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Filgotinib synthetic method

A synthesis method and condensation technology, applied in the direction of organic chemistry, etc., can solve the problems of intermediate products and final products containing many impurities and by-products, unfavorable industrial production promotion, cumbersome operation, etc., achieve high yield, simplify operation, Reasonable effect of technical solutions

Active Publication Date: 2015-10-21
SUZHOU FUSHILAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Since there are many steps in the whole synthetic route, and the intermediate products and final products contain more impurities and by-products, a large amount of solvents are required for purification, the operation is cumbersome, the yield is low, and the cost is high, which is not conducive to the promotion of industrial production, so It is necessary to explore the synthetic method of Filgotinib which is suitable for industrialized production due to its short process flow, simple operation and low cost

Method used

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Examples

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Embodiment 1

[0029]A) Preparation of 6-hydroxyl-2-tert-butoxycarbonylaminopyridine: first carry out condensation reaction by 6-chloro-2-aminopyridine and di-tert-butyl dicarbonate in dichloromethane under stirring, 6-chloro-2-aminopyridine The molar ratio of 2-aminopyridine, dichloromethane and di-tert-butyl dicarbonate is 1:10:1.2, the temperature of the condensation reaction is 60°C, and the time of the condensation reaction is 3h. The TLC spot plate confirms that the reaction is complete, and the reaction The liquid was concentrated to dryness by rotary evaporation to obtain 6-chloro-2-tert-butoxycarbonylaminopyridine, and then 6-chloro-2-tert-butoxycarbonylaminopyridine was dropped into a sodium hydroxide solution with a concentration of 9.9% by mass percentage, In a system composed of tetrabutylammonium chloride, 1,4-dioxane and water, the hydrolysis reaction is carried out under stirring, 6-chloro-2-tert-butoxycarbonylaminopyridine, the concentration of which is 9.9% by mass The mola...

Embodiment 2

[0042] A) Preparation of 6-hydroxyl-2-tert-butoxycarbonylaminopyridine: first carry out condensation reaction by 6-chloro-2-aminopyridine and di-tert-butyl dicarbonate in dichloroethane under stirring, 6-chloro - The molar ratio of 2-aminopyridine, dichloroethane and di-tert-butyl dicarbonate is 1:5:1.3, the temperature of the condensation reaction is 10°C, the time of the condensation reaction is 8h, and the TLC spot plate confirms that the reaction is complete , the reaction solution was concentrated to dryness by rotary evaporation to obtain 6-chloro-2-tert-butoxycarbonylaminopyridine, and then 6-chloro-2-tert-butoxycarbonylaminopyridine was dropped into potassium hydroxide with a mass percentage concentration of 20%. Solution, benzyltriethylammonium bromide, p-xylene and water constitute the system and carry out the hydrolysis reaction under stirring, 6-chloro-2-tert-butoxycarbonylaminopyridine, mass percent concentration of 20% hydrogen The molar ratio of potassium oxide ...

Embodiment 3

[0049] A) Preparation of 6-hydroxyl-2-tert-butoxycarbonylaminopyridine: Condensation reaction of 6-chloro-2-aminopyridine in 1,4-dioxane with di-tert-butyl dicarbonate under stirring , the molar ratio of 6-chloro-2-aminopyridine, 1,4-dioxane and di-tert-butyl dicarbonate is 1:30:1.5, the condensation reaction temperature is 80°C, and the condensation reaction time is After 0.5h, the TLC spot plate confirmed that the reaction was complete, and the reaction solution was concentrated to dryness by rotary evaporation to obtain 6-chloro-2-tert-butoxycarbonylaminopyridine, and then 6-chloro-2-tert-butoxycarbonylaminopyridine was put into the mass In a system composed of 33.4% cesium hydroxide solution, tetradecyltrimethylammonium chloride, N,N-2 methylformamide and water and under stirring, the hydrolysis reaction, 6-chloro- The molar ratio of 2-tert-butoxycarbonylaminopyridine, 33.4% cesium hydroxide solution, tetradecyltrimethylammonium chloride, N,N-2 methylformamide and water is...

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Abstract

The invention discloses a filgotinib synthetic method and belongs to the technical field of chemical synthesis of medicines. 6-chloro-2-aminopyridine and di-tert-butyl dicarbonate ester are subjected to condensation reaction to obtain 6-chloro-2-tert-butyloxycarbonyl aminopyridine; hydrolysis reaction is performed; the obtained 6-chloro-2-tert-butyloxycarbonyl aminopyridine and trifluorinated methyl sulfonic anhydride are subjected to trifluoromethanesulfonic acid esterification reaction; the obtained 2-tert-butyloxycarbonylamino-6-pyridyltrifluoromethanesulfonate and [(1,1-dioxo-4-thiomorpholinyl)methyl]benzo-4-boronic acid pinacol ester are subjected to condensation reaction to obtain a tert-butyl ester derivative; the tert-butyl ester derivative is treated by trifluoroacetic acid and subjected to de-protection; the obtained intermediate and ethoxycarbonyl isothiocyanate are subjected to isothiocyanate reaction; the obtained intermediate and hydroxylamine hydrochloride are subjected to ring closing reaction; the obtained intermediate and cyclopropane carbonyl chloride are subjected to amidation reaction to obtain the finished product. Operation is simplified; reagents are available; the concept of environment friendliness and environment protection is embodied.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of Filgotinib. Background technique [0002] Filgotinib is the JAK1 inhibitor Filgotinib (code name GLPG0634), its chemical name is N-[5-[4-[(1,1-dioxo-4-thiomorpholinyl)methyl]phenyl][1 ,2,4]triazolo[1,5-A]pyridin-2-yl]cyclopropanecarboxamide, its chemical structural formula is: [0003] [0004] Filgotinib is an oral JAK1 inhibitor for the treatment of rheumatoid arthritis. It is a new drug under research invented by the Belgian biopharmaceutical company Galapagos. It has completed the key clinical phase II research treatment trial and successfully achieved the experimental goals expected by researchers. The curative effect excellent. In addition, some studies have also shown that Filgotinib also has a good therapeutic effect on other autoinflammatory diseases such as Crohn's disease. [0005] US20100331319 disclose...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 莫国宁
Owner SUZHOU FUSHILAI PHARMA CO LTD
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