Preparation method of Filgotinib

A compound and alcohol solvent technology, which is applied in the field of preparation of Filgotinib, can solve the problems of cumbersome handling, unfriendly environment, and low product purity, and achieve the effects of improving product purity, simple post-treatment process, and high product yield

Active Publication Date: 2021-12-10
AURISCO PHARM(TIANJIN) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

b class="d_n">[0013] The technical problem to be solved by the present invention is exactly the problems such as unfriendly environment, complica

Method used

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  • Preparation method of Filgotinib
  • Preparation method of Filgotinib
  • Preparation method of Filgotinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Compound A (75.0g, 0.27mol), compound B (98.4g, 0.28mol), NaHCO 3 (27.7g, 0.33mol), Pd(dppf)Cl 2 (2.0g, 2.7mmol), ethanol (600mL) and water (150mL) were added to the reaction flask, and after nitrogen replacement, the temperature was raised to 70-80°C for 15-20hrs, followed by HPLC until the reaction was complete.

[0042] Cool the reaction solution to 15~30°C and stir for 2~3hr. Suction filtration, the filter cake was rinsed with ethanol (150mL×2) and water to obtain the crude product of Filgotinib.

[0043]The above-mentioned Filgotinib crude product was added in the reaction flask, acetonitrile (4200mL) and water (600mL) were added, and heated to 65~80°C under stirring. o C to get a clear solution, add palladium removal reagent, keep warm for 60~70 o Stir at C, filter with suction, rinse the filter cake with acetonitrile (75mL×2), concentrate to 2250mL~3000mL, reduce to 0~10 o C stirring for 1~2hrs. Suction filtration, the filter cake was rinsed with acetonitril...

Embodiment 2

[0045] Compound A (7.50g, 27mmol), compound B (9.84g, 28mmol), K 2 CO 3 (4.55g, 33mmol), Pd(dppf)Cl 2 (0.2g, 0.27mmol), isopropanol (60mL) and water (6mL) were added to the reaction flask, and after nitrogen replacement, the temperature was raised to 80-90°C for 10-15hrs, followed by HPLC until the reaction was complete.

[0046] Cool the reaction solution to 15~30°C and stir for 2~3hr. Suction filtration, the filter cake was rinsed with ethanol (150mL×2) and water to obtain the crude product of Filgotinib.

[0047] The above-mentioned Filgotinib crude product was added in the reaction flask, acetonitrile (420mL) and water (60mL) were added, and heated to 65~80°C under stirring. o C to get a clear solution, add palladium removal reagent, keep warm for 60~70 o Stir at C, filter with suction, rinse the filter cake with acetonitrile (7.5mL×2), concentrate to 225mL~300mL, reduce to 0~10 o C stirring for 1~2hrs. Suction filtration, the filter cake was rinsed with acetonitrile...

Embodiment 3

[0049] Compound A (75.0g, 0.27mol), compound B (98.4g, 0.28mol), NaHCO 3 (27.7g, 0.33mol), Pd(dppf)Cl 2 (6.0g, 8.1mmol), ethanol (600mL) and water (150mL) were added to the reaction flask, and after nitrogen replacement, the temperature was raised to 70-80°C for 15-20 hrs, followed by HPLC until the reaction was complete.

[0050] Cool the reaction solution to 15~30°C and stir for 2~3hr. Suction filtration, the filter cake was rinsed with ethanol (150mL×2) and water to obtain the crude product of Filgotinib.

[0051] The above-mentioned Filgotinib crude product was added in the reaction flask, acetonitrile (4200mL) and water (600mL) were added, and heated to 65~80°C under stirring. o C to get a clear solution, add palladium removal reagent, keep warm for 60~70 o Stir at C, filter with suction, rinse the filter cake with acetonitrile (75mL×2), concentrate to 2250mL~3000mL, reduce to 0~10 o C stirring for 1~2hrs. Suction filtration, the filter cake was rinsed with acetonitr...

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Abstract

The invention discloses a preparation method of filgotinib. The preparation method provided by the invention comprises the following steps: in a mixed solvent of an alcohol solvent and water, in the presence of a palladium catalyst and alkali, enabling a compound A (N-(5-bromo-[1, 2, 4] triazolo [1, 5-a] pyridine-2-yl) cyclopropyl formamide) and a compound B (4-[4-(4, 4, 5, 5-tetramethyl [1, 3, 2] dioxaborolan-2-yl) benzyl] thiomorpholine-1, 1-dioxide) to react. The preparation method has the advantages of environmental friendliness, low cost, simplicity and convenience in operation, high product purity, low impurity content, facilitation of industrialization and the like.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of Filgotinib. Background technique [0002] Filgotinib is a JAK1 inhibitor with the chemical name N-[5-[4-[(1,1-dioxo-4-thiomorpholinyl)methyl]phenyl][1,2,4]tri Azolo[1,5-A]pyridin-2-yl]cyclopropanecarboxamide, its chemical structural formula is: [0003] . [0004] Filgotinib is a novel once-daily oral JAK kinase inhibitor that preferentially inhibits JAK1. Approved by the European Commission and the Japanese Ministry of Health, Labor and Welfare, Jyseleca® (filgotinib maleate 200mg and 100mg tablets) was launched in the European Union and Japan in November 2020 for the treatment of rheumatoid arthritis (RA). In addition, the new indication application of the oral JAK1 inhibitor Jyseleca (filgotinib, 200mg) has been accepted by the European Medicines Agency (EMA) and has started review. The drug is intended for the treatment o...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 裴江郭万成蒋英豪房杰褚定军谢晓强
Owner AURISCO PHARM(TIANJIN) INC
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