Preparation method of tadalafil

Abstract

The invention discloses a preparation method of tadalafil, starting material D-Tryptophan methyl ester hydrochloride is reacted with oxalyl chloride to obtain an intermediate III, and the final product tadalafil (I) is obtained through cyclization, Grignard reaction, asymmetric reduction, substitution and condensation reaction. The use of national control chemical piperonal is avoided, an intermediate VI can be highly-selectively obtained by the asymmetric reduction, and the method has the advantages of simple postprocessing, short synthesis steps and high product total yield, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a preparation method of tadalafil. Background technique [0002] Tadalafil is a phosphodiesterase type V (PDE5) inhibitor. When sexual stimulation leads to the local release of nitric oxide, PDE5 is inhibited by tadalafil, which increases the level of cyclic guanosine monophosphate in the cavernous body of the penis, which leads to Smooth muscles relax and blood flows into the penile tissue, producing an erection. The compound was originally developed by GlaxoSmithKline and subsequently transferred to ICOS, and later jointly developed by ICOS and Eli Lilly. Approved by the FDA in 2003, tadalafil was listed in the United States as a drug for the treatment of male erectile dysfunction. At the beginning of 2014, the drug was approved by the US FDA as a new indication for the treatment of benign prostatic hyperplasia, and the future market capacity will be even broader. [...

AI Technical Summary

Problems solved by technology

[0007] It can be seen that the prior art of synthesizing tadalafil is mainly based on D-tryptophan methyl ester hydrochloride and piperonal as starting materials, through condensation cyclization, acylation, aminolysis cyclization synthetic route, Constructing the β-tetrahydrocarboline ring by asymmetric synthesis is the key to the whole synthetic route. On the one hand, the Pictet-Spengler (condensation ring closure) reaction is the most effective and commonly used means to construct the β-tetrahydrocarboline ring, but this reaction It is easy to lead to the production of cis- and trans-isomers, and usually requires cumbersome treatments such as column chromatography separation or recrystallization to obtain high-purity cis-carboline intermediates. On the other hand, the important raw material piperonal is subject to "dangerous Chemicals controlled by the Regulations on the Safety Management of Chemicals and the Regulations on the Management of Precursor Chemicals

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