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Preparation method of betrixaban

A technology of betrixaban and CH3, applied in the field of preparation of betrixaban, can solve the problems of high cost, large pollution, low yield of compound A and the like

Active Publication Date: 2021-11-09
JIANGXI SYNERGY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, compound A has high polarity and good water solubility, which leads to a low yield of compound A; experiments show that the yield of compound A obtained by this step of hydrolysis reaction is only 50%
In addition, expensive condensing agents are used in t

Method used

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  • Preparation method of betrixaban
  • Preparation method of betrixaban
  • Preparation method of betrixaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1 Lithium dimethylamide (LiN(CH 3 ) 2 ) preparation

[0058] Under the protection of nitrogen, put 30g of liquefied dimethylamine (0.67mol) into the reaction bottle, cool to -15℃~-10℃, add 256ml of butyllithium solution (2.5mol / L, 0.64mol) dropwise, keep stirring after dropping After 30 minutes, a lithium dimethylamide solution was obtained for later use.

Embodiment 2

[0059] Example 2 Lithium dimethylamide (LiN(CH 3 ) 2 ) preparation

[0060] Under the protection of nitrogen, put 30g of liquefied dimethylamine (0.67mol) into the reaction bottle, cool to -10℃~-5℃, add dropwise 268ml of hexyllithium solution (2.5mol / L, 0.67mol), keep stirring for 30min after dropping Obtain lithium dimethylamide solution for later use.

Embodiment 3

[0061] Example 3 Dimethylaminomagnesium Chloride (MgClN(CH 3 ) 2 ) preparation

[0062] Under the protection of nitrogen, put 30g of liquefied dimethylamine (0.67mol) into the reaction bottle, cool to -5°C ~ 0°C, add dropwise 335ml of n-propylmagnesium chloride solution (2.0mol / L, 0.67mol), keep stirring after dropping 1h to get dimethylaminomagnesium chloride solution for later use.

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Abstract

The invention provides a preparation method of betrixaban, which comprises the step that in liquid dimethylamine, a compound with a structural formula II or a salt thereof reacts with a dimethylamine solution of MN(CH3)2 to obtain betrixaban with a structural formula I, wherein M is Li or MgX; and X is one of Cl, Br and I. The preparation method disclosed by the invention is high in yield and high in product purity, can basically avoid the generation of monomethylamine impurities and dechlorination impurities, and greatly simplifies the subsequent refining process. In addition, only a single solvent is used in the preparation method, use of a mixed solvent is avoided, later solvent recovery and reuse are convenient, and the amount of three wastes can be reduced.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of betrixaban. Background technique [0002] Betrixaban, chemical name: N-(5-chloro-2-pyridyl)-2-[[4-[(dimethylamino)iminomethyl]benzoyl]amino]-5 -Methoxybenzamide, CAS number: 330942-05-7. Structural formula is shown in I. [0003] [0004] Betrixaban was approved for marketing for the first time in June 2017. It is the fourth direct factor Xa inhibitor anticoagulant drug to be marketed globally after rivaroxaban, apixaban and edoxaban, and has been approved by the FDA priority review. Betrixaban is clinically indicated for the prophylaxis of venous thromboembolism in hospitalized patients with acute medical illness who are at risk of thromboembolic complications due to moderate or severe limitation of activity and other thromboembolic risk factors. [0005] CN101595092B (published on December 2, 2009) discloses a preparation method of bet...

Claims

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Application Information

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IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 冯玉杰叶四明庞正伟曹玉婷范利星
Owner JIANGXI SYNERGY PHARMA