Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method of avanafil

A technology of avanafil and reaction solution, applied in organic chemistry methods, organic chemistry, etc., to achieve the effects of mild reaction conditions, easy operation, and high product yield

Inactive Publication Date: 2018-10-26
苏州盛达药业有限公司
View PDF2 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In order to solve the problems existing in the preparation method of avanafil, the purpose of the present invention is to provide a preparation method of avanafil, which has the advantages of easy-to-obtain raw materials, easy operation, mild reaction conditions and high yield

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of avanafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] A preparation method of avanafil, comprising the steps of:

[0029] S1, adding methylthiourea sulfate (75.2g, 0.4mol) into a mass fraction of 16% NaOH (250mL, 1.18mol) solution and stirring for 30min, then diethyl ethoxymethylene malonate (103.4 g, 0.48mol) was dissolved in 160mL ethanol and slowly dripped into the reaction solution. After the dropwise addition was completed, it was reacted at room temperature for 10 hours. 99.7%); ESE-MS (m / z): 249 [M+H] + , 236.9[M+Na] + , by comparison with the literature, it can be known that it is ethyl 4-hydroxy-2-methylthiopyrimidine-5-carboxylate;

[0030] S2. Add ethyl 4-hydroxy-2-methylthiopyrimidine-5-carboxylate (55.6 g, 0.26 mol) obtained in step S1 to 150 mL of acetonitrile, stir for 25 min, and slowly add 135 mL of POCl dropwise to the reaction solution 3 After the dropwise addition is completed, the reaction solution is heated to reflux for 6 hours, then the reaction solution is cooled slightly, the reaction solution ...

Embodiment 2

[0037] A preparation process of avanafil, comprising the steps of:

[0038] S1, adding methylthiourea sulfate (75.2g, 0.4mol) into a mass fraction of 24% NaOH (155mL, 1.17mol) solution and stirring for 30min, then diethyl ethoxymethylenemalonate (103.4 g, 0.48mol) was dissolved in 160mL ethanol and slowly dripped into the reaction solution. After the dropwise addition was completed, it was reacted at room temperature for 10h, and a white solid was precipitated. Suction filtration, washing with water, and vacuum drying gave a white solid (80.5g, 94.7%) ;ESE-MS(m / z): 249[M+H] + , 236.9[M+Na] + , by comparison with the literature, it can be known that it is ethyl 4-hydroxy-2-methylthiopyrimidine-5-carboxylate;

[0039] S2. Add ethyl 4-hydroxy-2-methylthiopyrimidine-5-carboxylate (55.6 g, 0.26 mol) obtained in step S1 to 150 mL of acetonitrile, stir for 25 min, and slowly add 135 mL of PCl dropwise to the reaction solution 3 , after the dropwise addition, the reaction solution ...

Embodiment 3

[0046] A preparation process of avanafil, comprising the steps of:

[0047] S1, adding methylthiourea sulfate (75.2g, 0.4mol) into a mass fraction of 16% NaOH (250mL, 1.18mol) solution and stirring for 30min, then diethyl ethoxymethylene malonate (103.4 , 0.48mol) was dissolved in 160mL ethanol and slowly dripped into the reaction solution. After the titration was completed, it was reacted at room temperature for 7h, and a white solid was precipitated, filtered by suction, washed with water, and dried in vacuo to obtain a white solid (72.8g, 85.7%); ESE -MS(m / z): 249[M+H] + , 236.9[M+Na] + , by comparison with the literature, it can be known that it is ethyl 4-hydroxy-2-methylthiopyrimidine-5-carboxylate;

[0048] S2. Add ethyl 4-hydroxy-2-methylthiopyrimidine-5-carboxylate (55.6 g, 0.26 mol) obtained in step S1 to 150 mL of acetonitrile, stir for 25 min, and slowly add 135 mL of PCl dropwise to the reaction solution 5 , after the dropwise addition, the reaction solution wa...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides a preparation method of avanafil, and specifically relates to the technical field of pharmaceutical chemistry. The preparation method of avanafil comprises the following steps:sequentially carrying out cyclization and chlorination reactions on methyl thiourea sulfuric acid and diethyl ethoxymethylene malonate which serve as initial raw materials to obtain 4-chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester; then substituting and hydrolyzing with 3-chloro-4-methoxybenzylamine; condensing with 2-pyrimidinemethanamine to obtain a key intermediate, namely, 4-[(3-chloro-methoxybenzyl)amino]-2-methylthio-N-(2-pyrimidine methyl)-5-pyrimidine formamide; oxidizing the intermediate and reacting with L-prolinol to generate the avanafil. The preparation method has theadvantages of easy availability of raw materials, easiness and convenience in operation, mild reaction conditions and higher product yield.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of avanafil. Background technique [0002] Avanafil (avanafil) is an oral rapid-acting highly selective phosphodiesterase 5 (phosphodiesterase 5, PDE5) inhibitor, the chemical name is (S)-4-[(3-chloro-4-methoxy Benzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide, the trade name is Stendra, produced by Japan Tanabe Mitsubishi Pharmaceutical Co., Ltd. authorized Vivus of the United States to develop a drug mainly for the treatment of erectile dysfunction. The drug was approved by the US FDA on April 27, 2012. Compared with similar drugs, sildenafil, avanafil lasts longer and is more effective for erectile dysfunction, and the incidence and severity of adverse reactions are relatively low. However, the unconventional preparation method of Avana has problems such as cumbersome steps, expensi...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D403/14
CPCC07B2200/07C07D403/14
Inventor 杨虎星黄军豪罗新祖
Owner 苏州盛达药业有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com