DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“NOVEL PROCESS FOR THE PREPARATION OF ELACESTRANT AND ITS INTERMEDIATES THEREOF”

GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block, Madhapur, Hyderabad,
Telangana, INDIA - 500 081

The following specification particularly describes the invention and the manner in which it is to be performed.
NOVEL PROCESS FOR THE PREPARATION OF ELACESTRANT AND ITS INTERMEDIATES THEREOF

FIELD OF INVENTION:
The present invention provides a novel process for the preparation of elacestrant and its intermediates thereof.

BACKGROUND OF THE INVENTION:
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 Ia.

Formula Ia

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:

The said process involves optical resolution of compound of formula (10) is performed by using chiral HPLC, which is expensive, time consuming and not suitable for large scale synthesis.

U.S. publication no. 2022/0162233 discloses a process for the preparation of elacestrant, which is schematically depicted in the following scheme:

The said process involves resolution of advanced intermediate compound of formula (d) using chiral resolving agent such as (+)-DBTA, which may lead to the loss of more than 50% of unwanted enantiomer and provides the wanted enantiomer, which represents a severe disadvantage of the above process with respect to cost effectiveness.

However, there is always a need for an alternative process, which involves use of reagents/solvents that are less expensive and easier to handle, environmental friendly, consume smaller amounts of solvents, and provide a higher yield of product with higher purity.

An enantio-selective processes, yielding a greater percentage of the desired product. The inventors have now discovered an efficient enantio-selective process for the preparation of elacestrant of formula I or salt thereof.

Hence, the main objective of the present invention is to provide a cost effective and commercially viable process for the preparation of elacestrant of formula I or salt thereof. Therefore, the present invented process is suitable for large scale operations and thereby commercially viable.

OBJECTIVES OF THE INVENTION:
The main objective of the present invention is to provides a novel process for the preparation of elacestrant of formula I or a salt thereof.

In another objective of the present invention is to provides a novel intermediate compounds and process for the preparation thereof.

In another objective of the present invention is to provides use of novel intermediate compounds in the preparation of elacestrant of formula I or a salt thereof.

SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a novel process for the preparation of elacestrant of formula I or a salt thereof, which comprises:
a) reacting compound of formula II with Wittig reagent in a suitable solvent in presence or absence of a base to provide a compound of formula III; wherein Pg is a protecting group; R is an alkyl group;

b) hydrolyzing the compound of formula III with a base in presence of a suitable solvent to provide a compound of formula IV;

c) converting the compound of formula IV into a compound of formula V;

d) condensing the compound of formula V with a compound of formula VI in presence of rhodium metal precursor and a chiral ligand, followed by treating with base and a suitable solvent to provide a compound of formula VII; wherein X is metal residue, halo group or pseudo halo group;

e) hydrogenating the compound of formula VII with a suitable hydrogenating agent in presence of a suitable solvent to provide a compound of formula VIII;

f) reacting the compound of formula VIII with a compound of formula IX in presence of a suitable reducing agent and a suitable solvent to provide a compound of formula X; and

g) deprotecting the compound of formula X with a suitable deprotecting agent in presence of a suitable solvent to provide a elacestrant of formula I or salt thereof.

In another aspect of the present invention provides a novel process for the preparation of elacestrant of formula I or salt thereof, which comprises:
a) protecting compound of formula XI with a suitable protecting agent in presence of a base and a suitable solvent to provide a compound of formula XII; wherein Pg is a protecting group; X is metal residue, halo group or pseudohalo group;

b) reacting the compound of formula XII with organolithium base in presence of a suitable solvent to provide a compound of formula IX; and

c) converting the compound of formula IX into elacestrant of formula I or salt thereof.

In another aspect of the present invention provides a novel process for the preparation of elacestrant of formula I or salt thereof, which comprises:
a) condensing the compound of formula III with a compound of formula VI in presence of rhodium metal precursor and a chiral ligand, followed by treating with a base and a suitable solvent to provide a compound of formula XVIII; wherein Pg is a protecting group; X is metal residue, halo group or pseudohalo group; R is an alkyl group;

b) hydrolyzing the compound of formula XVIII with a base in the presence of a suitable solvent to provide a compound of formula XVII;

c) cyclizing the compound of formula XVII into a compound of formula VII; and

d) converting the compound of formula VII into elacestrant of formula I or salt thereof.

In another aspect of the present invention provides novel intermediate compounds of formula:

wherein Pg is a protecting group; X is metal residue, halo group or pseudo halo group; R is an alkyl group.

In another aspect of the present invention is to provides use of novel intermediate compounds of formulae IV, VII, IX, IXa, XII, XIIa, XVII, XVIII and X, in the preparation of elacestrant of formula I or a salt thereof.

DETAILED DESCRIPTION:
The main embodiment of the present invention provides a novel process for the preparation of elacestrant of formula I and its intermediates thereof.

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, iso-propanol, n-butanol, iso-butanol and the like; ester is selected from the group consisting of ethyl acetate, isopropyl acetate; ketone is selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone; ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether, tetrahydrofuran (THF), 2-methyl tetrahydrofuran, cyclopentyl methyl ether, dioxane and the like; halogenated solvent is selected from the group consisting of dichloromethane (DCM), chloroform, chlorobenzene, bromobenzene and the like; hydrocarbons is selected from the group consisting of toluene, xylene, cyclohexane and the like; nitrile is selected from the group consisting of acetonitrile, 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; or mixtures thereof.

The term “base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide (LiOH), sodium hydroxide, potassium hydroxide (KOH) 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 tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like, ammonia and organic bases such as triethylamine, methylamine, ethylamine, 1,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl amino pyridine (DMAP), morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, 1,4-diazabicyclo [2.2.2]octane (DABCO) or mixtures thereof.

The term “acid” used in the present invention is selected from the group comprising of inorganic acid and organic acid; inorganic acid is selected from such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid; organic acids such as acetic acid, maleic acid, malic acid, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; chiral acids such as S-(+)mandelic acid, R-(-)mandelic acid, L(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (1R)-(-)-camphor sulfonic acid, (1S)-(+)-camphor sulfonic acid, (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromocamphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid (L-DBTA), (-)-Dibenzoyl-L-tartaricacid monohydrate, (+) -Dibenzoyl-D-tartaric acid (D-DBTA), (+)-Dibenzoyl-D-tartaric acid monohydrate, (+)-dipara-tolyl-D-tartaric acid (D-DTTA), (-)-dipara-tolyl-L-tartaricacid (L-DTTA), L(-)-pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid; or chiral amino acid selected from but not limited to D-isomers and L-isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, ornithine, 4-aminobutyric acid, 2-amino isobutyric acid, 3-amino propionic acid, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, N-acetyl-leucine and the like.

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; chiral acids such as S-(+)mandelic acid, R-(-)mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (1R)-(-)-camphor sulfonic acid, (1S)-(+)-camphor sulfonic acid (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromocamphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaricacid monohydrate, (+)-Dibenzoyl-D-tartaric acid, (+)-Dibenzoyl-D-tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-dipara-tolyl-L-tartaricacid, L(-)-pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid; or chiral amino acid and the like.
The term “Wittig reagent” is selected from but not limited to triethyl phosphonoacetate, trimethyl phosphonoacetate, triphenyl phosphonoacetate, ethyl (triphenylphosphoranylidene)acetate, methyl (triphenylphosphoranylidene) acetate, triphenyl[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin -5-ylmethyl]-phosphonium halide, methoxymethyltriphenylphosphonium chloride, methyl triphenylphosphonium halide, ethyltriphenylphosphonium halide and 4-pentenyltriphenylphosphonium halide and the like.

The term “suitable reducing agent” is selected from but not limited to Metal hydride including LiAlH4, NaAlH4, NaBH4, KBH4, mixture of NaBH4 & acetic acid, mixture of NaBH4 & trifluoroacetic acid, mixture of NaBH4 & iodine, mixture of NaBH4 & trimethylchlorosilane, mixture of NaBH4 & magnesium chloride, mixture of NaBH4 & calcium chloride, mixture of NaBH4 & one of transition metal chlorides, mixture of sodium borohydride BF3.etherate, sodium cyanoborohydride, sodium triacetoxy borohydride, Aluminium hydride (AlH3), diisobutylaluminium hydride (DIBAL), Vitride {=Sodium bis(2-methoxyethoxy) aluminum hydride}, Lithium Tri-tert-butoxyaluminum Hydride, Tributyltin Hydride; boranes such as but not limited to BH3-tetrahydrofuran, BH3-dimethyl sulfide; hydrazine; metal including but not limited to Na, Fe, Ni, Zn, Sn in presence of acidic medium; Na-liquid ammonia; Silanes including but not limited to tri(C1-C6)alkylsilanes, tri(C1-C6)alkylsilyl halides; and the like.

The term “hydrogenating agent” is selected from but not limited to Ni, Pd, Pt, Rh, Re, Ru and Ir, including their oxides, hydroxides, acetates and combinations thereof, Raney nickel, palladium catalyst such as Pd/C, Pd(OH)2/C, palladium acetate, Pd/SrCO3, Pd/Al2O3, Pd/MgO, Pd/CaCO3, Pd/ BaSO4, PdO, PdCl2, Rh/C, Ru/C, Re/C, Pt/C, platinum oxide, platinum black, PtO2, Rh/C, RuO2 and the like.

The term “suitable halogenating agent” is selected from but not limited to bromine, phenyltrimethylammonium tribromide, N-bromosuccinimide, tribromophosphine, hydroperbromic acid, borontribromide, 1,3-Dibromo-5,5-dimethylhydantoin, phosphorous oxy chloride, phosphorus trichloride, phosphorus pentachloride, phosphorous tribromide, phosphorus pentabromide, phosphorus triiodide, oxalyl chloride, thionyl chloride, thionyl bromide, HBr, TMSCl, TMSBr and, Hydrogen halide, mesyl halide, tosyl halide, nosyl halide and triflyl chloride halide and the like.

The term “Lewis acids” such as lithium chloride, lithium bromide, lithium iodide, AlCl3, AlBr3, BBr3, 1-dodecanethiol, methanesulfonic acid, pyridine hydrochloride, HBr optionally in combination with carboxylic acid such as formic acid, acetic acid and the like.

The term “metal residue” is selected from but not limited to MgCl, MgBr, B(OH)2, B(OCMe2CMe2O), BF3K, ZnCl, ZnBr, or ZnI, and suited halo or pseudohalo is selected from Cl, Br, I, F3CSO3, p-TolSO3, and MeSO3 and the like.

The term “rhodium metal precursor” is selected from but not limited to [Rh(monoolefin)2Cl]2, [Rh(diolefin)Cl]2, [Rh(monoolefin)2acetylacetonate], [Rh(diolefin)acetylacetonate], [Rh(monoolefin)4]X, or [Rh(diolefin)2]X wherein X is a non-coordinating anion selected from the group consisting of methanesulfonate, trifluoromethanesulfonate (Tf), tetrafluoroborate (BF4), hexafluorophosphate (PF6), or hexafluoroantimonate (SbF6). In one embodiment the rhodium metal precursor is [Rh(cod)Cl]2, [Rh(norbornadiene)Cl]2, [Rh(cod)2]X, or [Rh(norbornadiene)2]X and the like.

The term “suitable protecting group (Pg)” is selected from but not limited to 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.

The term “suitable 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 Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb) in presence of hydrogen source and the like.

The term "organolithium base" is selected from but not limited to methyl lithium, n-butyl lithium (n-BuLi), lithium diisopropylamide (LDA) and the like;

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, tricyclohexylphosphite, 2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (BINAP), l,2-bis(dimethylphosphino)ethane, l,2-bis(diethylphosphino)ethane, 1,2-bis(dipropylphosphino)ethane, 1,2-bis(diisopropylphosphino)ethane, l,2-bis(dibutylphosphino)ethane, l,2-bis(dicyclohexylphosphino)ethane, 1,3-bis(dicyclohexylphosphino)propane, 1,3-bis(diiso-propylphosphino)propane, 1,4-bis(diisopropylphosphino)-butane, 2,4-bis(dicyclohexylphosphino)pentane, 2-Dicyclohexylphosphino-2,6'-dimethoxybiphenyl, and 2-dicyclohexylphosphino-2', 4',6'-triisopropylbiphenyl, methyl 3a-Acetyloxy-12a-(biphenyl-2,2-diyl)phosphite-5ß-cholan-24-oate and like.

In one embodiment of the present invention provides a novel process for the preparation of elacestrant of formula I or a salt thereof, which comprises:
a) reacting compound of formula II with Wittig reagent in a suitable solvent in presence or absence of a base to provide a compound of formula III; wherein Pg is a protecting group; R is an alkyl group;

b) hydrolyzing the compound of formula III with a base in presence of a suitable solvent to provide a compound of formula IV;

c) converting the compound of formula IV into a compound of formula V;

d) condensing the compound of formula V with a compound of formula VI in presence of rhodium metal precursor and a chiral ligand, followed by treating with base in a suitable solvent to provide a compound of formula VII; wherein X is metal residue, halo group or pseudohalo group;

e) hydrogenating the compound of formula VII with a suitable hydrogenating agent in presence of a suitable solvent to provide a compound of formula VIII;

f) reacting the compound of formula VIII with a compound of formula IX in presence of a suitable reducing agent and a suitable solvent to provide a compound of formula X; and

g) deprotecting the compound of formula X with a suitable deprotecting agent in presence of a suitable solvent to provide elacestrant of formula I or salt thereof.

The starting compound of formula II can be prepared according to the methods known in the art and it is also commercially available.

In an embodiment, the step a) process involves reacting the compound of formula II; wherein Pg is a protecting group as defined above; preferably benzyl; with Wittig reagent in a suitable solvent in presence or absence of a base under appropriate reaction conditions to provide a compound of formula III; wherein R is an alkyl group is selected from but not limited to C1-6 alkyl such as methyl, ethyl, propyl and butyl; preferably ethyl; wherein the wittig reagent, suitable solvent and base are as defined above; preferably the wittig reagent is selected from but not limited to ethyl (diethoxyphosphoryl)acetate or (triphenylphosphoranylidene)acetic acid ethyl ester; the base is selected from but not limited to sodium hydride; and the suitable solvent is selected from but not limited to tetrahydrofuran and toluene.

In an embodiment, the step b) process involves hydrolyzing the compound of formula III with a base in presence of a suitable solvent under appropriate reaction conditions to provide a compound of formula IV; wherein the suitable solvent and base are as defined above; preferably the suitable solvent is selected from but not limited to tetrahydrofuran and water; and the base is selected from but not limited to lithium hydroxide.

In an embodiment, the step c) process involves converting the compound of formula IV into a compound of formula V can be carried out by reacting compound of formula IV with halogenating agent in presence of a suitable solvent followed by treating with Lewis acid under appropriate reaction conditions to provide a compound of formula V; wherein the halogenating agent, suitable solvent and Lewis acid are as defined above; preferably the halogenating agent is selected from but not limited to oxalyl choride; the Lewis acid is selected from but not limited to AlCl3; and the suitable solvent is selected from but not limited to dichloromethane and dimethylformamide.

In an embodiment, the step d) process involves condensing the compound of formula V; wherein X is metal residue, halo group or pseudohalo group; preferably metal residue is selected from but not limited to B(OH)2; in presence of rhodium metal precursor and a chiral ligand, followed by treating with base in a suitable solvent under appropriate reaction conditions to provide a compound of formula VII; wherein the rhodium metal precursor, chiral ligand, base and suitable solvent are as defined above; preferably the rhodium metal precursor is selected from but not limited to [RhCl(C2H4)2]2; the chiral ligand is selected from but not limited to methyl 3a-acetyloxy-12a-(biphenyl-2,2-diyl)phosphite-5ß-cholan-24-oate; the base is selected from but not limited to potassium hydroxide; and the suitable solvent selected from but not limited to water.

In an embodiment, the step e) process involves hydrogenating the compound of formula VII with a suitable hydrogenating agent in presence of a suitable solvent under appropriate reaction conditions to provide a compound of formula VIII; wherein the hydrogenating agent and solvent are as defined above; preferably the hydrogenating agent is selected from but not limited to Pd(OH)2/C; and the suitable solvent is selected from but not limited to methanol and tetrahydrofuran.

In an embodiment, the step f) process involves reacting the compound of formula VIII with a compound of formula IX in presence of a suitable reducing agent and a suitable solvent under appropriate reaction conditions to provide a compound of formula X; wherein the reducing agent and solvent are as defined above; preferably the reducing agent is selected from but not limited to NaBH(OAc)3; and the suitable solvent is selected from but not limited to tetrahydrofuran and n-heptane.

In an embodiment, the step g) process involves deprotecting the compound of formula X with a suitable deprotecting agent in presence of a suitable solvent under appropriate reaction conditions to provide elacestrant of formula I or salt thereof; wherein deprotecting agent and suitable solvent are as defined above; preferably the deprotecting agent is selected from but not limited to HCl; and the suitable solvent is selected from but not limited to ethanol and ethyl acetate.

In an embodiment, the steps a) to g) of aforementioned process can be carried out at a suitable temperature of about -50°C to about 150°C for a sufficient period of time till completion of the reaction; preferably of about 0°C to about 60°C.

In another embodiment of the present invention provides a novel process for the preparation of elacestrant of formula I or salt thereof, which comprises:
a) protecting compound of formula XI with a suitable protecting agent in presence of a base and a suitable solvent to provide a compound of formula XII; wherein Pg is a protecting group; X is metal residue, halo group or pseudohalo group;

b) reacting the compound of formula XII with organolithium base in presence of a suitable solvent to provide a compound of formula IX; and

c) converting the compound of formula IX into elacestrant of formula I or salt thereof.

The starting compound of formula XI can be prepared according to the methods known in the art and it is also commercially available.

In an embodiment, the step a) process involves protecting compound of formula XI; wherein X is metal residue, halo group or pseudohalo group; preferably X is a halo group; with a suitable protecting agent in presence of a base and a suitable solvent under appropriate reaction conditions to provide a compound of formula XII; wherein the protecting agent, base and suitable solvent are as defined above; preferably the protecting agent is selected from but not limited to (Boc)2O; the base is selected from but not limited to sodium hydroxide; and the suitable solvent is selected from but not limited to dichloromethane.

In an embodiment, the step b) process involves reacting the compound of formula XII with organolithium base in presence of a suitable solvent under appropriate reaction conditions to provide a compound of formula IX; wherein the organolithium base and suitable solvent are as defined above; preferably the organolithium base is selected from but not limited to n-BuLi; and the suitable solvent is selected from but not limited to tetrahydrofuran and dimethylformamide.

In an embodiment, the step c) process involves converting the compound of formula IX into elacestrant of formula I or salt thereof can be carried out by the process described in the steps f) and g) of first embodiment of the present invention.

In another embodiment, the steps a) to c) of aforementioned process can be carried out at a suitable temperature of about -50°C to about 150°C for a sufficient period of time till completion of the reaction; preferably of about -60°C to about 60°C.

In another embodiment of the present invention provides a novel process for the preparation of elacestrant of formula I or salt thereof, which comprises:
a) condensing the compound of formula III with compound of formula VI in presence of rhodium metal precursor and chiral ligand, followed by treating with base and a suitable solvent to provide a compound of formula XVIII; wherein Pg is a protecting group; X is metal residue, halo group or pseudohalo group; R is an alkyl group;

b) hydrolyzing the compound of formula XVIII with a base in the presence of a suitable solvent to provide a compound of formula XVII;

c) cyclizing the compound of formula XVII into a compound of formula VII; and

d) converting the compound of formula VII into elacestrant of formula I or salt thereof.

The starting compound of formula III & VI can be prepared according to the methods known in the art and it is also commercially available.

In an embodiment, the step a) process involves condensing the compound of formula III, wherein R is an alkyl group is selected from but not limited to C1-6 alkyl such as methyl, ethyl, propyl and butyl and the like; preferably ethyl; and Pg is a protecting group as defined above; preferably benzyl; with a compound of formula VI; wherein X is metal residue, halo group or pseudohalo group; preferably metal residue is selected from but not limited to B(OH)2; in presence of rhodium metal precursor and chiral ligand, followed by treating with base and a suitable solvent under appropriate reaction conditions to provide a compound of formula XVIII; wherein rhodium metal precursor, chiral ligand, base and a suitable solvent are as defined above; preferably rhodium metal precursor is selected from but not limited to [RhCl(C2H4)2]2; the chiral ligand is selected from but not limited to methyl 3a-acetyloxy-12a-(biphenyl-2,2-diyl)phosphite-5ß-cholan-24-oate; the base is selected from but not limited to potassium hydroxide; and the suitable solvent is selected from but not limited to 1,4-dioxane.

In an embodiment, the step b) process involves hydrolyzing the compound of formula XVIII with a base in the presence of a suitable solvent under appropriate reaction conditions to provide a compound of formula XVII; wherein the base and suitable solvent are as defined above; preferably the base is selected from but not limited to lithium hydroxide; and the suitable solvent is selected from but not limited to tetrahydrofuran and water.

In an embodiment, the step c) process involves cyclizing the compound of formula XVII with halogenating agent in a suitable solvent, followed by treating with a Lewis acid under appropriate reaction conditions to provide a compound of formula VII; wherein halogenating agent, suitable solvent and Lewis acid are as defined above; preferably the halogenating agent is selected from but not limited to oxalyl choride; the Lewis acid is selected from but not limited to AlCl3; and the suitable solvent selected from but not limited to dichloromethane and dimethylformamide.

In an embodiment, the step d) process involves converting the compound of formula VII into elacestrant of formula I or salt thereof can be carried out by the process described in the steps e) to g) of first embodiment of the present invention.

In an embodiment, the steps a) to d) of aforementioned process can be carried out at a suitable temperature of about -50°C to about 150°C for a sufficient period of time till completion of the reaction; preferably of about 0°C to about 60°C.

In another embodiment of the present invention provides novel intermediate compounds of formula:

wherein Pg is a protecting group; X is metal residue, halo group or pseudohalo group; R is an alkyl group.

In another embodiment of the present invention is to provides use of novel intermediate compounds of formulae IV, VII, IX, IXa, XII, XIIa, XVII, XVIII and X, in the preparation of elacestrant of formula I or a salt thereof.

In another embodiment of the present invention provides a process for the preparation of elacestrant or its salts, 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 or mixture thereof.

EXAMPLES:
The process details of the invention are provided in the examples given below, which
are provided by way of illustration only and therefore should not be construed to limit
the scope of the invention.

Example-1: Preparation of ethyl (E)-4-(4-(benzyloxy)phenyl)but-2-enoate:
To a stirred solution of ethyl (diethoxyphosphoryl)acetate (1.5 eq.) in THF (5 vol.) was cooled to 0 to 5oC under nitrogen atmosphere and 60% NaH (1.5 eq.) was added portion wise. After addition the reaction mass was stirred at same temperature for 1 to 2h and added 2-(4-(benzyloxy)phenyl)acetaldehyde (100 g; 1 eq.) in THF (2 vol.) solution at 0 to 5oC. Then slowly warmed the reaction mass to 20 to 30oC and stirred for 40 to 48h at same temperature. After completion of the reaction, the reaction mass was cooled to 0 to 5oC and slowly quenched with saturated NH4Cl solution (5 vol.) at same temperature. The layers were separated and extracted with EtOAc (2 x 5 vol.). The combined organic layer was dried and evaporated under reduced pressure to obtain crude and purified by column chromatography to obtained the title compound.

Alternative preparation:
To a clean and dry RBF (Round-bottom flask), (triphenylphosphoranylidene)acetic acid ethyl ester (1.2 eq.) was added to a solution of 2-(4-(benzyloxy)phenyl)acetaldehyde (1 eq.) in toluene (50 mL) and the reaction mass was stirred at reflux for 3 hours. After completion of the reaction, the solvent was distilled off to obtain a crude followed by purification in appropriate solvents like EtOAc, Hexane to obtained the title compound.

Example-2: Preparation of (E)-4-(4-(benzyloxy)phenyl)but-2-enoic acid:
To a stirred solution of (E)-4-(4-(benzyloxy)phenyl)but-2-enoate (80 g; 1 eq.) in THF (5 vol.) and water (5 vol.) solution and LiOH.H2O (4 eq.) was added lot wise at 0 to 5oC. Then slowly warmed the reaction mass to RT and maintained for 6 to 8 h. After completion of the reaction, the reaction mass was cooled to 0 to 5oC and neutralized with 1N aq.HCl solution to obtained the title compound.

Example-3: Preparation of 7-(benzyloxy)naphthalen-1(4H)-one:
To a clean and dry RBF (Round-bottom flask), (E)-4-(4-(benzyloxy)phenyl)but-2-enoic acid (60 g; 1 eq.) in dry CH2Cl2 (5 vol.) and oxalyl choride (4 eq.) were added at RT, the reaction mass was cooled to 0 to 10oC and two drops of dry DMF was added at same temperature. Then slowly warmed the reaction mixture to RT and stirred overnight at RT. After completion of the reaction, distilled off the solvent and excess amount of oxalyl choride at below 50oC under vacuum to obtain acid chloride. The residue was dissolved with dry DCM (5 vol.) and lot wise addition of AlCl3 (2.1 eq.) at 0 to 10oC under nitrogen atmosphere. Then slowly warmed the reaction mixture to RT and stirred at same temperature for 14 to 18 h. After completion of the reaction, slowly transferred the reaction mass to ice water solution (10 vol.). The layers were separated and extracted with DCM (2 x 5 vol.). The combined organic layer was washed with brine solution (3 vol.) and distilled off the solvent under vacuum at below 40oC to obtain a crude and purified by column chromatography to obtained the title compound.

Example-4: Preparation of (S)-7-(benzyloxy)-3-(4-methoxy-2-nitrophenyl)-3,4-dihydronaphthalen-1(2H)-one:
To a stirred solution of [RhCl(C2H4)2]2 (0.015 eq.) in 1,4-dioxane (3 vol.) was added to Methyl 3a-acetyloxy-12a-(biphenyl-2,2-diyl)phosphite-5ß-cholan-24-oate (0.06 eq.) at RT and stirred at same temperature for 3 to 4 h. Water (10 ml) and 1M aq. KOH (50 ml) solution were added at RT followed by addition of 4-methoxy-2-nitrophenylboronic acid (2 eq.) and 7-(benzyloxy)naphthalen-1(4H)-one (25 g; 1 eq.) at RT under nitrogen atmosphere and stirred the reaction mixture for 10 to 14 h at same temperature. After completion of the reaction, the reaction mixture was poured into 1M aq. NaHCO3 solution and extracted with diethyl ether (3 x 5 vol.). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to obtain crude product. The crude product was purified by column chromatography to obtained the title compound.

Example-5: Preparation of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol:
To a clean and dry RBF (Round-bottom flask), (S)-7-(benzyloxy)-3-(4-methoxy-2-nitrophenyl)-3,4-dihydronaphthalen-1(2H)-one (30 g; 1 eq.) in Methanol (7 vol.), THF (7 vol.) and 5% Pd(OH)2/C (3 g) were added at RT under nitrogen atmosphere. The reaction mixture was agitated under 100 psi hydrogen pressure for 12 to 16 h at 20 to 25oC. After completion of the reaction, hydrogen gas was removed and purge the reaction mass with nitrogen gas for 20 to 30 min., then filtered the reaction mass on Hyflo bed and wash with THF (1.5 vol.) and Methanol (1.5 vol.). The filtrate was distilled off under vacuum at below 45oC. Then strip of solid residue with EtOAc (3 x 2 vol.). EtOAc (5 vol.) was added to residue at RT and heated the reaction mass to 40 to 50oC and stirred for 1 h. The reaction mass was cooled to 20 to 25oC and stirred for 3 to 4 h at same temperature. The obtained solid was filtered, washed with EtOAc (1.4 vol.). Recrystallized the solid material with EtOAc and methanol to obtained the title compound.

Example-6: Preparation of tert-butyl (R)-ethyl(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl) carbamate:
To a clean and dry RBF (Round-bottom flask), (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (10 g; 1 eq.) in THF (5 vol.) and active molecular sieve (1 time) were added at RT and stirred for 1h. The solid was filtered and washed with THF (5 vol.). tert-butyl ethyl(4-formylphenethyl)carbamate (1.2 eq.) and n-heptane (7.5 vol.), DBTA (0.1 time) were added, heated to reflux temperature and cooled to RT, stirred for 4 to 5 h at RT. The solid was filtered and washed with n-heptane (2 vol.). The wet solid was dissolved in THF (40 vol.) and NaBH(OAc)3 (4.5 eq.) was added at RT. The reaction mass was heated to 50? and stirred for 16 h. After completion of the reaction, the reaction mass was cooled to 20oC and quenched with 3M aq.NaOH (15 vol.) solution up to pH 8 to 9 and stirred for 30min at 20oC. The aq. layer separated and organic layer distilled off up to 5 volumes under vacuum at below 45oC. The compound was extracted with EtOAc (2 x 5 vol.) and combined organic layer washed with brine solution followed by distilled off the organic layer completely and strip off the residue with n-heptane (2 x 3 vol.), degas well and obtained the title compound.

Example-7: Preparation of elacestrant dihydrochloride:
To a stirred solution of tert-butyl (R)-ethyl(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenethyl) carbamate (10 g; 1 eq.) in EtOAc (4 vol.). 3.3 molar HCl in ethanol solution at 15 to 25oC and stirred for 1 h. The reaction mass was slowly warmed to RT and stirred for 2 to 3 h at same temperature. The solvent was distilled off up to 4.6 volumes at below 45oC under vacuum. EtOAc (12 vol.) was added at 45oC and the reaction mass was cooled to RT and stirred for 2 h. The obtained solid was filtered, wash the solid with EtOAc (3 vol.) and dried the solid material with below 50oC under vacuum to obtained the title compound.

Example-8: Preparation of tert-butyl (4-bromophenethyl)(ethyl)carbamate:
To a stirred solution of 2-(4-bromophenyl)-N-ethylethan-1-aminium hydrochloride (4 g; 1 eq.) in DCM (vol.) was added 10% aq. NaOH (5 vol.) solution at RT and stirred for 10 min. The layers were separated and organic layer washed with water and brine solution. To this organic layer added dropwise (Boc)2O (2.0 eq.) at RT and stirred for 4 hours. After completion of the reaction, distilled off the solvent and quenched with water and extracted with EtOAc (3 x 10 vol.). Combined organic layer was washed with water and brine solution. Distilled off the organic layer to obtain the crude compound which was further purified in a mixture of n-Heptane and ether solvent to obtained the title compound.

Example-9: Preparation of tert-butyl ethyl(4-formylphenethyl)carbamate:
To a stirred solution of tert-butyl (4-bromophenethyl)(ethyl)carbamate (3 g; 1 eq.) in THF (5 vol.) was added n-BuLi (1.5 eq.) at -70 to -80oC, stirred for 1h and DMF (5 eq.) was added at same temperature and continued stirring for 1 h. After completion of the reaction, warmed to RT and distilled off the solvent and quenched reaction mass with saturated NH4Cl solution (4 vol.) followed by extraction of reaction mass with EtOAc (3 x 10 vol.). Combined organic layer was washed with water and brine solution. Distilled off the organic layer to obtain the crude compound which was further purified in a mixture of n-Heptane and ether solvent to obtained the title compound.

Example-10: Preparation of ethyl (S)-4-(4-(benzyloxy)phenyl)-3-(4-methoxy-2-nitrophenyl)butanoate:
To a stirred solution of [RhCl(C2H4)2]2 (0.015 eq.) in 1,4-dioxane (4 vol.) and Methyl 3a-acetyloxy-12a-(biphenyl-2,2-diyl)phosphite-5ß-cholan-24-oate (0.06 eq.) were added at RT, stirred for 3 to 4 h at same temperature. Water (10 ml) and 1M aq. KOH (50 ml) solution was added at RT followed by addition of 4-methoxy-2-nitrophenylboronic acid (2 eq.) and ethyl (E)-4-(4-(benzyloxy)phenyl)but-2-enoate (25 g, 1 eq.) at RT under nitrogen atmosphere. The reaction mixture was stirred for 10 to 14 h at RT under nitrogen atmosphere. After completion of the reaction, the reaction mixture was poured into 1M aq. NaHCO3 solution and extracted with diethyl ether (3 x 5 vol.). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to obtain crude product. The crude product was purified by column chromatography to obtained the title compound.

Example-11: Preparation of (S)-4-(4-(benzyloxy)phenyl)-3-(4-methoxy-2-nitrophenyl)butanoic acid:
To a stirred solution of (S)-4-(4-(benzyloxy)phenyl)-3-(4-methoxy-2-nitrophenyl)butanoate (80 g; 1 eq.) in THF (5 vol.) and water (5 vol.) and lot wise of LiOH.H2O (4 eq.) were added at 0 to 5oC. The reaction mass was warmed to RT and stirred for 6 to 8 h at same temperature. After completion of reaction the reaction, the reaction mass was cooled to 0 to 5oC and neutralized with 1N aq. HCl solution to obtained the title compound.

Example-12: Preparation of (S)-7-(benzyloxy)-3-(4-methoxy-2-nitrophenyl)-3,4-dihydronaphthalen-1(2H)-one:
To a stirred solution of (S)-4-(4-(benzyloxy)phenyl)-3-(4-methoxy-2-nitrophenyl)butanoic acid (50 g; 1 eq.) in dry CH2Cl2 (5 vol.) and oxalyl choride (4 eq.) were added at RT, the reaction mass was cooled to 0 to 10oC and two drops of dry DMF was added at same temperature. Then slowly warmed the reaction mixture to RT and stirred for overnight at RT. After completion of the reaction, distilled off the solvent and excess amount of oxalyl choride at below 50oC under vacuum to obtain acid chloride. The residue was dissolved with dry DCM (5 vol.) and lot wise addition of AlCl3 (2.1 eq.) at 0 to 10oC under nitrogen atmosphere. Then slowly warmed the reaction mass to RT and stirred at same temperature for 14 to 18 h. After completion of the reaction, slowly transferred the reaction mass to ice water solution (10 vol.). The layers were separated and extracted with DCM (2 x 5 vol.). The combined organic layer washed with brine solution (3 vol.) and distilled off the solvent under vacuum at below 40oC to obtain a crude and purified by column chromatography to obtained the title compound.

Dated this: 05th day of February, 2025.
Signature:
Name: Mr. Rama Rao Javvaji
Patent Agent Reg. No.: IN/PA-1669
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block,
Madhapur, Hyderabad, Telangana, INDIA-500 081
,CLAIMS:We Claim:
1. A process for the preparation of elacestrant of formula I or a salt thereof, which comprises:
a) reacting compound of formula II with Wittig reagent in a suitable solvent in presence or absence of a base to provide a compound of formula III; wherein Pg is a protecting group; R is an alkyl group;

b) hydrolyzing the compound of formula III with a base in presence of a suitable solvent to provide a compound of formula IV;

c) converting the compound of formula IV into a compound of formula V;

d) condensing the compound of formula V with a compound of formula VI in presence of rhodium metal precursor and a chiral ligand, followed by treating with a base and suitable solvent to provide a compound of formula VII; wherein X is a metal residue, halo group or pseudo halo group;

e) hydrogenating the compound of formula VII with a suitable hydrogenating agent in presence of a suitable solvent to provide a compound of formula VIII;

f) reacting the compound of formula VIII with a compound of formula IX in presence of a suitable reducing agent and a suitable solvent to provide a compound of formula X; and

g) deprotecting the compound of formula X with a suitable deprotecting agent in presence of a suitable solvent to provide a elacestrant of formula I or salt thereof.

2. The process as claimed in claim 1, wherein the protecting group “Pg” is selected from 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, Fmoc, 4-methoxy-2,3,6-trimethylbenzenesulphonyl, benzyl carbamate, acetamide, phthalimide, benzylamine, p-toluenesolfonamide and alkyl trifluoroacetyl.

3. The process as claimed in claim 1, wherein R is an alkyl group selected from C1-6 alkyl such as methyl, ethyl, propyl and butyl.

4. The process as claimed in claim 1, wherein X is selected from metal residue, halo group or pseudohalo group such as MgCl, MgBr, B(OH)2, B(OCMe2CMe2O), BF3K, ZnCl, ZnBr, and ZnI; Cl, Br, I, F3CSO3, p-TolSO3, and MeSO3.

5. The process as claimed in claim 1, wherein the step c) process is carried out by reacting compound of formula IV with halogenating agent in presence of a suitable solvent followed by treating with Lewis acid to provide a compound of formula V.

6. A process for the preparation of elacestrant of formula I or salt thereof, which comprises:
a) protecting compound of formula XI with a suitable protecting agent in presence of a base and a suitable solvent to provide a compound of formula XII; wherein Pg is a protecting group; X is metal residue, halo group or pseudohalo group;

b) reacting the compound of formula XII with organolithium base in presence of a suitable solvent to provide a compound of formula IX; and

c) converting the compound of formula IX into elacestrant of formula I or salt thereof.

7. A process for the preparation of elacestrant of formula I or salt thereof, which comprises:
a) condensing the compound of formula III with a compound of formula VI in presence of rhodium metal precursor and a chiral ligand, followed by treating with a base and a suitable solvent to provide a compound of formula XVIII; wherein Pg is a protecting group; X is metal residue, halo group or pseudohalo group; R is an alkyl group;

b) hydrolyzing the compound of formula XVIII with a base in the presence of a suitable solvent to provide a compound of formula XVII;

c) cyclizing the compound of formula XVII into a compound of formula VII; and

d) converting the compound of formula VII into elacestrant of formula I or salt thereof.

8. A novel intermediate compounds of formulae IV, VII, IX, IXa, XII, XIIa, XVII, XVIII and X:

wherein Pg is a protecting group;
X is metal residue, halo group or pseudo halo group; R is an alkyl group.

9. Use of novel intermediate compounds of formulae IV, VII, IX, IXa, XII, XIIa, XVII, XVIII and X as claimed in claim 8, in the preparation of elacestrant of formula I or a salt thereof.

Dated this: 05th day of February, 2025.
Signature:
Name: Mr. Rama Rao Javvaji
Patent Agent Reg. No.: IN/PA-1669
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block,
Madhapur, Hyderabad, Telangana, INDIA-500 081