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Improved tadalafil preparation method

A tadalafil and reaction technology, applied in the field of chemical raw material preparation, can solve the problems of low total yield, flammable and explosive, high price, etc., and achieve the effects of improving total yield, stable process and reducing cost.

Inactive Publication Date: 2014-02-05
ANHUI WANBANG MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] (1) The reaction route is longer, resulting in lower overall yield;
[0010] (2) In the reaction with methylamine, the organic solvent solution of methylamine is used. In addition to being expensive, the organic solvent solution of methylamine also has the problem of inflammability and explosion, and it is difficult to store and transport. Use this solution to react Not conducive to industrial production

Method used

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  • Improved tadalafil preparation method

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Embodiment 1

[0023] Example 1: 25.5 g (0.1 mol) of D-tryptophan methyl ester hydrochloride and 250 mL of dichloromethane were sequentially added into a 500 mL reaction flask, and stirred at room temperature for 1 h. 15.0 g (0.1 mol) of piperonal was added, the temperature was raised to reflux for 12 hours, and the end point of the reaction was controlled by TLC. Cool down to room temperature, add 20.2g (0.2mol) of triethylamine, 0.12g (about 0.001moL) of 4-dimethylaminopyridine, stir for 1h, cool down to 0°C, and keep the temperature at 0~5°C and add ethyl chloride dropwise Acyl chloride in dichloromethane solution 50mL (containing 11.3g of chloroacetyl chloride, about 0.1mol), stirred at room temperature for 1h after the drop was completed. The reaction solution was washed 3 times with purified water (100 mL×3), dichloromethane solution, and dried by adding anhydrous sodium sulfate. Filtration, dichloromethane was distilled off to obtain the intermediate 1-(1,3-benzodioxol-5-yl)-2-(chl...

Embodiment 2

[0024] Example 2: 28.0 g (0.11 mol) of D-tryptophan methyl ester hydrochloride and 250 mL of dichloromethane were sequentially added into a 500 mL reaction flask, and stirred at room temperature for 1 h. 16.5 g (0.11 mol) of piperonal was added, the temperature was raised to reflux for 12 hours, and the end point of the reaction was controlled by TLC. Cool down to room temperature, add 22.0g (0.22mol) of triethylamine, 0.12g (about 0.001moL) of 4-dimethylaminopyridine, stir for 1h, cool down to 0°C, and keep the temperature at 0~5°C and add ethyl chloride dropwise Acyl chloride in dichloromethane solution 50mL (containing 12.4g of chloroacetyl chloride, about 0.11mol), stirred at room temperature for 1h after the drop was completed. The reaction solution was washed 3 times with purified water (100 mL×3), dichloromethane solution, and dried by adding anhydrous sodium sulfate. Filtration, dichloromethane was distilled off to obtain the intermediate 1-(1,3-benzodioxol-5-yl)-2-(c...

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Abstract

The invention belongs to the field of preparation of chemical raw medicaments, and more in particular relates to an improved preparation method for a phosphodiesterase 5 inhibitor tadalafil. A specific synthesis route is shown in the specification. The method comprises the following steps of performing Pictet-Spengler cyclization reaction and chloroacetyl chloride acylation on starting reactants (D-tryptophan methyl ester hydrochloride and piperonal) to obtain an intermediate product, directly performing subsequent reaction on the intermediate product without purification, preparing an intermediate 1-(1,3-benzodioxol-5-yl)-2-(chloracetyl)-2,3,4,9-tetrahydro-1H-pyridino-[3,4,-B]indol-3-thiophenate methyl by using a one-pot reaction method, performing column chromatography purification to obtain a single cis-isomer, and finally reacting the single cis-isomer with methylamine hydrochloride in the presence of an inorganic base to obtain the tadalafil.

Description

technical field [0001] The invention belongs to the field of preparation of chemical raw materials, and more specifically relates to a preparation method of tadalafil, a phosphodiesterase 5 inhibitor. Background technique [0002] Tadalafil (Tadalafil) is a phosphodiesterase type 5 (PDE5) inhibitor originally developed by GlaxoSmithKline (GSK), and then transferred to ICOS, and later by ICOS and Eli Lilly (EliLillv) Jointly developed and approved by the FDA in 2003, it was marketed in the United States as a drug for the treatment of male erectile dysfunction (MED). [0003] The synthesis of tadalafil reported at present is mostly carried out with D-tryptophan methyl ester and piperonal as raw materials, and the difference is mainly in the intermediate cis-(1R,3R)-1-(1, 3-benzodioxolan-5-yl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-B]indole-3-carboxy In the preparation method of methyl ester (formula D), because the preparation method of the intermediate is differe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14
CPCC07D471/14
Inventor 陈国祥王鹏飞吴锡凤杨欣怡邵凤
Owner ANHUI WANBANG MEDICAL TECH
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