Preparation method of tadalafil

A technology of tadalafil and compounds, which is applied in the field of drug synthesis, can solve problems such as trans isomers, and achieve the effects of high total yield, stable process, and simple overall route

Active Publication Date: 2017-07-25
SHANDONG YUXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] It can be seen that the prior art of synthesizing tadalafil is mainly based on D-tryptophan methyl ester hydrochloride and piperonal as starting materials, through condensation cyclization, acylation, aminolysis cyclization synthetic route, Constructing the β-tetrahydrocarboline ring by asymmetric synthesis is the key to the whole synthetic route. On the one hand, the Pictet-Spengler (condensation ring closure) reaction is the most effective and commonly used means to constru...

Method used

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  • Preparation method of tadalafil
  • Preparation method of tadalafil
  • Preparation method of tadalafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of compound Ⅲ

[0031] Add 25.47g of D-tryptophan methyl ester hydrochloride, 15.82g of pyridine, and 200ml of ethyl acetate into the reaction vessel in sequence, stir to dissolve, keep the temperature in an ice bath at 0-5°C, and slowly add dropwise the solution containing 11.42g of oxalyl chloride 20ml of ethyl acetate solution, stirred for 2h to complete the reaction, washed 3 times with distilled water (200ml×3) after the reaction, added sodium sulfate to dry, distilled off the solvent, and crystallized with 95% ethanol to obtain 21.44g of compound III with a yield of 82%. 99.90% pure.

Embodiment 2

[0033] Preparation of compound Ⅲ

[0034] Add 25.47g of D-tryptophan methyl ester hydrochloride, 36.65g of 4-dimethylaminopyridine, and 200ml of dichloromethane in turn into the reaction vessel, stir to dissolve, keep the temperature in an ice bath at 0-5°C, and slowly add the 11.42 g of oxalyl chloride in 20 ml of dichloromethane solution, stirred for 2 hours to complete the reaction, washed 3 times with distilled water (200 ml × 3) after the reaction, added sodium sulfate to dry, distilled off the solvent, crystallized with 95% ethanol to obtain 21.96 g of compound III, Yield 84%, purity 99.93%.

Embodiment 3

[0036] Preparation of compound Ⅲ

[0037] Add 25.47g of D-tryptophan methyl ester hydrochloride, 30.35g of N-methylmorpholine, and 200ml of ethyl acetate into the reaction vessel in sequence, stir to dissolve, keep the temperature in an ice bath at 0-5°C, and slowly add the 11.42 g of oxalyl chloride in 20 ml of ethyl acetate solution, stirred for 2 h to complete the reaction, washed 3 times with distilled water (200 ml × 3), added sodium sulfate to dry, distilled off the solvent, crystallized with 95% ethanol to obtain 25.26 g of compound III, Yield 87%, purity 99.96%.

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Abstract

The invention discloses a preparation method of tadalafil, starting material D-Tryptophan methyl ester hydrochloride is reacted with oxalyl chloride to obtain an intermediate III, and the final product tadalafil (I) is obtained through cyclization, Grignard reaction, asymmetric reduction, substitution and condensation reaction. The use of national control chemical piperonal is avoided, an intermediate VI can be highly-selectively obtained by the asymmetric reduction, and the method has the advantages of simple postprocessing, short synthesis steps and high product total yield, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a preparation method of tadalafil. Background technique [0002] Tadalafil is a phosphodiesterase type V (PDE5) inhibitor. When sexual stimulation leads to the local release of nitric oxide, PDE5 is inhibited by tadalafil, which increases the level of cyclic guanosine monophosphate in the cavernous body of the penis, which leads to Smooth muscles relax and blood flows into the penile tissue, producing an erection. The compound was originally developed by GlaxoSmithKline and subsequently transferred to ICOS, and later jointly developed by ICOS and Eli Lilly. Approved by the FDA in 2003, tadalafil was listed in the United States as a drug for the treatment of male erectile dysfunction. At the beginning of 2014, the drug was approved by the US FDA as a new indication for the treatment of benign prostatic hyperplasia, and the future market capacity will be even broader. [...

Claims

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Application Information

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IPC IPC(8): C07D471/14
CPCC07B2200/07C07D471/14
Inventor 刘新泉孙运贝王广明刘庆利
Owner SHANDONG YUXIN PHARMA CO LTD
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