Synthetic method of alfaprostol

Abstract

The invention relates to the field of medicine preparation, and particularly relates to a synthetic method of alfaprostol. The synthesis method comprises the following steps: subjecting levobenzoyl corey lactone adopted as a raw material to oxidization by primary alcohol, and reaction with azido phosphate to obtain a compound a3; inducing chiral addition of the compound a3 and aldehyde by chiral ligand amine to generate a compound a4; performing reduction and a Wittig reaction to generate a compound a6; and finally, carrying out methylation reaction on terminal carboxyl of the compound a6 to prepare the alfaprostol. According to the synthesis method of the alfaprostol, provided by the invention, the levobenzoyl corey lactone is directly used as a raw material, the raw material is simple and easy to obtain, and the operation is simple; reaction steps are short, the yield of the whole process route is about 55-60%, and industrial production is easy to realize; the process conditions of each step of reaction are easy to realize, post-treatment is simple, and intermediates are easy to purify; only one-step chiral reaction is adopted, isomer impurities are easy to control, and the obtained product is high in optical purity.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a method for synthesizing alfaprostol. Background technique [0002] Alfaprostol is a more stable and PGF 2α An equally selective analog that is widely used as a luteinizing agent in cattle and mares with the potency of PGF 2α Ten times of that; at the same time, because of its more stable chemical structure, it has been used as PGF in Europe, America and other countries 2α Alternative drugs, and many pharmaceutical companies in the world are studying the application of alfaprostol and its analogues in the treatment of neuropsychiatric diseases by reducing adipose tissue. [0003] At present, there are few methods for chemically synthesizing alfaprostol. There are two more effective synthetic processes. The first one is Hannah Baars (Org. Lett. 2017, 19, 6008.) which discloses succinic dialdehyde as raw material through 11 steps Reaction, the method for obtaining the target...

AI Technical Summary

Problems solved by technology

[0003] At present, there are few methods for chemically synthesizing alfaprostol. There are two more effective synthetic processes. The first one is Hannah Baars (Org. Lett. 2017, 19, 6008.) which discloses succinic dialdehyde as raw material through 11 steps Reaction, the method for obtaining the target product, the method steps are tedious, the reaction yield is very low, the final yield of the whole route is only 2.68%, and the requirements for anhydrous and anaerobic operation in some aspects of the process are extremely harsh, and simple process conditions cannot Therefore, the preparation process is currently only limited to the laboratory research stage, and is not suitable for industrial scale-up production

[0004] The second kind is that Carmelo Gandolfi (US4035415) discloses a kind of method of synthesizing alfaprostol, and this technology is that raw material is synthesized alfaprostol through ten steps reaction with the benzoyl core lactone of protection, and its route is long, yield The rate is low; and highly toxic substances such as bromine and flammable and explosive dangerous goods such as sodium hydride are used, so further process optimization is required for scale-up production

[0005] Therefore there is yield low in the synthetic technique of alfaprostol at present, and synthetic route is long, is not suitable for industrial scale-up production

Images