Roxadustat key intermediate and synthetic method thereof

Abstract

The invention discloses a Roxadustat key intermediate and a synthetic method thereof. The Roxadustat key intermediate is 1-methyl-7-phenoxyisoquinoline-3-carboxylate. The synthetic method for the Roxadustat key intermediate comprises the following three steps that firstly, 4-phenoxybenzaldehyde and N-acetylglycine are subjected to Erlenmeyer-Pl-chl condensation reaction in the presence of acetic anhydride and sodium acetate or potassium acetate, then alcoholysis reaction is carried out with alcohol in the presence of alkali, and finally, Bischler-Napieralski cyclization reaction is carried outwith leiws acid in the presence of a solvent so as to obtain the Roxadustat key intermediate. The synthetic method has the advantages that the raw materials are easy to obtain, the reaction conditions are mild, the requirement for equipment is low, the yield is high, the synthesis steps of Roxadustat are shortened, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and synthesis of raw materials and intermediates, and specifically relates to a key intermediate of roxadustat and a synthesis method thereof. Background technique [0002] Roxadustat is the first oral small molecule HIF-PHI developed by Fibrogen, mainly for the treatment of renal anemia. It can inhibit HIF-prolyl hydroxylase under normal oxygen partial pressure, Stabilize HIF-α, promote endogenous erythropoietin, Erythropoietin, EPO production, improve iron absorption and utilization, and comprehensively regulate erythropoiesis. The results of two Phase III clinical trials in China for the treatment of anemia in dialysis-dependent (DD-CKD) and non-dialysis-dependent (NDD-CKD) chronic kidney disease patients met the primary efficacy endpoints. On December 18, 2017, roxadustat was included in the priority review by CDE as "compared with the existing treatment methods and has...

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Problems solved by technology

[0023] The object of the present invention is to provide a key intermediate of roxadustat for the problems of long synthesis reaction steps of roxadustat, harsh reaction conditions, high energy consumption, environmental pollution, and unsuitability for industrial production in the prior art. Its synthesis method is expected to shorten the synthesis steps of roxadustat by utilizing the intermediate, and the whole reaction process has mild conditions and is suitable for industrial production

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