Preparation method for rocuronium bromide key intermediate 2alpha, 3alpha-epoxy-16beta-(1-pyrrolidyl)-5alpha- androstane-17 hydroxy

Abstract

The invention belongs to the field of pharmaceutical chemistry synthesis, and relates to a preparation method for a key intermediate 2alpha, 3alpha-epoxy-16beta-(1-pyrrolidyl)-5alpha- androstane-17 hydroxy of rocuronium bromide of steroid muscle relaxant, which includes the steps: leading inexpensive and available 5alpha-androstane-2-alkene-17 ketone and isopropenyl acetate to undergo ester exchange to generate cresyl violet acetate, oxidizing the cresyl violet acetate by the meta-chloroperoxybenzoic acid to obtain an epoxy compound, carrying out an open-loop substitution reaction between the meta-chloroperoxybenzoic acid and pyrrolidine under the alkaline condition, and reducing via sodium borohydride so that the rocuronium bromide key intermediate 2alpha, 3alpha-epoxy-16beta-(1-pyrrolidyl)-5alpha-androstane-17 hydroxy is prepared. An ester group with large steric hindrance is generated at the 17th position when the 5alpha-androstane-2-alkene-17 ketone and the isopropenyl acetate undergo ester exchange in the process to lead stereoscopic steric hindrance of a whole steroid ring to be large, so that attack on the lower portion of the steroid ring can be performed when epoxidation is carried out, and further stereoselectivity is high when an epoxide is formed, and then a beta configuration can be directly formed when the pyrrolidine is used for substitution. The synthesis method is good in stereoselectivity.

Description

technical field [0001] The invention relates to the technical field of organic chemistry and medicinal chemistry, in particular to the key intermediate 2α, 3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstane-17 of steroidal muscle relaxant rocuronium bromide Preparation of Hydroxyl (I). Background technique [0002] Rocuronium bromide, its chemical name is: 1-[(2β,3α,5α,16β,17β)-17-(acetyloxy)-3-hydroxy-2-(4-morpholinyl)androstane- 16-yl]-1-(2-propenyl)pyrrolidinium bromide is a steroidal non-depolarizing muscle relaxant developed by Oknon, the Netherlands. Rocuronium bromide is characterized by rapid onset of action, can provide similar intubation conditions as succinylcholine, its dissociation constant is 0.71±0.09 μM, and its inhibitory effect on motor nerve terminals is similar to that of vecuronium bromide. More importantly, intravenous anesthetics do not affect the neuromuscular blocking effect of this product, and have no effect on the course of action. The strength of thi...

AI Technical Summary

Problems solved by technology

[0021] According to the synthesis method of the existing literature, 2α, 3α-epoxy-16α-bromo-5α-androstan-17 ketone was transformed into 2α, 3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17 In the process of sterane-17 ketone, 2α, 3α-epoxy-16α-bromo-5α-androstan-17 ketone has little steric hindrance due to the carbonyl group at the 17th position, and Br can be substituted from sterane The up and down attack of the body ring, so it is easy to form two isomers of α and β, which will lead to the generation of isomers when the tetrahydropyrrole is substituted in the next step, and the separation of the resulting isomers is more difficult

Therefore, the stereoselectivity of the synthetic route reported in the above-mentioned patent literature is relatively poor

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