WO2024069492A1 - Procédés de préparation et de fabrication de relugolix - Google Patents

Procédés de préparation et de fabrication de relugolix Download PDF

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Publication number
WO2024069492A1
WO2024069492A1 PCT/IB2023/059641 IB2023059641W WO2024069492A1 WO 2024069492 A1 WO2024069492 A1 WO 2024069492A1 IB 2023059641 W IB2023059641 W IB 2023059641W WO 2024069492 A1 WO2024069492 A1 WO 2024069492A1
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Prior art keywords
compound
methoxypyridazin
difluorobenzyl
dione
pyrimidine
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PCT/IB2023/059641
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English (en)
Inventor
Daniel Coughlin
Zhiyun Li
Jilong LUO
Xuewang XU
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Macfarlan Smith Limited
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Publication of WO2024069492A1 publication Critical patent/WO2024069492A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

  • 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.
  • GnRH gonadotropin-releasing hormone
  • 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-dioxothieno[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.
  • 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.
  • 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 2 ⁇ .
  • 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.
  • 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).
  • pharmaceutical composition is intended to encompass a pharmaceutically effective amount of the API relugolix of the invention and a pharmaceutically acceptable excipient.
  • compositions includes pharmaceutical compositions such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • 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.
  • treat refers to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder.
  • 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.
  • 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.
  • 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.
  • Figures 1-3 The synthetic chemistry of the manufacture of the API Relugolix is summarized in Figures 1-3.
  • a compound Methyl 2-(1H-imidazole-1-carboxamido)-4-methylthiophene-3-carboxylate (30) was prepared, having the chemical structure:
  • CDI 1,1’- Carbonyldiimidazole
  • DIPEA N,N-Diisopropylethylamine
  • 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).
  • NMP N-methyl-2- pyrrolidone
  • 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 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-carboxylate 34 by adding water to the mixture and maintaining heating of the mixture 60-65 o C for 3 hours to form 32.
  • 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
  • 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.
  • 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.
  • 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)-dione (compound 46) in a 92 % yield.
  • 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-tetrahydrothieno[2,3- 8 P101486US01 d]pyrimidin-5-yl)methoxy)-N,N,N-trimethyl-2-oxoethan-1-aminium 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.
  • 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).
  • Relugolix is prepared by a convergent synthesis of key intermediates 49 and 10.
  • 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 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.
  • 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.
  • 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.
  • compositions comprising the API or API salt (1), methods of treatment comprising the salt, and uses thereof
  • the present invention provides a pharmaceutical composition comprising: 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-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.
  • 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.
  • 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-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.
  • the API (1) or an API salt is in the form of an oral dosage taken by human subjects once per day.
  • 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.
  • 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 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 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 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.
  • 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.
  • MeOH 770 mL, 10 V
  • KHCO 3 13.42 g, 134 mmol, 1.0 eq.
  • 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.
  • 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.
  • 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.).
  • 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).
  • 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,
  • 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).
  • 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.
  • 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.
  • 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.
  • 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]pyrimidin-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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne des intermédiaires et des procédés destinés à la préparation de Relugolix, ainsi que des compositions pharmaceutiques contenant du Relugolix fabriqué par les procédés de l'invention.
PCT/IB2023/059641 2022-09-29 2023-09-27 Procédés de préparation et de fabrication de relugolix WO2024069492A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9758528B2 (en) 2012-09-28 2017-09-12 Takeda Pharmaceutical Company Limited Production method of thienopyrimidine derivative
EP3660017A1 (fr) * 2017-07-28 2020-06-03 Jiangsu Hengrui Medicine Co., Ltd. Procédé de préparation d'un dérivé de pyrimidone hétéroaryle et intermédiaire d'un dérivé de pyrimidone hétéroaryle
CN111333633A (zh) * 2020-04-01 2020-06-26 江西青峰药业有限公司 一种瑞卢戈利的中间体化合物及其制备方法和用途
WO2022214645A1 (fr) * 2021-04-09 2022-10-13 Farmhispania Group, S.L. Procédés et intermédiaires pour la préparation de rélugolix

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9758528B2 (en) 2012-09-28 2017-09-12 Takeda Pharmaceutical Company Limited Production method of thienopyrimidine derivative
US10150778B2 (en) 2012-09-28 2018-12-11 Takeda Pharmaceutical Company Limited Production method of thienopyrimidine derivative
US10544160B2 (en) 2012-09-28 2020-01-28 Takeda Pharmaceutical Company Limited Production method of thienopyrimidine derivative
EP3660017A1 (fr) * 2017-07-28 2020-06-03 Jiangsu Hengrui Medicine Co., Ltd. Procédé de préparation d'un dérivé de pyrimidone hétéroaryle et intermédiaire d'un dérivé de pyrimidone hétéroaryle
CN111333633A (zh) * 2020-04-01 2020-06-26 江西青峰药业有限公司 一种瑞卢戈利的中间体化合物及其制备方法和用途
WO2022214645A1 (fr) * 2021-04-09 2022-10-13 Farmhispania Group, S.L. Procédés et intermédiaires pour la préparation de rélugolix

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"The United States Pharmacopeia", 1995, pages: 1843 - 1844
REMINGTON: "The Science and Practice of Pharmacy", 2005, LIPPINCOTT, WILLIAMS AND WILKINS

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