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

A synthetic method and a technology for tadalafil are applied in the field of preparation of tadalafil, acylate intermediates and their synthesis, can solve problems such as inconvenience in purchase and use, and achieve the advantages of avoiding cumbersome processing, stable process and high yield. Effect

Active Publication Date: 2016-04-20
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 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 commonl

Method used

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

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] 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

[0047] 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 for 16 hours at 85 ° C 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

[0049] 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 basic reaction of the raw materials 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 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...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D471/14
CPCC07D471/04C07D471/14
Inventor 姚亮元钟爱军朱平凤侯岳华袁红波袁飞鹏金秉德邹斌彬文琛
Owner 湖南千金湘江药业股份有限公司
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