WO2025127790A1 - Procédé de préparation de rélugolix - Google Patents
Procédé de préparation de rélugolix Download PDFInfo
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- WO2025127790A1 WO2025127790A1 PCT/KR2024/096649 KR2024096649W WO2025127790A1 WO 2025127790 A1 WO2025127790 A1 WO 2025127790A1 KR 2024096649 W KR2024096649 W KR 2024096649W WO 2025127790 A1 WO2025127790 A1 WO 2025127790A1
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- chemical formula
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Classifications
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
Definitions
- the present invention relates to a method for producing relugolix, and more specifically, to a method for economically producing high-purity relugolix with a high yield.
- Relugolix (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), of the following chemical formula 1, is the active pharmaceutical ingredient (API) of Orgovyx ® , a drug for the treatment of prostate cancer.
- API active pharmaceutical ingredient
- U.S. Patent No. 10,150,778 discloses a method for producing relugolix by a total of 7 steps using ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate as a starting material, as shown in the following reaction scheme 1.
- One object of the present invention is to provide a method for economically producing high-purity relugolix in high yield.
- One embodiment of the present invention relates to a method for producing relugolix of the following chemical formula 1, wherein the method of the present invention comprises:
- R 2 is a halogen atom, a tosylate group, a mesylate group, or a nitrobenzenesulfonate group.
- reaction scheme 2 The method described in the following reaction scheme 2 is merely an example of a representatively used method, and the reaction reagents, reaction conditions, etc. may be changed at any time depending on the case.
- the above base is not particularly limited, and any known base can be used.
- the above amide coupling reaction can be performed in the presence or absence of a coupling reagent.
- Toluene, hexane, heptane, pentane, benzene, cyclohexane, diethyl ether, etc. can be used as the reaction solvent, and toluene is particularly preferred.
- the reaction temperature can be about 0 to 200°C, preferably 90 to 110°C.
- the reaction time can be from 1 to 24 hours, preferably from 1 to 4 hours.
- the compound of chemical formula 6 can be prepared by alkylating the compound of chemical formula 4 with the compound of chemical formula 5.
- Examples of compounds of the above chemical formula 5 that can be used include 2-(chloromethyl)-1,3-difluorobenzene, 2-(bromomethyl)-1,3-difluorobenzene, 2-(iodomethyl)-1,3-difluorobenzene, 2,6-difluorobenzyl 4-methylbenzenesulfonic acid, 2,6-difluorobenzyl methanesulfonic acid, and 2,6-difluorobenzyl 4-nitrobenzenesulfonic acid.
- the above alkylation reaction can be carried out in the presence or absence of a base.
- the above base is not particularly limited, and any known base can be used.
- the base may include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, etc., and these may be used alone or in combination of two or more.
- the base may be potassium carbonate.
- the above alkylation reaction can be carried out with or without a catalyst.
- the catalyst examples include potassium iodide, sodium iodide, cesium iodide, etc., and these can be used alone or in combination of two or more.
- the catalyst can be potassium iodide.
- the reaction is carried out in the presence of a solvent.
- a solvent There is no particular limitation on the type of reaction solvent as long as the reaction proceeds.
- DMF DMC
- NMP DMSO
- THF THF
- DMF preferably used as the reaction solvent
- the above base may be an organic base or an inorganic base.
- triethylamine it is preferable to use triethylamine as the base.
- the reaction temperature may be -10°C to reflux temperature, and preferably 0 to room temperature.
- Reaction times can range from 10 minutes to 30 hours.
- Step 5 Preparation of the compound of chemical formula 9 and its HBr salt
- the compound of chemical formula 9 can be prepared by reducing the nitro group of the compound of chemical formula 8.
- the above reduction reaction can be performed using a metal as a reducing agent in the presence of an acid.
- the metal used may be iron (Fe), tin (Sn), zinc (Zn), copper (Cu), or nickel (Ni), and iron (Fe) is preferred.
- the above metal can be used in an amount of 1 to 5 moles, preferably 2 to 3 moles, per 1 mole of the compound of chemical formula 8.
- the above acid can be hydrochloric acid, sulfuric acid, acetic acid, formic acid, phosphoric acid, nitric acid, etc., and hydrochloric acid is preferably used.
- the reaction time can generally be from 1 to 120 hours, preferably from 6 to 14 hours.
- the above methoxy ammonium chloride can be used in an amount of 1 to 2 moles per mole of the compound of chemical formula 9 or its HBr salt.
- Reaction times can range from 10 minutes to 36 hours.
- the compound of chemical formula 1 can be prepared by subjecting the compound of chemical formula 13 to an ester hydrolysis reaction in the presence of a base, followed by a cyclization reaction.
- the above base may be an organic base or an inorganic base.
- Examples of the above inorganic base include alkali metal carbonates such as cesium carbonate, potassium carbonate, and sodium carbonate; or alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide. These may be used alone or in combination of two or more.
- reaction solvents Methanol, ethanol, acetonitrile, tetrahydrofuran, water, etc. can be used as reaction solvents.
- Methyl chloroformate (124 g) as a compound of formula 3 was added dropwise to a solution of the compound of formula 2 (200 g) in toluene (600 mL) at 90 to 100°C, and the reaction mixture was stirred until less than 1% of the compound of formula 2 remained (HPLC).
- the reaction mixture was cooled to 60 to 70°C, and ethanol was added dropwise (1800 mL).
- the reaction mixture was cooled to 0 to 10°C and stirred at that temperature for 1 hour.
- the reaction mixture was filtered, and the cake was washed with 1000 mL of ethanol.
- the washed reaction product was dried under vacuum to obtain 232.5 g of the compound of formula 4 (yield: 97.8%, purity: 96.87%).
- the compound of chemical formula 1 obtained in the above Example 9 was placed in a container, 40 mL of dimethyl sulfoxide (DMSO) was added, and stirred at 40°C to completely dissolve. Then, activated carbon ( ⁇ 0.05) was added, and the mixture was stirred at the same temperature for an additional 30 minutes, and then the activated carbon was removed through filtration. The filtered solution was cooled to 35°C, and the seed compound of Form I (crystalline form prepared in Example 8 of U.S. Patent No. 10,464,945) was added, the temperature was raised to 50°C, and stirred for 2 hours. Thereafter, the temperature was lowered to 35°C again, reheated to 50°C, and 40 mL of ethanol was added.
- DMSO dimethyl sulfoxide
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
La présente invention concerne un procédé de préparation de manière économique de rélugolix de haute pureté à un haut rendement.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20230180032 | 2023-12-12 | ||
| KR10-2023-0180032 | 2023-12-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2025127790A1 true WO2025127790A1 (fr) | 2025-06-19 |
Family
ID=96058019
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2024/096649 Pending WO2025127790A1 (fr) | 2023-12-12 | 2024-12-10 | Procédé de préparation de rélugolix |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR20250090216A (fr) |
| WO (1) | WO2025127790A1 (fr) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN113501830A (zh) * | 2021-07-14 | 2021-10-15 | 山东百诺医药股份有限公司 | 瑞卢戈利的制备方法 |
| CN114409629A (zh) * | 2022-02-22 | 2022-04-29 | 浙江科聚生物医药有限公司 | 一种高纯度Relugolix关键中间体的制备方法及应用 |
| US20230357267A1 (en) * | 2022-05-05 | 2023-11-09 | Scinopharm Taiwan, Ltd. | Process for preparing relugolix and intermediates thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4119564A1 (fr) | 2012-09-28 | 2023-01-18 | Takeda Pharmaceutical Company Limited | Procédé de production de dérivés de thiénopyridine |
-
2024
- 2024-12-10 WO PCT/KR2024/096649 patent/WO2025127790A1/fr active Pending
- 2024-12-10 KR KR1020240182759A patent/KR20250090216A/ko active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN113501830A (zh) * | 2021-07-14 | 2021-10-15 | 山东百诺医药股份有限公司 | 瑞卢戈利的制备方法 |
| CN114409629A (zh) * | 2022-02-22 | 2022-04-29 | 浙江科聚生物医药有限公司 | 一种高纯度Relugolix关键中间体的制备方法及应用 |
| US20230357267A1 (en) * | 2022-05-05 | 2023-11-09 | Scinopharm Taiwan, Ltd. | Process for preparing relugolix and intermediates thereof |
Non-Patent Citations (1)
| Title |
|---|
| MIWA, K. ET AL.: "Discovery 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 (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin- releasing hormone receptor", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, 2011, pages 4998 - 5012, XP055012890, DOI: 10.1021/jm200216q * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20250090216A (ko) | 2025-06-19 |
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