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Avanafil

A technology of ivanafil and intermediates, applied in the field of drug synthesis, can solve the problems of affecting product yield, high synthesis cost, long synthesis time and the like

Inactive Publication Date: 2014-01-01
SUZHOU UUGENE BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Although this synthesis method finally obtained Ivanafil, the steps of this synthesis method are cumbersome, the reaction operation is complicated, and the reagents needed in the reaction are more, which not only leads to high synthesis cost and long synthesis time, but also seriously affects the yield of the product.

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0069] At room temperature, 21.1g of 2,4-dichloro-5-pyrimidinecarbonyl chloride was added to the reaction flask and dissolved in 180mL of dichloromethane to form the first reaction solution, and 11.4g of 2-methylaminopyrimidine and 10.6g of triethylamine were dissolved in Form the second reaction solution in 100mL of dichloromethane, lower the temperature of the first reaction solution to -10°C, slowly drop the second reaction solution into the first reaction solution under this temperature condition, and slowly raise the temperature to At room temperature, add 300 mL of water, separate layers, wash the organic phase with 100 mL of water three times, dry with anhydrous sodium sulfate, filter with suction, and evaporate the organic phase to dryness under reduced pressure to obtain 25.5 g of aivanafil intermediate A2,4-dichloro -N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide.

[0070] Dissolve 25.5g of the above-prepared avanafil intermediate A2,4-dichloro-N-(2-pyrimidinylmethy...

Embodiment 2

[0073]At room temperature, 23.5g of 2,4-dimethylthio-5-pyrimidinecarbonyl chloride was added to the reaction bottle and dissolved in 200mL of chloroform to form the first reaction solution, and 11.46g of 2-methylaminopyrimidine and 7.14g of imidazole were dissolved in Form the second reaction solution in 100mL of chloroform, cool the first reaction solution to -8°C, slowly add the second reaction solution dropwise to the first reaction solution at this temperature, and slowly raise the temperature to At room temperature, add 300 mL of water, separate layers, wash the organic phase with 100 mL of water three times, dry with anhydrous sodium sulfate, filter with suction, and evaporate the organic phase to dryness under reduced pressure to obtain 28.3 g of aivanafil intermediate A2,4-dimethyl Thio-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide.

[0074] Dissolve 28.3g of the avanafil intermediate A2,4-dimethylthio-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide prepared above in...

Embodiment 3

[0077] At room temperature, 26.8g of 4-bromo-2-methylthio-5-pyrimidinecarbonyl chloride was added to the reaction bottle and dissolved in 200mL of 1,2-dichloroethane to form the first reaction solution, and 11.46g of 2-methylaminopyrimidine Dissolve 8.3g of pyridine in 100mL of 1,2-dichloroethane to form the second reaction solution, lower the temperature of the first reaction solution to -3°C, and slowly add the second reaction solution to the first reaction solution dropwise at this temperature After the dropwise addition, slowly warm up to room temperature, add 300mL of water, separate layers, wash the organic phase with 120mL of water three times, dry with anhydrous sodium sulfate, filter with suction, and evaporate the organic phase to dryness under reduced pressure to obtain 30.3g of Ava Nafil Intermediate A4-Bromo-2-methylthio-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide.

[0078] Dissolve 30.3g of Aivanafil intermediate A4-bromo-2-methylthio-N-(2-pyrimidinylmethyl)-...

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Abstract

The invention provides an avanafil intermediate A and an avanafil intermediate B, and a synthetic method of the avanafil intermediates A and B and avanafil. The synthetic method of the avanafil comprises the following steps: reacting a compound with the formula (I) with 2-methylaminopyrimidine at a temperature ranging from -10 DEG C to 5 DEG C to obtain the avanafil intermediate A; agitating the avanafil intermediate A with 3-chloro-4-methoxybenzylamine at the temperature ranging from 0 DEG C to 3 DEG C and reacting for 0.2-0.4 hour to obtain the avanafil intermediate B; and agitating the avanafil intermediate B with L-prolinol at the room temperature and reacting for 18-22 hours to obtain the avanafil. The structural formulas of the avanafil intermediates A and B and the compound with the formula (I) are shown in the specification. The avanafil intermediates A and B provided by the invention are simple in structure and good in product quality; the cost of the synthetic method is low; the synthetic route of the whole process is short and reaction steps are few, so that the reaction time is shortened and the yield and the purity of the avanafil intermediates A and B, and the avanafil are also improved.

Description

technical field [0001] The invention relates to an ivanafil intermediate, a synthesis method thereof, and a synthesis method of ivanafil, and belongs to the technical field of medicine synthesis. Background technique [0002] Avanafil, whose chemical name is 4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N -(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide, the chemical formula is: [0003] [0004] Evanafil is a potent and highly selective phosphodiesterase 5 (PDE5) inhibitor, a research project transferred by Vivus from Mitsubishi Tanabe Pharmaceutical Co., Ltd., Japan, for the treatment of male erectile dysfunction (ED) . Data from clinical trials showed that Avanafil treated adequately for erections, a higher rate of vaginal penetration, a higher rate of adequately prolonged erections, and a higher rate of successful completion of intercourse with Avanafil compared with placebo. In addition to oral dosage forms, Vivus is also developing a urin...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D239/30C07D239/58C07D239/38C07D239/42C07D239/47
CPCC07D239/30C07D239/38C07D239/42C07D239/47C07D239/58C07D403/14
Inventor 李志强王伸勇王晓俊胡隽恺
Owner SUZHOU UUGENE BIOPHARMA
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