Cis-tetrahydrocarboline intermediate and synthesis method thereof, and application of cis-tetrahydrocarboline intermediate in preparing tadalafil

Abstract

The invention discloses a cis-tetrahydrocarboline intermediate and a synthesis method thereof, and application of the cis-tetrahydrocarboline intermediate in preparing tadalafil. D-tryptophan methyl ester hydrochloride and 3,4-dihydroxybenzaldehyde are used as raw materials to prepare the cis-tetrahydrocarboline intermediate, so that the raw materials are accessible, thereby overcoming the technical defects when the police-controlled precursor chemical heliotropin is used as the raw material in the prior art. The preparation method does not need any catalyst, and can be used for directly preparing the cis-tetrahydrocarboline intermediate by using lower alcohols, nitriles or nitroparaffins as a solvent; and after the reaction finishes, simple cooling and filtration are performed to obtain the product, wherein the mole yield is 90-97%. The cis-tetrahydrocarboline intermediate can be used for preparing tadalafil; and the synthesis method is simple and easy to implement, has the advantages of stable technique and high yield, and is suitable for industrial large-scale production. The structural formula of the cis-tetrahydrocarboline intermediate is disclosed as (I).

Description

technical field [0001] The present invention relates to the technical field of organic synthesis, more specifically, to a cis-tetrahydrocarboline 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, unde...

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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 chemicals, it is very inconvenient to buy and use

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