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

A synthetic method and technology for tadalafil, which are applied to key intermediates and synthetic methods thereof, and in the field of preparing tadalafil, can solve problems such as inconvenience in purchase and use

Active Publication Date: 2016-05-04
湖南千金湘江药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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,

Method used

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

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Add 25.5 grams of D-tryptophan methyl ester hydrochloride to the reaction flask, add 150 milliliters of isopropanol at room temperature, stir, add 1.2 equivalents of 3,4-dihydroxybenzaldehyde, and react at 85°C for 8 hours until the raw material The reaction was basically complete, cooled to room temperature, filtered, and the solid was washed with 50 ml of isopropanol, and then dried in an oven to constant weight. 34.6 g of compound I were obtained in a yield of 92%. The synthetic route map is attached figure 1 shown.

Embodiment 2

[0056] Add 25.5 grams of D-tryptophan methyl ester hydrochloride to the reaction flask, add 250 milliliters of propionitrile at room temperature, stir, add 1.5 equivalents of 3,4-dihydroxybenzaldehyde, and react at 85°C for 16 hours until the raw materials are basically After the reaction was complete, it was cooled to room temperature, filtered, and the solid was washed with 50 ml of isopropanol, and then dried in an oven to constant weight. 34.2 g of Compound I were obtained in a yield of 97%. The synthetic route map is attached figure 1 shown.

Embodiment 3

[0058] Add 25.5 grams of D-tryptophan methyl ester hydrochloride to the reaction flask, add 375 milliliters of methanol at room temperature, stir, add 1.5 equivalents of 3,4-dihydroxybenzaldehyde, and react at 60°C for 24 hours until the raw materials basically react completely, cooled to room temperature, filtered, the solid was washed with 50 ml of methanol, and then dried in an oven to constant weight. 33.8 g of compound I were obtained in a yield of 90%. The synthetic route map is attached figure 1 as shown..

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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...

Claims

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Application Information

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IPC IPC(8): C07D471/14
CPCC07D471/14
Inventor 姚亮元宿亮侯岳华袁红波向顺龙承基
Owner 湖南千金湘江药业股份有限公司
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