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The synthetic method of tadalafil

A technique for the synthesis of tadalafil, which is applied in the field of organic synthesis, can solve the problems of low yield, cumbersome routes, harsh reaction conditions, etc., and achieve the effects of simple treatment, easy recovery and application, and simple operation

Active Publication Date: 2018-01-30
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

The present invention overcomes the prior art using piperonal as a raw material, which is not easy to cause obstacles to synthetic production due to the purchase and use of raw materials, and overcomes the shortcomings and deficiencies of the prior art process such as low yield, cumbersome routes, harsh reaction conditions, etc., Provide a preparation route with high yield, simple post-treatment, high yield, mild reaction conditions, safety and environmental protection, which is easy for industrial production

Method used

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  • The synthetic method of tadalafil
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  • The synthetic method of tadalafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] 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 with a yield of 92%. The synthetic route map is attached figure 1 shown.

Embodiment 2

[0049] 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 with a yield of 97%. The synthetic route map is attached figure 1 shown.

Embodiment 3

[0051] 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 with a yield of 90%. The synthetic route map is attached figure 1 as shown..

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Abstract

A synthetic method of tadalafil is disclosed. The method adopts 3,4-dihydroxybenzaldehyde and methyl D-tryptophanate hydrochloride as initial raw materials, and prepares a product by condensation-cyclization, chloroacetylation, aminolysis-cyclization and methyl cyclization. The 3,4-dihydroxybenzaldehyde is adopted as the raw material. Nitrile, lower alcohol and nitroalkane are adopted as solvents for the condensation-cyclization. Ethyl acetate or dichloromethane is adopted as a solvent for the chloroacetylation. Lower alcohol which is cheap is adopted as a solvent for the aminolysis-cyclization. Compared with other routes, the method is characterized by simple and convenient separation and purification, simple reaction conditions, a high yield of each step (with the yield of each step being higher than 80%), a stable process and a short production period. The method is free of heliotropin with which narcotics can be prepared easily, is free of column chromatography and other purification processes and is suitable for industrial production.

Description

technical field [0001] The present invention relates to the technical field of organic synthesis, more specifically, to a method for synthesizing tadalafil. Background technique [0002] Tadalafil is a phosphodiesterase type V (PDE 5) 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 trifluoroacetic acid, P-S reaction (Pictet-Spengler) reac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14C07D471/04
CPCC07D471/04C07D471/14
Inventor 侯岳华王琼瑶姚亮元袁秀菊钟爱军袁红波
Owner 湖南千金湘江药业股份有限公司
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