Method for preparing antithrombotic medicament apixaban

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...

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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, there are following defects in the preparation process of Ⅰ: all use expensive iodine-containing organic compounds, the intermediates used directly are not easy to get, the amount of auxiliary reagents is large and the price is relatively expensive, which is not conducive to Prepare in an economical way Ⅰ

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