Method for preparing antithrombotic medicament apixaban

An antithrombotic drug, the technology of Apixaban, which is applied in the field of preparation of antithrombotic drug Apixaban, can solve the problems of unfavorable and economical preparation, large amount of auxiliary reagents, and difficult availability of intermediates, so as to avoid expensive raw materials and auxiliary materials. Use of reagents, shortening of reaction time, and improvement of reaction yield

Inactive Publication Date: 2011-02-09
EAST CHINA UNIV OF SCI & TECH +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Equally, the total yield of this route is low, and expensive reagents such as iodide are used in the reaction process, and the amount of auxiliary reagents is relatively large, which limits the application of this route
[0015] By analyzing the synthetic route of Ⅰ reported in the above literature, ther

Method used

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  • Method for preparing antithrombotic medicament apixaban
  • Method for preparing antithrombotic medicament apixaban
  • Method for preparing antithrombotic medicament apixaban

Examples

Experimental program
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[0073] Example 1

[0074] (1) Preparation of Compound V

[0075]

[0076] 40ml of anhydrous tetrahydrofuran was added into the reaction flask, and p-nitroaniline (11.04g, 0.08mol) and triethylamine (22ml, 0.16mol) were sequentially added under stirring. The reaction solution was cooled to 0°C with an ice-salt bath, and a mixed solution composed of 5-chlorovaleryl chloride (16ml, 18.6g, 0.12mol) and 20ml of anhydrous tetrahydrofuran was slowly added dropwise, and the temperature of the system was controlled at 0 to 5 °C range. After the addition, the reaction solution was slowly warmed up to room temperature for 4 hours, followed by TLC until the p-nitroaniline spots disappeared. The reaction solution was cooled to 0°C with an ice-salt bath, and NaH solid (5.76 g, 0.24 mol) was slowly added within 10 minutes. After the addition, the reaction solution was slowly warmed up to room temperature for 1 hour, followed by TLC until the intermediate spots disappeared. Stop the rea...

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Abstract

The invention discloses a method for preparing antithrombotic medicament apixaban. The method comprises the following steps of: obtaining a compound V by performing an amidation-cyclization two-step one-pot reaction on paranitroaniline serving as a raw material and a general purpose reagent 5-chlorine valeryl chloride under an alkaline condition; performing di-chlorination on the alpha-hydrogen of the V by using phosphorus pentachloride; performing a condensation-elimination reaction with excess morpholine to obtain a compound VI; reducing the VI into a compound VII by using sodium sulfide; performing the amidation-cyclization two-step one-pot reaction on the VII and the 5-chlorine valeryl chloride to obtain a key intermediate III; obtaining II by performing a [3+2] cyclization-elimination reaction on the III and another intermediate IV; and finally, obtaining I by performing aminolysis on the II. The method has the advantages that: process design is reasonable, expensive reagent is not used, reaction yield is high, raw material cost is low, and the method is simple and convenient to operate, has no harsh reaction condition, and is easy to perform large-scale production.

Description

【Technical field】 [0001] The present invention relates to the technical field of medicine manufacturing, in particular, it is a new method for preparing antithrombotic drug Apixaban (Apixaban, BMS-562247), that is, preparing 1-(4-methoxyphenyl)-7- Oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3 - A new approach to formamide. 【Background technique】 [0002] Apixaban (Apixaban, BMS-562247), chemical name: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)benzene Base]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, U.S. Chemical Abstracts Registry Number CAS: 503612-47-3, having formula I structure: [0003] [0004] Ⅰ is a new generation of oral antithrombotic drugs. Among many inhibitors of coagulation factor Xa, Ⅰ shows high selectivity, good bioavailability and high therapeutic effect, and its performance is much better than that of rezaxaban (Razaxaban), for the treatment of blood clots in the veins, including de...

Claims

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Application Information

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IPC IPC(8): B01J27/08C07D471/04
Inventor 冀亚飞江健安刘倩禹艳坤王超刘爱霞王毅
Owner EAST CHINA UNIV OF SCI & TECH
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