield: 171.57 g

[0304] Example-21: Preparation of Elacestrant:

[0305] To a clean and dry RB flask, 1,4-dioxane (200 mL), Pdi(dba)3 (0.81 g) and t-BuXPhos (0.94 g) were added at 25 to 35°C, heated to 55 to 65°C, reflux for 1 to 2 hours, then cooled to 25 to 35°C and stirred for 20 to 30 min at same temperature. The reaction mass was rinsed with 1,4-dioxane (200 mL) and dried under vacuum.

[0306] 1,4-Dioxane (1000 mL), tert-butyl (R)-(4-(((5-chloro-2-(6-hydroxy-l, 2,3,4-tetrahydronaphthalen-2-yl)phenyl)(ethyl)amino)methyl)phenethyl)(ethyl) carbamate (100 g), Pdi(dba)3 (1.62 g), t-BuXPhos (1.88 g), sodium tert-butoxide (41.33 g) and methanol (28.38 g) were added to the reaction mass at 25 to 35°C under nitrogen atmosphere, heated to 55 to 65°C and stirred for 8 to 10 hours at same temperature. The reaction mass was cooled to 25 to 35°C, 10% aq. ammonium chloride solution (100 g of ammonium chloride in 1000 mL of water) was added and stirred for 10 to 20 min at same temperature. The reaction mass was filtered through hyflow bed, washed with ethyl acetate, stirred for 10 to 20 min and settled for 10 to 20 min at 25 to 35°C. The aqueous and organic layers were separated, ethyl acetate (500 mL) was added to the aqueous layer at 25 to 35°C, stirred for 10 to 20 min and settled for 10 to 20 min at 25 to 35°C. The aqueous and organic layers were separated, 10% aq. sodium chloride solution (50 g of sodium chloride in 500 mL of water) at 25 to 35°C, stirred for 10 to 20 min and settled for 10 to 20 min at same temperature. The aqueous and organic layers were separated, distil the organic layer and co-distill with 1-propanol under vacuum at below 55°C. The reaction mass cooled to 25 to 35 °C, 1-propanol (200 mL) and con hydrochloric acid (75 mL) were added, heated to 45 to 55°C and stirred for 4 to 6 hours at same temperature. The reaction mass was cooled to 20 to 30°C, stirred for 1 to 2 hours, further cooled to 0 to 5°C, stirred for 3 to 4 hours, filtered, washed with 1-propanol and suck dry to get wet material. Water (1000 mL) was added to the reaction mass at 25 to 35°C, stirred for 5 to 15 min, 10% aq. sodium carbonate solution (40 g of sodium carbonate in 400 mL of water) was added to adjust the pH 8.0 to 9.5 and stirred for 10 to 20 min at same temperature. 2-Methyltetrahydrofuran (500 mL) was added to the reaction mass at 25 to 35°C, heated to 50 to 60°C, stirred for 10 to 20 min and settled for 10 to 20 min at same temperature. The aqueous and organic layers were separated, 2-methyltetrahydrofuran (500 mL) was added to the aqueous layer at 50 to 60°C, stirred for 10 to 20 min and settled for 10 to 20 min at same temperature. The aqueous and organic layers were separated, 2-methyltetrahydrofuran (300 mL) was added to the aqueous layer at 50 to 60°C, stirred for 10 to 20 min and settled for 10 to 20 min at same temperature. The aqueous and organic layers were separated, water (500 mL) was added to the organic layer at 50 to 60°C, stirred for 10 to 20 min and settled for 10 to 20 min at same temperature. The aqueous and organic layers were separated, aq. sodium chloride solution (50 g of sodium chloride in 500 mL of water) at 50 to 60°C, stirred for 10 to 20 min and settled for 10 to 20 min at same temperature. The aqueous and organic layers were separated, active carbon (10 g) was added to the organic layer at 50 to 60°C and stirred for 10 to 20 min at same temperature, filtered and washed with 2-methyltetrahydrofuran. Activated carbon (10 g) was added to the reaction mass at 50 to 60°C and stirred for 10 to 20 min at same temperature, filtered and washed with 2-methyltetrahydrofuran, distil the organic layer and co-distil with methanol under vacuum at below 60°C. The reaction mass was cooled to 35 to 45°C, methanol (210 mL) was added, heated to 45 to 55°C, stirred for 1 to 2 hours, water (5.1 g) was added and stirred for 10 to 20 min at same temperature. The reaction mass was cooled to 20 to 30°C, stirred for 30 to 40 min, further cooled to 10 to 20°C stirred for 3 to 4 hours, filtered, washed with methanol (0.5 V) and suck dry for 3 to 4 hours. Methanol (210 mL) was added to the wet solid at 25 to 35°C, heated to 45 to 55°C, stirred for 1 to 2 hours, water (5.1 g) was added, stirred for 10 to 20 min, cooled to 25 to 35°C, dichloromethane (16 mL) was added, stirred for 10 to 20 min, further cooled to 15 to 25 °C, stirred for 3 to 4 hours, filtered, washed with methanol, suck dry and dried under vacuum for 4 to 5 hours. Methanol (210 mL) was added to the wet solid at 25 to 35°C, heated to 45 to 55°C and stirred for 1 to 2 hours, water (5.1 g) was added, stirred for 10 to 20 min, cooled to 25 to 35°C, dichloromethane (16 mL) was added, stirred for 10 to 20 min, further cooled to 15 to 25°C, stirred for 3 to 4 hours, filtered, washed with methanol, suck dry and dried under vacuum for 4 to 5 hours. Dichloromethane (75 mL) was added to the wet solid at 25 to 35°C, heated to 35 to 45°C, stirred for 10 to 20 min, acetonitrile (175 mL) was added, stirred for 10 to 20 min, cooled to 15 to 25°C, stirred for 3 to 4 hours, filtered, washed with acetonitrile, suck dry and dried under vacuum for 3 to 4 hours to get the titled compound. Yield: 81.41 g

[0307] Example-22: Preparation of Elacestrant dihydrochloride:

[0308] To a clean and dry RB flask, elacestrant free base (100 g) and 1-propanol (400 mL) were added at 25 to 35°C, heated the reaction mass to 60 to 70°C and stirred for 1 to 2 hours at same temperature. Activated carbon (5 g) was added to the reaction mass at 60 to 70°C, stirred for 10 to 20 min, filtered on 0.2micron filter and washed with 1-propanol. The reaction mass was cooled to 35 to 45°C, con. hydrochloric acid (100 mL) was added slowly, stirred for 30 to 40 min, then cooled to 20 to 30°C, stirred for 1 to 2 hours, again cooled to 0 to 5°C and stirred for 3 to 4 hours at same temperature. The reaction mass was filtered, washed with 1-propanol, such dry for 1 to 2 hours, dried for 4 hours under vacuum at 45 to 55°C, heated to 50 to 60°C and dried for 14 to 16 hours under vacuum. The solid was cooled to 25 to 35°C, ethanol (400 mL) and ethyl acetate (100 mL) were added, heated to 50 to 60°C and stirred for 4 to 5 hours. The reaction mass cooled to 20 to 30°C, stirred for 20 to 24 hours, filtered, washed with ethyl acetate, suck dry for 1 to2 hours and dried for 4 hours under vacuum at 45 to 55°C, heated to 60 to 70°C and dried for 20 to 22 hours under vacuum. The reaction mass was cooled to 25 to 35 °C under vacuum and dried to get the titled compound. Yield: 98.51 g

Claims

CLAIMS:

1. A novel process for preparing elacestrant or a pharmaceutically acceptable salt thereof, comprising:a) reacting a compound of formula II with a borylation reagent to obtain a compound of formula III; wherein Pg is a hydrogen or a protecting group; X is a halogen; R is a borane group;b) condensing the compound of formula III with a compound of formula IV to obtain a compound of formula V; wherein Pg, X and R, are as defined above; Lg is a leaving group;c) reducing the compound of formula V with a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula VI; wherein Pg and Lg are as defined above;d) catalytic hydrogenating the compound of formula VI with a suitable hydrogenation catalyst in the presence of a suitable solvent to obtain a compound of formula VII; wherein Pg and Lg are as defined above;alternatively,catalytic hydrogenation of the compound of formula V with a suitable hydrogenation catalyst in the presence of a suitable solvent to obtain a compound of formula VII; wherein Pg and Lg are as defined above;e) contacting the compound of formula VII with a chiral acid in the presence of a suitable solvent to obtain a compound of formula VIII; wherein Lg is as defined above;f) treating the compound of formula VIII with a base in the presence of a suitable solvent to obtain a compound of formula IX; wherein Lg is as defined above;g) condensing the compound of formula VIII or compound of formula IX with a compound of formula X to obtain a compound of formula XI (in-situ); wherein Pg’ is hydrogen or protecting group and Lg is as defined above;h) reducing the compound of formula XI with a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XII; wherein Pg’ and Lg are as defined above;i) alkoxylating the compound of formula XII with a suitable alkoxylating agent to obtain a compound of formula XIII; wherein Pg’ and Lg are as defined above;j) deprotecting the compound of formula XIII with a suitable deprotecting agent in the presence of a suitable solvent to obtain elacestrant or a pharmaceutically acceptable salt thereof; when Pg’ is a protecting group; andk) optionally, purifying elacestrant or a pharmaceutically acceptable salt thereof in a suitable solvent or a mixture of solvents.

2. The process as claimed in claim 1, wherein in step a) is carried out in the presence of a base and a catalyst in a suitable solvent, step b) is carried out in the presence of a base and a suitable solvent; and step i) is carried out in the presence of a base, a catalyst and a ligand in a suitable solvent.

3. A novel process for preparing elacestrant or a pharmaceutically acceptable salt thereof, comprising:a) condensing a compound of formula VIII or compound of formula IX with a compound of formula X to obtain a compound of formula XI (in-situ)', wherein Pg’ is a hydrogen or a protecting group; Lg is a leaving group;b) reducing the compound of formula XI with a suitable reducing agent in the presence of a suitable solvent to obtain a compound of formula XII; wherein Pg’ and Lg are as defined above;c) alkoxylating the compound of formula XII with a suitable alkoxylating agent to obtain a compound of formula XIII; wherein Pg’ and Lg are as defined above;d) deprotecting the compound of formula XIII with a suitable deprotecting agent in the presence of a suitable solvent to obtain elacestrant or a pharmaceutically acceptable salt thereof; when Pg’ is a protecting group; ande) optionally, purifying elacestrant or a pharmaceutically acceptable salt thereof in a suitable solvent or a mixture of solvents.

4. A process for preparing a compound of formula IX, comprising:a) contacting a compound of formula VII with a chiral acid in the presence of a suitable solvent to obtain a compound of formula VIII; wherein Lg is a leaving group; andb) treating the compound of formula VIII with a base in the presence of a suitable solvent to obtain a compound of formula IX; wherein Lg is as defined above.

5. A process for preparing a compound of formula XIX, comprising alkoxylating compound of formula IX or a compound of formula IX’ with a suitable alkoxylating agent to obtain a compound of formula XIX; wherein Pg” is a hydrogen or a protecting group; Lg is a leaving group.

6. A compound selected from the group consisting of the compounds of formulae V, VI, VII, VIII, IX, IX’, XI, XII, XIV, XV and XVI.wherein Pg, Pg’ and Pg” are independently hydrogen or a protecting group;X is halogen; Lg is a leaving group.

7. Use of the compounds selected from the group consisting of the compounds of formulae V, VI, VII, VIII, IX, IX', XI, XII, XIV, XV, and XVI as claimed in claim 6, in the preparation of elacestrant or a pharmaceutically acceptable salt thereof.

8. A process for purifying elacestrant free base, comprising:a) deprotecting a compound of formula XIII with a suitable deprotecting agent in the presence of a suitable solvent to obtain an acid addition salt of elacestrant;b) treating the acid addition salt of elacestrant with a suitable base; or treating the step-a) reaction mass with a base; andc) isolating elacestrant in purified free base form.

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