A novel process for the preparation of (6R)-6-(2-(n-(4-(2- (ethylamino) ethyl) benzyl)-n-ethylamino)-4- methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-OL dihydrochloride and it's intemediates

Abstract

The present invention relates to a process for the preparation of (6R)-6-(2-(N-(4-(2- (ethylamino) ethyl) benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydro nap- hthalen-2-ol dihydrochloride (1) and its novel intermediates thereof. The present invention relates to a process for the preparation of amorphous solid dispersion of (6R)-6-(2-(N-(4-(2-(ethylamino) ethyl) benzyl)-N-ethylamino)-4- methoxyphenyl)-5,6,7,8-tetrahydro nap- hthalen-2-ol dihydrochloride (1). with at least one pharmaceutically acceptable excipient. and its novel intermediates thereof. Elacestrant dihydrochloride (1) The present invention further relates to a process for the preparation of intermediates of formula (D), formula (E1), formula (H1) & Elacestrant sulfate (2) with enantiomeric excess greater than 50%.

Description

[0001] “A NOVEL PROCESS FOR THE PREPARATION OF (6R)-6-(2-(N-(4-(2- (ETHYLAMINO) ETHYL) BENZYL)-N-ETHYLAMINO)-4-

[0002] METHOXYPHENYL)-5,6,7,8-TETRAHYDRONAPHTHALEN-2-OL DIHYDROCHLORIDE AND IT’S INTEMEDIATES”

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 202541073169 filed on Aug 01, 2025.

[0005] FIELD OF THE INVENTION

[0006] The present invention relates to a novel process for the preparation of (6R)-6-(2-(N- (4-(2-(ethylamino) ethyl) benzyl)-N-ethylamino)-4-methoxyphenyl)-5, 6,7,8- tetrahydr -onaphthalen-2-ol dihydrochloride (1) and its intermediates thereof. Further, the present invention relates to novel intermediates of formula C and formula D.

[0007] BACKGROUND OF THE INVENTION

[0008] Elacestrant dihydrochloride (1), is an estrogen receptor antagonist, for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESRI -mutated advanced or metastatic breast cancer. It is chemically designated as (6R)-6-(2-(N-(4-(2- (ethylamino) ethyl) benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydro naphthalen-2-ol dihydrochloride and is chemically represented by the following structural Formula

[0009] Elacestrant dihydrochloride (1)

[0010] US 7612114 B2 discloses Elacestrant and its salts for the first time which discloses a process for the preparation of Elacestrant, comprising a) reacting compound 2 with benzyl bromide in presence of dimethyl formamide to obtain compound 3; b) reacting compound 3 with bromine in presence of sodium borohydride, Toluene to obtain compound 4; c) reacting compound 4 with compound 5 in presence of catalyst, dimethyl sulfoxide to obtain compound 6; (d) compound 6 reacting with palladium, hydrochloric acid in presence of tetrahydrofuran, methanol to obtain formula A; (e) compound of formula A reacting with acetic anhydride, lithium aluminium hydride in presence of pyridine, tetrahydrofuran, aluminium chloride to obtain compound 8; f) reacting compound 8 with compound 9 in presence of tetrahydrofuran, sodium hydride to obtain compound 10; (g) reacting compound 10 with compound 11, in presence of 1,2-di chloroethane, Acetic acid to obtain compound 12; (h) compound 11 reacting with Oxalyl chloride, Ethylamine in presence of tetrahydrofuran, lithium aluminum hydride, aluminum chloride to obtain Elacestrant.

[0011] The above process is schematically shown as below:

[0012] US 20220162233 Al discloses Elacestrant and its salts which discloses a process for the preparation of Elacestrant , comprising; i) reacting compound (a) with bis(pinacolato)diboronin presence of Potassium acetate, Bis(triphenylphosphine) palladium(II) dichloride , Dimethyl ether to obtain compound (b); ii) reacting compound (b) with compound (c) in presence of Potassium bicarbonate, carbon, dichloromethane, ethanol to obtain compound (d); iii) reacting compound (d) with Palladium hydroxide on carbon, hydrogen in presence of tetrahydrofuran, methanol to obtain compound (e); iv) reacting compound (e) with hydrochloric acid in presence of methanol, 2-Methyltetrahydrofuran, sodium hydroxide, Potassium bicarbonate, water, heptane to obtain formula (A); v) reacting formula (A) with (+)- 2,3-dibenzoyl-D-tartaric acid in presence of acetonitrile, dichloromethane, Potassium bicarbonate, methanol to obtain a compound (g); vi) reacting compound (g) with compound (h) in presence of tetrahydrofuran, (+)-2,3-dibenzoyl- D-tartaric acid, heptane, sodium triacetoxyborohydride, ethyl acetate, sodium thiosulfate, hydrochloric acid, ethanol, methanol, Ethyl acetate to obtain Elacestrant; vii) reacting Elacestrant with hydrochloric acid in presence of methanol to obtain Elacestrant dihydrochloride. The above process is schematically shown as below:

[0013] The processes taught by prior art have several drawbacks namely not suitable for scale up at plant level, difficult, giving lower yields and less user friendly. Considering the drawbacks of the prior art process of Elacestrant, the present invention is simple, economical, financially cheaper plant friendly process, environment friendly process for the preparation of Elacestrant with better yields and purity.

[0014] There is always need for alternative preparative routes, which for example use reagents, solvents that are less expensive and, or easier to handle, consume smaller amounts of reagents and solvents provide a higher yield of product, have smaller and, or eco- friendly waste products and, or provide a product of higher purity.

[0015] OBJECTIVE OF THE INVENTION

[0016] The present invention relates to a novel process for the preparation of Elacestrant dihydrochloride (1) and its intermediates.

[0017] The present invention further relates to pure Elacestrant dihydrochloride (1) obtained by any of the methods described with purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.9% by HPLC.

[0018] Another objective of the present invention relates to a novel process for the preparation of Elacestrant sulfate (2) and its intermediates

[0019] The objective of the present invention relates to a process for the preparation of amorphous solid dispersion of Elacestrant and its salts (1).

[0020] The present invention further relates to amorphous solid dispersion of Elacestrant dihydrochloride (1) with pharmaceutically suitable excipient by using Elacestrant sulphate (2) as a starting material without isolation of Elacestrant dihydrochloride (1).

[0021] The present invention further relates to pure Elacestrant dihydrochloride (1) and its amorphous solid dispersion with pharmaceutically suitable excipient obtained by any of the described methods with purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.9% by HPLC. SUMMARY OF THE INVENTION

[0022] Accordingly, the present invention provides a novel process for the preparation of Elacestrant dihydrochloride (1) and its intermediates. Further in some embodiments, the present invention provides process for the preparation of intermediates with enantiomeric excess of greater than 50%.

[0023] In one aspect of the present invention provides a process for the preparation of Elacestrant dihydrochloride (1), as depicted in scheme-1, which comprises:

[0024] A) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (A) with compound of formula (B); in presence of suitable solvent, reducing agent and acid to provide compound of formula (C);

[0025] B) resolving the compound of formula (C) with chiral resolving agent in presence of suitable solvent to provide compound of formula (D);

[0026] C) reacting of the compound of formula (D) with acetaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula (E) ; and

[0027] D) converting compound of formula (E) into Elacestrant dihydrochloride (1).

[0028] In one aspect of the present invention provides a process for the preparation of Elacestrant dihydrochloride (1), as depicted in scheme-2, which comprises: a) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (A) with compound of formula (B); in presence of suitable solvent, reducing agent and acid to provide compound of formula (C); b) resolving the compound of formula (C) with in presence of suitable reducing agent, solvent and acid to provide compound of formula (F); c) reacting of the compound of formula (F) with chiral resolving agent in presence of suitable solvent to provide compound of formula (E); and d) converting compound of formula (E) into Elacestrant dihydrochloride (1).

[0029] In yet another aspect of the present invention provides a process for the preparation of pure Elacestrant dihydrochloride having purity greater than 99% which comprises of

[0030] I) dissolving a solution of crude Elacestrant dihydrochloride (1) in one or more solvents II) isolating pure compound of Elacestrant dihydrochloride.

[0031] In another aspect, the present invention is to provide Elacestrant dihydrochloride (1) obtained by any of the described methods is having purity greater than 99% by HPLC and more preferably greater than 99.5% and still preferably 99.98% by HPLC.

[0032] Further in some embodiments, the present invention provides process for the preparation of intermediates with enantiomeric excess of greater than 50%.

[0033] Accordingly, the present invention relates of preparation of amorphous solid dispersion of Elacestrant and its salts (1)

[0034] In another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient, as illustrated in scheme 4, which comprises:

[0035] A) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol formula (A) in the presence of base and solvent to provide compound of formula (B);

[0036] B) reacting the compound of formula (B) with compound of formula (C) in the presence of reducing agent and suitable solvent to provide compound of formula (D);

[0037] C) reacting of the compound of formula (D) with chiral resolving agent in presence of base, solvent, and acid to provide compound of formula (E);

[0038] D) reacting compound of formula (E) in the presence of base to provide formula (F).

[0039] E) reacting compound of formula (F) with acetaldehyde in presence of reducing agent in a solvent to provide formula (G).

[0040] F) reacting compound of formula (G) with sulfuric acid in presence of suitable solvent to provide Elacestrant Sulfate (2)

[0041] G) adding hydrochloric acid and least one pharmaceutically acceptable excipient in a solvent to the mixture of step F)

[0042] H) isolating the amorphous solid dispersion of Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient. In another aspect of the present invention provides a process for the preparation of Elacestrant sulfate (2), which comprises: a) reacting the compound of formula (A) in the presence of base and solvent to provide compound of formula (B); b) reacting the compound of formula (B) with compound of formula (C) in the presence of reducing agent and suitable solvent to provide compound of formula (D); c) reacting of the compound of formula (D) with chiral resolving agent in presence of base in solvent and acid to provide compound of formula (E); d) reacting compound of formula (E) in the presence of base to provide formula (F). e) reacting compound of formula (F) with acetaldehyde in presence of reducing agent in solvent to provide formula (G). f) adjusting pH of the reaction with sulphuric acid and isolating solid form of Elacestrant sulfate (2).

[0043] In yet another aspect of the present invention provides a process for the preparation of Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient, which is comprising of.

[0044] 1) dissolving Elacestrant sulfate (2) in suitable solvents or mixture of solvents,

[0045] 2) adding suitable base to the ration mixture in step 1)

[0046] 3) adding hydrochloric acid to the reaction mixture in step 2)

[0047] 4) adding at least one pharmaceutically acceptable excipient in a solvent to the mixture and

[0048] 5) isolating the solid dispersion of Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient.

[0049] In yet another aspect of the present invention provides a process for the preparation of pure Elacestrant sulfate having purity greater than 99%, comprising the steps of;

[0050] I) dissolving a solution of crude Elacestrant sulfate (2) in one or more solvents

[0051] II) isolating pure compound of Elacestrant sulfate (2). In another aspect of the present invention, provides a process for the preparation of compound of formula (H), as illustrated in scheme 5, comprising the steps of: i) reacting of the compound of formula (D) with chiral resolving agent in presence of base and acid in a suitable solvent to provide compound of formula (H);

[0052] In yet another aspect of the present invention provides, a novel compound of formula (C), formula (El), formula (D) formula (Hl) & Elacestrant sulfate (2).

[0053] Elacestrant Sulfate (2)

[0054] Wherein R is Hydrogen or amine protecting group. The above-mentioned novel intermediate compounds are useful in the preparation of Elacestrant dihydrochloride (1).

[0055] The present invention further relates to a process for the preparation of intermediates of formula (D), formula (El), formula (Hl), Elacestrant sulfate (2), with chiral purity greater than 90%.

[0056] In another aspect, the present invention is to provide amorphous solid dispersion of Elacestrant dihydrochloride (1) with pharmaceutically suitable excipient by using Elacestrant sulphate (2) without isolation of Elacestrant dihydrochloride (1).

[0057] In another aspect, the present invention is to provide pure Elacestrant dihydrochloride (1) and its amorphous solid dispersion with pharmaceutically suitable excipient obtained by any of the described methods with purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.9% by HPLC.

[0058] BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure-1: Illustrates the PXRD pattern of amorphous solid dispersion of Elacestrant dihydrochloride (1) with PVP 8:2 ratio, obtained according to reference example 17. Figure-2: Illustrates the PXRD pattern of amorphous solid dispersion of Elacestrant dihydrochloride (1) with PVP 9: 1 ratio, obtained according to reference example 17. Figure-3: Illustrates the PXRD pattern of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl beta cyclodextrin (HPpCD). obtained according to reference example 18. Figure-4: Illustrates the PXRD pattern of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Copovidone, obtained according to reference example 19. Figure-5: Illustrates the PXRD pattern of Crystalline form of Elacestrant sulfate (2). obtained according to reference example 16.

[0060] DETAILED DESCRIPTION OF THE INVENTION

[0061] The term “suitable solvent” used in the present invention until unless specified is selected from, but are not limited to “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; “chloro solvents” such as di chloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethylketone and the like; and water.

[0062] The term “suitable reducing agent” used in the present invention until unless specified is selected from, but are not limited to lithium aluminium hydride, sodium borohydride, sodium hydride, or sodium bi s(2-methy oxy ethoxy) aluminumhydride, sodium triacetoxyborohydrode, Aluminium hydride(AlH3), chlorohydroalane (A1H2C1), dichloroaluminum (A1HC12), Lithium borohydride (LiBH4), Lithium triethylborohydride (LiEt3BH), Borane(BH3), Borane tetrahydrofuran (BH3.THF), Zinc acetate(Zn(OAc)2), Triethoxysilane ((EtO)3SiH), Magnesium(Mg), Titanium tetrachloride(TiC14), Pinacolborane (HBpin), tris(4,4- dimethyl-2- oxazolinyl)phenylborateMgMe, Platinum (Pt) on alumina, palladium (Pd) on alumina, Palladium on carbon (Pd,C), palladium hydroxide on carbon ((Pd(OH2),C), Raney Ni, Rhodium on carbon (Rh,C), Rhodium on alumina (Rh,Al), Platinum on (Pt,C), Ruthenium (Ru,C), Platinum (IV) Oxide (PtO2), Sodium bis(2- methoxyethoxy)aluminium hydride (Red-Al), or combinations thereof.

[0063] The term “suitable acid” used in the present invention until unless specified is selected from, but are not limited to hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, alkyl, aryl sulfonic acids such as methanesulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid. The term “chiral resolving agent” used in the present invention until unless specified is selected from, but are not limited to Aspartic acid, Tartaric acid, O-Acetyl -Mandelic acid, cis-2-Benzamidocyclohexanecarboxylic acid, l,l'-Binapthyl-2,2'-diyl hydrogen phosphate, Camphoric acid, 10-Camphorsulfonic acid, trans- 1,2- Cyclohexanedicarboxylic acid, Dibenzoyl-Tartaric acid, Di acetyl -tartaric acid, Di-p- toluoyl -tartaric acid, N-(3,5-Dinitrobenzoyl)-a-phenylglycine, Di acetyl -tartaric anhydride, Di acetyl -tartaric acid, Glutamic acid, Malic acid, Mandelic acid, N-(a- methylbenzyl)phthalamic acid, 2-(6-Methoxy-2-napthyl)propionic acid, Pyroglutamic acid, Quinic acid and Tartaric acid, or combinations thereof.

[0064] The term “deprotecting agent” used in the present invention until unless specified is selected from, but are not limited to Platinum (Pt), Platinum on carbon (Pt,C), Platinum (IV) Oxide (PtO2), Palladium (Pd), Palladium on carbon (Pd,C), Rhodium (Rh), Ruthenium (Ru), Nikel (Ni) or Raney Nikel; Zink (Zn), Tin (Sn) or Iron (Fe) and an acid; A1H3-A1C13 ; hydrazine and a catalyst; Triiron dodecarbonyl [Fe3(CO)12]- methanol; hot liquid paraffin; formic acid or ammonium formate and a catalyst such as palladium on carbon (Pd,C); Lithium aluminium hydride (LiAlH4) ; and sulfides such as Sodium hydrosulfide (NaHS), Diammonium sulfide (NH4)2S or polysulfides.

[0065] The term “base” used in the present invention until unless specified is selected from, but are not limited to “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tertbutoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide; “acetate salts” such as sodium acetate, sodium diacetate, potassium acetate, calcium acetate, magnesium acetate, ammonium acetate; and the like ammonia and organic bases such as tri ethylamine, methylamine, ethylamine, 1,8- diazabicycle[5.4.0]undec7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-m ethylmorpholine (NMP), N-ethylmorpholine, piperidine, morpholine, pyridine, 2,6-lutidine, 2,4,6- collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.

[0066] The term “amine protecting group” used in the present invention until unless specified is selected from, but are not limited to, n-Acetyl, tert-butoxy carbonyl (BOC), benzyloxycarbonyl(CBz), triflouoroacetyl (TFA), benzyl (Bn), dibenzyl, phthalimido, tosyl (Ts), Di-tert-butyl dicarbonate(BOC anhydrate), p-m ethoxybenzylcarbonyl, 9- fluorenylmethyloxy carbonyl (FMOC), carbamate, pmethoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p- methoxyphenyl (PMP) and benzoyl (Bz).

[0067] As used herein the term “isolation techniques” as defined as involves removal of solvent by suitable techniques which includes but not limited to evaporation under reduced pressure, flash evaporation, rotary evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction mixture or by any other suitable techniques known in the art.

[0068] As used herein, the term “solid dispersion” refers to dispersion of drug in a solid matrix where the matrix is either a small molecule or polymer. Preferably solid dispersion relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two or more components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.

[0069] As used herein, the term “excipient” refers to play a significant role in stabilizing solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs.

[0070] The present invention relates to a process for the preparation of Elacestrant dihydrochloride (1) and its novel intermediates used in the preparation of Elacestrant dihydrochloride (1).

[0071] In one aspect of the present invention, provides a process for the preparation of Elacestrant dihydrochloride (1), as depicted in scheme-1, comprising the steps of:

[0072] Elacestrant dihydrochloride (1) Scheme-1

[0073] Wherein R is Hydrogen or amine protecting group.

[0074] The step A) of aforementioned process involves the reaction of compound of formula

[0075] (A) with compound of formula (B); in presence of reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium, sodium cyanoborohydride; a suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol; a suitable acid selected from but not limited to formic acid, acetic acid, trifluoroacetic acid; under appropriate reaction conditions to provide a compound of formula (C). The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0076] The step B) of aforementioned process involves the reaction of compound of formula (C) with chiral resolving agent selected from (+)-2,3-dibenzoyl-D-tartaric acid, Aspartic acid, O-Acetyl-Mandelic acid, cis-2-Benzamidocyclohexanecarboxylic acid, l,l'-Binapthyl-2,2'-diyl hydrogen phosphate, Camphoric acid, 10-Camphorsulfonic acid; a suitable solvent selected from but not limited to acetonitrile, acetone, methyl isobutyl ketone, methyl ethyl ketone, under appropriate reaction conditions to provide a compound of formula (D); The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0077] The step C) of aforementioned process involves reaction of compound formula (D) with acetaldehyde; in presence of reducing agent selected form but are not limited to lithium aluminium hydride, sodium borohydride, sodium hydride, DIBAL-H, Red- Al; in presence of suitable solvent selected form but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; under appropriate reaction conditions to provide a compound of formula (E); The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0078] The step D) of aforementioned process involves reaction of compound formula (E) with Hydrochloric acid in presence of suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol; under appropriate reaction conditions to provide Elacestrant dihydrochloride (1) , The said reaction is carried out at a suitable temperature of about 70°C-80°C to about reflux temperature of the solvent used, for a sufficient time.

[0079] In one aspect of the present invention, provides a process for the preparation of Elacestrant dihydrochloride (1), as depicted in scheme-2, comprising the steps of:

[0080]

[0081] Scheme-2

[0082] Wherein R is Hydrogen or amine protecting group.

[0083] The step a) of aforementioned process involves the reaction of compound of formula (A) with compound of formula (B); in presence of reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium, sodium cyanoborohydride; a suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol; a suitable acid selected from but not limited to formic acid, acetic acid, trifluoroacetic acid; under appropriate reaction conditions to provide a compound of compound of formula (C). The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0084] The step b) of aforementioned process involves reaction of compound formula (C) with acetaldehyde; in presence of reducing agent selected form but are not limited to lithium aluminium hydride, sodium borohydride, sodium hydride, DIBAL-H, Red-Al; in presence of suitable solvent selected form but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; under appropriate reaction conditions to provide a compound of formula (F); The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0085] The step c) of aforementioned process involves the reaction of compound of formula (F) with chiral resolving agent selected from (+)-2,3-dibenzoyl-D-tartaric acid, Aspartic acid, O-Acetyl-Mandelic acid, cis-2-Benzamidocyclohexanecarboxylic acid, l,l'-Binapthyl-2,2'-diyl hydrogen phosphate, Camphoric acid, 10-Camphorsulfonic acid; a suitable solvent selected from but not limited to acetonitrile, acetone, methyl isobutyl ketone, methyl ethyl ketone, under appropriate reaction conditions to provide a compound of formula (E); The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0086] The step d) of aforementioned process involves reaction of compound formula (E) with Hydrochloric acid in presence of suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol; under appropriate reaction conditions to provide Elacestrant dihydrochloride , The said reaction is carried out at a suitable temperature of about 70°C-80°C to about reflux temperature of the solvent used, for a sufficient time.

[0087] In yet another aspect of the present invention provides a process for the preparation of N-(4-formylphenethyl) acetamide (3) as depicted in scheme-3, which comprises:

[0088]

[0089] Scheme-3

[0090] Wherein R is Hydrogen or amine protecting group.

[0091] The step i) of Scheme-3 process involves reacting compound of 2-(4-bromophenyl) ethanol (F) with methanesulfonyl chloride, in presence of suitable solvent selected from but not limited to dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform, the add ethylamine in ethanol, under appropriate reaction conditions to provide compound of formula (G). The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0092] The step ii) of process involves reacting compound of formula (G) with amino protecting group selected from not n-Acetyl, Di-tert-butyl dicarbonate and like in presence of suitable base selected from but not limited to triethylamine, pyridine, n- butyl lithium; in presence suitable solvent selected from but not limited to dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform, tetrahydrofuran to provide compound of formula (H). The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0093] The step iii) of process involves reacting compound of formula (H) with Di-tert-butyl dicarbonate in presence of suitable base selected from but not limited to triethylamine, pyridine, n-butyl lithium; in presence suitable solvent selected from but not limited to dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform, tetrahydrofuran, and add ammonium chloride to the reaction mixture to provide compound of formula (B). The said reaction is carried out at a suitable temperature of about -78°C to about reflux temperature of the solvent used, for a sufficient time.

[0094] In yet another aspect of the present invention provides a process for the preparation of pure Elacestrant dihydrochloride (1) having purity greater than 99% which comprises.

[0095] I) dissolving a solution of crude Elacestrant dihydrochloride (1) in one or more solvents

[0096] II) isolating pure compound of Elacestrant dihydrochloride (1).

[0097] In another embodiment, the present invention is to provide Elacestrant dihydrochloride (1) obtained by any of the described methods is having purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.98% by HPLC.

[0098] In another embodiment Elacestrant dihydrochloride (1) obtained according to present invention could be amorphous or crystalline.

[0099] In another embodiment Elacestrant dihydrochloride (1) having chloride content in the range of 12.33% to 15.08%.

[0100] In another embodiment, the present invention provides a purification process to produce Elacestrant dihydrochloride (1) thereof having impurity levels less than 0.15% (w / w) and unspecified impurity should be less than 0.1% (w / w).

[0101] In the present invention, solid dispersion and premix are used interchangeably to describe solid states disclosed herein.

[0102] The present invention provides crystalline form, solid dispersion and premix are used interchangeably to describe solid states disclosed herein.

[0103] The present invention relates to a process for the preparation of Elacestrant dihydrochloride (1) and its novel intermediates used in the preparation of Elacestrant dihydrochloride (1).

[0104] In the first embodiment of the present invention, provides a process for the preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient, as illustrated in scheme 4, comprising one or more following steps:

[0105] Scheme-4 Wherein R is Hydrogen or amine protecting group.

[0106] The step A) of aforementioned process involves the reaction of compound of formula (Al) in presence of base selected from as triethylamine, methylamine, ethylamine, 1,8- diazabicycle[5.4.0]undec7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine

[0107] (NMP), N-ethylmorpholine, piperidine, morpholine, pyridine, 2,6-lutidine, 2,4,6- collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole and 1,4- diazabicyclo[2.2.2]octane (DABCO); solvent selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide; under appropriate reaction conditions to provide a compound of formula (B) in-situ. The said reaction is carried out at a suitable temperature of about -70°C to -90°C to about reflux temperature of the solvent used, for a sufficient time.

[0108] The step B) of aforementioned process involves the reaction of compound of formula

[0109] (B) with compound of formula (Cl) in presence of reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium, sodium cyanoborohydride; a suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol; a suitable acid selected from but not limited to formic acid, acetic acid, trifluoroacetic acid; under appropriate reaction conditions to provide a compound of formula (C) . The said reaction is carried out at a suitable temperature of about 25°C- 30°C to about reflux temperature of the solvent used, for a sufficient time.

[0110] The step C) of aforementioned process involves the reaction of compound of formula

[0111] (C) with chiral resolving agent selected from L-Proline, L-Phenylalanine, L-

[0112] Pyroglutamic Acid, L-Glutamic Acid, (+)-2,3-dibenzoyl-D-tartaric acid, Aspartic acid, O-Acetyl-Mandelic acid, cis-2-Benzamidocyclohexanecarboxylic acid, 1,1'- Binapthyl-2,2'-diyl hydrogen phosphate, Camphoric acid, 10-Camphorsulfonic acid; coupling agent selected from but not limited Hexafluorophosphate Azabenzotri azole Tetramethyl Uronium (HATU), O-Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(6-Chlorobenzotriazol- 1 -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HCTU),benzotriazol-l- yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP); a suitable solvent selected from but not limited to dimethylformamide, dimethylacetamide, dimethylsulfoxide; suitable base is selected from but not limited to triethylamine, methylamine, ethylamine, l,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n- butyllithium, tribenzylamine, isopropylamine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1- methylimidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) under appropriate reaction conditions to provide a compound of formula (El); The said reaction is carried out at a suitable temperature of about 30°C-50°C to about reflux temperature of the solvent used, for a sufficient time.

[0113] The step D) of aforementioned process involves reaction of compound formula (El) in presence of base selected form but are not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide; in presence of suitable solvent selected form but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol and water or mixture thereof; under appropriate reaction conditions to provide a compound of formula (D) The said reaction is carried out at a suitable temperature of about 70°C- 90°C to about reflux temperature of the solvent used, for a sufficient time.

[0114] The step E) of aforementioned process involves reaction of compound formula (D) with acetaldehyde in presence of reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium, sodium cyanoborohydride; suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol, dichloromethane or mixture thereof; a suitable acid selected from but not limited to formic acid, acetic acid, trifluoroacetic acid; under appropriate reaction conditions to provide a compound of formula (E); The said reaction is carried out at a room temperature of the solvent used, for a sufficient time.

[0115] The step F) of aforementioned process involves reaction of compound formula (E) with sulfuric acid in presence of suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol; under appropriate reaction conditions to provide Elacestrant sulfate (2) , The said reaction is carried out at a suitable temperature of about 70°C-80°C to about reflux temperature of the solvent used, for a sufficient time.

[0116] The step (G) of aforementioned process involves reaction of compound formula (2) with Cone. Hydrochloric acid and Polyvinylpyrrolidone (PVP, 1 -vinyl -2- pyrrolidinone polymer) in presence of suitable base is selected from but not limited to sodium carbonate, potassium carbonate, lithium carbonate and solvent is selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol dichloromethane, water or mixture thereof; under appropriate reaction conditions to provide Elacestrant dihydrochloride Polyvinylpyrrolidone (PVP, 1 -vinyl -2- pyrrolidinone polymer) (1).

[0117] In the second embodiment of the present invention provides a process for the preparation of Elacestrant sulfate (2), which comprises: a) reacting the compound of formula (A) in the presence of base and solvent to provide compound of formula (B); b) reacting the compound of formula (B) with compound of formula (Cl) in the presence of reducing agent and suitable solvent to provide compound of formula (C); c) reacting of the compound of formula (C) with chiral resolving agent in presence of base in solvent and acid to provide compound of formula (El); d) reacting compound of formula (El) in the presence of base to provide formula (D); e) reacting compound of formula (D) with acetaldehyde in presence of reducing agent in solvent to provide formula (E); f) adjusting pH of the reaction with suitable acid or base; and g) isolating solid form of Elacestrant sulfate (2).

[0118] In the process of the second embodiment, the base, solvent, reducing agent, chiral resolving agent and acid are selected from the list defined above.

[0119] In the third embodiment of the present invention provides a process for the preparation of Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient, which comprises:

[0120] 1) dissolving Elacestrant sulfate (2) in suitable solvents or mixture of solvents,

[0121] 2) adding suitable base to the ration mixture in step 1)

[0122] 3) adding hydrochloric acid to the reaction mixture in step 2)

[0123] 4) adding at least one pharmaceutically acceptable excipient in a solvent to the mixture and

[0124] 5) isolating the solid dispersion of Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient. In the process of the third embodiment, the base and solvent are selected from the list defined above.

[0125] In the process of the third embodiment, the pharmaceutically acceptable excipient is selected from but not limited to polyvinylpyrrolidone, (povidone or PVP; PVP of different grades like K-IS, K-30, K-60, K-90 and K-120 may be used), polyvinylpolypyrrolidone, crospovidone, copovidone, Eudragit, Soluplus, polyethylene glycol (macrogol or PEG), polyethylene glycol-6000 (PEG-6000), hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), sulfo butyl ether-P-cyclodextrin (SBECD), hydroxypropyl beta cyclodextrin (HPpCD), salcaprozate sodium, sodium caprylate, and the like

[0126] In the fourth embodiment of the present invention, provides a process for the preparation of compound of formula (Hl), as illustrated in scheme 5, comprising the steps of:

[0127] Scheme-5

[0128] Wherein R is Hydrogen or amine protecting group.

[0129] The step-i) of aforementioned process involves the reaction of compound of formula (C) with chiral resolving agent selected from L-Proline, L-Phenylalanine, L- Pyroglutamic Acid, L-Glutamic Acid, (+)-2,3-dibenzoyl-D-tartaric acid, Aspartic acid, O-Acetyl-Mandelic acid, cis-2-Benzamidocyclohexanecarboxylic acid, 1,1'- Binapthyl-2,2'-diyl hydrogen phosphate, Camphoric acid, 10-Camphorsulfonic acid; coupling agent selected from but not limited Hexafluorophosphate Azabenzotri azole Tetramethyl Uronium (HATU), O -Benzotri azol e-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O -(Benzotri azol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(6-Chlorobenzotriazol- 1 -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HCTU), benzotriazol- 1- yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP); a suitable solvent selected from but not limited to dimethylformamide, dimethylacetamide, dimethylsulfoxide; suitable base is selected from but not limited to triethylamine, methylamine, ethylamine, l,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n- butyllithium, tribenzylamine, isopropylamine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1- methylimidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) under appropriate reaction conditions to provide a compound of formula (Hl); The said reaction is carried out at a suitable temperature of about 30°C-50°C to about reflux temperature of the solvent used, for a sufficient time.

[0130] In the fourth embodiment of the present invention, provides a process for the preparation of compound of formula (A), as illustrated in scheme 6, comprising the steps of:

[0131]

[0132] Scheme-6

[0133] The step 1) of Scheme-6 process involves reacting compound of Formula (i) with compound of Formula (ii), in presence of coupling agent Bis(pinacolato)diboron (B2pin2); carboxylic acids Potassium acetate (KOAc); catalyst Bis(triphenylphosphine)palladium(II) dichloride; suitable solvent selected from but not limited to “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert- butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-di oxane and mixtures thereof, “ester solvents” such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like, a suitable base selected from “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; under appropriate reaction conditions to provide a compound of Formula (iii). The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0134] The step 2) of Scheme-6 process involves reacting compound of Formula (iii) with Raney nickel in presence of suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol; “ether solvents” tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “ester solvents” such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate and the like; “polar solvents” such as water or mixtures thereof, a suitable base selected from “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; under appropriate reaction conditions to provide a compound of Formula (A). The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0135] In the sixth embodiment of the present invention provides a process for the preparation of pure Elacestrant sulfate (2) having purity greater than 99% which comprises; i. dissolving a solution of crude Elacestrant sulfate (2) in one or more solvents ii. isolating pure compound of Elacestrant sulfate (2).

[0136] In the seventh embodiment of the present invention provides, a novel compound of formula (C), formula (D), formula (El), formula (Hl) & Elacestrant sulfate (2).

[0137]

[0138] Elacestrant Sulfate (2)

[0139] Wherein R is Hydrogen or amine protecting group.

[0140] The above-mentioned novel intermediate compounds are useful in the preparation of Elacestrant dihydrochloride (1).

[0141] The present invention further relates to a process for the preparation of intermediates of formula (El), formula (D), and formula (Hl), Elacestrant sulfate (2), with chiral purity greater than 90%.

[0142] In another embodiment, the present invention is to provide Elacestrant sulfate (2) obtained by any of the described methods is having purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.98% by HPLC.

[0143] In another embodiment, the present invention is to provide pure Elacestrant dihydrochloride (1) and its amorphous solid dispersion with pharmaceutically suitable excipient obtained by any of the described methods is having purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.98% by HPLC.

[0144] In another embodiment amorphous solid dispersion of Elacestrant dihydrochloride (1) obtained according to present invention could be amorphous or crystalline with purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.98% by HPLC.

[0145] In another embodiment Elacestrant dihydrochloride (1) having chloride content in the range of 12.33% to 15.08%.

[0146] In another embodiment, the present invention provides a purification process to produce amorphous solid dispersion of Elacestrant dihydrochloride (1) thereof having impurity levels less than 0.15% (w / w) and unspecified impurity should be less than 0.1% (w / w).

[0147] In another embodiment, the present invention provides amorphous solid dispersion of Elacestrant dihydrochloride (1) nitroso amine impurities less than 1.5%, more preferably less than 0.5%. further nitroso amine impurities are controlled as per ICH limits.

[0148] The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

[0149] Examples:

[0150] Example 1: Preparation of 2-(4-bromophenyl)-N-ethylethanamine (G)

[0151] 100 g of 2-(4-bromophenyl) ethanol was dissolved in in di chloromethane (100 mL) and cooled to 0-5°C, to this reaction solution triethylamine (76 g) and methanesulfonyl chloride (57 g) were added. Reaction mass temperature raised to 25-35° C and stirred for 10 hours, after completion of reaction, to the reaction mass water (500 mL) was added and stirred for 10 minutes layers were separated and collected methane dichloride layer and distilled methane dichloride completely under vacuum at below 30 °C. 500 mL of 30% ethylamine in ethanol was added to the reaction mass, temperature raised to 60-65 °C and stirred for 12 hours. After completion of reaction, the reaction mass cooled to 25-35 °C and charged 1000 mL of methane di chloride and 1000 mL water to the reaction mass. After stirring for 10 minutes layers were separated and collected methane dichloride, methane dichloride layer was distilled under vacuum below 40°C provided the 103g tittle compound. Yield: 91%; Purity: 99.5%.

[0152] Example 2: Preparation of tert-butyl 4-bromophenethyl(ethyl)carbamate (where in R= Di-tert-butyl dicarbonate)

[0153] 100 g of 2-(4-bromophenyl)-N-ethylethanamine dissolved in di chloromethane (1000 mL), to this reaction solution 67 g of tri ethylamine and 105 g Di-tert-butyl dicarbonate were added at 25-35 °C. Reaction mixture was stirred for 12 hours and quenched with 500 mL of water, then stirred for 10 minutes layers were separated and di chloromethane layer distilled under vacuum at below 40 °C to get 135 g of tittle compound. Yield: 94%; Purity: 99.6%.

[0154] Example 3: Preparation of tert-butyl ethyl(4-formylphenethyl) carbamate (B) (wherein R = acetyl)

[0155] 100 g of tert-butyl 4-bromophenethyl(ethyl)carbamate dissolved in dry tetrahydrofuran (800 mL) and the reaction solution was cooled to -78 °C under nitrogen atmosphere. Then n-Butyllithium (190 mL,2.4 M in tetrahydrofuran) was added slowly at -78 °C. After stirring for 1-hour, Dry dimethylformamide (60 mL) was added dropwise at -78 °C and the mixture was stirred at for another 1 hour. After the reaction was completed, slowly added 100 mL of 20% ammonium chloride solution into reaction mass. To this reaction mass 1000 mL of di chloromethane was added at 25-35 °C and stirred for 10 minutes at the same temperature. Layers were separated and distilled of MDC under reduced pressure below 40 °C provided the 75 g of tittle compound. Yield: 89%; Purity: 99.5%.

[0156] Scheme-1 and 2

[0157] Example 4: Preparation of N tert-butyl ethyl(4-((2-(6-hydroxy-l,2,3,4- tetrahydronaphthalen-2-yl)-5-methoxyphenylamino) methyl) phenethyl) carbamate (formula C).

[0158] 100 g of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (formula A) was dissolved in 1000 mL of Methanol and 50 mL of Acetic acid mixture. To this 103 g of tert-butyl ethyl(4-formylphenethyl) carbamate was added under nitrogen atmosphere at 25-30°C. After stirred for 1 hour, the resulting mixture was cooled to 0- 5°C and 50g of sodium cyanoborohydride was slowly added and stirred till completion of the reaction. After completion of reaction, 200 mL water was added to the reaction mass and temperature raised to 25-30°C. The solid was extracted into Ethyl acetate and organic layer was washed with 20% aqueous NaCl solution. Ethyl acetate layer was collected and distilled to get crude product. The crude product was dissolved in 200 mL Ethyl acetate at room temperature. The temperature of the reaction mass was raised to 50-55°C and stirred, then slowly cooled to 0-5°C for 2 hours. The solid was filtered and dried get the tittle compound. Yield: 88%; Purity: 99.6%.

[0159] Example 5: Process for preparation of (R)-tert-butyl ethyl(4-((2-(6-hydroxy- l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenylamino) methyl) phenethyl) carbamate (formula D).

[0160] 100 g of N tert-butyl ethyl(4-((2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5- methoxyphenylamino) methyl) phenethyl) carbamate (formula C) dissolved in 1000 mL of Acetonitrile was added 40g (+)-DBTA at 25-30°C. The resulting mixture was heated to reflux and stirred for 30 minutes to get clear solution. Reaction mass was filtered over Hyflow to remove undissolved particles at 80-85 °C. Filtrate was collected and slowly cooled to 25-30°C over a period of 4-5 hours and stirred for till the reaction completed. Solid product was filtered and washed with Acetonitrile. Wet material was collected and added 5% aqueous sodium hydroxide solution and 1000 mL dichloromethane. The resulting mixture stirred and separated layers. Di chloromethane layer was collected and washed with 20% aqueous sodium chloride solution. Dichloromethane distilled to get crude product. The crude product was dissolved in Methanol (100 mL) heated to 55-60 °C and stirred to get clear solution. Slowly cooled the reaction mass to 0-5°C. The solid was filtered and dried get the 41g of tittle compound. Yield: 41%; Purity: 99.4%.

[0161] Example 6: Preparation of (R)-6-(2-(ethyl(4-(2-(ethylamino) ethyl) benzyl) amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (formula E)

[0162] 100 g of (R)-tert-butyl ethyl(4-((2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5- methoxyphenylamino) methyl) phenethyl) carbamate (formula D) was dissolved in 700 mL tetrahydrofuran and 100 mL of Acetic acid mixture. To the reaction solution 20 g of Acetaldehyde was added at 0-5 °C, and then 60g of sodium cyanoborohydride was added. Reaction mass was stirred for 6-7 hours at the same temperature. After completion of reaction, 300 mL water was added into the reaction mass and temperature raised to 25-30°C. solid was extracted with di chloromethane and organic layer was washed with 20% aqueous sodium chloride solution. Dichloromethane layer distilled to get crude product. To this crude product 500 mL of Isopropanol was added and temperature raised to 70-75°C and stirred till clear solution. Reaction mass slowly cooled. The solid was filtered and dried to get 83g tittle compound. Yield: 79%; Purity: 99 5%.

[0163] Example 7: Preparation of tert-butyl ethyl(4-((ethyl(2-(6-hydroxy-l,2,3,4- tetrahydronaphthalen-2-yl)-5-methoxyphenyl) amino) methyl) phenethyl) carbamate (formula F)

[0164] 100 g N tert-butyl ethyl(4-((2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5- methoxyphenylamino) methyl) phenethyl) carbamate (formula C) dissolved in 1000 mL of Acetonitrile was added 40g (+)-DBTA at 25-30°C. The resulting mixture was heated to reflux and stirred for 30 minutes to get clear solution. Reaction mass was filtered over Hyflow to remove undissolved particles at 80-85 °C. Filtrate was collected and slowly cooled to 25-30°C over a period of 4-5 hours and stirred for till the reaction completed. Solid product was filtered and washed with Acetonitrile. Wet material was collected and added 5% aqueous sodium hydroxide solution and 1000 mL dichloromethane. The resulting mixture stirred and separated layers. Di chloromethane layer was collected and washed with 20% aqueous sodium chloride solution. Dichloromethane distilled to get crude product. The crude product was dissolved in Methanol (100 mL) heated to 55-60 °C and stirred to get clear solution. Slowly cooled the reaction mass to 0-5°C. The solid was filtered and dried get the 41g of tittle compound. Yield: 45%; Purity: 99.6%.

[0165] Example 8: Preparation of (R)-6-(2-(ethyl(4-(2-(ethylamino) ethyl) benzyl) amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (formula E)

[0166] 100 g of (tert-butyl ethyl(4-((ethyl(2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)- 5-methoxyphenyl) amino) methyl) phenethyl) carbamate (formula F) was dissolved in 700 mL tetrahydrofuran and 100 mL of Acetic acid mixture. To the reaction solution 20 g of Acetaldehyde was added at 0-5°C, and then 60g of sodium cyanoborohydride was added. Reaction mass was stirred for 6-7 hours at the same temperature. After completion of reaction, 300 mL water was added into the reaction mass and temperature raised to 25-30°C. solid was extracted with di chloromethane and organic layer was washed with 20% aqueous sodium chloride solution. Dichloromethane layer distilled to get crude product. To this crude product 500 mL of Isopropanol was added and temperature raised to 70-75°C and stirred till clear solution. Reaction mass slowly cooled. The solid was filtered and dried to get 83g tittle compound. Yield: 79%; Purity: 99 5%.

[0167] Example 9: Preparation of Elacestrant dihydrochloride (1).

[0168] 100g (R)-6-(2-(ethyl(4-(2-(ethylamino) ethyl) benzyl) amino)-4-methoxyphenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol (formula E) was dissolved in 800 mL Ethanol. To this reaction solution 200 mL of 20% HC1 in Ethanol was added at 25-30°C. Reaction mixture temperature 60-65 °C and stirred for 60 minutes. Slowly cooled reaction mass to 25-30°C over a period of 2-3 hours and stirred for another 4 hours. The solid was filtered and dried to get 80g tittle compound. Yield: 78%. Purity: 99.8%.

[0169] Examples:

[0170] Example 10: Preparation of tert-butyl ethyl(4-formylphenethyl) carbamate (Formula B) tert-butyl 4-bromophenethyl(ethyl)carbamate (Formula Al) (10g) was dissolved in dry THF (70ml) under inert atmosphere at RT and then cooled to -70 to -90 °C. Added nBuLi (1.6M in Hexanes) (30ml) to reaction mixture under inert atmosphere at -70 to -90 °C. Stirred reaction mixture for 30 minutes, then added N, N-dimethyl formamide (20 ml) at -70 to -90 °C. Continued stirring for 2hrs under inert atmosphere at -70 to - 90 °C. After completion, reaction mixture was quenched with aq. Ammonium chloride solution (100ml) at below -5 °C and extracted with Ethyl acetate (2X50ml). Organic layer washed with brine and dried on sodium sulfate then evaporated under vacuum at

[0171] 40-45 °C to provide 7.2 g of tittle compound. Yield: 84.18%; Purity: 99.5%.

[0172] Example 11: Preparation of tert-butyl ethyl(4-((2-(6-hydroxy-l,2,3,4- tetrahydronaphthalen-2-yl)-5-methoxyphenylamino) methyl)phenethyl) carbamate (Formula C) (where in R= Boc) 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (Formula Cl) (10g) and tert-butyl ethyl(4-formylphenethyl)carbamate (Formula B) (15.4g) was taken in isopropanol (100 ml) at RT. After stirring 30 min at RT added formic acid (1.0 ml) to reaction mixture. Stirring continued at RT for 4 hrs. Reaction mixture cooled to 5- 10°C. Added Sodium cyanoborohydride (7.0 g) lot wise into the reaction mixture at 5- 10 °C. Reaction continued stirring for 10-12 hrs at RT. Precipitated solid was filtered and washed with isopropanol and dried under vacuum at 50-55 °C for 10-12 hrs to provide 15.0 g of tittle compound. Yield: 76%; Purity: 99.6%.

[0173] Example 12: Preparation of (S)-((R)-6-(2-((S)-N-(4-(2-(tert- butoxycarbonyl(ethyl)amino)ethyl)benzyl)-5-oxopyrrolidine-2-carboxamido)-4- methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl) 5-oxopyrrolidine-2- carboxylate (Formula El) (wherein R = Boc)

[0174] L-Pyroglutamic acid (14.6g) and HATU (57.3g) was dissolved in tetrahydrofuran (200ml) at room temperature under inert atmosphere. The reaction mixture was raised to 40 °C. Added triethyl amine (38.1g) to the reaction mixture followed by treated with tert-butyl ethyl (4-((2-(6-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl)-5- m ethoxyphenylamino) methyl) phenethyl) carbamate (Formula C) (20g) under inert atmosphere at 30-40 °C. The reaction mixture stirred. After completion of the reaction mixture was quenched with saturated aq. ammonium chloride solution (200ml) at room temperature. Reaction mixture was extracted with Ethyl acetate. Organic layer was washed with brine (100ml) and dried on sodium sulfate. Volatiles were distilled out under vacuum at below 45 °C to get mixture of diastereomers. Crude Mixture of diastereomers was then separated through column chromatography using ethyl acetate / n-hexanes followed by 2-3 crystallizations from acetate / n-hexanes to provide pure 6.5 g of tittle of compound. Yield: 24.8%; Purity: 99.5%.

[0175] Example 13: Preparation of (S)-

[0176] ((R)-6-(2-(4-(2-(tert- butoxycarbonyl (ethyl)amino) ethyl) benzylamino)-4- methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl) 5-oxopyrrolidine-2- carboxylate (Formula Hl) (wherein R = Boc). tert-butyl ethyl (4-((2-(6-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl)-5- methoxyphenylamino)methyl)phenethyl)carbamate (20g) was dissolved in dimethylformamide (60ml) at room temperature under inert atmosphere, triethylamine (19.4g) was added to the reaction mixture and the reaction mixture was cooled to 10- 15 °C. L-Pyroglutamic acid (9.73g) and HATU (57.3g) were added into the reaction mixture at 10-15 °C. Added water (100 ml) into the reaction mixture and extracted with Ethyl acetate. Organic layer was washed with brine (100ml) and dried on sodium sulfate. Volatiles were distilled out under vacuum at below 45 °C to get mixture of diastereomers. Crude Mixture of diastereomers was then separated through column chromatography using ethyl acetate / n-hexanes followed by 2-3 crystallizations from acetate / n-hexanes to give pure desired (6.5 g) of tittle of compound. Yield: 24.3%;

[0177] Purity: 99 5%.

[0178] Example 14: Preparation of (R)-tert-butyl ethyl(4-((2-(6-hydroxy-l, 2.3.4- tetrahydronaphthalen-2-yl)-5- methoxyphenylamino) methyl) phenethyl) carbamate (Formula D) (wherein R = Boc).

[0179] (S)-((R)-6-(2-((S)-N-(4-(2-(tert-butoxycarbonyl(ethyl)amino)ethyl)benzyl)-5- oxopyrrolidine-2-carboxamido)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2- yl)5-oxopyrrolidine-2-carboxylate (Formula El) (10g) was suspended in methanol: water (3:7) (100 ml) at room temperature. Added 3N sodium hydroxide solution into the reaction mixture at room temperature. Temperature of the reaction was raised to 80 °C and stirring was continued for 3-4 hrs. After completion, reaction mixture was extracted with Ethyl acetate. Ethyl acetate layer was washed with brine and dried on sodium sulfate. Solvents were distilled out under vacuum at below 45 °C to provide 8.5 g tittle compound. Yield: 80.7%; Purity: 99.5%.

[0180] Example 15: Process for preparation of (R)-tert-butyl ethyl (4-((ethyl(2-(6- hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl) amino) methyl) phenethyl) carbamate (Formula E).

[0181] (R)-tert-butyl ethyl(4-((2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxy phenylamino) methyl) phenethyl) carbamate (10g) (Formula D) was dissolved in mixture of methanol: dichloromethane (1 : 1) (100 ml) at room temperature. Added 40% aq. Acetaldehyde solution (12.4g), formic acid (1.0 ml) and sodium cyanoborohydride (7.1 g) into the reaction mixture and continued stirring for 10-12 hrs at RT. Added water (50 ml) into the reaction mixture layers separated, aq. Layer extracted with dichloromethane, combined organic layers washed with brine solution and dried over sodium sulfate. Solvents evaporated under vacuum to get tittle compound. Yield: 41%; Purity: 99.4%.

[0182] Example 16: Preparation of (R)-6-(2-(ethyl(4-(2-

[0183] (ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8 tetrahydronaphthalen-2-ol sulfate (Elacestrant Sulfate (2))

[0184] (R)-tert-butyl ethyl(4-((ethyl(2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5- methoxyphenyl) amino) methyl) phenethyl) carbamate (10g) (Formula E) was dissolved in tetrahydrofuran (100 ml) and cooled it to 10-20 °C. Added cone. Sulfuric acid (3.95g) into the reaction mixture at 10-20 °C. Temperature raised to 50-60 °C and continued stirring for 12-15 hrs. Added water (50 ml) into the reaction mixture and washed with dichloromethane. pH of Aq. Layer was adjusted to 8-9 using 10% aq. Sodium carbonate solution. Then extracted with dichloromethane, combined organic layers and washed with brine (50 ml) and dried over sodium sulfate. Solvents evaporated under vacuum at below 35 °C. Residue was dissolved in ethanol (60 ml) and ethyl acetate (180 ml) at RT then cooled it to 5-10 °C. Added Cone. Sulfuric acid (1.80 g) to the reaction mixture at 5-10 oC. Reaction was stirred at 2 hrs at 5-10 °C.

[0185] Precipitated solid was filtered and washed with methyl tert-butyl ether. Wet residue is taken in methyl tert-butyl ether (50ml) and stirred for 1-2 hr at room temperature. Solid is filtered and washed with methyl tert-butyl ether. Solid dried under vacuum at 5-55 °C to give 6.0 g Elacestrant Sulfate as white solid. Yield: 60.2%; Purity: 99.4%. The PXRD pattern of the obtained compound is shown in figure-5.

[0186] Example 17: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with (l-Vinyl-2-pyrrolidinone-polymer) (PVP).

[0187] (R)-6-(2-(ethyl(4-(2-(ethylamino) ethyl) benzyl)amino)-4-methoxyphenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol sulfate (Elacestrant sulfate) (100 g) in water, di chloromethane (300 mL) was added, and the reaction mixture was stirred at 25- 35 °C for 10-15 minutes. Sodium carbonate was then added to the reaction mixture, followed by stirring at 25-35 °C for an additional 10-15 minutes. The resulting mixture was filtered. Methanol and hydrochloric acid were then added to the filtrate and the mixture was stirred. Polyvinylpyrrolidone (PVP, l-vinyl-2-pyrrolidinone polymer) was added to the solution and stirred. Spray dried the obtained solution using spray dryer through following conditions:

[0188] Inlet Temperature : 65-70 °C Outlet Temperature : 40-45 °C

[0189] N2 : 2.5 -3.5 kg / cm2

[0190] Pressure : 30-40 RPM

[0191] RPM

[0192] Yield: 84%; The PXRD pattern of the obtained compound is shown in figure- 1 & 2.

[0193] Example 18: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with hydroxypropyl beta cyclodextrin (HPpCD).

[0194] (R)-6-(2-(ethyl(4-(2-(ethylamino) ethyl) benzyl) amino)-4-methoxyphenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol sulfate (Elacestrant sulfate) (100 g) in water, di chloromethane (300 mL) was added, and the reaction mixture was stirred at 25- 35 °C for 10-15 minutes. Sodium carbonate was then added to the reaction mixture, followed by stirring at 25-35 °C for an additional 10-15 minutes. The resulting mixture was filtered. Methanol and hydrochloric acid were then added to the filtrate and the mixture was stirred. Hydroxypropyl beta cyclodextrin (HPpCD) was added to the solution and stirred. Spray dried the obtained solution using spray dryer through following conditions:

[0195] Inlet Temperature : 65-70 °C

[0196] Outlet Temperature : 40-45 °C

[0197] N2 : 2.5 -3.5 kg / cm

[0198] Pressure : 30-40 RPM

[0199] RPM

[0200] Yield: 82%; The PXRD pattern of the obtained compound is shown in figure-3.

[0201] Example 19: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Copovidone.

[0202] (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol sulfate (Elacestrant sulfate) (100 g) in water, di chloromethane (300 mL) was added, and the reaction mixture was stirred at 25- 35 °C for 10-15 minutes. Sodium carbonate was then added to the reaction mixture, followed by stirring at 25-35 °C for an additional 10-15 minutes. The resulting mixture was filtered. Methanol and hydrochloric acid were then added to the filtrate and the mixture was stirred. Copovidone was added to the solution and stirred. Spray dried the obtained solution using spray dryer through following conditions: Inlet Temperature : 65-70 °C

[0203] Outlet Temperature : 40-45 °C

[0204] N2 : 2.5 -3.5 kg / cm2

[0205] Pressure : 30-40 RPM

[0206] RPM

[0207] Yield: 83%; The PXRD pattern of the obtained compound is shown in figure-4.

[0208] Example 19: Preparation of compound of formula (iii) compound of Formula (i) with and compound of Formula (ii) was added Bis(pinacolato)diboron (B2pin2) added in dimethyl ether and Potassium acetate (KOAc), catalyst Bis(triphenylphosphine)palladium(II) dichloride. The reaction mixture was stirred at a temperature, after completion, and added ethyl acetate, acetonitrile and potassium bicarbonate and dry the material to get the tittle compound. Yield: 91%; Purity: 99.5%.

[0209] Example 20: Preparation of compound of formula (A) compound of Formula (iii) (700 Ml) of tetrahydrofuran and methanol at tempareture 25-35°C and was added Raney nickel, rais the reaction mass temperature raised to 45- 55°C and filter the reaction mass on 20g Hyflo bed and washed with tetrahydrofuran and methanol mixture and filtered MLs distilled under vacuum at below 50°C and to crud charge 140 mL of acetonitrile, cool the reaction mass to 10-20°C and added IPA.HC1 at 10-20°C at the reaction mass temperature to 55-65°C , filter the solid and wash with Isopropanol (50 mL), and added ethyl acetate and methanol at the reaction mass temperature raised to 55-66 C, After completion of reaction, the reaction mass cooled to 25-35 °C and stir 1-2 hrs at 25-35°C, filter the solid and wash with ethyl acetate (50 mL) dry the solid under vacuum at 45-55°C, and charge the methanol and water at cool the reaction mass to 10-20°C, was added reaction mass pH adjusted to 7.5-8.0 with 150 mL of potassium bicarbonate and its dissolved in water, raise the reaction mass temperature to 25-35°C, the reaction mass 2-4 hrs at 25-35°C, and filter the solid and wash with water, and dry the material at 45 -55 °C for 12-14 hr to get the tittle compound.

[0210] Yield: 60-75%; Purity: 99.5%.

Claims

We claim:

1. A process for the preparation of Elacestrant dihydrochloride (1).which comprises: a) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (A)with compound of formula (B)Formula B in presence of suitable solvent, reducing agent and acid to provide compound of formula (C)b) resolving the compound of formula (C) with chiral resolving agent in presence of suitable solvent to provide compound of formula (D)c) reacting of the compound of formula (D) with acetaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula (E)wherein; d) converting compound of formula (E) with Hydrochloric acid in presence of suitable solvent to provide Elacestrant dihydrochloride (1).Wherein R is Hydrogen or amine protecting group.

2. A process for the preparation of Elacestrant dihydrochloride (1), which comprises:a) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (A)with compound of formula (B)Formula B in presence of suitable solvent, reducing agent and acid to provide compound of formula (C);b) resolving the compound of formula (C) with acetaldehyde in presence of suitable reducing agent, solvent and acid to provide compound of formula (F);c) reacting of the compound of formula (F) with chiral resolving agent in presence of suitable solvent to provide compound of formula (E)wherein; d) converting compound of formula (E) with Hydrochloric acid in presence of suitable solvent to provide Elacestrant dihydrochloride (1). Wherein R is Hydrogen or amine protecting group.

3. A process for the preparation of pure Elacestrant dihydrochloride having purity greater than 99% which comprises; i. dissolving a solution of crude Elacestrant dihydrochloride (1) in one or more solvents ii. isolating pure compound of Elacestrant dihydrochloride.

4. The process as claimed in claim 1, 2 and 3, wherein Elacestrant dihydrochloride (1) is having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.98% by HPLC.

5. A process for the preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient, which comprises:a) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol formula (Al)Formula Al in the presence of base and solvent to provide compound of formula (B);b) reacting the compound of formula (B) with compound of formula (Cl)in the presence of reducing agent and suitable solvent to provide compound offormula (C):c) reacting of the compound of formula (C) with chiral resolving agent in presence of base, solvent, and acid to provide compound of formula (El):d) reacting compound of formula (El) in the presence of base and solvent to provide formula (D):e) reacting compound of formula (D) with acetaldehyde in presence of reducing agent in a solvent and acid to provide formula (E):f) reacting compound of formula (E) with sulfuric acid in presence of suitable solvent to provide crystalline form Elacestrant Sulfate (2):Elacestrant Sulfate (2) g) adding hydrochloric acid and least one pharmaceutically acceptable excipient in a base and solvent to the mixture of step F): h) isolating the amorphous solid dispersion of Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient.Wherein R is Hydrogen or amine protecting group.

6. The process as claimed in claim 5, pharmaceutically acceptable excipient is selected from pharmaceutically acceptable excipient is selected from but not limited to polyvinylpyrrolidone, (povidone or PVP; PVP of different grades like K-IS, K- 30, K-60, K-90 and K-120 may be used), polyvinylpolypyrrolidone, crospovidone, copovidone, Eudragit, Soluplus, polyethylene glycol (macrogol or PEG), polyethylene glycol-6000 (PEG-6000), hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), sulfo butyl ether-P-cyclodextrin (SBECD), hydroxypropyl beta cyclodextrin (HPpCD), salcaprozate sodium, sodium caprylate, and the like7. The process as claimed in claim 5, removal of solvent by suitable techniques which includes but not limited to evaporation under reduced pressure, flash evaporation, rotary evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction mixture or by any other suitable techniquesknown in the art.

8. The process as claimed in claim 5, wherein pure Elacestrant dihydrochloride (1) and its amorphous solid dispersion with pharmaceutically suitable excipient having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably 99.9% by HPLC.

9. A process for the preparation of pure Elacestrant sulfate having purity greater than 99% which comprises; i. dissolving a solution of crude Elacestrant sulfate (2) in one or more solvents ii. isolating pure compound of Elacestrant sulfate(2).

10. A process for the preparation of compound of formula (Hl), comprising the steps of: i. reacting of the compound of formula (C)with chiral resolving agent in presence of base in solvent and acid to provide compound of formula11. The process as claimed in claim 5 and 8, wherein the suitable base is selected from as triethylamine, methylamine, ethylamine, 1,8- diazabicycle [5.4.0] undec7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium diisopropyl amine (LDA), n-butyllithium, tribenzylamine, isopropyl amine, diisopropylamine (DIP A), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethyl morpholine, piperidine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole and 1,4- diazabicyclo[2.2.2]octane (DABCO); limited to lithium hydroxide, sodium hydroxide, potassium hydroxide;sodium carbonate, potassium carbonate, lithium carbonate.

12. The process as claimed in claim 5 and 8, wherein the coupling agent is selected from but not limited Hexafluorophosphate Azabenzotri azole Tetramethyl Uronium (HATU), O-Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate(HBTU), O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(6-Chlorobenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HCTU), benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP).

13. The process as claimed in any of the proceeding claims, wherein the reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium, sodium cyanoborohydride, sodium borohydride, lithium aluminium hydride, sodium hydride, DIBAL-H, Red-Al.

14. The process as claimed in any of the proceeding claims, wherein the suitable solvent is selected from but not limited to methanol, ethanol, isopropyl alcohol, n- propanol, butanol, step b) S-2 c) “nitrile solvents” acetonitrile, “ketone solvents” acetone, methyl isobutyl ketone, methyl ethyl ketone, step c) S-2 b) S-4 Step a) “ether solvents” tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; S-4 step c) S-5 i) “polar aprotic solvents” dimethylformamide, dimethylacetamide, dimethylsulfoxide; dichloromethane.

15. The process as claimed in any of the proceeding claims, wherein the suitable acid selected from but not limited to formic acid, acetic acid, trifluoroacetic acid.

16. The process as claimed in any of the proceeding claims, chiral resolving agent selected from L-Proline, L-Phenylalanine, L- Pyroglutamic Acid, L-Glutamic Acid, (+)-2,3-dibenzoyl-D-tartaric acid, Aspartic acid, O-Acetyl-Mandelic acid, cis-2- Benzamidocyclohexanecarboxylic acid, l,l '-Binapthyl-2,2'-diyl hydrogen phosphate, Camphoric acid, 10-Camphorsulfonic acid.

17. A Compound of Formula C, Formula El, Formula Hl, Formula D, Elacestrant sulfate (2).Wherein R is Hydrogen or amine protecting group.

18. The process as claimed in claim 15, wherein a process for the preparation of intermediates of formula (El), formula (D), formula (Hl), Elacestrant sulfate (2), with chiral purity greater than 90% and enantiomeric excess greater than 50%.

19. The process claimed in any of the preceding claims amino protecting group is selected from the group n-Acetyl, tert-butoxy carbonyl (BOC), benzyloxycarbonyl(CBz), triflouoroacetyl (TFA), benzyl (Bn), dibenzyl, phthalimido, tosyl (Ts), Di-tert-butyl dicarbonate(BOC anhydrate), p- methoxybenzyl carbonyl, 9-fluorenylmethyloxy carbonyl (FMOC), carbamate, pmethoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p- methoxyphenyl (PMP) and benzoyl (Bz).

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