Preparation method of Tadalafil compounds

Abstract

The invention discloses a preparation method of Tadalafil compounds. In the synthetic method, the compound IV is obtained by two-step acylation reaction of a starting material D-tryptophan methyl ester hydrochloride with chloroacetyl chloride and 3,4-dyhydroxy-benzoyl chloride, the compound is obtained by cyclization reaction of the compound IV with phosphorus acyl halide, the compound VI is generated from the compound V via asymmetric hydride reaction and is then reacted with methylamine, and the final Tadalafil compounds are obtained through cyclization reaction of dibromomethane. With the method, use of heliotropin of state controlled chemicals is avoided, cis-type carbine intermediate is obtained by adopting asymmetric hydrogenation, and ee value is above 99%; the preparation method is simple in operation and synthetic reaction, moderate in reaction condition, high in purity and yield, and 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 a tadalafil compound. 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 wi...

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