Synthetic method of beraprost

Abstract

The invention relates to a synthetic method of beraprost. The synthetic method comprises the following steps: with an intermediate I as an initial raw material, carrying out selective primary alcoholoxidation and a Witting reaction to obtain an intermediate V; carrying out reduction and column chromatography purification on the intermediate V to obtain an intermediate IV; and hydrolyzing the intermediate IV to obtain beraprost. According to the synthetic method disclosed by the invention, two hydroxyl groups of the intermediate I are selectively oxidized, so a hydroxyl protection reagent is prevented from being used; in the oxidation step, ultralow-temperature (-60 to -80 DEG C) reactions and use of a reagent DCC with relatively high toxicity are avoided; in the reduction step, diisobutylaluminum hydride is prevented from being used; process operation units are greatly reduced, reaction steps are shortened, emission of three wastes is reduced, and the reactions are more efficient andenvironment-friendlier; and the main peak content of the prepared beraprost reaches 99.0% or above, and total process yield reaches 26% or above. The invention provides the synthetic method which ismore beneficial for industrial production.

Description

technical field [0001] This field belongs to the field of compound preparation, and specifically relates to a synthetic method of beraprost. [0002] technical background [0003] Beraprost sodium (trade name Dorner) belongs to prostacyclin derivatives and is an antiplatelet drug developed by Japan Toray Co., Ltd. (Toray). Beraprost (Beraprost) was approved in Japan in 1992 as a drug for chronic arterial occlusion. Beraprost in the form of racemate for the treatment of pulmonary arterial hypertension (PAH) has been approved by the U.S. FDA to enter phase II clinical trials. In 2007, Toray and Astellas (formerly Yamanouchi) )’s Beraprost Sodium Sustained Release Tablets (Careload LA) was approved in Japan for the treatment of PAH, becoming the first sustained release agent among prostacyclins. [0004] [0005] The synthesis process of the beraprost bulk drug involves 9-10 synthesis steps, and the total yield is less than 1%. In particular, beraprost has 6 chiral centers...

AI Technical Summary

Problems solved by technology

[0008] This synthetic route has the following disadvantages: this synthetic route involves multiple operations on protecting groups and removing protecting groups, and the operation is cumbersome

[0011] This reaction route has the following disadvantages: the protective group on the secondary hydroxyl group is removed before the reduction, and the two-step reaction of Swern oxidation and reduction requires ultra-low temperature reaction at -60°C to -80°C

Diisobutylaluminum hydride (DIBAH) is used in the reduction step, and the reagent reacts violently with water to produce flammable and explosive hydrogen and isobutane, which poses a major safety hazard

In addition, the route involves anhydrous and anaerobic operations in many places, which requires high equipment conditions

Difficult to achieve industrial production

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