Preparation method of apixaban intermediate

Abstract

The invention provides a preparation method of an anti-thrombotic drug apixaban intermediate. The preparation method comprises the following steps: by taking paranitroaniline as a raw material, carrying out amidation, cyclization and reaction on paranitroaniline and 5-chloro valeryl chloride under an alkaline condition to obtain an intermediate (3); carrying out bicholo substation and condensation-elimination reaction on the intermediate (3) to obtain an intermediate (5); carrying out [1+3] dipolar cycloaddition reaction on the intermediate (5) and another intermediate (6) to obtain an intermediate (7); and carrying out morpholine removal and reduction reaction on the intermediate (7) to obtain the key apixaban intermediate 1-(4-methoxyl phenyl)-6-(4-amino phenyl)-7-oxo-4, 5, 6, 7-tetrahydro-1H-pyrazol[3, 4-c] pyridine-3-ethyl formate (I). The method adopting proper raw materials, solvents and catalysts is reasonable in design, mild in reaction condition, simple in posttreatment and high in reaction yield, and has certain feasibility of industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to an important intermediate of antithrombotic drug apixaban 1-(4-methoxyphenyl)-6-(4-aminophenyl)-7-oxo-4, Synthesis process of ethyl 5,6,7-tetrahydro-1H-pyrazol[3,4-c]pyridine-3-carboxylate. Background technique [0002] Apixaban, chemical name 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)-phenyl]-4,5 , 6,7-tetrahydro-1H-pyrazol[3,4-c]pyridine-3-carboxamide, American Chemical Abstracts Registry Number CAS NO: 503612-47-3, has the following structure: [0003] [0004] Apixaban is an anticoagulant jointly developed by Bristol-Myers Squibb and Pfizer, which directly acts on coagulation factor Xa. In May 2011, apixaban was approved by the European Union for marketing, and its trade name is Eliquis, which is used for the prevention and treatment of venous thromboembolism in hip or knee replacement surgery. It is considered to be a drug with "blockbuster" potential medici...

AI Technical Summary

Problems solved by technology

[0021] In this method, intermediate 3-morpholin-4-yl-1-(4-nitrophenyl)-5,6-dihydro-1H-pyridin-2-one (5) and intermediate 2-chloro -2-(2-(4-Methoxyphenyl)-hydrazone)ethyl acetate (6) undergoes a dipolar cyclization reaction in toluene under the action of triethylamine, followed by trifluoroacetic acid The demaline reaction takes place, and finally the hydrogenation reduction reaction takes place under palladium carbon catalysis to obtain the important intermediate (I) of apaxaban. The total yield of the three-step reaction is 72%. In this method, the yield of the first two steps is equal to Not high (75%), the reaction time is long, and the method of palladium carbon catalysis and hydrogen reduction is used in the nitro reduction reaction. The reaction reagents are expensive and the operation is relatively complicated, so it is not easy to realize industrialization

Images