DESC:The following specification describes particularly the invention and in the manner in which it is to be performed:

PROCESS FOR PREPARATION OF RELUGOLIX AND ITS INTERMEDIATES

FIELD OF INVENTION
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 R1.
BACKGROUND OF INVENTION
Relugolix is a gonadotropin-releasing hormone antagonist (GnRH antagonist) which is under development for use in treatment of endometriosis and prostate cancer. Relugolix is chemically known as N-[4-[l-[(2,6-difluorophenyl)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:

PCT patent application, W02004067535A1 (hereinafter referred as the WO’535 application) discloses relugolix specifically for the first time.
PCT patent application, WO2014051164A2 (hereinafter referred as the WO’ 164 application), CN110194776B, CN 111333633 A, CN112552312 A, CN112745304 A, CN113429423A, CN113444105A, CN113501830A and non-patent literature such as J. Med. Chem. 2011, 54, 4998–5012 discloses various processes for preparation of Relugolix. The reported processes suffer from major disadvantages including use of highly expensive reagents, solvents, low yields, longer reaction time, multiple purifications to get the desire purity.
Hence, there remains a need to provide alternative processes for the preparation of Relugolix, which is simple, economic and industrially viable.
SUMMARY OF THE INVENTION
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).

wherein R is R1 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)
;
e) reacting compound of formula (VI) with 3-Amino-6-methoxypyridazine to form compound of formula (V)
;
f) Converting compound of formula (V) to a compound of formula (IV)
;
g) converting compound of formula (IV) to a compound of formula (III)
;
h) optionally converting compound of formula (III) to a compound of formula (II)
;
i) converting compound of formula (II) to Relugolix (I) or pharmaceutically acceptable salts thereof,

wherein R is R1 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.
Fourth aspect of the present application relates to compounds of formula


wherein, X is a halogen. P1 and P2 are independently a hydrogen or an amine protecting group, provided that P1 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), (VIIIa), (VII), (VIIa), (VI), (VIa), (V), (Va), (IV), (IVa), (III) and (IIIa) 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), (VIIIa), (VII), (VIIa), (VI), (VIa), (V), (Va), (IV), (IVa), (III) and (IIIa) 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.

DETAILED DESCRIPTION OF THE INVENTION
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).

wherein R is R1 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.
Conversion of compound of formula (II) to Relugolix (I) may involves two steps.
Step (i) involves the reaction of compound of formula (II) with the compound of formula (A). In the 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.
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)
;
e) reacting compound of formula (VI) with 3-Amino-6-methoxypyridazine to form compound of formula (V)
;
f) Converting compound of formula (V) to a compound of formula (IV)
;
g) converting compound of formula (IV) to a compound of formula (III)
;
h) optionally converting compound of formula (III) to a compound of formula (II)
;
i) converting compound of formula (II) to Relugolix (I) or pharmaceutically acceptable salts thereof,
.
wherein R is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; X is a halogen; P1 and P2 are independently a hydrogen or an amine protecting group.
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.
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.
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.
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-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), N-(Dimethylaminopropyl)-N'-ethyl-carbodiimide.
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.
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 BocNH2, CbzNH2, FmocNH2, TsNH2, NsNH2, Boc2NH, 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 Pd2(dba)3 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.
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.
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.
In an aspect of the present application, 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.
Providing solution of 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.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
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.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise.
As used 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.
The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
“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. The term "aryl group having 6-12 carbon atoms" also refers to “heteroaryl” ring systems. The term “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).
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “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.
A “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. Examples of “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, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C12 aromatic hydrocarbons and the like.
An “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.
A “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.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “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.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C10 ketones” include acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones and the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “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;
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.
EXAMPLES
Example 1: Preparation of Ethyl 2-amino-5-(4-chlorophenyl)-4-methylthiophene-3-carboxylate (XIa):
To a solution of 1-(4-chlorophenyl)propan-2-one (22.0 g) in toluene (55 mL) was added ethyl cyanoacetate (16.2 g), ammonium acetate (2.01 g) and acetic acid (5.8 mL) under nitrogen atmosphere. The reaction mixture was heated to reflux at 110 °C for 20 hours. Water from the reaction mixture was removed azeotropically using Dean Stark apparatus. Resultant reaction mixture was concentrated under reduced pressure. Saturated solution of sodium bicarbonate (50 mL) was added to the reaction mixture and the product was extracted with dichloromethane (3x200mL). Combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to get crude intermediate (ethyl (E)-4-(4-chlorophenyl)-2-cyano-3-methylbut-2-enoate). The resultant crude intermediate (34 g), ethanol (110 mL), sulfur powder (4.598 g) and diethyl amine (14.95 mL) charged in to round bottom flask under nitrogen atmosphere at ambient temperature and the resultant reaction mixture was heated to reflux and stirred for 2 hours. Reaction mixture was washed with brine (50 mL) at ambient temperature and product was extracted with dichloromethane (3x200mL). Combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to get crude title compound (XIa) (38 g).
Example 2: Preparation of Ethyl 5-(4-chlorophenyl)-2-((ethoxycarbonyl)amino)-4-methylthiophene-3-carboxylate (Xa):
Ethyl chloroformate (24.56 mL) was added to a solution of ethyl 2-amino-5-(4-chlorophenyl)-4-methylthiophene-3-carboxylate (38.0 g) in toluene (114 mL) under nitrogen atmosphere at ambient temperature. The reaction mixture was heated to 100 °C and stirred at the same temperature for 3 hours. Isopropyl alcohol (342 mL) was added to the reaction mixture at 0 °C and stirred for 1 hour. The resulting solid was filtered and washed with isopropyl alcohol (76 mL) to get title compound (22.5 g).
Purity by HPLC: 99.38%; 1H NMR (400 MHz, DMSO-d6): d 10.44 (s, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.8 Hz, 2H), 4.33 (q, J=7.2 Hz, 2H), 4.25 (q, J=7.2 Hz, 2H), 2.29 (s, 3H), 1.33 (t, J=7.2 Hz, 3H), 1.27 (t, J=7.2 Hz, 3H)
Example 3: Preparation of Ethyl 5-(4-chlorophenyl)-2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-methylthiophene-3-carboxylate (IXa):
Potassium iodide (1.98 g) and anhydrous potassium carbonate (16.53 g) was added to a solution of ethyl 5-(4-chlorophenyl)-2-((ethoxycarbonyl)amino)-4-methylthiophene-3-carboxylate (22.0 g) in DMF (132 mL) at 0 °C. 2, 6-difluorobenzyl chloride (11.66 g) in DMF (22 mL) was slowly added to the reaction mixture and the resultant reaction mixture was stirred at ambient temperature for 16 hours. Reaction mixture was diluted with water and extracted with methyl tertiary butyl ether (3x100 mL). Combined organic layers were washed with water, brine and concentrated under reduced pressure to get the title compound (27 g).
Purity by HPLC: 98.18%; 1H NMR (400 MHz, CDCl3): d 7.35 (d, J=8.4 Hz, 2H), 7.28-7.21 (m, 3H), 6.84 (t, J=7.6 Hz, 2H), 4.95 (brs, 2H), 4.25 (q, J=7.2 Hz, 2H), 4.20-4.10 (brs, 2H), 2.33 (s, 3H), 1.32 (t, J=7.2 Hz, 3H), 1.25-1.15 (brs, 3H).
Example 4: Preparation of Ethyl 5-(4-chlorophenyl)-2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)thiophene-3-carboxylate (VIIa):
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. A 2.0 M N,N-dimethylamine solution in THF (30.0 mL) and DIPEA (20.0 mL) were added to the reaction mixture at 0 °C and the resultant reaction mixture was stirred at ambient temperature for 16 hours. Reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL) followed by water (2x50 mL) and brine (2x50 mL). Combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resultant crude product was purified using silica gel column chromatography (17-20% ethyl acetate in hexane) to obtain the title compound (12.2 g).
1H NMR (400 MHz, CDCl3): d 7.37-7.34 (brs, 4H), 7.25-7.20 (m, 1H), 6.84 (t, J=7.6 Hz, 2H), 5.00 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 4.20-4.10 (brs, 2H), 3.46 (s, 2H), 2.02 (s, 6H), 1.30 (t, J=7.2 Hz, 3H), 1.25-1.15 (brs, 3H).
Example 5: Preparation of 5-(4-chlorophenyl)-2-((2,6-difluorobenzyl) (ethoxycarbonyl)amino)-4-((dimethylamino)methyl)thiophene-3-carboxylic acid (VIa):
Aqueous KOH solution (48% solution; 3.11 mL) was slowly added to a solution of ethyl 5-(4-chlorophenyl)-2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino) methyl)thiophene-3-carboxylate (6.5 g) in ethanol (58.0 mL) and water (17.0 mL) at ambient temperature. The reaction mixture was heated to 60-65 °C and stirred at the same temperature for 22 hours. Water (20 mL) was added to the reaction mixture at ambient temperature and the reaction mass pH was adjusted to 7-8 using 1N hydrochloric acid. Product was extracted with ethyl acetate (3 X 100 mL), combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the title compound (5.0 g).
1H NMR (400 MHz, CDCl3): d 7.40 (d, J=8.4 Hz, 2H), 7.25-7.18 (m, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.82 (t, J=8 Hz, 2H), 5.06 (brs, 2H), 4.40-4.10 (brm, 2H), 3.57 (s, 2H), 2.38 (s, 6H), 1.20-1.10 (brs, 3H).
Example 6: Preparation of ethyl (5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)thiophen-2-yl)(2,6-difluorobenzyl)carbamate (Va):
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. The 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 1N sodium hydroxide. Product was extracted with methyl tertiary butyl ether (3x100 mL), combined organic layers were washed with water (3x20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the title compound (5.0 g)
1H NMR (400 MHz, CDCl3): d 13.93 (brs, 1H), 8.55 (d, J=9.6 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 1H), 7.11 (t, J=7.2 Hz, 1H), 6.98 (d, J=9.6 Hz, 1H), 6.73 (t, J=7.6 Hz, 2H), 5.00 (brs, 2H), 4.25-4.15 (brs, 2H), 4.11 (s, 3H), 3.46 (brs, 2H), 2.19 (s, 6H), 1.25-1.15 (brs, 3H).
Example 7: Preparation of 6-(4-chlorophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (IVa):
Sodium methoxide (0.13 g) was added to a solution of ethyl (5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)thiophen-2-yl)(2,6-difluorobenzyl)carbamate (5 g) in methanol (50 mL) and tetrahydrofuran (10 mL) at ambient temperature. The reaction mixture was heated to 65 °C and stirred at the same temperature for about 1 hour. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (200 mL) and washed with water (2x50 mL). Combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude product was purified using silica gel column chromatography (6% MeOH in DCM) to obtain the title compound (2.8 g).
1H NMR (400 MHz, CDCl3): d 7.54 (d, J=8.4 Hz, 2H), 7.43-7.38 (m. 3H), 7.36-7.31 (m, 1H), 7.12 (d, J=9.2 Hz, 1H), 6.92 (t, J=8.0 Hz, 2H), 5.35 (brs, 2H), 4.18 (S, 3H), 3.65 (brs, 2H), 2.14 (s, 6H).
Example 8: Preparation of tert-butyl (4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)carbamate (IIIa):
A mixture of Pd2dba3 (80 mg) and Xphos (62 mg) was taken in a sealed tube, which was then sparged with nitrogen gas for about 10 minutes. To the mixture was added tert-butyl carbamate (0.41 g), cesium carbonate (1.717 g), 6-(4-chlorophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.0 g) and dry 1,4-Dioxane (20.0mL) and sparged again with nitrogen gas for 30 minutes. The 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). The combined filtrate and washings were concentrated under reduced pressure to get the title compound (1.1 g)
1H NMR (400 MHz, CDCl3): d 7.48-7.40 (m, 4H), 7.28-7.32 (m. 1H), 7.13 (d, J=9.2Hz, 1H), 6.90 (t, J=8 Hz, 2H), 6.64 (brs, 1H), 5.32 (brs, 2H), 4.17 (s, 3H), 3.75 (brs, 2H), 2.23 (s, 6H), 1.53 (s, 9H).
Example 9: Preparation of 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (II):
Trifluroacetic acid (11 mL) was slowly added to a solution of tert-butyl (4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-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. Reaction mixture was diluted with dichloromethane (50 mL) and washed with 10% saturated aqueous sodium bicarbonate solution (33 mL). The organic layers were combined and concentrated under reduced pressure. Resultant crude material was triturated with methyl tertiary butyl ether (2x10 mL) to obtain the title compound (II) as a light brown solid (800 mg).
1H NMR (400 MHz, CDCl3): d 7.48-7.43 (d, J=9.2 Hz, 1H), 7.37-7.28 (m. 1H), 7.28-7.23 (m, 2H), 7.12 (d, J=9.2 Hz, 1H), 6.90 (t, J=8.4 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 5.32 (brs, 2H), 4.18 (s, 3H), 3.88 (brs, 2H), 2.23 (s, 6H).
Example 10: Preparation of 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea (Relugolix) (I):
Phenyl chloroformate (213 mg) in in acetonitrile (1 mL) was slowly added to the solution of 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,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. The reaction mixture was slowly heated to 80 °C and stirred for 24 hours at the same temperature. 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).
Example 11: Preparation of 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea (Relugolix) (I):
6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,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 tert-butyl 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. 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. Filtered the reaction mass, washed with water (25 mL) and dried at 40 °C to afford title compound.
Example 12: Preparation of 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea (Relugolix) (I):
6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (5 g) and dimethylacetamide (50 mL) charged in to flask and cooled to 2 °C. Pyridine (1.44 g) was added to the solution at 10 °C and stirred for 15 minutes. Phenyl chloroformate (1.57 g) was slowly added to the reaction mass at 10 °C and the resultant reaction mixture was stirred at 10 °C for 1 hour. Methyl tert-butyl 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. Filtered the reaction mass, washed with water (25 mL). Charged resultant solid and dimethylsulfoxide (10 mL) into flask, heated to 40 °C and stirred for 30 minutes. Isopropyl alcohol (40 mL) was added to the reaction mass and stirred at ambient temperature for 3 hours. Filter the solid and dried to afford title compound.
Example 13: Preparation of Relugolix Form R1.
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 R1 seed (prepared by following procedure given in WO2020230094A1) 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.
Example 14: Preparation of Relugolix Form R1.
Relugolix (10 g) and dimethylsulfoxide (17 mL) charged into flask, heated to 45°C and stirred for 45 minutes. Filter the reaction mass, washed with dimethylsulfoxide (2 mL). Mixture of acetonitrile (115 mL) and water (11.5 mL) was added to the filtrate at ambient temperature. Relugolix Form R1 seed (0.2 g prepared by following procedure given in WO2020230094A1) was added and the resultant reaction mass was stirred for 1 hour at ambient temperature, cooled to 0 °C and stirred at 0 °C for 12 hours. Filtered the reaction mass and washed with pre-cooled acetonitrile (20 mL). Wet compound slurried in acetonitrile (50 mL), filtered and dried at 80 °C to afford title compound.

Dated: 23rd day of December 2022
Signature_______________
Dr. B. Dinesh Kumar
Intellectual Property Management,
Dr. Reddy’s Laboratories Limited.
,CLAIMS:CLAIMS:

1. 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) and methoxy amine.

wherein R is R1 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.

2. The process according to claim 1, wherein the compound of formula (A) is selected from phenyl chloroformate, 4-nitrophenyl chloroformate, Benzyl chloroformate, pivaloyl chloride.

3. The process according to claim 1, wherein the compound of formula (A) is phenyl chloroformate or 4-nitrophenyl chloroformate.

4. The process according to claim 1, wherein the conversion of compound of formula (II) to Relugolix carried out in two steps.

5. The process according to claim 1, reaction of compound of formula (II) with compound of formula (A) carried out in the presence of base.

6. The process according to claim 5, wherein the base is selected from triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, N-methyl pyrrolidone, Imidazole.

7. The process according to claim 5, wherein the base is selected from triethylamine, diisopropylethylamine, pyridine.

8. A 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.

9. The process according to claim 8, wherein the first solvent is selected from dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone.

10. The process according to claim 8, wherein the first solvent is dimethylsulfoxide and second solvent is acetonitrile.