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Preparation method of edoxaban p-toluenesulfonate monohydrate

A technology of p-toluenesulfonate and p-toluenesulfonic acid, which is applied in the field of preparation of edoxaban p-toluenesulfonate monohydrate, can solve the problems of low product purity, complicated process, and low total yield, and achieve The effect of promoting rapid reaction, increasing yield and product purity

Active Publication Date: 2018-09-04
北京阳光诺和药物研究股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The existing preparation process of edoxaban p-toluenesulfonate monohydrate has many defects, such as many synthetic steps, complicated process, low product purity, and low overall yield, etc.

Method used

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  • Preparation method of edoxaban p-toluenesulfonate monohydrate

Examples

Experimental program
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Effect test

Embodiment

[0049] 1. Preparation of DXB-AC

[0050] Add 2.1g of 1-butyl-3-methylimidazole hydroxide, 100.0g of DXB-A, 85g of DXB-C and 600ml of acetonitrile into the three-necked flask, stir, add 113g of triethylamine and 21g of pyridine, stir the turbid solution, and start Raise the temperature and stir. When the temperature of the system rises to 45-60°C, the system becomes viscous and the stirring is difficult. Add 100ml of acetonitrile in portions, and the system gradually returns to a non-viscous state after proper adjustment. The reaction was continued for 4h (TLC reaction was complete). Stop heating, cool down in an ice-water bath, add 1.4L of water, stir and crystallize for 30min. Suction filtration, the filter cake was washed with 700ml of water, and air-dried at 60°C to obtain the product with a yield of 96%;

[0051] 2. Preparation of DXB-ABC

[0052]Add 100g of DXB-AC and 2L of acetonitrile into the three-necked flask, stir, and the system becomes a white turbid liquid. A...

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Abstract

The invention provides a preparation method of edoxaban p-toluenesulfonate monohydrate. According to the preparation method, an appropriate amount of a specific ionic liquid is added, a specific ratioof a combination of triethylamine and pyridine is selected as a base, the rapid progress of a reaction is facilitated, and improvements on the production rate and the product purity are facilitated.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of edoxaban p-toluenesulfonate monohydrate. Background technique [0002] Edoxaban, chemical name N-(5-chloropyridin-2-yl)-N'-[(lS,2R,4S)-4-(N,N dimethylcarbamoyl)] -2-[(5-Methyl-4,5,6,7-tetrahydro-1,3-thiazolo[5,4-c]-pyridine-2-carboxamido)cyclohexyl]oxamide, is The blood coagulation factor Xa inhibitor developed by Daiichi Sankyo Co., Ltd. was first launched in Japan in April 2011. The trade name is Lixiana. The active ingredient is edoxaban p-toluenesulfonic acid monohydrate. It is clinically used to prevent lower limb orthopedics Venous thromboembolism after surgery. There are 3 chiral centers in the structure of Edoxaban, and its configuration is (1S, 2R, 4S), introduced by the synthesis of a six-membered ring. [0003] The existing preparation process of edoxaban p-toluenesulfonate monohydrate has many defects, for example, many synthesis steps, complex...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04C07C303/32C07C309/30
CPCC07B2200/13C07D513/04
Inventor 罗桓刘宇晶利虔袁伟锋孙跃军张文腾谌宗永
Owner 北京阳光诺和药物研究股份有限公司
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