Synthetic method of novel apixaban precursor compound

Abstract

The invention discloses a synthetic method of a novel apixaban precursor compound. The synthetic method comprises the following steps: the apixaban precursor compound (5) (shown in the specification) is subjected to cyclization to obtain the lactam target product apixaban precursor compound I (shown in the specification). According to the invention, the apixaban precursor compound (5) is adopted to prepare ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate, the yield can reach 87%, and in the entire synthetic route, the lowest yield of each step can reach over 80%, the total yield can reach about 49%, and valuable catalysts or reagents polluting the environment seriously are not used in the entire process.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis method of an apixaban precursor compound. Background technique [0002] Apixaban (apixaban), is an oral selective activated factor X inhibitor, jointly developed by Pfizer and Bristol-Myers Squibb. It can prevent thrombosis, but the adverse reaction of bleeding is lower than that of the old drug warfarin. It is used for the prevention of thrombosis in patients who have undergone hip or knee replacement surgery. The chemical name is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetra Hydrogen-1H-pyrazole[3,4-c]pyridine-3-carboxamide has completed relevant clinical trials for the prevention of venous thromboembolism (VTE) after total hip and total knee arthroplasty, and was approved in May 2011. Obtained the European Union's marketing authorization for this indication in March, and in early 2013, China approved the regimen of apixaban 2....

AI Technical Summary

Problems solved by technology

[0006] In the above-mentioned synthetic method, in the process of synthesizing the apixaban precursor compound I, several important reactions need to go through: the [3+2] ring-closure reaction of intermediates III and II, the ring-closure reaction must add a large amount of Organic base, the yield of the cyclization reaction product is only 72%; At the same time, when the intermediate V reacts with phosphorus pentachloride, a large amount of acid gas will be generated, and the subsequent treatment will form a large amount of waste acid, which is easy to cause pollution; the final raw material is one-step method to achieve intermediate Body V, the post-treatment purification is more difficult, and the use of mixed solvents has created new problems for the recovery and utilization of solvents

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