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Preparation method of key intermediate of edoxaban

An equation and reaction system technology, applied in the direction of organic chemistry, etc., can solve the problems of low reaction yield, poor stability of hydrochloride, affecting reaction progress, etc., to improve the reaction yield, improve the reaction yield and purity, and reduce the dosage. Effect

Pending Publication Date: 2022-01-25
JIANGSU VCARE PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the existing process for preparing this compound, both raw material compound A and compound B participate in the reaction in the form of a salt, but the hydrochloride of compound B has poor stability, and a large amount of alkali needs to be used in the reaction system to neutralize and participate in the reaction. A large amount of solvent needs to be used, and a large amount of salt exists in the reaction system, which affects the progress of the reaction, resulting in a generally low reaction yield

Method used

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  • Preparation method of key intermediate of edoxaban
  • Preparation method of key intermediate of edoxaban
  • Preparation method of key intermediate of edoxaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040] DMF (120g) was placed in a 500mL reaction flask, followed by adding compound A (22.5g, 0.079mol, 1.00eq.), compound B (18.9g, 0.083mol, 1.05eq.) and sodium acetate (6.5g, 0.079mol , 1.00eq.), heated to 95 ° C for 8h. Add 240 g of water, keep it at 85°C for 1 hour, solids precipitate out, filter with suction, rinse the filter cake with water, and dry to obtain 32.5 g of compound I as an off-white solid, with a yield of 88.1% and a purity of 98.2%.

Embodiment 2

[0042]

[0043] DMF (120g) was placed in a 500mL reaction flask, followed by adding compound A (22.5g, 0.079mol, 1.00eq.), compound B (18.9g, 0.083mol, 1.05eq.) and sodium acetate (9.7g, 0.118mol , 1.50eq.), heated to 90 ° C for 7h. Add 240g of water, keep it at 85°C for 1 hour, solids precipitate out, filter with suction, rinse the filter cake with water, and dry to obtain 34.3g of compound I as an off-white solid, with a yield of 93.0% and a purity of 98.9%.

Embodiment 3

[0045]

[0046] DMF (120g) was placed in a 500mL reaction flask, followed by adding compound A (22.5g, 0.079mol, 1.00eq.), compound B (18.9g, 0.083mol, 1.05eq.) and sodium acetate (19.4g, 0.236mol , 3.00eq.), heated to 85 ° C for 6h. Add 240g of water, continue to keep warm at 85°C for 1h, solids precipitate out, filter with suction, rinse the filter cake with water, and dry to obtain 34.1g of compound I as off-white solid, yield: 92.5%, purity: 98.6%.

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Abstract

The invention relates to a preparation method of a key intermediate of edoxaban which is a blood coagulation factor X (FXa) blocker drug, in particular to a preparation method of a compound I that is tert-butyl [(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl) amino]-2-oxoacetyl] amino]-5-(dimethylaminocarbonyl) cyclohexyl] carbamate. According to the method, the compound I is prepared from a compound A and a compound B in a free state in a reaction system with N,N-dimethylformamide as a solvent in the presence of sodium acetate. The raw materials adopted by the method are safe and stable, the reaction yield is high, and the method is suitable for industrial mass production.

Description

technical field [0001] The present invention relates to a kind of preparation method of the key intermediate of coagulation factor X (FXa) blocker drug edoxaban, be specifically related to a kind of compound I: [(1R, 2S, 5S)-2-[[2-[ A preparation method of (5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylaminocarbonyl)cyclohexyl]carbamate tert-butyl belongs to the technical field of medicinal chemistry. Background technique [0002] Chinese patent CN103214414B discloses a preparation method of compound I. In acetonitrile, in the presence of triethylamine (4.6 equivalents), the oxalate of compound A reacts with the hydrochloride of compound B at 60°C. However, this method is unsatisfactory on an industrial level, and the experimental yield of the compound I product is only 62%, and a large amount of base triethylamine is also needed in the reaction, and the volume ratio of triethylamine: acetonitrile is 1: 3.3 , the application of a large amount of triethylamine ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 秦小飞阳军张标解知慧周西朋刘永强龚彦春杨尚彦梁兆娟
Owner JIANGSU VCARE PHARMATECH
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