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WO2023119333A1 - Procédé de préparation de rélugolix et de ses intermédiaires - Google Patents

Procédé de préparation de rélugolix et de ses intermédiaires Download PDF

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Publication number
WO2023119333A1
WO2023119333A1 PCT/IN2022/051121 IN2022051121W WO2023119333A1 WO 2023119333 A1 WO2023119333 A1 WO 2023119333A1 IN 2022051121 W IN2022051121 W IN 2022051121W WO 2023119333 A1 WO2023119333 A1 WO 2023119333A1
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Prior art keywords
formula
compound
relugolix
process according
preparation
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PCT/IN2022/051121
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Inventor
Srinivas ORUGANTI
Saikat Sen
Magesh SAMPATH
Vishnu Vardhana Vema Reddy EDA
Rehani Rajeev Budhdev
Naga Raju M
Sreenadha Charyulu K
Veera Venkata Satyanarayana Chiranjeevi GEDA
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Dr Reddys Laboratories Ltd
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Dr Reddys Laboratories Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present application relates to a process for preparation of relugolix or its pharmaceutically acceptable salts thereof.
  • the present application also provide process for preparation of Relugolix crystalline Form Rl.
  • Relugolix is a gonadotropin-releasing hormone antagonist (GnRH antagonist) which is under development for use in treatment of endometriosis and prostate cancer.
  • GnRH antagonist gonadotropin-releasing hormone antagonist
  • Relugolix is chemically known as N-[4-[l-[(2,6-difhrorophenyl)methyl]-5- [(dimethylamino]-methyl]-3-(6-methoxy-3- pyridazinyl]-2,4-dioxo-l,2,3,4-tetrahydro- thieno[2,3-d]pyrimidin-6-yl]phenyl]-N’-methoxyurea and has following structural formula:
  • W02004067535A1 discloses relugolix specifically for the first time.
  • First aspect of the present application relates to a process for preparation of Relugolix (I) or pharmaceutically acceptable salts thereof, comprising converting compound of formula (II) to Relugolix (I) or pharmaceutically acceptable salts thereof using halo compound of formula (A).
  • R is Ri or O-R2;
  • R1 and R2 is a linear or branched alkyl group having 1- 10 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl -alkyl group having 7- 12 carbon atoms;
  • X is a halogen.
  • Second aspect of the present application relates to a process for preparation of Relugolix (I) or pharmaceutically acceptable salts thereof comprising reacting compound of formula (II) with phenyl chloroformate and methoxy amine to get Relugolix (I) or pharmaceutically acceptable salts thereof
  • Third aspect of the present application relates to a process for preparation of Relugolix (I) or pharmaceutically acceptable salts thereof, comprising the steps of: a) converting compound of formula (XI) to a compound of formula (X) b) reacting compound of formula (X) with 2,6-difluorobenzyl halide to form compound of formula (IX) c) converting compound of formula (IX) to a compound of formula (VII) d) hydrolysis of compound of formula (VII) to compound of formula (VI)
  • Fourth aspect of the present application relates to compounds of formula wherein, X is a halogen.
  • Pi and P2 are independently a hydrogen or an amine protecting group, provided that Pi and P2 both are not a hydrogen.
  • Fifth aspect of the present application relates to the conversion of any one of compounds of formula selected from (XI), (Xia), (X), (Xa), (IX), (IXa), (VIII), (Villa), (VII), (Vila), (VI), (Via), (V), (Va), (IV), (IVa), (III) and (Illa) to Relugolix (I) or pharmaceutically acceptable salts thereof.
  • Sixth aspect of the present application relates to the use of any one of compounds of formula selected from (XI), (Xia), (X), (Xa), (IX), (IXa), (VIII), (Villa), (VII), (Vila), (VI), (Via), (V), (Va), (IV), (IVa), (III) and (Illa) for the preparation of Relugolix (I) or pharmaceutically acceptable salts thereof.
  • Seventh aspect of the present application relates to the process for preparation of crystalline form R1 of relugolix comprising: a) providing a solution of relugolix in a suitable first solvent or mixtures thereof; b) stirring the solution for sufficient time; and c) adding second solvent selected from nitrile, alcohol, water or mixture thereof d) isolating crystalline form R1 of relugolix.
  • First aspect of the present application relates to a process for preparation of Relugolix (I) or pharmaceutically acceptable salts thereof, comprising converting compound of formula (II) to Relugolix (I) or pharmaceutically acceptable salts thereof using halo compound of formula (A).
  • R is Ri or O-R2;
  • R1 and R2 is a linear or branched alkyl group having 1- 10 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl -alkyl group having 7- 12 carbon atoms;
  • X is a halogen.
  • Step (i) involves the reaction of compound of formula (II) with the compound of formula (A).
  • step (ii) the compound obtained in step (i) was reacted with methoxy amine to get the Relugolix (I)
  • Suitable solvents that may be used in the step (i) and step (ii) include but not limited to polar aprotic solvents, nitriles, halogenated hydrocarbons, ketones, esters, ethers, or any mixtures thereof.
  • Suitable base that may be used in step (i) include but not limited to organic bases such as, triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP), N-methyl pyrrolidone, Imidazole, diethylamine, hexylamine, 2,6-lutidine, piperidine, morpholine and the like; metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal phosphate base such as potassium phosphate, sodium phosphate and the like; metal carbonate bases such as potassium carbonate, cesium carbonate and the like.
  • organic bases such as, triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP), N-methyl pyrrolidone, Imidazole, diethylamine, hexylamine, 2,6-lutidine, piperidine
  • Second aspect of the present application relates to a process for preparation of Relugolix (I) or pharmaceutically acceptable salts thereof comprising reacting compound of formula (II) with phenyl chloroformate and methoxy amine to get Relugolix (I) or pharmaceutically acceptable salts thereof
  • Third aspect of the present application relates to a process for preparation of Relugolix (I) or pharmaceutically acceptable salts thereof, comprising the steps of: a) converting compound of formula (XI) to a compound of formula (X) b) reacting compound of formula (X) with 2,6-difluorobenzyl halide to form compound of formula (IX)
  • Step a) involves converting compound of formula (XI) to a compound of formula (X)
  • Suitable solvent that may be used in step (a) include ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or any mixtures thereof.
  • Step (b) involves reaction of compound of formula (X) with 2,6-difluorobenzyl chloride to form compound of formula (IX)
  • Suitable solvent that may be used in step (b) include ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or any mixtures thereof.
  • Suitable base that may be used in step (b) include but not limited to metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal carbonate bases such as potassium carbonate, sodium carbonate and the like; metal hydroxide bases such as lithium hydroxide, sodium hydroxide and the like; organometallic base, such as lithium diisopropylamide (LDA), n-butyl lithium, lithium bis(trimethylsilyl)amide (LiHMDS) and the like; organic bases such as triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP), 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) and the like.
  • metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like
  • metal carbonate bases such as potassium carbonate, sodium carbonate and the like
  • metal hydroxide bases such as lithium
  • Step b) further comprise the use of catalytic amounts of metal halide such as potassium iodide.
  • the reaction may be carried out at a temperature of about 10 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature about 25 °C to about 35 °C.
  • Step c) involves converting compound of formula (IX) to a compound of formula (VII)
  • Conversion of compound of formula (IX) to a compound of formula (VII) involves halogenation of compound of Formula (IX) followed by amination.
  • Suitable halogenating agents that may be used in step (c) include but not limited to N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), N-chlorosuccinimide (NCS), azobisisobutyronitrile (AIBN) or any other suitable halogenating agent known in the art.
  • Suitable bases that may be used in amination reaction include but not limited to triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP) and the like.
  • DIPEA diisopropylethylamine
  • DMAP dimethylaminopyridine
  • Suitable solvent that may be used in step (c) include ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or any mixtures thereof.
  • Step d) involves conversion of compound of formula (VII) to compound of formula (VI)
  • Suitable base that may be used in step (d) include but not limited to metal carbonate bases such as potassium carbonate, sodium carbonate and the like; metal hydroxide bases such as lithium hydroxide, sodium hydroxide and the like.
  • Suitable solvent that may be used in step (d) include water, alcohols, ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or any mixtures thereof.
  • Step e) involves conversion of compound of formula (VI) to compound of formula (V)
  • Suitable base that may be used in step (e) include but not limited to triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP) and the like.
  • DIPEA diisopropylethylamine
  • DMAP dimethylaminopyridine
  • Suitable coupling agent that may be used in step (e) include but not limited to Carbonyl diimidazole (CDI), Dicyclohexylcarbodiimide (DCC), Propylphosphonic anhydride (cyclic trimer, T3P), O-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-CI), 2-Chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), N-(Dimethylaminopropyl)-N'-ethyl- carbodiimide.
  • CDI Carbonyl diimidazole
  • DCC Dicyclohexylcarbodiimide
  • T3P Propylphosphonic anhydride
  • HBTU O-(Benzotriazol-l-yl)-N
  • Suitable solvent that may be used in step (e) include alcohols, ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or any mixtures thereof.
  • the reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature about 55 °C to about 70 °C.
  • Step f) involves conversion of compound (V) to compound of formula (IV)
  • Suitable base that may be used in step (f) include but not limited to metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal carbonate bases such as potassium carbonate, sodium carbonate and the like; metal hydroxide bases such as lithium hydroxide, sodium hydroxide and the like; organometallic base, such as lithium diisopropylamide (LDA), n-butyl lithium, lithium bis(trimethylsilyl)amide (LiHMDS) and the like; organic bases such as triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP), 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) and the like.
  • metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like
  • metal carbonate bases such as potassium carbonate, sodium carbonate and the like
  • metal hydroxide bases such as lithium
  • Suitable solvent that may be used in step (f) include alcohols, ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or any mixtures thereof.
  • the reaction may be carried out at a temperature of about -35 °C to about boiling point of the solvent. Specifically, the reaction carried out at a temperature about 55 °C to about 70 °C.
  • Step g) involves conversion of compound of formula (IV) to compound of formula (III)
  • Compound of formula (IV) is converted to compound of formula (III) by reacting compound of formula (IV) with a suitable ammonia surrogate in presence of suitable catalyst and base in a suitable solvent.
  • Suitable ammonia surrogates that may be used in step (g) include but not limited to B0CNH2, CbzNH2, FmocNI , TsNEL, NsNEL, B0C2NH, benzophenone imine, sodium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide and the like.
  • Suitable catalyst that may be used in step (g) include but not limited to palladium catalyst such as Pdildba); or any other suitable catalyst known in the art.
  • Suitable base that may be used in step (g) include but not limited to metal carbonate bases such as potassium carbonate, cesium carbonate and the like; metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal phosphates such as potassium phosphate, sodium phosphate and the like; organic bases such as triethylamine, diisopropylethylamine (DIPEA) and the like; metal carbonate such as potassium carbonate, cesium carbonate and the like.
  • metal carbonate bases such as potassium carbonate, cesium carbonate and the like
  • metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like
  • metal phosphates such as potassium phosphate, sodium phosphate and the like
  • organic bases such as triethylamine, diisopropylethylamine (DIPEA) and the like
  • metal carbonate such as potassium carbonate, cesium carbonate and the like.
  • Suitable solvent that may be used in step (g) include ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or any mixtures thereof.
  • the reaction may be carried out at a temperature of about 40 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature about 70 °C to about 90 °C.
  • Step h) involves conversion of compound of formula (III) to compound of formula (II)
  • Suitable solvents that may be used in step (h) include water, alcohols, ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or any mixtures thereof.
  • the reaction may be carried out at a temperature of about 10 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature about 20 °C to about 30 °C.
  • Step i) involves conversion of compound of formula (II) to Relugolix of formula (I).
  • Suitable base that may be used in step (i) include but not limited to organic bases such as, triethylamine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP) and the like; metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal phosphate base such as potassium phosphate, sodium phosphate and the like; metal carbonate bases such as potassium carbonate, cesium carbonate and the like.
  • organic bases such as, triethylamine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP) and the like
  • metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like
  • metal phosphate base such as potassium phosphate, sodium phosphate and the like
  • metal carbonate bases such as potassium carbonate, cesium carbonate and the like.
  • Suitable solvents that may be used in the step (i) include but not limited to polar aprotic solvents, nitriles, halogenated hydrocarbons, ketones, esters, ethers, or any mixtures thereof.
  • compound of formula (IX) or (IXa) can be prepared by any method known in the art. Particularly, compound of formula (IX) or (IXa) can be prepared in an analogous manner to the process disclosed in EP300972A1.
  • Seventh aspect of the present application relates to the process for preparation of crystalline form R1 of relugolix comprising: a) providing a solution of relugolix in a suitable first solvent or mixtures thereof; b) stirring the solution for sufficient time; and c) adding second solvent selected from nitrile, alcohol, water or mixture thereof d) isolating crystalline form R1 of relugolix.
  • step (a) involves the use of any physical form of the Relugolix known in the literature may be used.
  • Suitable first solvents that may be used in step (a) include polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, dimethylacetamide and the like or any other suitable solvents.
  • Suitable second solvents that may be used in step (c) include nitrile, alcohol, water or mixture thereof, preferably acetonitrile, methanol or ethanol or mixture thereof.
  • a name used herein to characterize a crystalline form should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information also presented herein.
  • the terms “comprising” and “comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited.
  • the terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
  • Halogen is defined as non-metallic elements found in group VII of the periodic table and is selected from fluorine, bromine, chlorine and iodine.
  • Alkyl group having 1-10 carbon atoms is defined as straight or branched chain alkyl having 1-6 carbon atoms. Examples may be methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl and the like.
  • Aryl group having 6-12 carbon atoms is defined as monocyclic, bicyclic, and tricyclic ring systems having a total of six to twelve ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl group having 6-12 carbon atoms also refers to “heteroaryl” ring systems.
  • heteroaryl refers to monocyclic, bicyclic, and tricyclic ring systems having a total of six to twelve ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members.
  • Aryl or hetero aryl may optionally substituted with alkyl or halogen.
  • Aryl -alkyl group having 7-12 carbon atoms is defined as an aryl group, as previously defined, attached to the principal carbon chain through an alkyl group, as previously defined. “Substitution” on an “Aryl-alkyl group having 7-12 carbon atoms” is defined by a substitution over the aryl group. Examples may be benzyl, 4-methoxy- benzyl and the like.
  • Amino protecting group is defined as any amino protecting group as known in Greene et al., Protecting groups in organic chemistry, Third Edition, 1999. Examples include benzyloxycarbonyl (Cbz) and tert-Butyloxycarbonyl (Boc), acetyl and the like Preferably, the amino protecting group may be tert-Butyloxycarbonyl (Boc).
  • C1-C6 alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2- propanol (isopropyl alcohol), 2-methoxyethanol, 1 -butanol, 2-butanol, i-butyl alcohol, t- butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3 -pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, phenol, glycerol and the like.
  • hydrocarbon solvent is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds or aromatic.
  • C5-C15 aliphatic or aromatic hydrocarbons include n-pentane, isopentane, neopentane, n-hexane, isohexane, 3 -methylpentane, 2,3 -dimethylbutane, neohexane, n-heptane, isoheptane, 3 -methylhexane, neoheptane, 2,3 -dimethylpentane, 2,4-dimethylpentane, 3, 3 -dimethylpentane, 3 -ethylpentane, 2,2,3-trimethylbutane, n- octane, isooctane, 3 -methylheptane, neooctane,
  • ether is an organic compound containing an oxygen atom -O- bonded to two other carbon atoms.
  • C2-C6 ethers include diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole and the like.
  • halogenated hydrocarbon is an organic compound containing a carbon bound to a halogen.
  • Halogenated hydrocarbons include dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1 -trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride and the like.
  • C3-C10 esters include ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate and the like.
  • C3-C10 ketones include acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones and the like.
  • C2-C6 Nitriles include acetonitrile, propionitrile, butanenitrile and the like.
  • a “polar aprotic solvents” include N, N-dimethylformamide, N, N- dimethylacetamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone and the like;
  • N-bromosuccinimide (7.28 g) and AIBN (0.664 g) was added to a solution of ethyl 5-(4-chlorophenyl)-2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4- methylthiophene-3 -carboxylate (20.0 g) in ethyl acetate (200 mL) under nitrogen atmosphere at ambient temperature.
  • the reaction mixture was heated to 85 °C and stirred at the same temperature for about 22 hours.
  • N, N-Diisopropylethylamine (2.43 mL) and 3-amino-6-methoxypyridazine (1.72 g) was added to a solution of ethyl 5-(4-chlorophenyl)-2-((2,6-difluorobenzyl) (ethoxycarbonyl)amino)-4-((dimethylamino)methyl)thiophene-3-carboxylic acid (5 g) in N, N-dimethylacetamide (25.0 mL) at ambient temperature.
  • reaction mixture was heated to 50 °C and propyl phosphoric anhydride (T3P) (9.4 mL, 50% solution in ethyl acetate) was slowly added at 50 °C. The resultant mixture was stirred at 50 °C for 2 hours. Water (50 mL) was added to the reaction mixture at ambient temperature and the reaction mass pH was adjusted to 8-8.5 using IN sodium hydroxide.
  • T3P propyl phosphoric anhydride
  • Example 8 Preparation of tert-butyl (4-(l-(2,6-difluorobenzyl)-5- ((dim ethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-l, 2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)carbamate (Illa):
  • reaction mixture was heated to 85 °C and stirred at the same temperature for about 16 hours.
  • Reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (20 mL).
  • the reaction mixture was filtered through a cilite pad and washed with ethyl acetate (50 mL).
  • Trifluroacetic acid (11 m ) was slowly added to a solution of tert-butyl (4-(l- (2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo- l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)carbamate (1.1 g) in dichloromethane (11 mL) at 0 °C and the resultant reaction mixture was stirred at ambient temperature for about 16 hours.
  • Phenyl chloroformate (213 mg) in in acetonitrile (1 mL) was slowly added to the solution of 6-(4-aminophenyl)-l-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (0.5 g) in acetonitrile (5 mL) at 0 °C and the resultant reaction mixture was stirred at ambient temperature for 3 hours.
  • Reaction mixture was concentrated under reduced pressure to obtain the crude phenylcarbamate intermediate, which was then triturated with methyl tert-butyl ether (5 mL) and dried under vacuum.
  • the resulting solid (620 mg) was mixed with tetrahydrofuran (6.0 mL) and acetonitrile (6.0 mL) at ambient temperature under nitrogen atmosphere.
  • N, N-diisopropylethylamine (DIPEA) (469 mg) and methoxyamine hydrochloride (90.9 mg) were added.
  • DIPEA N-diisopropylethylamine
  • methoxyamine hydrochloride 90.9 mg
  • Reaction mixture was quenched with ice cold water (50 mL) and extracted with ethyl acetate (2 X 50 mL). Combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude material as an orange colored oil, which was then purified by silica gel column chromatography (10-15% methanol in DCM) to obtain a pale yellow oil, which was then triturated with methyl tert-butyl ether (5 mL) to obtain the title compound as a pale yellow solid. (330 mg).
  • 6-(4-aminophenyl)-l-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione (5 g) and acetonitrile (50 mL) charged in to flask and cooled to 2 °C. Pyridine (1.44 g) was added to the solution at 2 °C and stirred for 15 minutes.
  • Phenyl chloroformate (2.13 g) in acetonitrile (10 mL) was slowly added to the reaction mass at 0 °C and the resultant reaction mixture was stirred at ambient temperature for 3 hours. Reaction mixture was concentrated under reduced pressure and methyl / rt-but l ether (50 mL) was added and stirred for 90 minutes. Filtered the reaction mass, washed with methyl tert-butyl ether (10 mL) and dried under vacuum. The resulting solid and dimethylacetamide (25 mL) charged into flask.
  • Methyl / rt-but l ether (50 mL) was added to the reaction mass at 10 °C and stirred for 20 minutes at ambient temperature. Filtered the reaction mass, washed with methyl tert-butyl ether (10 mL) and dried under vacuum. The resulting solid and dimethylacetamide (25 mL) charged into flask. Diisopropylethylamine (4.69 g) and methoxyamine hydrochloride (0.91 g) charged into flask and the resultant reaction mixture was heated to 70 °C and stirred for 3 hours at the same temperature. Water (100 mL) was added to the reaction mass at ambient temperature and stirred for 30 minutes.
  • Relugolix (5 g) and dimethylsulfoxide (10 mL) charged into flask, heated to 45 °C and stirred for 15 minutes. Acetonitrile (125 mL) was added to the reaction mass at 30°C.
  • Relugolix Form Rl seed (prepared by following procedure given in W02020230094A1) solution with 1.0% seed was added and the resultant reaction mass was stirred for 30 minutes at ambient temperature, cooled to 0 °C and stirred at 0 °C for 2 hours. Filtered the reaction mass, washed with pre-cooled acetonitrile (15 mL) and dried at 80 °C to afford title compound.

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  • Pregnancy & Childbirth (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de rélugolix ou de ses sels pharmaceutiquement acceptables. La présente invention concerne également le procédé de préparation de la forme cristalline R1 du rélugolix.
PCT/IN2022/051121 2021-12-25 2022-12-23 Procédé de préparation de rélugolix et de ses intermédiaires Ceased WO2023119333A1 (fr)

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CN117736221A (zh) * 2023-12-19 2024-03-22 杭州善礼生物医药科技有限公司 瑞卢戈利中间体化合物及瑞卢戈利的制备方法
CN119859135A (zh) * 2023-10-19 2025-04-22 浙江工业大学 一种瑞卢戈利中间体及其制备方法
CN119859152A (zh) * 2023-10-19 2025-04-22 诚达药业股份有限公司 瑞卢戈利及其三步合成方法
CN119859136A (zh) * 2023-10-19 2025-04-22 诚达药业股份有限公司 一种瑞卢戈利关键中间体化合物g及其制备方法
US12338249B2 (en) 2019-10-10 2025-06-24 Sumitomo Pharma Switzerland Gmbh Crystalline forms of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

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WO2014051164A2 (fr) * 2012-09-28 2014-04-03 Takeda Pharmaceutical Company Limited Procédé de production d'un dérivé de thiénopyrimidine

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WO2014051164A2 (fr) * 2012-09-28 2014-04-03 Takeda Pharmaceutical Company Limited Procédé de production d'un dérivé de thiénopyrimidine

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MIWA, K. ET AL.: "Discovery of 1-{4-[1-(2,6-Difluorobenzyl)-5- [(dimethylamino)methyl]-3-(6-methoxy pyridazin-3-yl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3- methoxy urea (TAK-385) as a Potent, Orally Active, Non-Peptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, no. 14, 2011, pages 4998 - 5012, XP055012890, DOI: 10.1021/jm200216q *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12338249B2 (en) 2019-10-10 2025-06-24 Sumitomo Pharma Switzerland Gmbh Crystalline forms of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea
CN119859135A (zh) * 2023-10-19 2025-04-22 浙江工业大学 一种瑞卢戈利中间体及其制备方法
CN119859152A (zh) * 2023-10-19 2025-04-22 诚达药业股份有限公司 瑞卢戈利及其三步合成方法
CN119859136A (zh) * 2023-10-19 2025-04-22 诚达药业股份有限公司 一种瑞卢戈利关键中间体化合物g及其制备方法
CN117736221A (zh) * 2023-12-19 2024-03-22 杭州善礼生物医药科技有限公司 瑞卢戈利中间体化合物及瑞卢戈利的制备方法

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