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) activating the carboxylic moiety of compound of formula II with a suitable activating agent in presence of a suitable solvent and reacting it with Meldrum's acid in presence of a base and a suitable solvent to provide a compound of formula III; wherein Pg is a protecting group;

b) reacting the compound of formula III with 2-amino-2-methyl-1-propanol in presence of a suitable solvent to provide a compound of formula IV;

c) condensing the compound of formula IV with a compound of formula V in presence of a suitable reducing agent, a chiral ligand and a suitable solvent to provide a compound of formula VI; X is metal residue, halo group or pseudohalo group;

d) cyclizing the compound of formula VI into a compound of formula VII;

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.

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) coupling compound of formula XI with a chiral auxiliary in presence of a suitable coupling agent, a base and a suitable solvent to provide a compound of formula XII; wherein Pg is a protecting group; A is a chiral auxiliary;

b) condensing the compound of formula XII with a compound of formula V to provide a compound of formula XIII; wherein X is metal residue, halo group or pseudohalo group;

c) deprotecting the compound of formula XIII with a suitable deprotecting agent in presence of suitable solvent to provide a compound of formula VI;

d) cyclizing the compound of formula VI into a compound of formula VII; and

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

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

wherein Pg is a protecting group; A is a chiral auxiliary.

In another aspect of the present invention is to provides use of novel intermediate compounds of formulae III, IV, XII and XIII, 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, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, dioxane and the like; halogenated solvent is selected from the group consisting of dichloromethane 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, 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, 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 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 “suitable coupling agent” is selected from but not limited to PyBOP, BOP, TBTU, EDCl, HATU, HBTU, HCTU, DCC, CDI, DIC, isobutylchloroformate, pivaloyl chloride, oxalyl chloride, thionyl chloride, 1-propanephosphonic , EDC.HCl, HOBt, DMAP, HOAt, HOCt, HOSu, BOMI, BDMP, BMPI or CMPI and the like.

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, polyphosphoric 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 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 “chiral auxiliary” includes, but not limited to, oxazolidinone, 8-phenylmenthol, N-substituted bornane-2,10-sultams (e.g., 10,10-dimethyl-3-thia-4-aza-tricyclo[5.2.1.01.5]decane-3,3-dioxide), trans-phenyl cyclohexanone. camphorsultam, pseudoephedrine (R,R) or (S,S), or pseudoephenamide (R,R) or (S,S), alkyl thiazolidine-2-thione derivatives or N-(-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)-N-phenylbenzenesulfonamide and the like. preferably the chiral auxiliary is selected from but not limited to oxazolidinone compound of formula A, wherein G is -O-, -S- or -N(C1-C6 alkyl); Q is =O or =S; R is C1-C6 alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, C1-C6 alkoxycarbonyl or benzyl, wherein the substituents on phenyl and naphthyl are 1-3 substituents selected from the group consisting of C1-C6 alkyl, phenyl and benzyl; Formula A is R or S enantiomer.

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 “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 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) activating the carboxylic moiety of compound of formula II with a suitable activating agent in presence of a suitable solvent and reacting it with Meldrum's acid in presence of a base and a suitable solvent to provide a compound of formula III; wherein Pg is a protecting group;

b) reacting the compound of formula III with 2-amino-2-methyl-1-propanol in presence of a suitable solvent to provide a compound of formula IV;

c) condensing the compound of formula IV with a compound of formula V in presence of a suitable reducing agent, a chiral ligand and a suitable solvent to provide a compound of formula VI; X is metal residue, halo group or pseudohalo group;

d) cyclizing the compound of formula VI into a compound of formula VII;

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 compound of formula II; wherein Pg is a protecting group as defined above; preferably benzyl; with a suitable activating agent in presence of a suitable solvent to form an activated species which is directly reacted with Meldrum's acid in presence of a base and a suitable solvent under appropriate reaction conditions to provide a compound of formula III. The activating agent is selected from but not limited to acyl chloride (such as pivaloyl chloride, iso-propoyl chloride), acid anhydride (such as pivalic anhydride, of isopropylanhydride) or reagent such as thionyl chloride, oxalyl chloride, sulfonyl chloride and the like; preferably thionyl chloride. The base and the suitable solvent are as defined above; preferably the base is selected from but not limited to DIPEA 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 III with 2-amino-2-methyl-1-propanol in presence of a suitable solvent under appropriate reaction conditions to provide a compound of formula IV; wherein the suitable solvent is as defined above; preferably toluene.

In an embodiment, the step c) process involves condensing the compound of formula IV with a compound of formula V; wherein X is metal residue, halo group or pseudohalo group; preferably metal residue is selected from but not limited to MgBr; in presence of a suitable reducing agent, a chiral ligand and a suitable solvent under appropriate reaction conditions to provide a compound of formula VI. The reducing agent, a chiral ligand and suitable solvent are as defined above; preferably the reducing agent is selected from but not limited to triethyl silane; the chiral ligand is selected from phosphine ligands; and the solvent is selected from but not limited to tetrahydrofuran.

In an embodiment, the step d) process involves cyclizing the compound of formula VI is carried out by reaction the compound of formula VI with a suitable acid under appropriate reaction conditions to provide a compound of formula VII; wherein the acid is as defined above; preferably the acid is selected from but not limited to polyphosphoric acid.

Alternatively:
In an embodiment, the step d) process involves cyclizing the compound of formula VI is carried out by reaction the compound of formula VI 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. 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 solvent is selected from but not limited to dichloromethane and dimethylformamide; and the Lewis acid is selected from but not limited to AlCl3.

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 suitable hydrogenating agent and suitable solvent are as defined above; preferably the hydrogenating agent is selected from but not limited to Pd(OH)2/C; and the 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; wherein Pg is a protecting group as defined above; preferably Boc; 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 the solvent are as defined above; preferably the reducing agent is selected from but not limited to NaBH(OAc)3; and the solvent is selected from but not limited to tetrahydrofuran.

In an embodiment, step g) deprotecting the compound of formula X with 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 solvent are as defined above; preferably the deprotecting agent is selected from but not limited to HCl; and the 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 100°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) coupling compound of formula XI with a chiral auxiliary in presence of a suitable coupling agent, a base and a suitable solvent to provide a compound of formula XII; wherein Pg is a protecting group; A is a chiral auxiliary;

b) condensing the compound of formula XII with a compound of formula V to provide a compound of formula XIII; wherein X is metal residue, halo group or pseudohalo group;

c) deprotecting the compound of formula XIII with a suitable deprotecting agent in presence of suitable solvent to provide a compound of formula VI;

d) cyclizing the compound of formula VI into a compound of formula VII; and

e) converting the compound of formula VII 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 reacting compound of formula XI; wherein Pg is a protecting group as defined above; preferably benzyl; with a chiral auxiliary in presence of a suitable coupling agent, a base and a suitable solvent under appropriate reaction conditions to provide a compound of formula XII; wherein the chiral auxiliary, coupling agent, a base and a suitable solvent are as defined above; preferably the chiral auxiliary is selected from but not limited to (R)-4-(tert-butyl)oxazolidin-2-one or (R)-4-phenyloxazolidin-2-one; the coupling agent is selected from but not limited to DCC; the base is selected from but not limited to DMAP and the solvent is selected from but not limited to dichloromethane.

In an embodiment, the step b) process involves condensing the compound of formula XII with a 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; under appropriate reaction conditions to provide a compound of formula XIII. The reaction can be carried out in presence of a suitable hydrogenating agent is selected from but not limited to Palladium(II) acetate (or) CuX.SMe2 complex (X is a halo group such as Cl, Br etc.) in presence of a cat. Iodine optionally in combination with metal (eg: Li, Mg, Zn etc.); preferably Palladium(II) acetate; and a suitable solvent is as defined above; preferably methanol and water.

In an embodiment, the step c) process involves deprotecting the compound of formula XIII with a suitable deprotecting agent in presence of suitable solvent under appropriate reaction conditions to provide a compound of formula VI; wherein the deprotecting agent and solvent are as defined above; preferably the deprotecting agent is selected from but not limited to ytterbium(III) triflate; and the solvent is selected from but not limited to acetonitrile and water.

In an embodiment, the step d) process involves cyclizing the compound of formula VI is carried out by reaction the compound of formula VI with a suitable acid under appropriate reaction conditions to provide a compound of formula VII; wherein the acid is as defined above; preferably the acid is selected from but not limited to polyphosphoric acid.

Alternatively:
In an embodiment, in step d) process involves cyclizing the compound of formula VI is carried out by reaction the compound of formula VI 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. 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 solvent is selected from but not limited to dichloromethane and dimethylformamide; and the Lewis acid is selected from but not limited to AlCl3.

In an embodiment, the step e) 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 e) 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 100°C.

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

wherein Pg is a protecting group; A is a chiral auxiliary.

In another embodiment of the present invention is to provides use of novel intermediate compounds of formulae III, IV, XII and XIII, 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 4-(4-(benzyloxy)phenyl)-3-oxobutanoic acid:
To a clean and dry RBF (Round-bottom flask), 2-(4-(benzyloxy)phenyl)acetic acid (10 g; 1 eq.) in DCM (10 vol.) and thionyl chloride (2 eq.) were added at RT. The reaction mass was heated to reflux temperature and stirred for 2h at the same temperature. After completion of the reaction, distilled off the solvent. The obtained residue was dissolved in DCM (5 vol.). Meldrum's acid (2 eq.) and DIPEA (2 eq.) were added at 0°C, after the reaction mass was warmed to RT and stirred for 2h at the same temperature. After completion of the reaction, diluted with DCM (5 vol.), followed by addition of 10% aq.NaOH solution and the layers were separated. The aq.layer was diluted with DCM (5 vol.) and adjust the pH about 2 to 3 by using 1N aq.HCl solution. The organic layer was separated and distilled off. The obtained crude compound was purified in a mixture of n-Heptane and ether solution to obtained the title compound.

Example-2: Preparation of 1-(4-(benzyloxy)phenyl)-3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)propan-2-one:
To a stirred solution of 4-(4-(benzyloxy)phenyl)-3-oxobutanoic acid (30 g; 1 eq.) in toluene (10 vol.) and 2-amino-2-methyl-1-propanol (3 eq.) were added at RT. The reaction mass was heated to 110oC and stirred for 6 to 7 h at the same temperature. After completion of the reaction, the reaction mas was cooled to 10 to 20oC and quenched the reaction mass with 2% aq. acetic acid (3 vol.) solution. The obtained compound was extracted with toluene (3 x 5 vol.) and the combined toluene layer was washed with 5% aq. Na2CO3 solution followed by brine solution then distilled off the solvent completely and crystallized using n-Heptane (5 vol.) to obtained the title compound.

Example-3: Preparation of (S)-4-(4-(benzyloxy)phenyl)-3-(4-methoxy-2-nitrophenyl)butanoic acid:
To a stirred solution of 1-(4-(benzyloxy)phenyl)-3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)propan-2-one (5 g; 1 eq.) in THF (7 vol.) and chiral ligand (0.1 eq.) was added at RT under nitrogen atmosphere. The reaction mass was cooled to 0 to 10oC, 1M solution of (4-methoxy-2-nitrophenyl)magnesium bromide (1.3 eq.) was added slowly and stirred the reaction mass for 2 to 3h at the same temperature. After completion of the reaction, Triethyl silane (1.5 eq.) was added at 0 to 10oC then warmed the reaction mass to RT and stirred for 5 to 6h at the same temperature. After completion of the reaction, quenched the reaction mass with 2N aq. HCl (5 vol.) solution at RT and stirred for 3 to 4 h. The compound was extracted with EtOAc (3 x 5 vol.), the combined organic layer was washed with water (5 vol.) and brine (5 vol.) solution. The organic layer was distilled off and crude compound was 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 (S)-4-(4-(benzyloxy)phenyl)-3-(4-methoxy-2-nitrophenyl)butanoic acid (10 g; 1 eq.) in Polyphosphoric acid (5 vol.), the reaction mass was slowly heated to 90°C and stirred for 20 to 24h at the same temperature. After completion of the reaction, the reaction mass was cooled to 0 to 5oC and chilled water (20 vol.) was slowly added then stirred for 20 to 30 min at the same temperature. The compound was extracted with EtOAc (3 x 7 vol.), the combined organic layer was washed with water and brine solution then distilled off the solvent. The crude compound was purified by column chromatography to obtained the title compound.

Alternative preparation:
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.

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 (R,E)-3-(4-(4-(benzyloxy)phenyl)but-2-enoyl)-4-(tert-butyl)oxazolidin-2-one:
To a clean and dry RBF (Round-bottom flask), (E)-4-(4-(benzyloxy)phenyl)but-2-enoic acid (50 g; 1 eq.) in DCM (5 vol.), (R)-4-(tert-butyl)oxazolidin-2-one (1.2 eq.), and DMAP (0.22 eq.) were added at 0°C, under argon atmosphere. DCC (1 eq.) was added in one portion and stirred for 10 min then the reaction mass temperature was raised to RT, stirring was continued until no starting material has left as confirmed by TLC. The dicyclohexylurea formed was filtered and the precipitate washed with DCM. The filtrate was washed with sat. NaHCO3, dried with MgSO4 and concentrated at reduced pressure to furnish the crude product, which was purified by silica gel chromatography to obtained the title compound.

Example-9: Preparation of (R)-3-((S)-4-(4-(benzyloxy)phenyl)-3-(4-methoxy-2-nitrophenyl)butanoyl)-4-(tert-butyl)oxazolidin-2-one:
To a stirred solution of (R,E)-3-(4-(4-(benzyloxy)phenyl)but-2-enoyl)-4-(tert-butyl)oxazolidin-2-one (30 g; 1 eq.) in Methanol (5 vol.) and water (15 vol.) were added at RT. (4-methoxy-2-nitrophenyl)boronic acid (1.2 eq.) and Palladium(II) acetate (0.2 eq.) were added at RT then the reaction mass was heated to 80oC, stirred for 16 to 20h at the same temperature. After completion of the reaction, the reaction mass was cooled to 45oC and distilled off the methanol then the reaction mass was cooled to RT. The compound was extracted with EtOAc (3 x 5 vol.) and the combined organic layer was washed with water and brine solution then distilled off the solvent and crude compound was purified by column chromatography to obtained the title compound.

Example-10: Preparation of (S)-4-(4-(benzyloxy)phenyl)-3-(4-methoxy-2-nitrophenyl)butanoic acid:
To a stirred solution of (R)-3-((S)-4-(4-(benzyloxy)phenyl)-3-(4-methoxy-2-nitrophenyl)butanoyl)-4-(tert-butyl)oxazolidin-2-one (20 g; 1 eq.) in acetonitrile (12 mL) and water (4 mL), ytterbium(III) triflate (0.1 eq.) was added at RT. The reaction mass was heated to 90oC and stirred for 24 h at the same temperature. After completion of the reaction, the reaction mass was cooled to RT and the compound was extracted with EtOAc (3 x 20 ml). The combined organic layer was washed with water and brine solution. The organic layer was distilled off and crude compound was purified by column chromatography to obtained the title compound.

Example-11: Preparation of (R,E)-3-(4-(4-(benzyloxy)phenyl)but-2-enoyl)-4-phenyloxazolidin-2-one:
To a clean and dry RBF (Round-bottom flask), (E)-4-(4-(benzyloxy)phenyl)but-2-enoic acid (50 g; 1 eq.) in DCM (5 vol.), (R)-4-phenyloxazolidin-2-one (1.2 eq.), and DMAP (0.22 eq.) were added at 0°C, under argon atmosphere. DCC (1 eq.) was added in one portion and stirred for 10 min then the reaction mass temperature was raised to RT, stirring was continued until no starting material has left as confirmed by TLC. The dicyclohexylurea formed was filtered and the precipitate washed with DCM. The filtrate was washed with sat. NaHCO3, dried with MgSO4 and concentrated at reduced pressure to furnish the crude product, which was purified by silica gel chromatography to obtained the title compound.

Example-12: Preparation of (R)-3-((S)-4-(4-(benzyloxy)phenyl)-3-(4-methoxy-2-nitrophenyl)butanoyl)-4-phenyloxazolidin-2-one:
To a stirred solution of Mg (2 eq.) in THF (10 vol.), 1-bromo-4-methoxy-2-nitrobenzene (2 eq.), and cat. amount of Iodine was added at RT. The reaction mass was slowly warmed to 50oC and stirred for 2 h at the same temperature, under nitrogen atmosphere. After 2h, the reaction mass was cooled to RT, further cooled to -40oC and CuBr.SMe2 (2 eq.) was added at the same temperature under nitrogen atmosphere.
A solution of (R,E)-3-(4-(4-(benzyloxy)phenyl)but-2-enoyl)-4-phenyloxazolidin-2-one (20 g; 1 eq.) in THF (8 vol.) was added dropwise to the above Grignard reaction mass at -40oC for 1.5 h, then allowed to warm slowly to ambient temperature. The reaction was quenched with 20% aq. NH4Cl, and the crude product was extracted with EtOAc (5 x 3 vol.). The combined organic fractions washed with water and brine, dried over MgSO4, and concentrated in vacuo to obtain crud compound. The crude compound was purified by column chromatography to obtained the title compound.

Example-13: Preparation of (S)-4-(4-(benzyloxy)phenyl)-3-(4-methoxy-2-nitrophenyl)butanoic acid:
To a stirred solution of (R)-3-((S)-4-(4-(benzyloxy)phenyl)-3-(4-methoxy-2-nitrophenyl)butanoyl)-4-phenyloxazolidin-2-one (20 g; 1 eq.) in acetonitrile (12 mL) and water (4 mL), ytterbium(III) triflate (0.1 eq.) was added at RT. The reaction mass was heated to 90oC and stirred for 24 h at the same temperature. After completion of the reaction, the reaction mass was cooled to RT and the compound was extracted with EtOAc (3 x 20 ml). The combined organic layer was washed with water and brine solution. The organic layer was distilled off and crude compound was 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) activating the carboxylic moiety of compound of formula II with a suitable activating agent in presence of a suitable solvent and reacting it with Meldrum's acid in presence of a base and a suitable solvent to provide a compound of formula III; wherein Pg is a protecting group;

b) reacting the compound of formula III with 2-amino-2-methyl-1-propanol in presence of a suitable solvent to provide a compound of formula IV;

c) condensing the compound of formula IV with a compound of formula V in presence of a suitable reducing agent, a chiral ligand and a suitable solvent to provide a compound of formula VI; X is metal residue, halo group or pseudohalo group;

d) cyclizing the compound of formula VI into a compound of formula VII;

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.

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 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.

4. The process as claimed in claim 1, wherein the step d) cyclization process carried out by reacting the compound of formula VI with a suitable acid to provide a compound of formula VII or by reacting the compound of formula VI with halogenating agent in a suitable solvent, followed by treating with a Lewis acid to provide a compound of formula VII.

5. A process for the preparation of elacestrant of formula I or salt thereof, which comprises:
a) coupling compound of formula XI with a chiral auxiliary in presence of a suitable coupling agent, a base and a suitable solvent to provide a compound of formula XII; wherein Pg is a protecting group; A is a chiral auxiliary;

b) condensing the compound of formula XII with a compound of formula V to provide a compound of formula XIII; wherein X is metal residue, halo group or pseudohalo group;

c) deprotecting the compound of formula XIII with a suitable deprotecting agent in presence of suitable solvent to provide a compound of formula VI;

d) cyclizing the compound of formula VI into a compound of formula VII; and

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

6. The process as claimed in claim 5, 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.

7. The process as claimed in claim 5, 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.

8. A novel intermediate compounds of formulae III, IV, XII and XIII:


wherein Pg is a protecting group; A is a chiral auxiliary.

9. Use of novel intermediate compounds of formulae III, IV, XII and XIII 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