Method for preparing tadalafil

A technology of tadalafil and its compounds, which is applied in the field of preparation of tadalafil, can solve problems such as difficult storage and transportation, unfavorable industrial production, inflammability and explosion, and achieve easy industrial production, low production cost and cheap price Effect

Active Publication Date: 2014-11-12
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The organic solvent solution of methylamine is not only expensive, but also has the problem of being flammable and explosive, and it is difficult to store and transport, which is not conducive to industrial production
The impurity of the product that adopts this reagent to prepare simultaneously is higher (product purity 98.00%, HPLC), needs further recrystallization treatment just can prepare qualified product

Method used

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  • Method for preparing tadalafil
  • Method for preparing tadalafil
  • Method for preparing tadalafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 Preparation of Compound B

[0030] Compound B is prepared according to the method in patent WO2004011463. The prepared compound B has a purity of 97.00% and is HPLC.

Embodiment 2

[0032] Add 1200ml of purified water to 100g of compound B prepared in Example 1, add 4.66g of tetrabutylammonium bromide under stirring, slowly add 300ml of methylamine aqueous solution, and then heat the system to 80℃~85℃, keep warm for reaction After 6h, start the TLC dot plate. After the reaction is over, stop the reaction. Cool the system to 20℃~25℃, keep the temperature for 3.0h~4.0h, filter, wash the filter cake with 20ml purified water, scrape the filter cake, 65~70 After vacuum drying at ℃ for 7-8 hours, 88.48 g of tadalafil was obtained with a yield of 97.0% and a purity of 99.96% by HPLC.

Embodiment 3

[0034] Add 1500ml of purified water to 100g of compound B prepared in Example 1, add 4.80g of tetrabutylammonium bromide under stirring, slowly add 300mlg of methylamine aqueous solution, and then heat the system to 80℃~85℃, keep the temperature and react for 6h Start TLC and stop the reaction when the reaction is over. Cool the system to 20℃~25℃, keep for 3.0h~4.0h for crystallization, filter, wash the filter cake with 20ml purified water, scrape off the filter cake, and vacuum at 65~70℃ After drying for 7-8 hours, 88.50 g of tadalafil was obtained with a yield of 97.0% and an HPLC purity of 99.93%.

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Abstract

The invention discloses a method for preparing tadalafil. The method comprises the steps that water and catalyst tetrabutyl ammonium bromide are added to a compound B, a methylamine water solution is added to the compound B, and the temperature of the mixed solution is increased to the range from 60 DEG C to 90 DEG C to be kept for 6-10 hours for reaction; after reaction, the mixed solution is cooled to the temperature ranging from 20 DEG C to 35 DEG C, the temperature is kept, devitrifying is carried out for 3-6 hours, filtering is carried out, and filter cakes are washed and dried to obtain finished tadalafil. Compared with the prior art, the price of the adopted methylamine water solution is lower than that of a methylamine methylamine solution, water is adopted as reaction solvent, production cost is greatly reduced, and water is safe and friendly to the environment. The purity of the tadalafil prepared through the method is more than 99.90 percent, and recrystallization process is not needed. The method is easy to operate, low in production cost and pollution and easier to produce in an industrial mode.

Description

Technical field [0001] The invention relates to a preparation method of tadalafil, belonging to the technical field of medicine. Background technique [0002] Tadalafil, chemical name: (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; molecular weight: 389.41; molecular formula: C 22 H 19 N 3 O 4 ; The structural formula is as follows: [0003] [0004] Tadalafil is a selective and reversible inhibitor of cyclic guanosine phosphate (cGMP) specific phosphodiesterase 5 (PDE5). When sexual stimulation leads to the local release of nitric oxide, PDE5 is inhibited by tadalafil, which increases the cGMP level in the corpus cavernosum, which leads to relaxation of smooth muscles, blood flow into penile tissues, and erections. Tadalafil was originally developed by Glaxo Wellcome Laboratories, then transferred to ICOS, and then jointly developed by ICOS and Eli Lilly. Approved by the US FDA in 2003, the product name is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14
CPCC07D471/14
Inventor 杨波勇杨庆坤李保勇吴柯张兆珍董廷华李亚鹏高大龙江海平
Owner 山东安信制药有限公司
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