Compound acyl intermediate as well as synthetic method thereof and application thereof in preparing tadalafil

Abstract

The invention discloses a compound acyl intermediate as well as a synthetic method and application thereof in preparing tadalafil. The synthetic method comprises the following steps: preparing (1R, 3R)-methyl-1-(3,4-dihydroxyphenyl)-2,3,4,9-tetrahydro-1H-pyridino[3,4-b]indol-3-carboxylic acid (compound I) by taking D-tryptophan methyl ester hydrochloride and 3,4-dihydroxy benzaldehyde as raw materials, and allowing the compound I to have chloroacetylation with chloroacetyl chloride to generate the compound acyl intermediate. By adopting the method, raw materials are easy to get, so that the technical weakness caused by using the poisonable chemical heliotropin controlled by the public security department in the prior art as a raw material is overcome. The preparation process requires no catalyst, and the yield is high. The obtained compound acyl intermediate can be used for preparing the tadalafil, and is simple and easy, stable in process, low in cost, and suitable for industrialized mass production. The structural formula of the compound acyl intermediate is shown as formula (II): (see the description) (II).

Description

technical field [0001] The present invention relates to the technical field of organic synthesis, more specifically, to an acylate 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...

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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 and construction of β-tetrahydrocarboline ring is the key to the whole synthetic route. On the one hand, condensation ring closure Pictet-Spengler reaction is the most effective and commonly used means to construct β-tetrahydrocarboline ring, but this reaction easily leads to The production of formula and trans isomers usually requires cumbersome treatments such as column chromatography separation or recrystallization to obtain high-purity cis-carboline intermediates. It is very inconvenient to purchase and use the chemicals controlled by the Regulations on the Administration of Product Safety and the Regulations on the Administration of Precursor Chemicals

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