Simple preparation process of tadalafil

A tadalafil, multiple technology, applied in the field of organic synthesis, can solve the problems of low reaction yield isomers, cumbersome operation, long reaction route, etc., to achieve the effect of shortening the production cycle, improving process efficiency and shortening the route

Inactive Publication Date: 2013-08-07
ZHANG JIA GANG VINSCE BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] To sum up, there are many synthetic routes of tadalafil. The domestic mass production uses D-tryptophan as the starting material, but most of them are changed from the Pictet-Spengler reaction, and many reactions have low yi

Method used

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  • Simple preparation process of tadalafil
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Examples

Experimental program
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Effect test

Embodiment 1

[0035] Preparation of cis-tetrahydrocarline intermediate

[0036] D-tryptophan methyl ester hydrochloride 20g, piperonal 10.2~12.2ml, isopropanol 160~200ml in a 250ml three-necked flask equipped with a reflux device and a thermometer, heat and reflux and stir for 9~10h, after the reaction is complete, stir Cool down to room temperature, filter, and dry the filter cake to obtain a pale yellow cis-tetrahydrocarline intermediate with a molar yield of 94-96%.

Embodiment 2

[0038] Preparation of cis-tetrahydrocarbazine intermediate

[0039] D-tryptophan methyl ester hydrochloride 20g, piperonal 10.2~12.2ml, nitromethane 160~200ml in a 250ml three-necked flask equipped with a reflux device and a thermometer, heat and reflux and stir for 9~10h, after the reaction is over, stir Cool to room temperature, filter, and dry the filter cake to obtain a pale yellow cis-tetrahydrocarline intermediate with a molar yield of 90-92%.

Embodiment 3

[0041] Preparation of chloroacetyl intermediate

[0042] Stir 160-200ml of ethyl acetate and 33-43g of potassium carbonate in a 250ml three-necked flask equipped with a thermometer for about 30min, then put in the cis-tetrahydrocarline intermediate prepared in the previous step, and control the temperature in an ice bath below 3-5°C Slowly add chloroacetyl chloride (8.8-10.6ml) diluted 5-6 times with ethyl acetate dropwise, continue the reaction for 1-1.5h, then rise to room temperature and react for about 1.5h, the reaction is complete, add about 400ml of water, extract, The organic phase was concentrated under reduced pressure to become a brown powder solid with a molar yield of 78-80%.

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Abstract

The invention relates to a preparation method of tadalafil. A product is obtained through condensation and cyclization, chloromethylation and aminolysis cyclization reaction based on D-tryptophan methyl ester hydrochloride and heliotropin as starting preparation materials. The simple preparation process is characterized in that condensation and cyclization are used for solving an isomer problem caused by Pictet-Spengler reaction by using isopropanol or nitromethane as a solvent; the yield of ethyl acetate in the aminolysis cyclization reaction is obviously improved; the aminolysis cyclization route includes three preparation steps, wherein the reaction yield of each step is high, the relevant impurities are easy to separate, the reaction conditions are simple, the production period is shorter, and toxic and highly corrosive reagents are not used, and therefore, the simple preparation process is safe and environment-friendly and easy to industrially produce, so that the high-purity qualified products are obtained.

Description

technical field [0001] The invention belongs to the organic synthesis technology and relates to a simple and convenient preparation method of tadalafil. Background technique [0002] Tadalafil is a phosphodiesterase type V (PDE5) inhibitor, which mainly treats male erectile dysfunction (ED). It increases the vasodilator effect of NO by inhibiting the decomposition of cGMP, so that ED patients regain penile erection. ability, its chemical structure is shown in the attached figure 1 . It was developed by GSK and transferred to Lilly-ICOS. It was approved by the FDA for marketing in the United States in 2003. It is the third drug for the treatment of ED after sildenafil and vardenafil. Scientific research shows that the incidence of ED accounts for about 50% of adult males, but at present, non-organic ED is mainly treated by the above three drugs, and compared with similar drugs, tadalafil has a faster onset time and a longer duration of drug effect It is nearly 10 times tha...

Claims

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Application Information

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IPC IPC(8): C07D471/14
CPCC07D471/14
Inventor 赵金召张梅彭学东王龙
Owner ZHANG JIA GANG VINSCE BIO PHARM
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