New preparation method for Tadalafei crystal form I

A tadalafil, amorphous technology, applied in organic chemistry and other directions, can solve problems such as failure to meet industrialization requirements

Active Publication Date: 2011-09-14
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In Example 1, it is mentioned that N,N-dimethylformamide is used as the crystallization solvent. Although the solv

Method used

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  • New preparation method for Tadalafei crystal form I
  • New preparation method for Tadalafei crystal form I
  • New preparation method for Tadalafei crystal form I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Add 10.0 g of tadalafil crude product, add 100 ml of 1,3-dioxane, heat to reflux (about 74° C.), and stir until a clear and transparent solution. Slowly lowered to room temperature, stirred for 30 minutes, then cooled to -5°C to 0°C with an ice-salt bath, a large amount of solid was precipitated, kept stirring for 2 hours, filtered, and dried to obtain 8.5 g of tadalafil type I crystals.

[0049] Yield 85% DSC: 299~302°C HPLC: 99.98%

[0050] Chiral isomer HPLC: 0.02% Trans isomer HPLC: 0.05%

Embodiment 2

[0052] Add 10.0 g of tadalafil crude product, add 50 ml of 1,3-dioxane, heat to reflux (about 74° C.), and stir until a clear and transparent solution. Add 150 ml of water, slowly reduce to room temperature, and then cool to -5 ° C ~ 0 ° C with an ice-salt bath, separate out a large amount of solid, keep stirring for 2 hours, filter, and dry to obtain 9.0 g of tadalafil type I crystals

[0053] Yield 90% DSC: 299.7~303℃

Embodiment 3

[0055] 10.0 g of crude tadalafil was added to 400 ml of ethylene glycol dimethyl ether, heated to dissolve, and stirred to a clear and transparent solution. Slowly lowered to room temperature, then cooled to -5 ° C ~ 0 ° C with an ice-salt bath, a large amount of solid was precipitated, kept stirring for 2 hours, filtered, and dried to obtain 8.0 g of tadalafil type I crystals.

[0056] Yield 80%

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Abstract

The invention provides a preparation method for Tadalafei I type. The preparation method comprises the following steps of: heating a Tadalafei crude product to the temperature of between 50 and 140 DEG C; dissolving the Tadalafei crude product in ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monomethyl ether, 1,3-dioxolane or a mixed solvent of two or three thereof; cooling a system to obtain a crystal; and separating to obtain a precipitate. The preparation method has the characteristics of low solvent consumption and high yield. By the method, a pure I type Tadalafei crystal can be obtained; and by the crystallization method, the product can be purified and optical purity can be improved.

Description

Field of Invention [0001] The present invention relates to a new preparation method of tadanafil crystal form I. Background of the Invention [0002] Erectile dysfunction (ED) is a common disease in adult men. The research and development of phosphodiesterase (V) inhibitors for the treatment of ED has entered a new era since sildenafil (viagra) was launched as the first clinical drug for the treatment of erectile dysfunction in men. Tadalafil is a novel oral phosphodiesterase (V) inhibitor jointly developed by Eli Lilly and Icos, and its trade name is Cialis. It was approved by the European Union in 2002, approved by the FDA in November 2003 for listing in the United States, and approved in China in 2005. This product has strong selectivity, few adverse reactions, long duration of action, and high-fat diet will not interfere with its absorption. [0003] US Pat. No. 5,859,006, which first reported this compound, discloses (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4...

Claims

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Application Information

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IPC IPC(8): C07D471/14
Inventor 向科陈国财
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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