P101486US01  Processes for the Preparation and Manufacture of Relugolix The present invention relates to Intermediates and processes for the preparation of Relugolix, and to pharmaceutical compositions containing Relugolix manufactured by the invented processes. Background Relugolix is used to treat advanced prostate cancer (cancer that begins in the prostate [a male reproductive gland] and uterine fibroids [a female reproductive gland in women] in adults. Relugolix is in a class of medications called gonadotropin-releasing hormone (GnRH) receptor antagonists. It works by decreasing the amount of testosterone (a male hormone) produced by the body. This may slow or stop the spread of prostate cancer cells that need testosterone to grow. It is also under development for use in the treatment of endometriotosis, the API is in the form of an oral dosage taken by human subjects once per day. Relugolix is a non-peptide small molecule that is orally active. It suppresses sex hormone levels to the post-menopausal or castration range in both women and men with administration once per day. As of February 2019, Relugolix is in Phase III clinical trials for endometriosis. It was approved for use for the treatment of uterine fibroids in Japan in January 2019, and for the treatment of prostate cancer in the United States in December 2020. Relugolix has the IUPAC name of 1-[4-[1-[(2,6-difluorophenyl)methyl]-5- [(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-diox othieno[2,3- d]pyrimidin-6-yl]phenyl]-3-methoxyurea (1) and has the chemical structure illustrated below:   1     P101486US01  US Pat. Nos. 9,758,528; 10,150,778 and 10,544,160 disclose methods and intermediates for preparing Relugolix, as shown in Scheme 1. F F H Br F F NO   The process includes claimed intermediate compounds VII, VIII, X, XI and XII. Inventors have discovered an alternative process that does not use intermediate compounds VII, VIII, X, XI and XII. The invented process for preparing Relugolix is a more efficient and convergent manufacturing process that includes new intermediates, including those that involve a Suzuki catalyzed aryl carbon- carbon bond coupling convergent synthesis invented herein. DETAILED DESCRIPTION OF THE INVENTION Definitions The term “about” or “approximately” means an acceptable error for a particular value as determined by a person of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term 2     P101486US01  “about” or “approximately” means within 1, 2, 3 or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. In certain embodiments and with reference to X-ray powder diffraction two-theta peaks, the terms “about” or “approximately” means within ± 0.2 ^o 2θ. The term “ambient temperature” means one or more room temperatures between about 15 ^o C to about 30 ^o C, such as about 15 ^o C to about 25 ^o C. The term “consisting” is closed and excludes additional, unrecited elements or method steps in the claimed invention. The term “consisting essentially of” is semi-closed and occupies a middle ground between “consisting” and “comprising”. “Consisting essentially of” does not exclude additional, unrecited elements or method steps which do not materially affect the essential characteristic(s) of the claimed invention. The term “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps in the claimed invention. The term is synonymous with “including but not limited to”. The term “comprising” encompasses three alternatives, namely (i) “comprising”, (ii) “consisting”, and (iii) “consisting essentially of”. The term “crystalline” and related terms used herein, when used to describe a compound, substance, modification, material, component or product, unless otherwise specified, means that the compound, substance, modification, material, component or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, Md. (2005); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995). The term “pharmaceutical composition” is intended to encompass a pharmaceutically effective amount of the API relugolix of the invention and a pharmaceutically acceptable excipient. As used herein, the term “pharmaceutical 3     P101486US01  compositions” includes pharmaceutical compositions such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations. The term “excipient” refers to a pharmaceutically acceptable organic or inorganic carrier substance. Excipients may be natural or synthetic substances formulated alongside the active ingredient of a medication, included for the purpose of bulking-up formulations that contain potent active ingredients (thus often referred to as "bulking agents," "fillers," or "diluents"), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption or solubility. Excipients can also be useful in the manufacturing process, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation over the expected shelf life. The term “patient” refers to an animal, preferably a human, who has been the object of treatment, observation, or experiment. Preferably, the patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. Further, a patient may not have exhibited any symptoms of the disorder, disease or condition to be treated and/prevented, but has been deemed by a physician, clinician or other medical professional to be at risk for developing said disorder, disease or condition. The terms “treat”, “treating” and “treatment” refer to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more therapeutic agents to a patient with such a disease or disorder. In some embodiments, the terms refer to the administration of the crystalline salt provided herein, with or without other additional active agents, after the onset of symptoms of a disease. Brief Description of the Figures 4     P101486US01  Certain aspects of the embodiments described herein may be more clearly understood by reference to the drawings, which are intended to illustrate but not limit, the invention, and wherein: Figure 1 summarizes the synthetic routes for the synthesis of intermediates used to prepare Relugolix. Figure 2 summarizes the synthetic routes for the synthesis of intermediates used to prepare Relugolix. Figure 3 summarizes the synthetic routes for the synthesis of intermediates used to prepare Relugolix and the final synthesis of Relugolix.   Intermediates The synthetic chemistry of the manufacture of the API Relugolix is summarized in Figures 1-3. According to one embodiment of the invention, a compound Methyl 2-(1H-imidazole-1-carboxamido)-4-methylthiophene-3-carboxyla te (30) was prepared, having the chemical structure: The compound Methyl 2-(1H-imidazole-1-carboxamido)-4-methylthiophene-3 carboxylate, 30, was prepared by a process comprising the step of: acylating Methyl 2-amino-4-methylthiophene-3-carboxylate (2) using 1,1’- Carbonyldiimidazole (CDI) and N,N-Diisopropylethylamine (DIPEA) in an organic solvent at ambient temperature. In a specific embodiment, the organic solvent is dichloromethane (DCM) and the acylating reaction is carried out at 25 ^o C. The intermediate product 30 is prepared in 90% yield. 5     P101486US01  According to a Methyl 2- (1H-imidazole-1-carboxamido)-4-methylthiophene-3-carboxylate (compound 30) is reacted with 6-chloropyridazin-3-amine (compound 5) in N-methyl-2- pyrrolidone (NMP) with heating to 70° C for 3 hours to form an intermediate, namely the urea, methyl 2-(3-(6-chloropyridazin-3-yl)ureido)-4- methylthiophene-3-carboxylate (compound 33). The reaction mixture is cooled, then acetonitrile is added to reaction mixture. The resulting suspension is cooled with stirring and the precipitated solid is collected by filtration to furnish methyl 2-(3-(6-chloropyridazin-3-yl)ureido)-4-methylthiophene-3-car boxylate (compound 33) in an 88% yield. According to a separate embodiment, the previous intermediate Methyl 2-(3-(6- chloropyridazin-3-yl)ureido)-4-methylthiophene-3-carboxylate (compound 33) is cyclized and the chloro group of the pyridazine replaced with a methoxy group using methanol, a base and water, with heating to 60-65 ^o C. The reaction mixture was concentrated and the resulting suspension is acidified then cooled. The solid is collected by filtration and dried in vacuum to afford 3-(6-methoxypyridazin-3- 6     P101486US01  yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (compound 32) in a 94% yield. This reaction occurs in two steps. The compound 3-(6-methoxypyridazin-3-yl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 32 is prepared by a process comprising the steps of: (a) cyclizing a mixture of the compound 33 having the structure: with sodium hydroxide and the mixture to 60-65 ^o C for 1.5 hours, to form a compound 34 having the structure: H O ^N _S (b) replacing the chloro group a group on the pyridazine ring of 2- (3-(6-chloropyridazin-3-yl)ureido)-4-methylthiophene-3-carbo xylate 34 by adding water to the mixture and maintaining heating of the mixture 60-65 ^o C for 3 hours to form 32. According to one embodiment, the first step compound 33 is cyclized to compound 34, which is not isolated, and is further methoxylated to form compound 32 in the second step. 7     P101486US01  According to a separate embodiment, the intermediate 3-(6-methoxypyridazin-3- yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (compound 32) is alkylated with 2-(chloromethyl)-1,3-difluorobenzene (compound 14), KI and K ₂ CO ₃ in NMP at 30 ^o C for 1 hour. The reaction mixture is poured into water and filtered to afford 1-(2,6-difluorobenzyl)-3-(6-methoxypyridazin-3-yl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (compound 7) in 97% yield. According to a separate embodiment, the intermediate 1-(2,6-difluorobenzyl)-3- (6-methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2, 4(1H,3H)-dione (compound 7) is brominated with Br ₂ in acetonitrile (ACN) at 0-5 ^o C for 23 hours. The reaction mixture is added dropwise to a co-solvent of toluene and aqueous base at 20-30 ^o C. Purification by crystallization from heptane affords the intermediate 6-bromo-5-(bromomethyl)-1-(2,6-difluorobenzyl)-3-(6- methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio ne (compound 46) in a 92 % yield.   According to a separate embodiment, 46 is esterified with betaine in NMP with heating for 1 hour to give the intermediate, 2-((6-bromo-1-(2,6-difluorobenzyl)- 3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothie no[2,3- 8     P101486US01  d]pyrimidin-5-yl)methoxy)-N,N,N-trimethyl-2-oxoethan-1-amini um bromide salt (compound 55) which is not isolated. Compound 55 is hydrolized using KHCO ₃ in MeOH at 30-35 ^o C for additional 1 hour. Water is added to the resulting mixture. The suspension is stirred at 15-20 ^o C for 30 minutes. The solid is collected by filtration and dried in vacuum at 50 ^o C to afford 6-bromo-1-(2,6-difluorobenzyl)- 5-(hydroxymethyl)-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]py rimidine- 2,4(1H,3H)-dione (compound 49) in 93% yield overall. of Relugolix (compound 1). According to a separate embodiment, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)aniline (compound 11) is acylated by phenyl chloroformate with DIPEA in acetonitrile at 20 ^o C for a short period of time to form compound 111, which is not isolated. Then O-methylhydroxylamine hydrochloride and DIPEA are added to the reaction mixture. The resulting reaction mixture is stirred while heating to 50 °C for 0.5 hour to form, the urea 1-methoxy-3-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl) urea (compound 10). The reaction mixture is cooled to 30 °C and the solvent is exchanged with EtOAc, then precipitated using heptane and cooling to furnish 1-methoxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl)urea (compound 10) in a 78% yield. 9     P101486US01    According to an exemplary embodiment of the invention, Relugolix is prepared by a convergent synthesis of key intermediates 49 and 10. The first key intermediate 6-bromo-1-(2,6-difluorobenzyl)-5-(hydroxymethyl)-3-(6-methox ypyridazin-3- yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (compound 49) is reacted with 1- methoxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph enyl)urea (compound 10), Pd(dtbpf)Cl ₂ and KHCO ₃ in a co-solvent of THF and H ₂ O, with heating at 60-65 ^o C for 4 hours under N ₂ atmosphere. After cooling, the precipitated solid is collected by filtration to furnish the intermediate 1-(4-(1-(2,6- difluorobenzyl)-5-(hydroxymethyl)-3-(6-methoxypyridazin-3-yl )-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-meth oxyurea (compound 47) in 91% yield.   According to the embodiment, the Suzuki coupled intermediate 1-(4-(1-(2,6- difluorobenzyl)-5-(hydroxymethyl)-3-(6-methoxypyridazin-3-yl )-2,4- dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)- 3-methoxyurea (compound 47) is chlorinated by SOCl ₂ in acetonitrile at 0-5 ^o C for 1 hour. Then saturated NaHCO ₃ solution is added dropwise to reaction mixture with cooling. The solid is collected by filtration and dried in vacuum to afford 1-(4-(5- (chloromethyl)-1-(2,6-difluorobenzyl)-3-(6-methoxypyridazin- 3-yl)-2,4-dioxo- 1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea (compound 48). 10     P101486US01  Synthesis of API (active pharmaceutical ingredient) Relugolix, Compound 1 According to the last embodiment, the intermediate 1-(4-(5-(chloromethyl)-1- (2,6-difluorobenzyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea (compound 48) is reacted with dimethylamine (2M in THF) in NMP at ~25 ^o C for 1 hour. The reaction mixture is concentrated at 25 °C and added to 20% aqueous of dipotassium hydrogen phosphate dropwise over 2 hours. The suspension is stirred at ~20 ^o C for 0.5 hours. The solid is collected by filtration and re-slurried in water, filtered and then dried by nitrogen sweep to afford the API Relugolix 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-methoxyurea (compound 1) in 96% yield.     API Purification and Salt Process Embodiments The API is recovered as a crystalline solid or an amorphous solid. The crystalline or amorphous solid may be recovered by directly by filtering, decanting or centrifuging. If a suspension is obtained, the suspension may be mobilised with additional portions of the solvent prior to recovery of the crystalline solid. 11     P101486US01  Alternatively, a proportion or substantially all of the solvent may be evaporated prior to recovery of the crystalline solid. The solvent may be as described above. Howsoever the crystalline salt of the API is recovered, the separated salt may be washed with solvent (e.g. as described above) and dried. Drying may be performed using known methods, for example, at temperatures in the range of about 10 ^o C to about 60 ^o C, such as about 20 ^o C to about 40 ^o C, for example, ambient temperature under vacuum (for example about 1 mbar to about 30 mbar, such as about 25 mbar) for about 1 hour to about 24 hours, such as about 6 hours. Alternatively or in combination with another drying method, the crystalline salt may be left to dry under ambient temperature naturally i.e. without the active application of vacuum. It is preferred that the drying conditions are maintained below the point at which the salt decomposes and so when the salt is known to decompose within the temperature or pressure ranges given above, the drying conditions should be maintained below the decomposition temperature or vacuum pressure. The crystalline or amorphous API salt may be optionally recrystallised from a solvent as described above. The crystalline or amorphous API salt may be dissolved in the solvent and treated for a period of time at one or more temperatures greater than ambient i.e. greater than 30 ^o C and below the boiling point of the reaction mixture as described above in connection with step (a) (e.g. at about 50 to about 60 ^o C). The solution may then be cooled (e.g. to about 5 ^o C) and the recrystallised or amorphous API salt may be recovered, optionally washed and dried as described above. Pharmaceutical compositions comprising the API or API salt (1), methods of treatment comprising the salt, and uses thereof In another aspect, the present invention provides a pharmaceutical composition comprising: 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methy l]-3- (6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6- yl]phenyl]-3- methoxyurea (1) or an API salt, as described herein and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is an oral dosage form, such as a tablet, capsule, syrup, or dissolution film which may dissolve when placed e.g. under the tongue. 12     P101486US01  In another aspect, the present invention provides a method for treating diseases selected from endometriotosis, prostate cancers, and uterine fibroids in a patient comprising administering a therapeutically effective amount of 1-[4-[1-[(2,6- difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methox ypyridazin-3- yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyur ea (1) or an API salt, as described herein and a pharmaceutically acceptable excipient. According to one therapeutic embodiment, the API (1) or an API salt is in the form of an oral dosage taken by human subjects once per day. According to a separate embodiment, an orally active API (1) or an API salt is in the form of an oral dosage taken by human subjects once per day, to post-menopausal female subjects or male subjects, wherein castration range in both women and men with administration once per day. Embodiments and/or optional features of the invention have been described above. Any aspect of the invention may be combined with any other aspect of the invention, unless the context demands otherwise. Any of the embodiments or optional features of any aspect may be combined, singly or in combination, with any aspect of the invention, unless the context demands otherwise. 13     P101486US01  The invention will now be described further by reference to the following examples, which are intended to illustrate but not limit, the scope of the invention. Examples Abbreviations API active pharmaceutical ingredient EtOH Ethanol MeOH Methanol DCM Dichloromethane rpm revolutions per minute RH relative humidity RT ambient temperature SCXRD single crystal X-ray diffraction Analytical method In-Process and final API product UPLC Method (10-90-10min-FA, Example 1): Column: Agilent XDB-C18, 3.5 micron, 150x4.6mm Flow Rate: 1.0 mL/min Detection W _avelength: ^{254 nm, Bw 4 nm, Reference off} Column T _emperature: ^{25 ^C} Injection Volume: 0.5 µL with needle wash Mobile Phase A: 0.1% HCOOH in Water Mobile Phase B: Acetonitrile Data Collection: 10.0 mins Re-equilibration: 1.0 min Run Time: 11.0 mins Gradient Program: Time (min) MP A (%) MP B (%) 14     P101486US01  Example 1 Intermediate Compound 30 ( according to the invention) A 1-L jacketed four-neck flask equipped with a Teflon impeller, thermometer, a 100-mL pressure-equalizing dropping funnel and vacuum line was purged with nitrogen. The flask was charged with CDI (52.09 g, 0.321 mol, 1.1 eq) and anhydrous DCM (500 mL, 10 V.) The flask was purged with nitrogen and the agitator set to 208 rpm. Methyl 2-amino-4-methylthiophene-3-carboxylate (compound 2, 50 g, 0.292 mol, 1.0 eq.) was charged to reaction mixture. After compound 2 addition was completed, the flask was cooled to an internal temperature of 13 ^o C). DIPEA (45.29 g, 0.350 mol, 1.2 eq.) was added dropwise to the reaction mixture at 13-17 ^o C for 15 minutes (Note 1). The reaction mixture was warmed to 25 ^o C and was stirred at 25 °C for 17.5 hours IPC. Reaction was complete if unreacted compound 2 is < 3.0% AUC. The reaction mixture was concentrated to ~150 mL (3 V). The residue was swapped with acetonitrile (150 mL, 3 V). The reaction mixture was concentrated to dryness (~ 104 g brown solid). The solid was re-slurried in anhydrous acetonitrile (150 mL, 3 V) at 20 ^o C for 2 hours. The precipitated solid was collected by filtration and rinsed with anhydrous acetonitrile (100 mL, 2 V). The solid was dried in vacuum under nitrogen atmosphere for 5 hours to afford 69.8 g of compound 30 as an off-white solid in 99.9% purity (UV, UPLC) and 90% yield. UV (MeOH) λ _max : 226 nm (methanol derivative of compound 30). ¹ H-NMR (400 Hz, CDCl ₃ ) δ: 2.35 (3H, d, J=0.8 Hz), 3.92 (3H, s), 6.46 (1H, m), 7.16 (1H, m), 7.48 (1H, m), 8.26 (1H, m), 12.16 (1H, s). ¹³ C-NMR (101 Hz, CDCl ₃ ) δ: 167.65, 149.88, 145.33, 136.29, 135.40, 131.61, 115.60, 113.70, 113.34, 52.16, 52.15, 52.14, 17.79, 17.77. ESI-MS m/z: 230.0 [M+H] ⁺ (methanol derivative of compound 30). Example 2 Intermediate Compound 33 ( according to the invention) 15     P101486US01  A 1000 mL jacketed four-neck flask equipped with a Teflon impeller, thermometer and vacuum line was purged with nitrogen. The flask is charged with compound 30 (63 g, 0.237 mol, 1.0 eq), compound 5 (36.9 g, 0.285 mol, 1.2 eq) and NMP (315 mL, 5 V.) The suspension was warmed to 70 ^o C and stirred at 70 °C for 3 hours. Reaction was complete if unreacted compound 30 is < 0.5% AUC. The reaction mixture was cooled to 30 ^o C. Acetonitrile (315 mL, 5 V) was added to reaction mixture. The suspension was cooled to 10 ^o C and stirred at 10 ^o C for 30 minutes. The suspension was filtered, the filter cake was rinsed with acetonitrile (126 mL, 2 V). The solid was dried in vacuum under nitrogen atmosphere for 5 hours to afford 68.8 g of compound 33 as a yellow solid in 99.4% purity (UV, UPLC) and 88% yield. UV (NMP) λ _max : 226 nm. ¹ H-NMR (400 Hz, d ₆ -DMSO) δ: 2.27 (3H, d, J=0.8 Hz), 3.89 (3H, s), 6.61 (1H, s), 7.83 (2H, s), 11.12 (1H, s), 11.90 (1H, s). ¹³ C-NMR (101 Hz, d ₆ -DMSO) δ: 164.63, 155.63, 151.32, 150.98, 149.80, 135.12, 131.23, 121.61, 113.76, 112.07, 52.16, 18.01. ESI-MS m/z: 327.0 [M+H] ⁺ . Example 3 Intermediate Compound 32 ( according to the invention) A 1-L jacketed four-neck flask equipped with a Teflon impeller, thermometer, and vacuum line was purged with nitrogen. The flask was charged with compound 33 (60 g, 0.184 mol, 1.0 eq.), methanol (1380 mL, 23 V) and NaOH (36.7 g, 0.918 mol, 5.0 eq.). The flask was purged with nitrogen and the agitator set to 220 rpm. The reaction mixture was warmed to 60-64 ^o C and stirred at 60-64 ^o C for 1.5 hours. The reaction mixture was monitored (target: compound 33 is < 0.3% AUC). Water (360 mL, 6 V) was charged into reaction mixture at 55-62 °C. The reaction mixture was stirred at 62 °C for 3 hours. The reaction mixture was complete if intermediate compound 34 is < 0.2% AUC. The reaction mixture was 16     P101486US01  concentrated to 14 V (~ 840 ml). Water (60 mL, 1 V) was charged to the residue. The residue was adjusted to pH=2 with aqueous HCl (6M in water, 144 mL, 2.4 V) at 30 ^o C. The suspension was cooled to 15-20 ^o C and was stirred at 15-20 ^o C for 1 hours. The suspension was filtered, the filter cake was rinsed with methanol (120 mL, 2 V). The product was dried with nitrogen sweep on a vacuum Buchner funnel at 20-30 °C for approximately 2 hours to afford 50.02 g compound 32 as an off-white solid in 99.2% purity (UV, UPLC) and 93.8% yield. UV (MeOH) λ _max : 236 nm. ¹ H-NMR (400 Hz, d ₆ -DMSO) δ: 2.29 (3H, d, J=1.2 Hz), 4.05 (3H, s), 6.73 (1H, d, J=1.2 Hz), 7.39 (1H, d, J=9.2 Hz), 7.73 (1H, d, J=9.2 Hz), 12.45 (1H, s). ¹³ C-NMR (101 Hz, d ₆ -DMSO) δ: 165.37, 159.58, 153.33, 150.68, 150.46, 134.69, 132.35, 119.86, 113.56, 112.68, 55.41, 16.08. ESI-MS m/z: 291.0 [M+H] ⁺ . Example 4 Intermediate Compound 7 ( according to the invention) A 500 mL jacketed four-neck flask equipped with a Teflon impeller, thermometer and nitrogen inlet was purged with nitrogen. The reactor was charged with compound 32 (47 g, 0.162 mol, 1.0 eq.) and NMP (235 mL, 5 V). Compound 14 (26.32 g, 0.162 mol, 1.0 eq.), KI (2.69 g, 0.016 mol, 0.1 eq.) and K ₂ CO ₃ (325 mesh, 44.75 g, 0.324 mol, 2.0 eq.) were charged to reaction mixture. The reactor was inerted with vacuum/nitrogen once and the agitator set to 200 rpm. The mixture was warmed to 30 ^o C and stirred at 30 ^o C for 1 hour. The reaction mixture was complete if unreacted compound 32 is < 0.1% AUC. The reaction mixture was poured into water (352.5 mL, 7.5 V) at 23-35 ^o C. The suspension was cooled to 20 ^o C and was stirred at 20 ^o C for 30 minutes. The solid product was filtered by vacuum on a Buchner funnel and excess solvent is removed. The filter cake was rinsed with water (47 mL, 1 V) and water/methanol (1 V/2 V, 141 mL, 3 V), vacuum filtered, and residual solvent was removed by vacuum. The product was dried by nitrogen sweep under vacuum at 20-25 °C for approximately 2 hours to afford 65.7 g compound 7 as a yellow solid in 97.2% purity (UV, UPLC) and 97% yield. UV (MeOH) λ _max : 234 nm. ¹ H-NMR (400 Hz, d ₆ -DMSO) δ: 2.31 (3H, d, J=1.2 Hz), 4.05 (3H, s), 5.14 (1H, s), 5.32 (1H, s), 6.86 (1H, d, J=1.6 Hz), 7.09 (2H, m), 7.42 (2H, m), 7.71 (1H, d, J=9.2 Hz). ¹³ C-NMR (101 Hz, d ₆ -DMSO) δ: 165.45, 162.83, 162.75, 160.35, 160.27, 158.70, 154.90, 150.52, 150.25, 135.78, 132.15, 131.58, 120.04, 114.13, 113.79, 112.52, 112.46, 112.33, 112.27, 110.97, 110.79, 55.45, 16.32. ESI-MS m/z: 417.0 [M+H] ⁺ . 17     P101486US01  Example 5 Intermediate Compound 46 ( according to the invention) A 2000 mL jacketed three-neck flask was equipped with a Teflon impeller and a thermometer. The reactor was charged with compound 7 (65.25 g, 156.58 mmol, 1.0 eq.) and acetonitrile (653 mL, 10 V). The reaction mixture was stirred and cooled to 0-5 ^o C. Molecular Br ₂ (250.23 g, 1565.8 mmol, 10 eq.) was added dropwise to reaction mixture at 0-5 ^o C. The reaction mixture was stirred at 0-5 ^o C for 23 hours. The reaction was complete if no compound 7 remained by AUC. (derivation by Me ₂ NH). The reaction mixture was added dropwise to a stirring mixture of toluene (1304 mL, 20 V) and aqueous. NaOH (8 M, 489 mL, 7.5 V) at 20 ± 5 ^o C. The upper organic layer was separated and washed with water (652 mL, 10 V) and brine (652 mL, 10 V). The organic phase was separated and dried over anhydrous sodium sulfate. The solution was filtered to remove sodium sulfate and the filter was rinsed with toluene (326 mL, 5 V). The filtrate was concentrated to ~652 mL under reduced pressure on a rotary evaporator. Heptane (978 mL) was dropped slowly to the above mixture at 50-55 ^o C and an off-white solid precipitated from the resulting mixture. The suspension was cooled and stirred at 0-5 ^o C for 30 minutes. The mixture was filtered and the filter cake was rinsed with heptane (326 mL). The filtered crude material was suspended in heptane (587 mL, 9 V) and the suspension of crude product was stirred at 25-30 ^o C for 2 hours. The resulting suspension was filtered and the filter cake is rinsed with heptane (196 mL, 3V). The filter cake was dried at 50 ^o C under reduced pressure on a rotary evaporator to afford 82.7 g of compound 46 as an off-white solid in 98.1% purity (UV, UPLC) and 92.0% yield. The toluene residual was 1.47% based on HS-GC analysis. UV (MeCN) λ _max : 233 nm. ¹ H-NMR (400 Hz, CDCl ₃ ) δ: 4.16 (3H, s), 4.72 (2H, s), 5.25 (2H, s), 6.93 (2H, m), 7.11 (1H, d, J=8.8 Hz), 7.33 (1H, m), 7.38 (1H, d, J=9.2 Hz). ¹³ C-NMR (101 Hz, CDCl ₃ ) δ: 165.28, 162.92, 162.85, 160.41, 160.34, 156.98, 153.60, 149.67, 148.92, 135.57, 131.40, 131.29, 131.19, 130.45, 129.13, 128.32, 125.39, 119.46, 112.46, 112.19, 112.13, 111.99, 111.95, 111.93, 109.45, 109.27, 109.10, 106.91, 55.45, 40.42, 40.39, 40.35, 23.59, 21.55. ESI-MS m/z: 574.8 [M+H] ⁺ . Example 6 18     P101486US01  Intermediate Compound 49 ( according to the invention) A and a was was with compound 46 (77 g, 134 mmol, 1.0 eq.), NMP (385 mL, 5 V) and betaine (17.28 g, 148 mmol, 1.1 eq.). The reaction mixture was warmed and stirred at 70-75 ^o C for 1 hour. The reaction mixture was complete when compound 46 is < 1% AUC). The reaction mixture was cooled to 30-35 °C. MeOH (770 mL, 10 V) and KHCO ₃ (13.42 g, 134 mmol, 1.0 eq.) were charged into the reaction mixture. The reaction mixture was stirred at 30-35 °C for additional 1 hour. The reaction mixture was complete if no intermediate compound 55 remained. Water (1155 mL, 15 V) was added to the resulting suspension. The suspension was cooled and stirred at 15- 20 ^o C. for 30 minutes. The suspension was filtered and the filter cake was rinsed with water (154 mL, 2 V). The filtered product was dried at 50 ^o C in vacuum to afford 63.8 g of compound 49 as an off-white solid in 96.7% purity (UV, UPLC) and 93.0% yield. UV (NMP) λ _max : 234 nm. ¹ H-NMR (400 Hz, d ₆ -DMSO) δ: 4.05 (3H, s), 4.55 (2H, s), 4.88 (1H, m), 5.14 (1H, s), 5.28 (1H, s), 7.11 (2H, m), 7.44 (2H, m), 7.71 (1H, d, J=9.2 Hz). ¹³ C-NMR (101 Hz, d6-DMSO) δ: 165.55, 162.82, 162.75, 160.34, 160.27, 157.61, 154.71, 150.18, 149.73, 139.07, 132.01, 131.86, 131.75, 120.16, 113.39, 112.59, 112.53, 112.34, 110.79, 110.61, 110.44, 104.27, 56.27, 55.51. ESI-MS m/z: 510.9 [M+H] ⁺ . Example 7 Intermediate Compound 10 ( according to the invention) A 500 mL three-necked flask was equipped with a Teflon impeller, a thermometer and a nitrogen inlet. The flask was purged with nitrogen and the agitator set to 19     P101486US01  220 rpm. The flask was charged with compound 11 (50.00 g, 228 mmol, 1.0 eq.) and acetonitrile (275 mL, 5.5 V). The agitator was set to 220 rpm. DIPEA (88.35 g, 684 mmol, 3.0 eq.) was charged into the reaction mixture at 15-20 °C (Note 1). Phenyl chloroformate (39.25 g, 251 mmol, 1.1 eq.) was added dropwise into the reaction mixture at 15-20 °C for 15 mins. The resulting reaction solution was stirred at 15-20 °C for 5 mins. Reaction was complete if unreacted compound 11 is < 2% AUC. O-methylhydroxylamine hydrochloride (28.56 g, 342 mmol, 1.5 eq) was added into the reaction mixture at 15-25 °C. DIPEA (8.85 g, 68.5 mmol, 0.3 eq.) was added into the reaction mixture. The resulting suspension was warmed to 50 °C over 0.5 hour. The reaction mixture was kept 50 °C for 3 hours. The reaction was complete if unreacted activated intermediate (compound 111) is < 1% AUC. The reaction mixture was cooled to 30 °C. The reaction mixture was concentrated to 350 mL (7.0 vol.) and the solvent was swapped with EtOAc (350 mL) and concentrated to 350 mL. The resulting mixture was further swapped with EtOAc (350 mL) twice. The resulting solution (7.0 Vol.) was washed with 10% aqueous of NaCl (450 mL, 9.0 Vol.) and brine (225 mL x 2, 9.0 Vol.). The upper organic layer was separated and dried over anhydrous Na ₂ SO ₄ (17.5 g). The resulting mixture was filtered and rinsed with EtOAc (50 mL, 1.0 Vol.). The filtrate was concentrated under reduced pressure to 205 mL (4.1 vol.). Heptane (275 mL, 5.5 vol.) was charged into the resulting suspension and stirred at 15-25 °C for 0.5 hours. The solid was collected by filtration, rinsed with Heptane (50 mL) and dried in vacuum to give 52.3 g of compound 10 as an off-white solid in 98.9% purity (UV, UPLC) and 78.4% yield. UV (MeCN) λ _max : 256 nm. ¹ H-NMR (400 Hz, CDCl ₃ ): δ 1.34 (s, 12H), 3.80 (s, 3H), 7.27 (s, 1H), 7.50 (d, 2H, J =8.8 Hz), 7.60 (s, 1H), 7.77 (d, 2H, J =8.4 Hz). ¹³ C-NMR (101 MHz, DMSO-d6) δ: 157.3, 142.7, 135.6, 118.8, 83.9, 64.5, 25.2. ESI-MS m/z: 293.0 [M+H] ⁺ . Example 8 Intermediate Compound 47 ( according to the invention) A 1000 mL jacketed four-neck flask equipped with a Teflon impeller, thermometer and vacuum line was purged with nitrogen. The flask is charged with compound 49 (19.61 g, 38.36 mmol, 1.0 eq.), compound 10 (12.33 g, 42.19 mmol, 1.1 eq.), Pd(dtbpf)Cl ₂ (2.50 g, 3.84 mmol, 0.1 eq.), KHCO ₃ (11.52 g, 115.08 mmol, 3.0 eq.), THF (196 mL, 10 V,) and H ₂ O (196 mL, 10 V). The reaction mixture was evacuated and back-filled with N ₂ three times. The reaction mixture was stirred under an N ₂ atmosphere at 60-65 ^o C (internal temperature) for 4 hours. The 20     P101486US01  reaction was complete if no compound 49 remained. The resulting reaction mixture was cooled and stirred at 15-20 ^o C for 1 hours. A gray solid precipitated from the resulting mixture. The resulting suspension was filtered and the filter cake was rinsed with DCM (60 mL, 3 V). Approximately 22.12 g of the gray solid was obtained after drying at 50 ^o C in vacuum (Pd residual, 460 ppm). A 500 mL flask is charged with the above crude product (gray solid), acetonitrile (110 mL, 5 V/W) and 10% N-acetylcysteine aqueous solution (110 mL, 5 V/W). The suspension was stirred at 25-30 ^o C for 16 hours. The resulting suspension was filtered and rinsed with H ₂ O (44 mL, 2 V/W) and DCM (44 mL, 2 V/W). The solid was dried at 50 ^o C in vacuum to afford 18.87 g of compound 47 as an off-white solid in 98.3% purity (UV, UPLC) and 82.5% yield. Pd residual, 330 ppm. UV (MeCN) λ _max : 248 nm. ¹ H-NMR (400 Hz, d ₆ -DMSO) δ: 3.61 (3H, s), 4.06 (3H, s), 4.55 (2H, d, J=10.4 Hz), 4.91 (1H, m), 5.19 (1H, s), 5.36 (1H, s), 7.10 (2H, m), 7.44 (4H, m), 7.72 (3H, m), 9.06 (1H, s), 9.60 (1H, s). ¹³ C-NMR (101 Hz, d ₆ - DMSO) δ: 165.51, 162.84, 162.76, 160.36, 160.28, 158.61, 157.40, 153.50, 150.44, 149.90, 140.39, 134.38, 133.03, 132.10, 131.69, 129.89, 125.58, 120.24, 120.09, 114.73, 112.56, 112.32, 111.08, 110.90, 110.73, 67.55, 64.46, 55.48, 25.66. ESI-MS m/z: 597.1 [M+H] ⁺ . Example 9 Intermediate Compound 48 ( according to the invention) A 1-L jacketed four-neck flask equipped with a magnetic stir bar, thermometer, and vacuum line was purged with nitrogen. The flask was charged with compound 47 (15.5 g, 0.026 mol, 1.0 eq.) and actonitrile (93 mL, 6 V). The flask was purged with nitrogen and the agitator set to 220 rpm and cooled to 0-5 ^o C. Thionyl chloride (5.56 g, 0.047 mol, 1.8 eq.) was added dropwise to reaction mixture at 0-5 ^o C for 30 seconds. The reaction mixture was stirred at 0-5 ^o C for 1 hour. The reaction mixture was monitored (target: compound 47 is < 0.6% AUC). Saturated aqueous NaHCO ₃ (279 mL, 18 V) was added dropwise to reaction mixture at 10-17 °C for 3 minutes. The suspension was stirred at 15-20 ^o C for 20 minutes. The suspension was filtered, the cake is rinsed with water (31 mL, 2 V) and water/acetonitrile (2 V/1 V, 31 mL, 2 V). The filtered product was dried with nitrogen sweep on a vacuum Buchner funnel at 20-30 °C for approximately 2 hours to afford 14.5 g compound 48 as a light-brown solid in 97.16% purity (UV, UPLC) and 90.8% yield. UV (MeCN) λ _max : 228 nm. ¹ H-NMR (400 Hz, d ₆ -DMSO) δ: 3.61 (3H, s), 4.06 (3H, s), 4.83 (2H, s), 5.19 (1H, s), 5.33 (1H, s), 7.10 (2H, m), 7.44 (4H, m), 7.76 (3H, m), 9.13 (1H, s), 9.64 (1H, s). ¹³ C-NMR (101 Hz, d ₆ -DMSO) δ: 165.55, 162.83, 162.76, 160.35, 160.28, 158.06, 157.36, 153.81, 150.27, 149.82, 140.91, 134.69, 132.10, 131.73, 129.74, 129.72, 124.55, 120.42, 120.17, 113.25, 21     P101486US01  112.57, 112.32, 110.83, 110.66, 64.49, 55.50, 41.57, 38.96. ESI-MS m/z: 615.1 [M+H] ⁺ . Example 10 API Compound 1 ( according to the invention) A 250-mL and vacuum was . 1) was charged with compound 48 (12.00 g, 0.0195 mol, 1.0 eq.) and NMP (48 mL, 4 V). The flask (Reactor 1) was purged with nitrogen and the agitator was set to 300 rpm. Dimethylamine in THF (39 mL, 0.0780 mol, 4.0 eq., 2M) was added to reaction mixture at 24-26 ^o C over 5 mins. The reaction mixture was stirred at 24-26 ^o C for 1 hour. The reaction mixture was monitored (target: compound 48 is < 0.5% AUC). The reaction mixture was concentrated to 66 mL (5.5 Vol.) residue at 25 °C over 0.5 hours. A second 500-mL three-neck flask was equipped with a magnetic stir bar, thermometer, and vacuum line was purged with nitrogen (Reactor 2). The flask (Reactor 2) was charged with dipotassium hydrogen phosphate trihydrate (72.0 g, 0.315 mol, 16.2 eq.) and water (199.7 mL, 16.6 Vol.) with stirring to give 240 mL of aqueous dipotassium hydrogen phosphate (240 mL). Residue (66 mL, Reactor 1) was added dropwise to Reactor 2 at 18-22 °C for 2 hours. The suspension was stirred at 18-22 °C for 30 minutes. The suspension was filtered, the cake was rinsed with water (24 mL, 2 V) twice. The filter cake was slurried in water (120 mL) at 18-22 °C for 40 minutes. The suspension was filtered, and the cake was rinsed with water (24 mL, 2 V) twice. The filtered product was dried with nitrogen sweep on a vacuum Buchner funnel at 20-30 °C for approximately 20 hours to afford 11.65 g compound 1 as a light-brown solid in 96.7% purity (UV, UPLC) and 96% yield. UV (MeCN) λ _max : 216 nm. ¹ H-NMR (400 Hz, DMSO-d6): δ 2.05 (s, 6H), 3.69- 3.54 (m, 5H), 4.11 (s, 3H), 5.31 (m, 2H), 7.15 (t, 2H), 7.46 (d, 2H, J =9.2 Hz), 7.54 (d, 2H, J =8.8 Hz), 7.75 (t, 3H), 9.09 (s, 1H), 9.65 (s, 1H). ¹³ C-NMR (101 MHz, DMSO-d6) δ: 164.9, 162.3, 162.2, 159.8, 159.7, 157.8, 156.9, 152.7, 150.1, 149.4, 139.6, 132.6, 131.8, 131.6, 131.1, 129.9, 125.5, 119.6, 119.5, 114.6, 112.0, 111.8, 110.6, 110.4, 110.3, 63.9, 54.9, 52.7, 44.5, 40.9. ESI-MS m/z: 624.2 [M+H] ⁺ . Purification of Relugolix (Compound 1) Re-slurry in Acetonitrile 22     P101486US01  The API Relugolix 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]pyr imidin-6- yl)phenyl)-3-methoxyurea (compound 1) is re-slurried in acetonitrile (3 V) at 20-25 °C for 2 hours. Acetonitrile (1 V) is added to the mixture and then the suspension was filtered. The filter cake is dried with nitrogen sweep in vacuum. The suspension of the solid in acetonitrile is stirred at 55-60 °C for 1 hour. The resulting suspension is cooled to 20-25 °C and filtered. The filter cake is dried with nitrogen sweep in vacuum to afford 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-methoxyurea (compound 1). UV (MeCN) λmax: 216 nm. ¹ H-NMR (400 Hz, DMSO-d6): δ 2.05 (s, 6H), 3.69- 3.54 (m, 5H), 4.11 (s, 3H), 5.31 (m, 2H), 7.15 (t, 2H), 7.46 (d, 2H, J =9.2 Hz), 7.54 (d, 2H, J =8.8 Hz), 7.75 (t, 3H), 9.09 (s, 1H), 9.65 (s, 1H). ¹³ C-NMR (101 MHz, DMSO-d6) δ: 164.9, 162.3, 162.2, 159.8, 159.7, 157.8, 156.9, 152.7, 150.1, 149.4, 139.6, 132.6, 131.8, 131.6, 131.1, 129.9, 125.5, 119.6, 119.5, 114.6, 112.0, 111.8, 110.6, 110.4, 110.3, 63.9, 54.9, 52.7, 44.5, 40.9. ESI-MS m/z: 624.2 [M+H] ⁺ . Example 11 Purification of Relugolix by salt formation Step 1. PTSA salt formation Crude compound 1 (3.0 g, 4.8 mmol, 1.0 eq., initial purity 96.6%) and 4- methylbenzenesulfonic acid (828 mg, 4.8 mmol, 1.0 eq.) was dissolved in acetonitrile (30 mL) at 20 °C. The solution turned to a suspension after stirring for 10 minutes. The resulting suspension was stirred at 20 °C for 1 hour. The solid was collected by filtration and rinsed with acetonitrile (18 mL, 6V) to afford PTSA salt of compound 1 in 99.2% purity. Step 2. Neutralization of PTSA salt to get the free base of Relugolix API 23     P101486US01  PTSA salt of compound 1 (6.59 g wet) was dissolved in a co-solvent of acetonitrile (7.5 mL) and water (12.5 mL). The solution was filtered. Then aqueous KHCO ₃ (10.2 mL, 10% w/w) was added to the filtrate. After the resulting suspension stirred at 20 °C for 1 hour, additional water (15.6 mL) was added. After the resulting suspension was stirred at 20 °C for additional 1 hours, the solid was collected by filtration and rinsed with water (9 mL) to afford compound 1 in 99.2% purity and 62.6% yield. 24