Edoxaban intermediate and preparation method thereof

A technology for edoxaban and intermediates, which is applied in the field of anticoagulant edoxaban intermediates and its preparation, can solve the problems of cumbersome post-processing, long steps for synthesizing products, and large solvent consumption, and achieve product quality Stable and reliable, mild reaction conditions, less waste

Inactive Publication Date: 2015-12-30
天津药物研究院药业有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Including the Chinese patent CN104761571A which discloses a synthesis method of edoxaban and other prior art preparation methods, etc., there are long steps to synthesize the product, cumbersome post-processing of the product, large solvent consumption, low purity, high impurity content, and difficult to carry out Industrial production

Method used

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  • Edoxaban intermediate and preparation method thereof
  • Edoxaban intermediate and preparation method thereof
  • Edoxaban intermediate and preparation method thereof

Examples

Experimental program
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Effect test

example 1

[0039] Example 1: the preparation of compound 2:

[0040] (1s)-3-cyclohexene-1-carboxylic acid (48g, 380mmol), dichloromethane (580ml), potassium iodide (82.1g, 494mmol), sodium bicarbonate (42.0g, 500mmol), water (530ml), cool down to 5°C, start stirring, slowly add I 2 (125.4g, 494mmol). After the addition, it was raised to 20°C and reacted for 3h. Add 800ml of 1N sodium thiosulfate solution to the reaction system, extract with 500ml of dichloromethane, wash the organic phase with sodium thiosulfate (300ml), water (500ml), saturated sodium chloride (300ml), anhydrous sulfuric acid Magnesium was dried, filtered, and distilled under reduced pressure to obtain a colorless solid 2 .

example 2

[0041] Example 2: Compound 2 Preparation of:

[0042] (1s)-3-cyclohexene-1-carboxylic acid (48g, 380mmol), dichloromethane (580ml), potassium iodide (82.1g, 494mmol), sodium bicarbonate (42.0g, 200mmol), water (530ml), cool down to 8°C, start stirring, slowly add I 2(125.4g, 494mmol). After the addition, it was raised to 25°C and reacted for 3h. Add 800ml of 1N sodium thiosulfate solution to the reaction system, extract with 500ml of dichloromethane, wash the organic phase with sodium thiosulfate (300ml), water (500ml), saturated sodium chloride (300ml), anhydrous sulfuric acid Magnesium was dried, filtered, and distilled under reduced pressure to obtain a colorless solid 2 .

example 3

[0043] Example 3: Compound 3 Preparation of:

[0044] compound 2 Add (89.3g, 354mmol) into a 2L four-neck flask containing absolute ethanol (810ml) solution, start stirring, slowly add 2N sodium hydroxide solution (213ml, 425mmol), stir and react at 20°C for 3h, and keep the reaction solution at Rotary evaporation under reduced pressure at 40°C, then add 500ml of water, extract once each with 500ml and 300ml of dichloromethane, wash the organic phase with 300ml of water, dry over anhydrous magnesium sulfate, filter, rotary evaporation under reduced pressure, and column purification (petroleum ether : ethyl acetate = 85: 15), to obtain a gray oil 3 .

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Abstract

The invention relates to an edoxaban intermediate and a preparation method thereof. The preparation method of the edoxaban intermediate comprises steps as follows: (a), (1s)-3- cyclohexene-1-formic acid is taken as a raw material, and a compound 2 is generated in the presence of a catalyst, a halogen and a weak base; (b), the compound 2 generates a compound 3 under the action of strong base in an absolute ethanol solution; (c), the compound 3 generates a compound 4 in an ammonia and ethanol solution; (d), the compound 4 reacts with a protecting group of amino under the action of a catalyst, and a compound 5, (1S,3R,4R)-3-[(t-butyloxycarboryl)amino]-4-hydroxycyclohexyl ethyl formate, is generated. Raw materials and reagents required in the synthesis method of the edoxaban intermediate are easy to obtain, the yield is high, the cost is low, reaction conditions are mild, three wastes are relatively fewer, and the quality of the product is stable and reliable.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to an anticoagulant edoxaban intermediate and a preparation method thereof. Background technique [0002] The chemical name of Edoxaban is N-(5-chloropyridin-2-yl)-N''-[(1S,2R,4S)-4-(N,N-dimethylaminoacyl)]-2- [(5-Methyl-4,5,6,7-tetrahydro-1,3-thiazolo[5,4-c]--2-carboxamido)cyclohexyl]oxamide, a highly selective It is an oral drug that directly inhibits factor Xa. By inhibiting factor Xa, it can interrupt the intrinsic and extrinsic pathways of the blood coagulation cascade, inhibit the generation of thrombin and the formation of thrombus. The structural formula is as follows: [0003] Edoxaban is a small molecule oral anticoagulant developed by Daiichi Sankyo Co., Ltd., which is a factor X (FXa) blocker. During the blood coagulation process, activated coagulation factor X (FXa) activates prothrombin (FII) into thrombin (FIIa), which promotes the formation of fibrin ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/24C07C269/04C07D513/04
CPCY02P20/55
Inventor 李果张智强宋金津赵钊任晓峰李惠龙赵欣王凯张宁
Owner 天津药物研究院药业有限责任公司
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