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WO2025210581A1 - 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 - Google Patents

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

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Publication number
WO2025210581A1
WO2025210581A1 PCT/IB2025/053575 IB2025053575W WO2025210581A1 WO 2025210581 A1 WO2025210581 A1 WO 2025210581A1 IB 2025053575 W IB2025053575 W IB 2025053575W WO 2025210581 A1 WO2025210581 A1 WO 2025210581A1
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Prior art keywords
formula
compound
elacestrant
acid
solvent
Prior art date
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Pending
Application number
PCT/IB2025/053575
Other languages
French (fr)
Inventor
Manik Reddy Pullagurla
Bhaskar Reddy Pitta
Jagadeesh Babu Rangisetty
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Biophore India Pharmaceuticals Pvt Ltd
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Biophore India Pharmaceuticals Pvt Ltd
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Publication of WO2025210581A1 publication Critical patent/WO2025210581A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings

Definitions

  • 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 (3), formula (4), formula (4a), formula (5), formula (5a), formula (6), formula (6a), formula (7), formula (7a), formula (9) and formula (10).
  • Elacestrant dihydrochloride (1) 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 (2) with compound of formula (3) in presence of suitable reducing agent, solvent and acid to provide compound of formula (4); b) reductive amination of the compound of formula (4) with acetaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula (5); c) resolving the compound of formula (5) with chiral resolving agent in presence of suitable solvent to provide compound of formula (5a); d) reducing the compound of formula (5a) with suitable reducing agent in presence of suitable solvent to provide Elacestrant(l A); e) converting Elacestrant into Elacestrant dihydrochloride (1).
  • Stage D resolving the Elacestrant (lb) with suitable chiral resolving agent in presence of suitable solvent to provide Elacestrant (1 A).
  • Stage c) reacting the compound of formula (9) with 9-Borabicyclo[3.3.1]nonane or (9-BBN) in presence of suitable solvent to provide compound of formula (io);
  • a process for the preparation of pure Elacestrant dihydrochloride having purity greater than 99% which comprises; a) dissolving a solution of crude Elacestrant dihydrochloride (1) in one or more solvents b) isolating pure compound of Elacestrant dihydrochloride.
  • R is n-acetyl or amine protecting group
  • the present invention further relates to a process for the preparation of intermediates of formula (4a), formula (5a), formula (6a), and formula (7a) with chiral purity greater than 90%.
  • 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.
  • 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 dichloromethane, ethylene dichloride, carbon tetrachloride, chlor
  • 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 bis(2-methyoxyethoxy) aluminumhydride, sodium triacetoxyborohydrode, Aluminium hydride(AlH3), chlorohydroalane (AIH2CI), dichloroaluminum (AIHQ2), Lithium borohydride (LiBHj), Lithium triethylborohydride (LiEtsBH), Borane(BH3), Borane tetrahydrofuran (BH3.THF), Zinc acetate(Zn(0Ac)2), Triethoxysilane ((EtOjsSiH), Magnesium(Mg), Titanium tetrachloride(TiC14), Pinacolborane (HBpin) ,tris(4,4-dimethyl-2- oxazolinyl)phenylborate
  • 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.
  • chiral resolving agent used in the present invention until unless specified is selected from, but are not limited to Aspartic 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-Cy cl ohexanedi carboxylic acid, Dibenzoyl-L-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-(
  • 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 (PK ), 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; AIH3-AICI3 ; hydrazine and a catalyst; Triiron dodecarbonyl [Fe3(CO)i2]- methanol; hot liquid paraffin; formic acid or ammonium formate and a catalyst such as palladium on carbon (Pd,C); Lithium aluminium hydride (LiAlEL) ; and sulfides such as Sodium hydrosulfide (NaHS), Diammonium sulfide (NEL ⁇ S or polysulfides.
  • 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, e
  • amine protecting group used in the present invention until unless specified is selected from, but are not limited to tert-butoxy carbonyl (BOC), benzyloxycarbonyl(CBz), triflouoroacetyl (TFA), benzyl (Bn), dibenzyl, phthalimido, tosyl (Ts), p-methoxybenzylcarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), carbamate, pmethoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p- methoxyphenyl (PMP) and benzoyl (Bz).
  • the present invention relates to a process for the preparation of Elacestrant dihydrochloride (I) and its novel intermediates used in the preparation of Elacestrant dihydrochloride (I).
  • the present invention provides a process for the preparation of
  • Elacestrant dihydrochloride (1) comprising the steps of:
  • R is n-acetyl or amine protecting group.
  • the step A) of aforementioned process involves the reaction of compound of formula (2) with compound of formula (3); in presence of reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium; a suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; 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 (4).
  • 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.
  • the step B) of aforementioned process involves the reaction of compound of formula (4) 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 ethylketone, under appropriate reaction conditions to provide a compound of formula (5);
  • 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.
  • the step C) of aforementioned process involves reaction of compound formula (5) 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 (6); 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.
  • reducing agent selected form but are not limited to lithium aluminium hydride, sodium borohydride, sodium hydride, DIBAL-H, Red-Al
  • suitable solvent selected form but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane
  • the step D) of aforementioned process involves reaction of compound formula (6) with suitable reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium hydride; in presence of suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; under appropriate reaction conditions to provide Elacestrant ,
  • suitable reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium hydride
  • suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane
  • 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.
  • the step E) of aforementioned process involves converting Elacestrant into its salt 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,
  • suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol, under appropriate reaction conditions to provide Elacestrant dihydrochloride.
  • R is n-acetyl or amine protecting group.
  • the step a) of aforementioned process involves the reaction of compound of formula (2) with compound of formula (3); in presence of reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium; a suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; 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 (4).
  • 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.
  • the step c) of aforementioned process involves the reaction of compound of formula (5) with chiral resolving agent selected from (+)-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; a suitable solvent selected from but not limited to acetonitrile, acetone, methyl isobutyl ketone, methyl ethylketone, under appropriate reaction conditions to provide a compound of formula (5a);
  • 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.
  • the step d) of aforementioned process involves reaction of compound formula (5a) with suitable reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium hydride; in presence of suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; under appropriate reaction conditions to provide Elacestrant ,
  • suitable reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium hydride
  • suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane
  • 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.
  • the step e) of aforementioned process involves converting Elacestrant into its salt 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,
  • suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol, under appropriate reaction conditions to provide Elacestrant dihydrochloride.
  • the step II) of aforementioned process involves the reaction of compound of formula (6) 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 ethylketone, under appropriate reaction conditions to provide a compound of formula (6a);
  • 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.
  • the step III) of aforementioned process involves the reaction of compound of formula (6a) with compound of formula (3); in presence of reducing agent selected from but not limited to sodium triacetoxyborohydrode, Red-Al, lithium aluminium; a suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tertbutyl ether, dioxane; 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 (7a).
  • 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.
  • the step IV) of aforementioned process involves reaction of compound formula (7a) with deprotecting agent selected from but not limited to Pt, Pt,C, PtCb , Pd, Pd,C, Rh, Ru, Ni or Raney Ni; and then recti on with acetaldehyde; in presence of suitable solvent selected form but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol; under appropriate reaction conditions to provide a compound of formula (5a); The said reaction is carried out at a suitable temperature of about 25°C-40°C to about reflux temperature of the solvent used, for a sufficient time.
  • deprotecting agent selected from but not limited to Pt, Pt,C, PtCb , Pd, Pd,C, Rh, Ru, Ni or Raney Ni
  • suitable solvent selected form but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol
  • suitable solvent selected form but not limited to methanol,
  • the step V) of aforementioned process involves reaction of compound formula (5a) with suitable reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium hydride; in presence of suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; under appropriate reaction conditions to provide Elacestrant ,
  • suitable reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium hydride
  • suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane
  • 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.
  • the step VI) of aforementioned process involves converting Elacestrant into its salt 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,
  • suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol, under appropriate reaction conditions to provide Elacestrant dihydrochloride.
  • R is n-acetyl or amine protecting group.
  • step i) of aforementioned process involves the reaction of compound of formula
  • the step ii) of aforementioned process involves the reaction of compound of formula (6) with chiral resolving agent selected from but not limited to (+)-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 ethylketone, under appropriate reaction conditions to provide a compound of formula (6a);
  • 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.
  • the step iii) of aforementioned process involves the reaction of compound of formula (6a) with compound of formula (3); in presence of reducing agent selected from but not limited to sodium triacetoxyborohydrode, Red-Al, lithium aluminium; a suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tertbutyl ether, dioxane; 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 (7a).
  • 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.
  • the step iv) of aforementioned process involves reaction of compound formula (7a) with deprotecting agent selected from but not limited to Pt, Pt,C, PtCb , Pd, Pd,C, Rh, Ru, Ni or Raney Ni; and then rection with acetaldehyde; in presence of suitable solvent selected form but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol; under appropriate reaction conditions to provide a compound of formula (5a);
  • the said reaction is carried out at a suitable temperature of about 25°C-40°C to about reflux temperature of the solvent used, for a sufficient time.
  • the step v) of aforementioned process involves reaction of compound formula (5a) with suitable reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium hydride; in presence of suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; under appropriate reaction conditions to provide Elacestrant ,
  • suitable reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium hydride
  • suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane
  • 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.
  • the step vi) of aforementioned process involves converting Elacestrant into its salt 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,
  • suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol, under appropriate reaction conditions to provide Elacestrant dihydrochloride.
  • the stage A) of aforementioned process involves the reaction of compound of formula (2) 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 (8); 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.
  • reducing agent selected form but are not limited to lithium aluminium hydride, sodium borohydride, sodium hydride, DIBAL-H, Red- Al
  • suitable solvent selected form but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane
  • the said reaction is carried out at a suitable temperature
  • stage B) of aforementioned process involves the reaction of compound of formula
  • stage C) of aforementioned process involves the reaction of compound of formula
  • the stage D) of aforementioned process involves the reaction of compound of formula (IB) with suitable chiral resolving agent selected form but not limited to (+)-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 ethylketone, under appropriate reaction conditions to provide a compound of formula (1A);
  • 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.
  • the stage E) of aforementioned process involves converting Elacestrant into its salt 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,
  • suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol, under appropriate reaction conditions to provide Elacestrant dihydrochloride.
  • the stage a) of aforementioned process involves the reaction of compound of formula (2) 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 (8); 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.
  • the stage b) of aforementioned process involves the reaction of compound of formula (2) 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
  • stage c) of aforementioned process involves the reaction of compound of formula
  • stage d) of aforementioned process involves the reaction of compound of formula
  • the stage e) of aforementioned process involves the reaction of compound of formula (IB) with suitable resolving agent selected form but not limited to (+)-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 ethylketone, under appropriate reaction conditions to provide a compound of formula (1A);
  • 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.
  • the stage f) of aforementioned process involves converting Elacestrant into its salt 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,
  • suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol, under appropriate reaction conditions to provide Elacestrant dihydrochloride.
  • In another embodiment of the present invention provides optionally converting Elacestrant to Elacestrant dihydrochloride premix without isolating Elacestrant dihydrochloride.
  • Polyvinylpyrrolidone (PVP) (4.0 g) was added to the reaction mixture and stirred to get a clear solution. Spray dried the obtained solution using spray dryer through following conditions:

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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. Elacestrant dihydrochloride (1) The present invention further relates to a process for the preparation of intermediates of formula (3), formula (4), formula (4a), formula (5), formula (5a), formula (6), formula (6a), formula (7), formula (7a), formula (9) and formula (10). with enantiomeric excess greater than 50%.

Description

"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"
FIELD OF THE INVENTION
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 (3), formula (4), formula (4a), formula (5), formula (5a), formula (6), formula (6a), formula (7), formula (7a), formula (9) and formula (10).
BACKGROUND OF THE INVENTION
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 (1)
Elacestrant dihydrochloride (1)
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 compound 7; (e) compound of formula 7 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 aluminium hydride , Aluminium chloride to obtain Elacestrant . The above process is schematically shown as below: US 20220162233 Aldiscloses Elacestrant and its salts for the first time which discloses a process for the preparation of Elacestrant , comprising; i) reacting compound (a) with bis(pinacolato)diboron in 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 , di chloromethane , 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 compound (f); v) reacting compound (f) with (+)-2,3-dibenzoyl-D-tartaric acid in presence of acetonitrile , di chloromethane, 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:
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.
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.
OBJECTIVE OF THE INVENTION
The present invention relates to a novel process for the preparation of Elacestrant dihydrochloride (1) and its novel intermediates thereof. The present invention further relates to pure Elacestrant dihydrochloride (1) 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
Accordingly, the present invention provides a novel process for the preparation of Elacestrant dihydrochloride (I) and its intermediates. Further in some embodiments, the present invention provides process for the preparation of intermediates with enantiomeric excess of greater than 50%.
In one aspect of the present invention provides a process for the preparation of Elacestrant dihydrochloride (1), as depicted in scheme-1, which comprises:
A) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (2) with compound of formula (3); in presence of suitable reducing agent, solvent and acid to provide compound of formula (4);
B) resolving the compound of formula (4) with chiral resolving agent in presence of suitable solvent to provide compound of formula (4a);
C) reductive amination of the compound of formula (4a) with acetaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula (5a);
D) reducing the compound of formula (5a) with suitable reducing agent in presence of suitable solvent to provide Elacestrant(l A);
E) converting Elacestrant into Elacestrant dihydrochloride (1).
In another 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 (2) with compound of formula (3) in presence of suitable reducing agent, solvent and acid to provide compound of formula (4); b) reductive amination of the compound of formula (4) with acetaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula (5); c) resolving the compound of formula (5) with chiral resolving agent in presence of suitable solvent to provide compound of formula (5a); d) reducing the compound of formula (5a) with suitable reducing agent in presence of suitable solvent to provide Elacestrant(l A); e) converting Elacestrant into Elacestrant dihydrochloride (1).
In yet another aspect of the present invention provides a process for the preparation of Elacestrant dihydrochloride (1), as depicted in scheme-3 which comprises:
I) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol
(2) with benzaldehyde in presence of suitable reducing agent, solvent and acid to provide compound of formula (6);
II) resolving the compound of formula (6) with chiral resolving agent in presence of suitable solvent to provide compound of formula (6a);
III) reacting the compound of formula (6a) with a compound of formula (3) in presence of suitable reducing agent, solvent and acid to provide a compound of (7 a);
IV) deprotecting the compound of formula (7a) with suitable deprotecting agent and acetaldehyde in presence of suitable solvent to provide a compound of (5a);
V) reducing the compound of formula (6) with suitable reducing agent in presence of suitable solvent to provide Elacestrant(l A);
VI) converting Elacestrant into Elacestrant dihydrochloride (1).
In yet another aspect of the present invention provides a process for the preparation of Elacestrant dihydrochloride (1), as depicted in scheme-4 which comprises: i) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (2) with benzaldehyde in presence of suitable reducing agent, solvent and acid to provide compound of formula (6); ii) reacting the compound of formula (6) with a compound of formula (3) in presence of suitable reducing agent, solvent and acid to provide a compound of (7); iii) resolving the compound of formula (7) with chiral resolving agent in presence of suitable solvent to provide compound of formula (7a); iv) deprotecting the compound of formula (7a) with suitable deprotecting agent and acetaldehyde in presence of suitable solvent to provide a compound of (5a); v) reducing the compound of formula (5a) with suitable reducing agent in presence of suitable solvent to provide Elacestrant(l A); vi) converting Elacestrant into Elacestrant dihydrochloride (1).
In one aspect of the present invention provides a process for the preparation of Elacestrant dihydrochloride (1), as depicted in scheme-1, which comprises:
Stage A) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (2) with acetaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula (8).
Stage B) reacting compound of formula (8) with vinyl benzaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula 9;
Stage C) reacting the compound of formula (9) with ethylamine in presence of suitable solvent and base to provide Elacestrant racemic compound (lb);
Stage D) resolving the Elacestrant (lb) with suitable chiral resolving agent in presence of suitable solvent to provide Elacestrant (1 A).
Stage E) converting Elacestrant into Elacestrant dihydrochloride (1).
In one aspect of the present invention provides a process for the preparation of Elacestrant dihydrochloride (1), as depicted in scheme-1, which comprises: Stage a) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (2) with acetaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula (8).
Stage b) reacting compound of formula (8) with vinyl benzaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula 9;
Stage c) reacting the compound of formula (9) with 9-Borabicyclo[3.3.1]nonane or (9-BBN) in presence of suitable solvent to provide compound of formula (io);
Stage d) reacting compound of formula (10) with Ethyl amine in presence of Methanesulfonyl chloride, suitable base and suitable solvent to provide Elacestrant (IB);
Stage e) resolving the Elacestrant (IB) with suitable chiral resolving agent in presence of suitable solvent to provide Elacestrant (1 A).
Stage f) converting Elacestrant into Elacestrant dihydrochloride (1).
In yet another aspect of the present invention provides a process for the preparation of a compound of (3), as depicted in scheme 5 which comprises:
1) reacting 2-(4-bromophenyl)ethanamine(ll) with amine protecting agent in presence of suitable solvent to provide a compound of (12) wherein R is n- acetyl or amine protecting group;
2) reacting compound of formula (12) with suitable base in presence suitable solvent to provide compound of formula (3) wherein R is n-acetyl or amine protecting group.
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; a) dissolving a solution of crude Elacestrant dihydrochloride (1) in one or more solvents b) isolating pure compound of Elacestrant dihydrochloride. In yet another aspect of the present invention provides, a novel compound of formula (3), formula (4), formula (4a), formula (5), formula (5a), formula (6), formula (6a), formula (7), formula (7a), formula 9, and formula (10), represented by following structures. wherein R is n-acetyl or amine protecting group The above-mentioned novel intermediate compounds are useful in the preparation of Elacestrant dihydrochloride (1).
The present invention further relates to a process for the preparation of intermediates of formula (4a), formula (5a), formula (6a), and formula (7a) with chiral purity greater than 90%.
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 more preferably 99.98% by HPLC.
DETAILED DESCRIPTION OF THE INVENTION
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 dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide 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.
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 bis(2-methyoxyethoxy) aluminumhydride, sodium triacetoxyborohydrode, Aluminium hydride(AlH3), chlorohydroalane (AIH2CI), dichloroaluminum (AIHQ2), Lithium borohydride (LiBHj), Lithium triethylborohydride (LiEtsBH), Borane(BH3), Borane tetrahydrofuran (BH3.THF), Zinc acetate(Zn(0Ac)2), Triethoxysilane ((EtOjsSiH), 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.
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, O-Acetyl-Mandelic acid, cis-2- Benzamidocyclohexanecarboxylic acid, l,l'-Binapthyl-2,2'-diyl hydrogen phosphate, Camphoric acid, 10-Camphorsulfonic acid, trans- 1,2-Cy cl ohexanedi carboxylic acid, Dibenzoyl-L-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.
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 (PK ), 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; AIH3-AICI3 ; hydrazine and a catalyst; Triiron dodecarbonyl [Fe3(CO)i2]- methanol; hot liquid paraffin; formic acid or ammonium formate and a catalyst such as palladium on carbon (Pd,C); Lithium aluminium hydride (LiAlEL) ; and sulfides such as Sodium hydrosulfide (NaHS), Diammonium sulfide (NEL^S or polysulfides.
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), lithium diisopropylamine (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) or mixtures thereof.
The term “amine protecting group” used in the present invention until unless specified is selected from, but are not limited to tert-butoxy carbonyl (BOC), benzyloxycarbonyl(CBz), triflouoroacetyl (TFA), benzyl (Bn), dibenzyl, phthalimido, tosyl (Ts), p-methoxybenzylcarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), carbamate, pmethoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p- methoxyphenyl (PMP) and benzoyl (Bz).
The present invention relates to a process for the preparation of Elacestrant dihydrochloride (I) and its novel intermediates used in the preparation of Elacestrant dihydrochloride (I). In one embodiment of the present invention, provides a process for the preparation of
Elacestrant dihydrochloride (1), comprising the steps of:
Scheme-1
Wherein R is n-acetyl or amine protecting group.
The step A) of aforementioned process involves the reaction of compound of formula (2) with compound of formula (3); in presence of reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium; a suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; 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 (4). 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.
The step B) of aforementioned process involves the reaction of compound of formula (4) 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 ethylketone, under appropriate reaction conditions to provide a compound of formula (5); 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.
The step C) of aforementioned process involves reaction of compound formula (5) 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 (6); 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.
The step D) of aforementioned process involves reaction of compound formula (6) with suitable reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium hydride; in presence of suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; under appropriate reaction conditions to provide Elacestrant , 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.
The step E) of aforementioned process involves converting Elacestrant into its salt 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 60°C-65°C to about reflux temperature of the solvent used, for a sufficient time.
In another embodiment of the present invention, provides a process for the preparation of Elacestrant dihydrochloride (1), comprising the steps of:
Scheme-2
Wherein R is n-acetyl or amine protecting group.
The step a) of aforementioned process involves the reaction of compound of formula (2) with compound of formula (3); in presence of reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium; a suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; 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 (4). 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.
The step b) of aforementioned process involves reaction of compound formula (4) 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 (5); 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.
The step c) of aforementioned process involves the reaction of compound of formula (5) with chiral resolving agent selected from (+)-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; a suitable solvent selected from but not limited to acetonitrile, acetone, methyl isobutyl ketone, methyl ethylketone, under appropriate reaction conditions to provide a compound of formula (5a); 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.
The step d) of aforementioned process involves reaction of compound formula (5a) with suitable reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium hydride; in presence of suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; under appropriate reaction conditions to provide Elacestrant , 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.
The step e) of aforementioned process involves converting Elacestrant into its salt 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 60°C-65°C to about reflux temperature of the solvent used, for a sufficient time.
In yet another embodiment of the present invention, provides a process for the preparation of Elacestrant dihydrochloride (1), comprising the steps of:
Scheme-3
Wherein R is n-acetyl or amine protecting group.
The step I) of aforementioned process involves the reaction of compound of formula (2) with Benzaldehyde in presence of reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium; a suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; 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 (6). 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.
The step II) of aforementioned process involves the reaction of compound of formula (6) 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 ethylketone, under appropriate reaction conditions to provide a compound of formula (6a); 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.
The step III) of aforementioned process involves the reaction of compound of formula (6a) with compound of formula (3); in presence of reducing agent selected from but not limited to sodium triacetoxyborohydrode, Red-Al, lithium aluminium; a suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tertbutyl ether, dioxane; 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 (7a). 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.
The step IV) of aforementioned process involves reaction of compound formula (7a) with deprotecting agent selected from but not limited to Pt, Pt,C, PtCb , Pd, Pd,C, Rh, Ru, Ni or Raney Ni; and then recti on with acetaldehyde; in presence of suitable solvent selected form but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol; under appropriate reaction conditions to provide a compound of formula (5a); The said reaction is carried out at a suitable temperature of about 25°C-40°C to about reflux temperature of the solvent used, for a sufficient time.
The step V) of aforementioned process involves reaction of compound formula (5a) with suitable reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium hydride; in presence of suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; under appropriate reaction conditions to provide Elacestrant , 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. The step VI) of aforementioned process involves converting Elacestrant into its salt 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 60°C-65°C to about reflux temperature of the solvent used, for a sufficient time.
In yet another embodiment of the present invention, provides a process for the preparation of Elacestrant dihydrochloride (1), comprising the steps of:
Scheme- 4
Wherein R is n-acetyl or amine protecting group.
The step i) of aforementioned process involves the reaction of compound of formula
(2) with Benzaldehyde in presence of reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium; a suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; 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 (6). 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.
The step ii) of aforementioned process involves the reaction of compound of formula (6) with chiral resolving agent selected from but not limited to (+)-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 ethylketone, under appropriate reaction conditions to provide a compound of formula (6a); 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.
The step iii) of aforementioned process involves the reaction of compound of formula (6a) with compound of formula (3); in presence of reducing agent selected from but not limited to sodium triacetoxyborohydrode, Red-Al, lithium aluminium; a suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tertbutyl ether, dioxane; 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 (7a). 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.
The step iv) of aforementioned process involves reaction of compound formula (7a) with deprotecting agent selected from but not limited to Pt, Pt,C, PtCb , Pd, Pd,C, Rh, Ru, Ni or Raney Ni; and then rection with acetaldehyde; in presence of suitable solvent selected form but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol; under appropriate reaction conditions to provide a compound of formula (5a); The said reaction is carried out at a suitable temperature of about 25°C-40°C to about reflux temperature of the solvent used, for a sufficient time. The step v) of aforementioned process involves reaction of compound formula (5a) with suitable reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium hydride; in presence of suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; under appropriate reaction conditions to provide Elacestrant , 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.
The step vi) of aforementioned process involves converting Elacestrant into its salt 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 60°C-65°C to about reflux temperature of the solvent used, for a sufficient time.
In yet another embodiment of the present invention, provides a process for the preparation of Elacestrant dihydrochloride (1), comprising the steps of:
Scheme-5
The stage A) of aforementioned process involves the reaction of compound of formula (2) 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 (8); 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.
The stage B) of aforementioned process involves the reaction of compound of formula
(8) with 4-vinylbenzaldehyde in presence of reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium; a suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; 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 (9). 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.
The stage C) of aforementioned process involves the reaction of compound of formula
(9) with Ethyl amine in presence of base selected from but not limited to triethylamine, methylamine, ethylamine; in presence of suitable solvent selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol, butanol, under appropriate reaction conditions to provide compound of formula (1 A), The said reaction is carried out at a suitable temperature of about 70°C-75°C to about reflux temperature of the solvent used, for a sufficient time.
The stage D) of aforementioned process involves the reaction of compound of formula (IB) with suitable chiral resolving agent selected form but not limited to (+)-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 ethylketone, under appropriate reaction conditions to provide a compound of formula (1A); 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. The stage E) of aforementioned process involves converting Elacestrant into its salt 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 60°C-65°C to about reflux temperature of the solvent used, for a sufficient time.
In yet another embodiment of the present invention, provides a process for the preparation of Elacestrant dihydrochloride (1), comprising the steps of:
Scheme-6
The stage a) of aforementioned process involves the reaction of compound of formula (2) 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 (8); 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. The stage b) of aforementioned process involves the reaction of compound of formula
(8) with 4-vinylbenzaldehyde in presence of reducing agent selected from sodium triacetoxyborohydrode, Red-Al, lithium aluminium; a suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; 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 (9). 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.
The stage c) of aforementioned process involves the reaction of compound of formula
(9) with 9-Borabicyclo[3.3.1]nonane or (9-BBN) ; in presence of suitable solvent selected from but not limited to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; under appropriate reaction conditions to provide compound of formula (10), The said reaction is carried out at a suitable temperature of about 0°C-5°C to about reflux temperature of the solvent used, for a sufficient time.
The stage d) of aforementioned process involves the reaction of compound of formula
(10) with Ethyl amine; in presence of in presence of Methanesulfonyl chloride, suitable base selected form 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 (IB). 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.
The stage e) of aforementioned process involves the reaction of compound of formula (IB) with suitable resolving agent selected form but not limited to (+)-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 ethylketone, under appropriate reaction conditions to provide a compound of formula (1A); 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.
The stage f) of aforementioned process involves converting Elacestrant into its salt 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 60°C-65°C to about reflux temperature of the solvent used, for a sufficient time.
In another embodiment of the present invention provides optionally converting Elacestrant to Elacestrant dihydrochloride premix without isolating Elacestrant dihydrochloride.
In yet another embodiment of the present invention provides a process for the preparation of N-(4-formylphenethyl) acetamide (3) as depicted in scheme-5, which comprises: p
N -(4-f ormylphenethyl)
Formula 11 Formula 12 acetamide
Formula 3
Scheme-7
The step 1) of scheme-5 process involves reacting compound of formula (11) with amino protecting agent, amino protecting agent is selected from but not limited to acetic anhydride, acetyl chloride, benzyl chloride and tert-Butyloxycarbonyl chloride; in presence of suitable solvent selected from but not limited to dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform under appropriate reaction conditions to provide compound of formula (12). 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. The step 2) of process involves reacting compound of formula (12) with 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 (3). 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.
In yet another embodiment of the present invention provides a process for the preparation of pure Elacestrant dihydrochloride (1) having purity greater than 99% which comprises; a) dissolving a solution of crude Elacestrant dihydrochloride (1) in one or more solvents b) isolating pure compound of Elacestrant dihydrochloride (1).
In yet another embodiment of the present invention provides, a novel compound of formula (3), formula (4), formula (4a), formula (5), formula (5a), formula (6), formula (6a), formula (7), formula (7a), formula 9, and formula (10), represented by following structures.
wherein R is n-acetyl or amine protecting group
The above-mentioned novel intermediate compounds are useful in the preparation of Elacestrant dihydrochloride (1). The present invention further relates to a process for the preparation of intermediates of formula (4a), formula (5a), formula (6a), and formula (7a) with chiral purity greater than 90%.
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.
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.
Examples:
Example 1: Preparation of N-(4)-bromophenethyl)acetamide (12)
100 g of 2-(4-bromophenyl)ethanamine dissolved in dichloromethane(ll) (800 mL), and cooled to 0-5°C under nitrogen atmosphere, to this solution acetic anhydride (54g) was slowly added for 1-2 hours and stirred for 5-6 hours at the same temperature, reaction mass was poured into ice cold water (500 mL) and stirred for 10-15 minutes at 25-30°C. Layers were separated and the separated organic layer was distilled under vacuum to get 115g of tittle compound. Yield %: 96%.
Example 2: Preparation of N-(4-formylphenethyl)acetamide (3)
100 g of N-(4-bromophenethyl)acetamide dissolved in 500 mL of dry tetrahydrofuran this solution was cooled to -78°C under nitrogen atmosphere, to this solution n-Butyl lithium (344 mL,2.4 M in THF) was added slowly at the same temperature. And stirred for 1 hour, 60 mL of dimethylformamide was added dropwise at the same temperature and this reaction mixture was stirred for another 1 hour. After the reaction completed, the solvent was removed under reduced pressure. The residue was dissolved in water, then the aqueous solution was extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to get 65g of tittle compound. Yield %: 82.
Example 3: Preparation of N-(4-((2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2- yl)-5-methoxyphenylamino)methyl)phenethyl)acetamide (4) (if wherein R = Acetyl group)
100 g of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (2) was dissolved in 600 mL dry tetrahydrofuran and 100 mL of Acetic acid mixture, to this solution 71 g of N-(4-formylphenethyl)acetamide (3) was added under nitrogen atmosphere at 25-30° C. The resulting mixture was cooled to 0-5°C and 158g of sodium triacetoxyborohydrode was slowly added, then the reaction mass was stirred for 10-12 hours at the same temperature. After completion of reaction, to the reaction mass 200 mL water was added and temperature was raised to 25-30°C, compound was extracted into 2x500 mL of ethyl acetate and organic layer was washed with 200 mL 20% aqueous sodium chloride solution, ethyl acetate layer was collected and distilled under vacuum completely below 45°C to get crude product. To this crude 200 mL ethyl acetate was added and temperature was raised to 50-55°C and stirred for 30 minutes at the same temperature, reaction mass was slowly cooled to 0-5°C for 2 hours, the obtained product was collected by filtration and dried get 135g of tittle compound.
Yield %: 82
Example 4: Preparation of (R)-N-(4-((2-(6-hydroxy-l,2,3,4- tetrahydronaphthalen-2-yl)-5-methoxyphenylamino) methyl) phenethyl) acetamide (4a) (if wherein R = Acetyl group)
100 g of a compound of formula (4) was dissolved in 1000 mL Acetonitrile, to this solution 81g (+)-2,3-dibenzoyl-D-tartaric acid was added 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 and maintained for sufficient time, the obtained solid product was filtered, and filter cake washed with 50 mL acetonitrile, wet material was collected and to this 300 mL 5% aqueous sodium hydroxide solution and 1000 mL dichloromethane was added, the resulting mixture stirred for 10-15 minutes and layers were separated, dichloromethane layer was collected and washed with 100 mL 20% aqueous sodium chloride solution, di chloromethane distilled completely under vacuum below 40°C to get crude product, to the reaction mass methanol (100 mL) was added and heated to 55-60 °C and stirred for 30-60 minutes clear solution was obtained, and the reaction mass was slowly cooled to 0-5 °C for 1- 2 hours and stirred for 5-6 hours. The precipitated solid product was collected by filtration and dried to get 41g of tittle compound. Yield %: 41. Example 5: Preparation of (R)-N-(4-((ethyl(2-(6-hydroxy-l,2,3,4-tetrahydro naphthalen-2-yl)-5 methoxyphenyl) amino) methyl)phenethyl) acetamide (5) (if wherein R = Acetyl group)
100 g of a compound of formula (4) was dissolved in 700 mL tetrahydrofuran and 100 mL of Acetic acid mixture, to this solution 15 g of Acetaldehyde was added at 25- 30°C. The resulting mixture was cooled to 0-5°C and 95g of sodium triacetoxyborohydrode was slowly added. The reaction mass was stirred for 6-7 hours at the same temperature. After completion of reaction, to the reaction mass 300 mL water was added and temperature was raised to 25-30°C. Compound was extracted into 3x400 mL of di chloromethane and the organic layer was washed with 300 mL 20% aqueous sodiumchloride solution, dichloromethane layer was collected and distilled under vacuum completely below 35°C to get crude product. To this crude product 500 mL isopropanol was added and temperature was raised to 70-75°C and stirred for sufficient time to obtained clear solution. The reaction mass was slowly cooled to 10-15°C for 6 hours. The obtained product was collected by filtration and dried to get 79g of tittle compound. Yield %: 74
Example 6: Preparation of (R)-N-(4-((ethyl(2-(6-hydroxy-l,2,3,4- tetrahydronaphthalen-2-yl)-5-methoxyphenyl) amino) methyl) phenethyl) acetamide (5a) (if wherein R = Acetyl group)
100 g of a compound of formula (5) was dissolved in 1000 mL acetonitrile, to this solution 81g (+)-2,3-dibenzoyl-D-tartaric acid was added 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 and maintained for sufficient time, the obtained solid product was filtered, and filter cake washed with 50 mL acetonitrile, wet material was collected and 300 mL 5% aqueous sodium hydroxide solution and 1000 mL dichloromethane was added, the resulting mixture stirred for 10-15 minutes and layers were separated, di chloromethane layer was collected and washed with 100 mL 20% aqueous sodium chloride solution, dichloromethane distilled completely under vacuum below 40°C to get crude product, to this crude product methanol (100 mL) was added and heated to 55-60°C and stirred for 30-60 minutes clear solution was obtained and slowly cooled the reaction mass to 0-5°C for 1-2 hours and stirred for 5- 6 hours. The precipitated solid product was collected by filtration and dried to get 41g of tittle compound. Yield %: 41.
Example 7: preparation of 6-(2-(benzylamino)-4-methoxyphenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol (6)
100 g of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (2) was dissolved in 600 mL of dry tetrahydrofuran and 100 mL of acetic acid mixture, to this solution 40 g of benzaldehyde was added under nitrogen atmosphere at 25-30°C. The reaction mass was cooled to 0-5°C. To the reaction mass 158g of sodium triacetoxyborohydrode was added and stirred for 10-12 hours at the same temperature. After completion of reaction, to the reaction mass 200 mL water was added and the temperature was raised to 25-30°C. Compound was extracted into 2x500 mL of Ethyl acetate and organic layer was washed with 200 mL 20% aqueous sodium chloride solution. Ethyl acetate layer was collected and distilled under vacuum completely below 45 °C to get crude product. To this crude produt 200 mL Ethyl acetate was added and temperature raised to 50-55°C and stirred for 30 minutes at the same temperature. The reaction mass slowly cooled to 0-5°C for 2 hours. The obtained product was collected by filtration and dried to get 107g of tittle compound. Yield %: 80
Example 8: Preparation of (R)-6-(2-(benzylamino)-4-methoxyphenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol (6a)
100 g of compound of formula (6) was dissolved in 1000 mL acetonitrile, to this solution 81g (+)-2,3-dibenzoyl-D-tartaric acid was added at 25-30 °C. The resulting mixture was heated to reflux and stirred for 30 minutes to get clear solution. The reaction mass was filtered over Hyflow to remove undissolved particles at 80-85°C. Filtrate was collected and slowly cooled to 25-30°C for 4-5 hours and stirred for 4-5 hours. The obtained solid product was filtered, and filter cake washed with 50 mL acetonitrile. Wet material was collected and added 300 mL 5% aqueous NaOH solution and 1000 mL di chloromethane. The resulting mixture stirred for 10-15 minutes and separated layers. Dichloromethane layer was collected and washed with 100 mL 20% aqueous sodium chloride solution. Di chloromethane distilled completely under vacuum below 40 °C to get crude product. To the reaction mass Methanol (100 mL) was added and heated to 55-60 °C and stirred for 30-60 minutes clear solution was obtained. The reaction mass was slowly cooled to 0-5 °C for 1-2 hours and stirred for 5-6 hours. The precipitated solid product was collected by filtration and dried to get 39 g of tittle compound. Yield %: 39
Example 9: Preparation of N-(4-((benzyl(2-(6-hydroxy-l,2,3,4- tetrahydronaphthalen-2-yl)-5-methoxyphenyl) amino) methyl) phenethyl) acetamide (7) (if wherein R = Acetyl group)
100 g of compound formula (6) dissolved in 600 mL dry tetrahydrofuran and 100 mL of Acetic acid mixture, to this solution 54 g of compound of formula (3) was added under nitrogen atmosphere at 25-30°C. The resulting mixture was cooled to 0-5°C and slowly added 158g of sodium triacetoxyborohydrode. Reaction mass was stirred for 10-12 hours at the same temperature. After completion of reaction, 200 mL water was added into the reaction mass and temperature raised to 25-30°C. Compound was extracted into 2x500 mL of Ethyl acetate and organic layer was washed with 200 mL 20% aqueous sodium chloride solution. Ethyl acetate layer was collected and distilled under vacuum completely below 45°C to get crude product. 200 mL Ethyl acetate was added into crude product and temperature raised to 50-55°C and stirred for 30 minutes at the same temperature. Reaction mass slowly cooled to 0-5°C for 2 hours. The obtained product was collected by filtration and dried to get 116g of tittle compound.
Yield %: 78
Example 10: preparation of N-(4-((benzyl(2-(6-hydroxy-l,2,3,4- tetrahydronaphthalen-2-yl)-5-methoxyphenyl) amino) methyl) phenethyl) acetamide (7a) (if wherein R = Acetyl group)
100 g of compound of formula (7) dissolved in 1000 mL Acetonitrile, to this solution 81g (+)-2,3-dibenzoyl-D-tartaric acid was added at 25-30 °C. The resulting mixture was heated to reflux and stirred for 30 minutes. Reaction mass was filtered over Hyflo to remove undissolved particles at 80-85°C. Filtrate was cooled to 25-30°C and solid was filtered, and the cake was washed with 50 mL Acetonitrile. Wet material was collected, and 300 mL 5% aqueous sodium hydroxide solution and 1000 mL di chloromethane were added. The resulting mixture was stirred for 10-15 minutes and separated layers. Dichloromethane layer was collected and washed with 100 mL 20% aqueous sodium chloride solution. Di chloromethane distilled completely under vacuum below 40 °C to get crude product. Methanol (100 mL) was added to the reaction mass and heated to 55-60 °C and stirred for 30-60 minutes to get clear solution. The reaction mixture was cooled to 0-5 °C and the precipitated solid was collected by filtration and dried to get 39 g of tittle compound. Yield %: 39
Example 11: preparation of 6-(2-(ethylamino)-4-methoxyphenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol (8)
100 g of 6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (2) was dissolved in 600 mL dry tetrahydrofuran and 100 mL of acetic acid mixture to this solution 30 g of acetaldehyde was added under nitrogen atmosphere at 25-30 °C. The resulting mixture was cooled to 0-5°C and 158g of sodium triacetoxyborohydrode was slowly added. Reaction mass was stirred for 10-12 hours at the same temperature. After completion of reaction, to the reaction mass 200 mL water was added and temperature raised to 25-30°C. Compound was extracted into 2x500 mL of Ethyl acetate and organic layer was washed with 200 mL 20% aqueous sodium chloride solution. Ethyl acetate layer was collected and distilled under vacuum completely below 45°C to get crude product. To this crude 200 mL Ethyl acetate was added and temperature raised to 50-55°C and stirred for 30 minutes at the same temperature. Reaction mass slowly cooled to 0-5°C for 2 hours. The obtained product was collected by filtration and dried to get 105 g of tittle compound. Yield%: 74
Example 12: preparation of 6-(2-(ethyl(4-vinylbenzyl)amino)-4-methoxyphenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol (9)
100 g of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (8) was dissolved in 600 mL dry tetrahydrofuran and 100 mL of acetic acid mixture to this solution 45 g of 4-vinylbenzaldehyde was added under nitrogen atmosphere at 25-30 °C. The resulting mixture was cooled to 0-5°C and 145 g of sodium triacetoxyborohydrode was slowly added. Reaction mass was stirred for 10-12 hours at the same temperature. After completion of reaction, to the reaction mass 200 mL water was added, and temperature raised to 25-30°C. Compound was extracted into 2x500 mL of ethyl acetate and organic layer was washed with 200 mL 20% aqueous sodium chloride solution. Ethyl acetate layer was collected and distilled under vacuum completely below 45°C to get crude product. To this crude 200 mL Ethyl acetate was added and temperature raised to 50-55°C and stirred for 30 minutes at the same temperature. Reaction mass slowly cooled to 0-5°C for 2 hours. The obtained product was collected by filtration and dried to get 90.5 g of tittle compound. Yield%: 82
Example 13: preparation of 6-(2-(ethyl(4-(2-hydroxyethyl)benzyl)amino)-4- methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (10)
100 g of 6-(2-(ethyl(4-vinylbenzyl)amino)-4-methoxyphenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol (9) dissolve in 100 mL Tetrahydrofuran (THF) was cooled to 0-5 °C. To the reaction mixture 500 mL 9-Borabicyclo[3.3.1]nonane (9-BBN) (0.5M in THF) was added over a period of 2-3 hours and stirred for 4-5 hours at 0-5 °C. This solution was treated with 100 mL H2O2 solution followed by 200 mL NaOH (4 M solution) was added and stirred for 6-8 hours at 25-30 °C. Reaction mixture was diluted with 200 mL water and product extracted with 2x500 mL ethyl acetate. Combined ethyl acetate layers washed with 500 mL of 20% NaCl solution and distilled under vacuum to get 74 g title compound. Yield: 71%.
Example 14: Preparation of racemic Elacestrant (IB).
100 g of 6-(2-(ethyl(4-(2-hydroxyethyl)benzyl)amino)-4-methoxyphenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol (10) was dissolved in 700 mL dichloromethane, this solution was cooled to 0-5 °C to the reaction mass 50 mL triethylamine and 30 g methanesulfonyl chloride was added. The reaction mixture was stirred for 60 minutes and followed by water was added and layers are separated at 25-30 °C. Organic layer distilled under vacuum and 500 mL tetrahydrofuran was added to the compound at 25- 30 °C. Reaction mixture was cooled to 0-5 °C and purged 20 g Ethyl amine gas to the reaction mixture. Temperature raised slowly to 25-30 °C and stirred for 24 hours. After completion reaction, tetrahydrofuran was distilled under vacuum to get crude product which was isolated from ethanol to get pure 72g of tittle compound. Yield%: 68
Example 15: Preparation of Elacestrant (1A)
100 g of 6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-m ethoxyphenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol (IB) was dissolved in 1000 mL acetonitrile to this solution 79g (+)-2,3-dibenzoyl-D-tartaric acid was added at 25-30 oC. The resulting mixture was heated to reflux and stirred for 30 minutes, and clear solution was obtained. Reaction mass was filtered over Hyflow to remove undissolved particles at 80-85°C. Filtrate was collected and slowly cooled to 25-30°C for 4-5 hours and stirred for 4-5 hours. The obtained solid product was filtered, and filter cake washed with 50 mL acetonitrile. Wet material was collected and added 300 mL 5% aqueous sodium hydroxide solution and 1000 mL di chloromethane. The resulting mixture stirred for 10-15 minutes and layers were separated. Di chloromethane layer was collected and washed with 100 mL 20% aqueous sodium chloride solution. Dichloromethane distilled completely under vacuum below 40°C to get crude product. To this crude product 100 mL of Methanol was added and the reaction mass heated to 55-60°C and stirred for 30-60 minutes and solution obtained. Slowly cooled the reaction mass to 0- 5 °C for 1-2 hours and stirred for 5-6 hours. The precipitated solid product was collected by filtration and dried to get tittle 35g of compound. Yield%: 35
Example 16: Preparation of Elacestrant (1A)
100g (R)-N-(4-((ethyl(2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5 methoxy phenyl)amino)methyl)phenethyl)acetamide (5 a) if wherein R = Acetyl group was dissolved in tetrahydrofuran (500 mL), to this 150g Red-Al was added at 25-30°C. Resulting mixture was slowly heated to 70-80 °C and maintained for 60 minutes, continued stirring till completion of reaction (10-12 hours) at the same temperature. After completion of reaction, mass was cooled to 25-30°C and added 1000 mL ethyl acetate followed by 500 mL water and stirred for 10 hours, layers were separated, and ethyl acetate was collected and distilled under vacuum below 45°C. Ethanol (500 ml) was added and heated to 60-65 °C and stirred for 4-5 hours, reaction mass was slowly cooled to 25-30 °C. Solid product was filtered and dried to get 60g of title product. Yield %: 62g; Purity: 99.95
Example 17: Preparation of Elacestrant dihydrochloride (1)
100g Elacestrant was dissolved in 800 mL Ethanol, to this 200 mL of 20% hydrochloric acid in ethanol was added at 25-30°C, reaction mixture was heated to 60- 65°C and stirred for 60 minutes. The reaction mass was cooled to 25-30°C and maintained for 2-3 hours and stirred for another 4 hours. The obtained product was collected by filtration and dried under vacuum to get 80g of tittle compound.
Yield%: 78 Purity (%): 99.98 Example 18: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP)
Elacestrant free base (5.0 g) was added to methanol (15 vol) at room temperature and stirred to get a clear solution. To the obtained solution, aqueous hydrochloric acid (1.1 eq) was added. To this methylene dichloride (25 vol) was added and stirred, then
Polyvinylpyrrolidone (PVP) (4.0 g) was added to the reaction mixture and stirred to get a clear solution. Spray dried the obtained solution using spray dryer through following conditions:
Inlet Temperature : 75 °C
Outlet Temperature : 45°C
Aspirator : 70%
Feeding rate : 20 mL/min
N2 Pressure : 2.0 kg/cm2
Yield: 75%;

Claims

We Claim:
1. A process for the preparation of Elacestrant dihydrochloride (1),
Elacestrant diydrochloride (1) which comprises: A) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (2)
Formula 2 with compound of formula (3);
Formula 3 wherein R is n-acetyl or amine protecting group. in presence of suitable reducing agent, solvent and acid to provide compound of formula (4); wherein R is n-acetyl or amine protecting group.
B) resolving the compound of formula (4) with chiral resolving agent in presence of suitable solvent to provide compound of formula (4a);
Formula 4a wherein R is n-acetyl or amine protecting group.
C) reductive amination of the compound of formula (4a) with acetaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula (5a); wherein R is n-acetyl or amine protecting group. D) reducing the compound of formula (5a) with suitable reducing agent in presence of suitable solvent to provide Elacestrant (1 A);
E) converting Elacestrant into Elacestrant dihydrochloride (1).
2. A process for the preparation of Elacestrant dihydrochloride (1),
Elacestrant diydrochloride (1) which comprises: a) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (2)
Formula 2 with compound of formula (3)
Formula 3 in presence of suitable reducing agent, solvent and acid to provide compound of formula (4); b) reductive amination of the compound of formula (4) with acetaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula (5); c) resolving the compound of formula (5) with chiral resolving agent in presence of suitable solvent to provide compound of formula (5a); d) reducing the compound of formula (5a) with suitable reducing agent in presence of suitable solvent to provide Elacestrant(l A); e) converting Elacestrant into Elacestrant dihydrochloride (1).
3. A process for the preparation of Elacestrant dihydrochloride (1),
Elacestrant dihyrochloride (1) which comprises:
I) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (2)
Formula 2 with benzaldehyde in presence of suitable reducing agent, solvent and acid to provide compound of formula (6);
Formula 6
II) resolving the compound of formula (6) with chiral resolving agent in presence of suitable solvent to provide compound of formula (6a);
Formula 6a III) reacting the compound of formula (6a) with a compound of formula (3) in presence of suitable reducing agent, solvent and acid to provide a compound of (7a);
IV) deprotecting the compound of formula (7a) with suitable deprotecting agent and acetaldehyde in presence of suitable solvent to provide a compound of (5a);
Formula 5a V) reducing the compound of formula (6) with suitable reducing agent in presence of suitable solvent to provide Elacestrant(l A);
Elacestrant (1A)
VI) converting Elacestrant into Elacestrant dihydrochloride (1)
4. A process for the preparation of Elacestrant dihydrochloride (1),
Elacestrant dihyrochloride (1) which comprises: i) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (2) with benzaldehyde in presence of suitable reducing agent, solvent and acid to provide compound of formula (6);
Formula 6 ii) reacting the compound of formula (6) with a compound of formula (3) in presence of suitable reducing agent, solvent and acid to provide a compound of (7); iii) resolving the compound of formula (7) with chiral resolving agent in presence of suitable solvent to provide compound of formula (7a); iv) deprotecting the compound of formula (7a) with suitable deprotecting agent and acetaldehyde in presence of suitable solvent to provide a compound of (5a); v) reducing the compound of formula (5a) with suitable reducing agent in presence of suitable solvent to provide Elacestrant(l A);
Elacestrant(lA) vi) converting Elacestrant into Elacestrant dihydrochloride (1).
5. A process for the preparation of Elacestrant dihydrochloride (1),
Elacestrant dihyrochloride (1) which comprises:
Stage A) reacting 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2- ol (2)
Formula 2 with acetaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula (8).
Formula 8
Stage B) reacting compound of formula (8) with vinyl benzaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula 9;
Stage C) reacting the compound of formula (9) with ethylamine in presence of suitable solvent and base to provide Elacestrant racemic compound (IB); Stage D) resolving the Elacestrant (1A) with suitable chiral resolving agent in presence of suitable solvent to provide Elacestrant (1 A).
Stage E) converting Elacestrant into Elacestrant dihydrochloride (1). 6. A process for the preparation of Elacestrant dihydrochloride (1),
Elacestrant dihyrochloride (1) which comprises:
Stage a) reacting 6-(2-amino-4-methoxyphenyl)-5,
6,7,8-tetrahydronaphthalen-2- ol (2)
Formula 2 with acetaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula (8).
Formula 8
Stage b) reacting compound of formula (8) with vinyl benzaldehyde in presence of suitable reducing agent, solvent, and acid to provide compound of formula 9;
Stage c) reacting the compound of formula (9) with 9-Borabicyclo[3.3.1]nonane or (9-BBN) in presence of suitable solvent to provide compound of
Stage d) reacting compound of formula (10) with Ethyl amine in presence of Methanesulfonyl chloride, suitable base and suitable solvent to provide Elacestrant (IB);
Stage e) resolving the Elacestrant (IB) with suitable chiral resolving agent in presence of suitable solvent to provide Elacestrant (1 A).
Stage f) converting Elacestrant into Elacestrant dihydrochloride (1).
7. The process as claimed in preceding claims 1-6, wherein suitable solvent is selected from methanol, ethanol, isopropyl alcohol, n-propanol, butanol, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, toluene, xylene, cyclohexane, hexane, heptane, n-pentane dichloromethane, ethylene dichloride, dimethylformamide, dimethylacetamide, dimethylsulfoxide acetonitrile, acetone, methyl isobutyl ketone, methyl ethyl ketone, water, and reducing agent is selected from sodium triacetoxyborohydrode, Rhodium on alumina (Rh,Al), Platinum on (Pt,C), Ruthenium (Ru,C), Platinum (IV) Oxide (PK ), Sodium bis(2- methoxyethoxy)aluminium hydride (Red-Al), chiral resolving agent selected from Dibenzoyl-L-Tartaric acid, 10-Camphorsulfonic acid, Pyroglutamic acid, and acid selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, formic acid, acetic acid and base selected from sodium carbonate, potassium carbonate, lithium carbonate deprotecting agent selected from Platinum (Pt), Platinum on carbon (Pt,C), Platinum (IV) Oxide (PtO2), Palladium (Pd), Palladium on carbon (Pd,C).
8. A process for the preparation of a compound of (3),
Formula 3 which comprises: reacting 2-(4-bromophenyl)ethanamine(l 1)
Formula 11 with amine protecting agent in presence of suitable solvent to provide a compound of (12)
Formula 12 reacting compound of formula (12) with suitable base in presence suitable solvent to provide compound of formula (3) 9. The process as claimed in preceding claims 8, wherein amino protecting agent is acetic anhydride, acetyl chloride, benzyl chloride and tert-Butyloxycarbonyl chloride; and suitable solvent selected from dichloromethane, ethylene dichloride, carbon tetrachloride chloroform and base selected form but not limited to triethylamine, pyridine, and n-butyl lithium. 10. A compound selected from:
Formula 10 wherein R is n-acetyl or amine protecting group
PCT/IB2025/053575 2024-04-04 2025-04-04 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 Pending WO2025210581A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113348163A (en) * 2019-02-12 2021-09-03 雷迪厄斯制药公司 Methods and compounds
WO2023064519A1 (en) * 2021-10-14 2023-04-20 Teva Pharmaceuticals International Gmbh Solid state forms of elacestrant and processes for preparation thereof
WO2025055671A1 (en) * 2023-09-13 2025-03-20 奥锐特药业(天津)有限公司 Method for synthesizing elacestrant and intermediate thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113348163A (en) * 2019-02-12 2021-09-03 雷迪厄斯制药公司 Methods and compounds
WO2023064519A1 (en) * 2021-10-14 2023-04-20 Teva Pharmaceuticals International Gmbh Solid state forms of elacestrant and processes for preparation thereof
WO2025055671A1 (en) * 2023-09-13 2025-03-20 奥锐特药业(天津)有限公司 Method for synthesizing elacestrant and intermediate thereof

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