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Method for refining tadalafil

A tadalafil and quality technology, applied in the field of refining tadalafil, can solve problems such as reducing the utilization rate of crude products, achieve significant economic value and environmental protection value, improve yield, and achieve the effect of recycling

Inactive Publication Date: 2017-05-17
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this method obtains the yield of crystal form A in the binary mixed solvent of alcohol and acetic acid is only 50%, has reduced the utilization rate of crude product greatly

Method used

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  • Method for refining tadalafil
  • Method for refining tadalafil
  • Method for refining tadalafil

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Reference Example 1: Preparation of Tadalafil Crude Product

[0028] Referring to patent WO2004011463, crude tadalafil was prepared, with purity (HPLC): 99.42%, impurity A (HPLC): 0.26%, other maximum single impurities (HPLC): 0.17%.

[0029] Example 1

[0030] At room temperature, take 5.5 g of the crude product of tadalafil prepared in Reference Example 1 and add it into a 500 mL four-necked bottle. Then add 100.0 g of methanol and 100.0 g of acetic acid, and start stirring. Raise the temperature to 80-85°C, heat the material and stir for 1-2 hours after the material is dissolved. After distilling off 133g of the mixed solvent, crystals gradually precipitated. Slowly lower the temperature to 0°C and continue crystallization for 1-2 hours, filter, wash with about 5g of methanol, and dry in vacuum at 50°C for 8 hours to obtain 5.09g of tadalamorph A, yield 92.5%, purity (HPLC): 99.86 %, impurity A (HPLC): 0.05%, other maximum single impurity (HPLC): 0.07%.

Embodiment 2

[0032] At room temperature, take 10.0 g of the crude product of tadalafil prepared in Reference Example 1 and add it into a 500 mL four-necked bottle. Add 50.0 g of methanol and 150.0 g of acetic acid, and start stirring. Raise the temperature to 80-85°C, heat the material and stir for 1-2 hours after the material is dissolved. After distilling off 133g of the mixed solvent, crystals gradually precipitated. Slowly lower the temperature to 0°C and continue crystallization for 1-2 hours, filter, wash with about 5g of methanol, and dry in vacuum at 50°C for 8 hours to obtain 9.29g of tadalamorph A, yield 92.9%, purity (HPLC): 99.88 %, impurity A (HPLC): 0.04%, other maximum single impurity (HPLC): 0.07%.

Embodiment 3

[0034] At room temperature, take 15.0 g of the crude tadalafil product prepared in Reference Example 1 and add it into a 500 mL four-necked bottle. Add 20.0 g of methanol and 180.0 g of acetic acid, and start stirring. Raise the temperature to 80-85°C, heat the material and stir for 1-2 hours after the material is dissolved. After distilling off 133g of the mixed solvent, crystals gradually precipitated. Slowly lower the temperature to 0°C and continue crystallization for 1-2 hours, filter, wash with about 5g of methanol, and dry in vacuum at 50°C for 8 hours to obtain 14.04g of tadalamorph A, yield 93.6%, purity (HPLC): 99.99 %, impurity A (HPLC): N.D, other maximum single impurity (HPLC): 0.01%.

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Abstract

The invention provides a method for refining tadalafil. The method comprises the following steps: 1) dispersing a tadalafil crude product into a mixed solvent of methanol and acetic acid, heating the material to perform dissolved clarification on the crude product; 2) steaming the material to remove a part of the solvent, gradually precipitating crystals; 3) slowly cooling the material, continuously crystallizing the product; and 3) filtering the material, washing the material, and drying the material to obtain the tadalafil crystal form A. Compared with a direct cooling crystallization method, the product yield is obviously increased, production power is increased, recovery and utilization of the mixed solvent are realized, and the method has obvious economic value and environmental protection value.

Description

technical field [0001] The invention relates to a method for refining tadalafil. Background technique [0002] The chemical name of tadalafil is (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12, 12a-hexahydropyrazino[1',2',1,6]pyrido[3,4-b]indole-1,4-dione, the structural formula is as follows: [0003] [0004] Tadalafil is a second-generation phosphodiesterase inhibitor type 5 (PDE5 inhibitor), developed by Eli Lilly and Company of the United States, mainly for the treatment of male sexual dysfunction, that is, by inhibiting the degradation of cyclic guanosine monophosphate (cGMP) type 5 Phosphodiesterase activity increases intracellular cGMP concentration, leading to smooth muscle relaxation, increasing arterial blood flow in the penile cavernous body, and erection. [0005] From the tadalafil synthetic route that has been retrieved so far, the synthetic route with D-tryptophan and piperonal as key materials is widely used because of the advantages of simple re...

Claims

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Application Information

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IPC IPC(8): C07D471/14
CPCC07B2200/13C07D471/14
Inventor 郭永刚金从阳张文灵
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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