A kind of preparation method of tadalafil related substance f

A technology related to substances, tadalafil, applied in the field of medicine, can solve the problems of undiscovered synthesis methods and the like

Active Publication Date: 2019-12-20
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Through literature search, no synthetic method report of the substance was found

Method used

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  • A kind of preparation method of tadalafil related substance f
  • A kind of preparation method of tadalafil related substance f
  • A kind of preparation method of tadalafil related substance f

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Add glycine methyl ester hydrochloride (37.67g, 300mmol), piperonal (64.86g, 432mmol), 452.00g methyl tert-butyl ether, 25.56g anhydrous sodium sulfate into a 1L reaction flask, and cool down to -5~5°C . Control the temperature at -5~5°C, add triethylamine (45.54g, 450mmol) dropwise, and react at room temperature 20~30°C for 48h after the dropwise completion. Suction filter, rinse with 226.00g of methyl tert-butyl ether, let the filtrate stand at 10~20°C for 1h, then stir at 5~10°C for 3h. After suction filtration, the solid was air-dried at 40°C to obtain compound I as a white solid (19.02 g, yield 28.7%).

[0034] Add compound I (19.00g, 85.9mmol), silver acetate (21.51g, 128.9mmol), triethylamine (10.70g, 105.7mmol) into a 1L reaction flask, add 232.40g of toluene, protect with nitrogen, and cool down to -5~ 5°C. Take 209.00g of toluene and cool it down to -10~0°C, mix it with nitroethylene (5.65g, 77.3mmol), and drop it into the above reaction flask. After dropp...

Embodiment 2

[0042] Add glycine methyl ester hydrochloride (37.67g, 300mmol), piperonal (64.86g, 432mmol), 452.00g tetrahydrofuran, and 25.56g anhydrous sodium sulfate into a 1L reaction flask, and cool down to -5~5°C. Control the temperature at -5~5°C, add pyridine (35.60g, 450mmol) dropwise, and react at room temperature 20~30°C for 48h. Suction filter, rinse with 226.00g of tetrahydrofuran, let the filtrate stand at 10~20°C for 1h, then stir at 5~10°C for 3h. After suction filtration, the solid was air-dried at 40°C to obtain compound I as a white solid (18.62 g, yield 28.0%).

[0043] Add compound I (18.00g, 81.4mmol), silver acetate (20.38g, 122.1mmol), pyridine (7.92g, 100.1mmol) into a 1L reaction flask, add 220.17g of toluene, protect with nitrogen, and cool down to 5~15°C. Take 198.00g of toluene and cool it down to -10~0°C, mix it with nitroethylene (5.13g, 73.2mmol), and drop it into the above reaction flask. After dropping, the temperature was controlled at 5~15°C for 6 hours...

Embodiment 3

[0051] Add glycine methyl ester hydrochloride (37.67g, 300mmol), piperonal (45.04g, 300mmol), 452.00g methyl tert-butyl ether, 25.56g anhydrous sodium sulfate into a 1L reaction flask, and cool down to -5~5°C . Control the temperature at -5~5°C, add triethylamine (45.54g, 450mmol) dropwise, and react for 48h at room temperature at 10~20°C. Suction filter, rinse with 226.00g of methyl tert-butyl ether, let the filtrate stand at 10~20°C for 1h, then stir at 5~10°C for 3h. After suction filtration, the solid was air-dried at 40°C to obtain compound I as a white solid (16.55 g, yield 24.9%).

[0052] Add compound I (14.00g, 63.3mmol), silver acetate (18.85g, 95.0mmol), triethylamine (7.69g, 76.0mmol) into a 1L reaction flask, add 232.40g of toluene, protect with nitrogen, and cool down to -5~ 5°C. Take 154.00g of toluene and cool it down to -10~0°C, mix it with nitroethylene (4.16g, 56.9mmol), and drop it into the above reaction flask. After dropping, the temperature was contr...

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PUM

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Abstract

The invention relates to a preparation method of a tadalafil related substance F, wherein the method takes heliotropin and glycine methyl ester hydrochloride as starting materials, and through a seven-step reaction and then through column chromatography separation, the tadalafil related substance F meeting the requirements of Pharmacopoeia is obtained with high purity.

Description

technical field [0001] The invention relates to a preparation method of tadalafil-related substance F, which belongs to the technical field of medicine. Background technique [0002] Tadalafil is a selective and reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5). When sexual stimulation results in the local release of nitric oxide, PDE5 is inhibited by tadalafil, increasing cGMP levels in the corpus cavernosum, which leads to smooth muscle relaxation, blood flow into penile tissue, and an erection. Tadalafil was jointly developed by ICOS and Eli Lilly, and was approved for marketing in the United States in August 2003. The product name is "Cialis", and the indication is male erectile dysfunction (ED). In May 2009, the FDA approved its second indication—pulmonary arterial hypertension; in October 2011, it approved the drug for the treatment of secondary benign prostatic hyperplasia. my country approved its domestic listing in M...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/20
CPCC07D498/20
Inventor 梁松军曹德强王宁宁刘丽霞苗华明蔡亚辉
Owner 迪嘉药业集团股份有限公司
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