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WO2023090859A1 - Procédé de préparation d'un dérivé d'isoxazole et nouvel intermédiaire associé - Google Patents

Procédé de préparation d'un dérivé d'isoxazole et nouvel intermédiaire associé Download PDF

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Publication number
WO2023090859A1
WO2023090859A1 PCT/KR2022/018117 KR2022018117W WO2023090859A1 WO 2023090859 A1 WO2023090859 A1 WO 2023090859A1 KR 2022018117 W KR2022018117 W KR 2022018117W WO 2023090859 A1 WO2023090859 A1 WO 2023090859A1
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Prior art keywords
formula
compound
pharmaceutically acceptable
acceptable salt
preparing
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English (en)
Korean (ko)
Inventor
이윤석
김경선
김정아
문안나
송동근
정주영
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Ildong Pharmaceutical Co Ltd
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Ildong Pharmaceutical Co Ltd
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Priority claimed from KR1020220153245A external-priority patent/KR20230072438A/ko
Publication of WO2023090859A1 publication Critical patent/WO2023090859A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel process for preparing an isoxazole derivative useful as an agonist for farnesoid X receptor (FXR, NR1H4), a novel intermediate used in the process, and a process for preparing the intermediate. .
  • Isoxazole derivative compounds that act as agonists for farnesoid X receptors (FXR, NR1H4) and can be usefully used in the manufacture of pharmaceuticals for treating metabolic diseases, cholestatic liver diseases or organ fibrosis diseases are known ( International Publication WO 2018/190643, Patent Document 1).
  • One aspect is to provide a method for preparing an isoxazole derivative.
  • Another aspect is to provide a novel intermediate that can be used in the above production method.
  • Another aspect is to provide a method for preparing a novel intermediate that can be used in the above method.
  • One aspect provides a method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an isoxazole derivative.
  • Another aspect provides a compound of Formula 2 or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the preparation method.
  • Another aspect provides a method for preparing the compound of Formula 2 or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the above preparation method.
  • the manufacturing method according to the present invention can produce isoxazole derivative compounds in high yield and high purity, minimizes the production of by-products during the manufacturing process, and is more suitable for manufacturing pharmaceuticals by using commercially available and safe reagents. . In addition, it is easier to remove the organic solvent remaining in the final material, and it is superior in that large-scale production is possible more conveniently and efficiently than the prior art.
  • One aspect provides a method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an isoxazole derivative.
  • a step of preparing a compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof may be included.
  • each R 1 is independently hydrogen, halogen, or trifluoromethyl
  • each R 2 is independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy
  • R 3 is -CO 2 -C 1-3 alkyl
  • R 4 is a carboxyl group
  • X 1 is halogen
  • p is an integer from 0 to 4.
  • q is an integer from 0 to 4.
  • the step of preparing a compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof
  • An azodicarboxylate compound, triphenylphosphine (PPh 3 ), or a combination thereof may be added.
  • a catalyst may be used in the step of preparing the compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof.
  • the step of preparing the compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof may use an azodicarboxylate compound as a catalyst. there is.
  • the azodicarboxylate compound is diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD), di-tert-butyl azodicarb It may be selected from di-tert-butyl azodicarboxylate (DBAD), dibenzyl azodicarboxylate, diphenyl azodicarboxylate, and combinations thereof.
  • the azodicarboxylate compound may be diisopropyl azodicarboxylate (DIAD).
  • triphenylphosphine may be added. there is.
  • the preparation step may proceed through a Mitsunobu reaction using an azodicarboxylate compound and triphenylphosphine (PPh 3 ).
  • the azodicarboxylate compound and triphenylphosphine (PPh 3 ) may be added in combination in a molar ratio of 1:0.5 to 1:2.5, for example, about 1:1 to 1:2.
  • the azodicarboxylate compound and triphenylphosphine (PPh 3 ) may be added in an amount of 0.5 to 2.5 moles, respectively, based on 1 mole of the compound of Formula 2 or a pharmaceutically acceptable salt thereof. .
  • the step may be performed in an organic solvent, preferably the organic solvent may be tetrahydrofuran (THF).
  • organic solvent may be tetrahydrofuran (THF).
  • the step of preparing the compound of Formula 3 or a pharmaceutically acceptable salt thereof from the compound of Formula 2 or a pharmaceutically acceptable salt thereof may be carried out under mild reaction conditions, for example, at a low temperature and a relatively short reaction time.
  • reaction by-products such as triphenylphosphine oxide and DIAD residues can be removed through a simple process, and the target compound can be prepared in high yield of about 90% and high purity of about 90%.
  • the preparation method comprises the compound of Formula 5 or a pharmaceutically acceptable salt thereof by reacting the compound of Formula 3 or a pharmaceutically acceptable salt thereof with the compound of Formula 4 or a pharmaceutically acceptable salt thereof. It may further include the step of preparing.
  • each R 1 is independently hydrogen, halogen, or trifluoromethyl
  • each R 2 is independently hydrogen, halogen, trifluoromethyl or trifluoromethoxy
  • R 3 is -CO 2 -C 1-3 alkyl
  • p is an integer from 0 to 4.
  • q is an integer from 0 to 4.
  • preparing the compound of Formula 5 or a pharmaceutically acceptable salt thereof by reacting the compound of Formula 3 or a pharmaceutically acceptable salt thereof with the compound of Formula 4 or a pharmaceutically acceptable salt thereof. may be due to the Sonogashira reaction.
  • the reaction may use a palladium catalyst under base conditions.
  • the palladium catalyst is bis(tri-tert-butylphosphine)palladium(0)(Pd[P( t -Bu) 3 ]); bis(allyl)dichloropalladium (Pd(allyl)Cl] 2 ) and tri-tert-butylphosphonium tetrafluoroborate ([HP( t- Bu) 3 ]BF 4 ); bis(tri-tert-butylphosphine)palladium(0) (Pd( t -Bu 3 P) 2 ); or bis(allyl)dichloropalladium ([Pd(allyl)Cl] 2 ), but is not limited thereto.
  • the base may be 1,4-diazabicyclo[2.2.2] octane (DABCO) or 4-dimethylaminopyridine (MDAP), but is not limited thereto.
  • DABCO 1,4-diazabicyclo[2.2.2] octane
  • MDAP 4-dimethylaminopyridine
  • the base may be added in an amount of 0.5 to 4 moles
  • the palladium catalyst may be added in an amount of 0.005 to 0.02 moles.
  • the reaction may be conducted in an organic solvent.
  • organic solvents that can be used include nitriles such as acetonitrile; alcohols such as ethanol and isopropanol; ethers such as tetrahydrofuran, diisopropyl ether, dioxane, and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene and toluene; Amides such as dimethylacetamide and dimethylformamide may be exemplified, but are not limited thereto.
  • preparing the compound of Formula 5 or a pharmaceutically acceptable salt thereof by reacting the compound of Formula 3 or a pharmaceutically acceptable salt thereof with the compound of Formula 4 or a pharmaceutically acceptable salt thereof. added 1,4-diazabicyclo[2.2.2]octane (DABCO) and bis(tri-tert-butylphosphine)palladium(0)(Pd[P(t-Bu) 3 ]) in an organic solvent. can proceed.
  • DABCO 1,4-diazabicyclo[2.2.2]octane
  • DABCO 1,4-diazabicyclo[2.2.2]octane
  • bis(tri-tert-butylphosphine)palladium(0)(Pd[P(t-Bu) 3 ]) in an organic solvent. can proceed.
  • the organic solvent may be acetonitrile (MeCM).
  • the compound of Formula 3 or a pharmaceutically acceptable salt thereof and the compound of Formula 4 or a pharmaceutically acceptable salt thereof may be added in a molar ratio of 1:0.5 to 1:2, for example about 1:1. there is.
  • 1,4-diazabicyclo[2.2.2]octane may be added in an amount of 0.5 to 4 moles based on 1 mole of the compound of Formula 3 or a pharmaceutically acceptable salt thereof, and bis( Tri-tert-butylphosphine)palladium(0) may be added in an amount of 0.005 to 0.01 mol.
  • the generation of by-products other than the compound of Formula 5, such as homocoupled by-products that may be produced by combining the compounds of Formula 4 with each other, is minimized, and the yield is about 80% and about 99%.
  • the target compound can be prepared with a high purity of % or higher.
  • the preparation method may further include reducing the compound of Formula 5 or a pharmaceutically acceptable salt thereof.
  • the reduction step may be performed by adding a reducing agent such as lithium hydroxide in an organic solvent such as tetrahydrofuran (THF).
  • Formula 1 or a pharmaceutically acceptable salt thereof may be prepared from the compound of Formula 5 or a pharmaceutically acceptable salt thereof.
  • the manufacturing method is a liquid crystal in one embodiment.
  • R 3 is -CO 2 -C 1-3 alkyl
  • X 1 and X 2 are each a halogen independently selected from chlorine, bromine, and iodine.
  • the substituent of X 2 is removed by a substitution reaction between the compound of Formula 2-1 or a pharmaceutically acceptable salt thereof and the compound of Formula 2-2 or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof.
  • the present inventors have conducted synthesis experiments under various conditions to find reaction conditions that can minimize the production of byproducts in the substitution reaction, and as a result, when the substitution reaction is performed under THF solvent and free base conditions, other It is possible to minimize the formation of unnecessary by-products other than the target compound of Formula 2 compared to the treatment with an organic solvent such as DIPEA, TEA, pyridine, or another kind of inorganic base such as KHCO 3 , K 2 CO 3 , NaHCO 3 , and NaOH. I found something that could be done.
  • the step of preparing the compound of Formula 2 or a pharmaceutically acceptable salt thereof may be performed in an organic solvent, and preferably, the organic solvent may be tetrahydrofuran (THF).
  • the organic solvent may be tetrahydrofuran (THF).
  • the above step may be treated under conditions in which no base is added (free base).
  • the target compound can be prepared with a high yield of about 97% and a high purity of about 99%.
  • the step of preparing the compound of Formula 2 or a pharmaceutically acceptable salt thereof may be performed at 10 to 40°C, for example, 15 to 30°C.
  • the compound of Formula 2-1 or a pharmaceutically acceptable salt thereof and the compound of Formula 2-2 or a pharmaceutically acceptable salt thereof are mixed in a relative molar ratio of 1:0.5 to 1:2. may be added.
  • the pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt of the compound of the present invention, which can be prepared by any suitable method useful to those skilled in the art.
  • Another aspect provides a compound of Formula 2 or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the above preparation method.
  • R 3 is -CO 2 -C 1-3 alkyl
  • X 1 is halogen
  • Another aspect provides a method for preparing the compound of Formula 2 or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the above preparation method.
  • the manufacturing method is a liquid crystal in one embodiment.
  • a step of reacting a compound of Formula 2-1 or a pharmaceutically acceptable salt thereof with a compound of Formula 2-2 or a pharmaceutically acceptable salt thereof may be included.
  • R 3 is -CO 2 -C 1-3 alkyl
  • X 1 and X 2 are each a halogen independently selected from chlorine, bromine, and iodine.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be Formula 1a below or a pharmaceutically acceptable salt thereof.
  • a step of preparing a compound of Formula 3a or a pharmaceutically acceptable salt thereof from a compound of Formula 2a below or a pharmaceutically acceptable salt thereof may be included.
  • the step of preparing a compound of Formula 3a or a pharmaceutically acceptable salt thereof from the compound of Formula 2a or a pharmaceutically acceptable salt thereof
  • An azodicarboxylate compound, triphenylphosphine (PPh 3 ), or a combination thereof may be added.
  • a catalyst may be used in the step of preparing the compound of Formula 3a or a pharmaceutically acceptable salt thereof from the compound of Formula 2a or a pharmaceutically acceptable salt thereof.
  • the step of preparing the compound of Formula 3a or a pharmaceutically acceptable salt thereof from the compound of Formula 2a or a pharmaceutically acceptable salt thereof may use an azodicarboxylate compound as a catalyst. there is.
  • the azodicarboxylate compound is diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD), di-tert-butyl azodicarboxylate (DBAD), dibenzyl azodicarboxylate, diphenyl azodicarboxylate, and combinations thereof.
  • DIAD diisopropyl azodicarboxylate
  • DEAD diethyl azodicarboxylate
  • DBAD di-tert-butyl azodicarboxylate
  • dibenzyl azodicarboxylate diphenyl azodicarboxylate, and combinations thereof.
  • triphenylphosphine may be added. there is.
  • the step may be performed in an organic solvent, preferably the organic solvent may be tetrahydrofuran (THF).
  • organic solvent may be tetrahydrofuran (THF).
  • the preparation method includes the compound of Formula 5a or a pharmaceutically acceptable salt thereof by reacting the compound of Formula 3a or a pharmaceutically acceptable salt thereof with a compound of Formula 4a or a pharmaceutically acceptable salt thereof. It may further include the step of preparing.
  • the preparation method may further include reducing the compound of Formula 5a or a pharmaceutically acceptable salt thereof. Accordingly, Formula 1a or a pharmaceutically acceptable salt thereof may be prepared from the compound of Formula 5a or a pharmaceutically acceptable salt thereof.
  • the manufacturing method is a liquid crystal in one embodiment.
  • the step of preparing the compound of Formula 2 or a pharmaceutically acceptable salt thereof may be performed in an organic solvent, and preferably, the organic solvent may be tetrahydrofuran (THF).
  • the organic solvent may be tetrahydrofuran (THF).
  • the step may be performed under conditions in which no base is added (free base).
  • the compound of Formula 2 or a pharmaceutically acceptable salt thereof is prepared in the THF solvent and free base conditions, the production of unnecessary by-products in addition to the target compound can be minimized.
  • Another embodiment provides a compound of Formula 2a or a pharmaceutically acceptable salt thereof as an intermediate that can be used in the above preparation method.
  • a step of reacting a compound of Formula 2-1a or a pharmaceutically acceptable salt thereof with a compound of Formula 2-2a or a pharmaceutically acceptable salt thereof may be included.
  • a method for preparing the compound of Formula 1a or a pharmaceutically acceptable salt thereof is shown in Formula 1 below together with the yield and purity of the compound obtained in each step.
  • DIAD diisopropyl azodicarboxylate
  • Pd[P( t -Bu) 3 ] Bis(tri-tert-butylphosphine)palladium(0) (bis(tri-tert-butylphosphine)palladium(0))
  • a compound of Formula 1 or a pharmaceutically acceptable salt thereof for example, an isoxazole derivative represented by a compound of Formula 1a or a pharmaceutically acceptable salt thereof, is an FXR agonist or a pharmaceutical containing the same. can be used in manufacturing.
  • the compound or a pharmaceutically acceptable salt thereof is an agonist of the farnesoid X receptor (FXR, NR1H4), which can be used for various physiological processes such as bile acid (BA) regulation, lipid/sugar metabolism, inflammation and fibrosis. It can be used in the manufacture of pharmaceuticals to control
  • the compound or a pharmaceutically acceptable salt thereof is a drug for treating metabolic disease, cholestatic liver disease or organ fibrosis disease, such as high cholesterol, cycloproteinemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, It can be used for the manufacture of medicines for the treatment of cholestasis/fibrosis, cholesterol gallstone disease, hyperglycemia, diabetes, insulin resistance, metabolic rigidity, nephropathy, liver disease, atherosclerosis, cancer, inflammatory disorders, osteoporosis, or skin aging.
  • metabolic disease cholestatic liver disease or organ fibrosis disease
  • organ fibrosis disease such as high cholesterol, cycloproteinemia, hypertriglyceridemia, dyslipidemia, lipodystrophy
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • Step 1 Preparation of methyl 5-bromo-3-(cyclopropanecarboxamido)-2-hydroxybenzoate
  • methyl 3-amino-5-bromo-2-hydroxybenzoate (compound of formula 2-1a) (800 g, 3.25 mol, 1 wt, 1.0 eq.) and tetrahydrofuran (THF) (8000 mL, 10 vol, 8.9 wt) and stirred under nitrogen conditions at 15 degrees to 25 degrees, and then cyclopropanecarbonyl chloride (Formula 2-2a compound) (344mL, 3.74mol, 0.43vol, 0.49wt, 1.15eq.) and tetra A mixture of hydrofuran (THF) (2400 mL, 3 vol, 2.7 wt) was added slowly.
  • THF tetrahydrofuran
  • the reaction mixture was heated to 45 degrees to 50 degrees and stirred for 1 hour to 3 hours. After confirming the completion of the reaction, the reaction mixture was cooled to 15 degrees to 25 degrees. To the reaction mixture, 7.5% w/w aqueous sodium chloride solution (3200 mL) and 18% w/w aqueous potassium bicarbonate solution (3200 mL) were slowly added in that order and stirred for 15 minutes. The separated organic layer was extracted, washed with 7.5% w/w aqueous sodium chloride solution, and then concentrated at 40 degrees or less.
  • Step 2 Methyl 5-bromo-2-cyclopropylbenzo[ d Preparation of ]oxazole-7-carboxylate
  • Methyl 5-bromo-3-(cyclopropanecarboxamido)-2-hydroxybenzoate (compound of formula 2a) prepared in step 1 (950 g, 3.02 mol, 1.0 wt, 1.0 eq.), triphenyl Phosphine (PPh 3 ) (1,235g, 4.83mol, 1.3wt, 1.6eq.) and tetrahydrofuran (THF) (9,500mL, 10.0vol., 8.9wt.) were charged into a reaction vessel and separated after stirring under nitrogen conditions.
  • triphenyl Phosphine PPh 3
  • THF tetrahydrofuran
  • Step 3 Methyl 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2- Cyclopropylbenzo[ d Preparation of ]oxazole-7-carboxylate
  • the compound of Formula 3a obtained in step 2 (900 g, 1 wt, 1.0 eq.), 4-((3-chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2, 6-dichlorophenyl) isoxazole (compound of Formula 4a) (1,179 g, 1.3 wt, 0.92 eq.), 1,4-diazabicyclo [2.2.2] octane (DABCO) (684 g, 0.76 wt, 2.0 eq . ) , and acetonitrile (MeCM) (9,000 mL, 10 vol) was filled and stirred for 16 to 24 hours under nitrogen conditions at 15 to 25 degrees.
  • DABCO 1,4-diazabicyclo [2.2.2] octane
  • MeCM acetonitrile
  • Step 4 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2-cyclo propyl benzo[ d Preparation of ]oxazole-7-carboxylic acid
  • reaction mixture After sufficiently dissolving lithium hydroxide (422.4g, 0.33wt, 2.3eq.) and purified water (3,840mL, 3vol, 3wt) in a separate suitable container, the reaction mixture was slowly added while maintaining 10 to 15 degrees, and then 5 time to 7 hours. After confirming the completion of the reaction mixture, pH was adjusted by adding a mixture of 1N aqueous hydrochloric acid and 18% w/w aqueous sodium chloride solution, and then the organic layer was extracted and washed with 18% w/w aqueous sodium chloride solution.
  • a solid, tetrahydrofuran (THF), and isopropanol (iPrOH) are filled in a reaction vessel, heated to 70 to 80 degrees, completely dissolved, and slowly cooled to 0 to 5 degrees to crystallize. The resulting solid was filtered, washed with cold isopropanol (iPrOH), and dried to obtain the title compound (compound of Formula 1a) (951 g, yield 75.7%, purity 99.49%).

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Abstract

La présente invention concerne : un nouveau procédé de préparation d'un dérivé d'isoxazole, qui est utile en tant qu'agoniste du récepteur farnésoïde X (FXR, NR1H4) ; un nouvel intermédiaire utilisé dans le procédé de préparation ; et un procédé de préparation de l'intermédiaire de préparation, et, plus particulièrement, un nouveau procédé de préparation du dérivé d'isoxazole, un nouvel intermédiaire utilisé dans celui-ci, et un procédé de préparation du nouvel intermédiaire.
PCT/KR2022/018117 2021-11-17 2022-11-16 Procédé de préparation d'un dérivé d'isoxazole et nouvel intermédiaire associé Ceased WO2023090859A1 (fr)

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KR10-2021-0158716 2021-11-17
KR20210158716 2021-11-17
KR10-2022-0153245 2022-11-16
KR1020220153245A KR20230072438A (ko) 2021-11-17 2022-11-16 아이속사졸 유도체의 제조 방법 및 그의 신규한 중간체

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011020615A1 (fr) * 2009-08-19 2011-02-24 Phenex Pharmaceuticals Ag Nouveaux composés se liant au fxr (nr1 h4) et modulant son activité
KR20170135938A (ko) * 2015-04-15 2017-12-08 셀젠 콴티셀 리서치, 인크. 브로모도메인 억제제
WO2018190643A1 (fr) * 2017-04-12 2018-10-18 Il Dong Pharmaceutical Co., Ltd. Dérivés d'isoxazole en tant qu'agonistes du récepteur nucléaire et leur utilisation
KR20180115233A (ko) * 2017-04-12 2018-10-22 일동제약(주) 핵 수용체의 효능제인 아이속사졸 유도체 및 이의 용도
WO2021057890A1 (fr) * 2019-09-25 2021-04-01 南京明德新药研发有限公司 Dérivés 2h-benzopyrane utilisables en tant qu'inhibiteurs de crac
WO2022068772A1 (fr) * 2020-09-29 2022-04-07 深圳信立泰药业股份有限公司 Dérivé de benzimidazole, son procédé de préparation et son utilisation médicale

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011020615A1 (fr) * 2009-08-19 2011-02-24 Phenex Pharmaceuticals Ag Nouveaux composés se liant au fxr (nr1 h4) et modulant son activité
KR20170135938A (ko) * 2015-04-15 2017-12-08 셀젠 콴티셀 리서치, 인크. 브로모도메인 억제제
WO2018190643A1 (fr) * 2017-04-12 2018-10-18 Il Dong Pharmaceutical Co., Ltd. Dérivés d'isoxazole en tant qu'agonistes du récepteur nucléaire et leur utilisation
KR20180115233A (ko) * 2017-04-12 2018-10-22 일동제약(주) 핵 수용체의 효능제인 아이속사졸 유도체 및 이의 용도
WO2021057890A1 (fr) * 2019-09-25 2021-04-01 南京明德新药研发有限公司 Dérivés 2h-benzopyrane utilisables en tant qu'inhibiteurs de crac
WO2022068772A1 (fr) * 2020-09-29 2022-04-07 深圳信立泰药业股份有限公司 Dérivé de benzimidazole, son procédé de préparation et son utilisation médicale

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