Key intermediate and synthesis method thereof, and application of key intermediate in preparing tadalafil

Abstract

The invention discloses a key intermediate and a synthesis method thereof, and application of the key intermediate in preparing tadalafil. The synthesis method comprises the following steps: by using D-tryptophan methyl ester hydrochloride and 3,4-dihydroxybenzaldehyde as raw materials, carrying out condensation cyclization, chloracetylation and aminolysis cyclization to generate the key intermediate for preparing tadalafil. The method has the advantage of accessible raw materials, and overcomes the technical defects due to the use of the police-controlled precursor chemical heliotropin as the raw material in the prior art. The method has the advantages of no need of any catalyst and high yield in the preparation process. The obtained key intermediate can be used for preparing tadalafil. Thus, the synthesis method is simple and easy to implement, has the advantages of stable technique and low cost, and is suitable for industrial large-scale production. The structural formula of the key intermediate is disclosed as Formula (III).

Description

technical field [0001] The present invention relates to the technical field of organic synthesis, more specifically, to a key intermediate, its synthesis method and its application in the preparation of tadalafil. Background technique [0002] Tadalafil is a phosphodiesterase type V (PDE5) inhibitor originally developed by GlaxoSmithKline (GSK) and approved by the FDA in 2003 as a treatment for male erectile dysfunction (ED). The drug is marketed in the United States. Because tadalafil has the advantages of high selectivity, long half-life, greater autonomy of patients, and unique pharmacological effects in the clinical treatment of ED, domestic and foreign experts have conducted extensive research on the chemical synthesis of tadalafil, and Certain results have been achieved. [0003] The synthetic route that U.S. Patent US5859006 reports, this route is to be raw material with tryptophan methyl ester and piperonal, with dichloromethane as solvent, under the catalysis of t...

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Problems solved by technology

[0005] It can be seen that the main synthetic route of synthesizing tadalafil is to take D-tryptophan methyl ester hydrochloride and piperonal as starting materials, through the route of condensation cyclization, acylation, aminolysis cyclization synthesis, through Asymmetric synthesis to construct β-tetrahydrocarboline ring is the key to the whole synthetic route. On the one hand, the Pictet-Spengler (condensation and ring closure) reaction is the most effective and commonly used means to construct β-tetrahydrocarboline ring, but this reaction is easy It leads 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 regulated by the public security department It is very inconvenient to purchase and use the chemicals listed in the Regulations on the Safety Management of Hazardous Chemicals and the Regulations on the Management of Precursor Chemicals

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