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Preparation method of pharmaceutical compound avanafil

An avanafil and compound technology, which is applied in the field of synthesis of pharmaceutical compounds, can solve the problems of insufficient intermediate purity, poor selectivity, influence on product quality and the like, and achieves the effects of short reaction steps, mild conditions and low cost.

Active Publication Date: 2019-01-29
重庆奥舍生物化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the reported synthetic routes, there are either harsh reaction conditions or relatively poor selectivity in the reaction, which may easily lead to insufficient purity of intermediates, thereby affecting the quality of the final product.

Method used

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  • Preparation method of pharmaceutical compound avanafil
  • Preparation method of pharmaceutical compound avanafil
  • Preparation method of pharmaceutical compound avanafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of compound 2

[0029] In a 500mL autoclave, add Compound 1 (214g, 1mol) and 200mL of hydrogen peroxide with a mass fraction of 30%, and gradually raise the temperature to 120°C for reaction. Recrystallization gave a white solid with a yield of 95% and a purity of 98.5% by HPLC. 1 H NMR(DMSO-d6):δ9.64(s,1H),8.37(d,2H),4.07(q,2H),2.50(s,3H),1.20(t,3H).ESI-MS(m / z):247[M+1] + .

[0030] Preparation of compound 3

[0031] In the reaction flask, add compound 2 (246g, 1mol), toluene 492mL and diisopropylethylamine 182mL, slowly add phosphorus oxychloride 94mL dropwise under stirring, heat up to reflux reaction, cool to 0°C after the reaction is completed, Wash with ice water, dry the toluene phase, add dropwise a mixture containing 173g of 3-chloro-4-methoxybenzylamine, 182mL of isopropylethylamine and 492mL of toluene for reaction, wash with brine and water after the reaction , dried and then spin-dried to obtain compound 3 with a yield of 96.8% and a purit...

Embodiment 2

[0040] Preparation of compound 2

[0041] In a 500mL autoclave, add Compound 1 (214g, 1mol) and 200mL of hydrogen peroxide with a mass fraction of 30%, and gradually raise the temperature to 120°C for reaction. Recrystallization gave a white solid with a yield of 95% and a purity of 98.5% by HPLC. ESI-MS(m / z):247[M+1] + .

[0042] Preparation of compound 3

[0043] In the reaction flask, add compound 2 (246g, 1mol), toluene 1230mL and diisopropylethylamine 364mL, slowly add phosphorus oxychloride 186mL dropwise under stirring, heat up to reflux reaction, cool to 0°C after the reaction is completed, Wash with ice water, dry the toluene phase, add dropwise a mixture containing 180g of 3-chloro-4-methoxybenzylamine, 182mL of isopropylethylamine and 492mL of toluene for reaction, wash with brine and water after the reaction , dried and spin-dried to obtain compound 3 with a yield of 96.1% and a purity of 98.7% by HPLC. ESI-MS(m / z):400[M+1] + .

[0044] Preparation of Compou...

Embodiment 3

[0051] Preparation of Compound 2

[0052] In a 500mL autoclave, add Compound 1 (214g, 1mol) and 200mL of hydrogen peroxide with a mass fraction of 30%, and gradually raise the temperature to 120°C for reaction. Recrystallization gave a white solid with a yield of 95% and a purity of 98.5% by HPLC. ESI-MS(m / z):247[M+1] + .

[0053] Preparation of compound 3

[0054] In the reaction flask, add compound 2 (246g, 1mol), toluene 100mL and diisopropylethylamine 250mL, slowly add phosphorus oxychloride 110mL dropwise under stirring, heat up to reflux reaction, cool to 0°C after the reaction, Wash with ice water, dry the toluene phase, add dropwise a mixture containing 175g of 3-chloro-4-methoxybenzylamine, 182mL of isopropylethylamine and 492mL of toluene for reaction, wash with brine and water after the reaction , dried and spin-dried to obtain compound 3 with a yield of 97.2% and a purity of 98.9% by HPLC. ESI-MS(m / z):400[M+1] + .

[0055] Preparation of Compound 4

[0056]...

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Abstract

The invention discloses a preparation method of a pharmaceutical compound avanafil, and belongs to the technical field of synthesis of pharmaceutical compounds. The key point of the technical scheme of the invention is as follows: a synthesis route of the synthetic method of the pharmaceutical compound avanafil is shown in the specification. The synthetic method has the advantages that the yield is high, the cost is low, the method is economical and environmentally friendly and is suitable for industrialization, the product purity is high and the like, and the method is a synthetic method withindustrial production values.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical compounds, and in particular relates to a preparation method of the pharmaceutical compound avanafil. Background technique [0002] Avanafil, the Chinese chemical name is (S)-4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidine Base]-N-(2-pyrimidinemethyl)-5-pyrimidinecarboxamide is a drug developed by American Virus Company authorized by Japan Tanabe Mitsubishi Pharmaceutical Co., Ltd. for the treatment of male erectile dysfunction. It was released on April 27, 2012 Nikkei US FDA approved to market in the United States, the product name is Stendra. The drug is an oral rapid-acting highly selective phosphodiesterase-5-(PDE) inhibitor. The drug is favored due to its fast oral absorption and shorter onset time than sildenafil and vartanafil. [0003] [0004] The current method for synthesizing avanafil, the synthetic route disclosed in the international p...

Claims

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Application Information

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IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 崔振伟张玮玮张甫青
Owner 重庆奥舍生物化工有限公司