Avanafil impurity D as well as synthesis method and application thereof

A technology of avanafil and synthesis method, which is applied in the field of organic synthesis and can solve the problems of efficacy and safety impact of the final product

Inactive Publication Date: 2022-01-04
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These impurities may have a significant impact on the effectiveness and safety of the final product

Method used

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  • Avanafil impurity D as well as synthesis method and application thereof
  • Avanafil impurity D as well as synthesis method and application thereof
  • Avanafil impurity D as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1: Avanafil is synthesized by dehydration esterification reaction with carboxylic acid Avanafil impurity D

[0021] synthetic route:

[0022] .

[0023] Synthesis process: Add dichloromethane, avanafil, EDCI and 4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-( Hydroxymethyl) pyrrolidin-1-yl] pyrimidine-5-carboxylic acid, after reacting for 3-7h, the reaction solution was quenched, and the oil was obtained after post-treatment, which contained about 20% avanafil by liquid phase detection Impurities D. The oil was purified on the preparative apparatus and evaporated to dryness to obtain avanafil impurity D as a pale yellow solid.

Embodiment 2

[0024] Embodiment 2: Avanafil impurity D and synthetic route are as follows:

[0025] .

[0026] Synthesis of M1: SM2, appropriate amount of H 2 O was added to the three-necked flask, stirred to dissolve and then added excess Na 2 CO 3 , heated in a water bath to 20-30°C, after dissolving, add 2 equivalents of SM1 dropwise, the system is light yellow-green, a large amount of solids precipitate out, stir overnight. The pH was adjusted with concentrated hydrochloric acid to generate a large amount of gas, filtered and washed, and the filter cake was air-dried to obtain a white solid with a yield of 84%.

[0027] Synthesis of M2: Add M1 and toluene into a three-necked flask, raise the temperature to 90-100°C, and add excess POCl dropwise 3 , After heating up to 90°C, a yellow turbid solution was obtained, reacted for 2-3h, and gradually cooled down to room temperature. Drop water into the reaction solution, speed up the stirring, stand to separate the layers, separate the ...

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Abstract

The invention provides an avanafil impurity D as well as a synthesis method and application thereof. According to the novel avanafil impurity and the synthesis method thereof, the structure of the impurity is determined by synthesizing and characterizing the impurity, the drug impurity spectrum of avanafil is perfected, and the obtained product is high in purity and can be used as a reference substance for drug quality control research.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to the structure, synthesis method and application in quality research of a drug impurity avanafil impurity D. Background technique [0002] Avanafil, an oral, fast-acting, highly selective phosphodiesterase-5 (PDE-5) inhibitor, was launched in the United States in 2012 for the treatment of male erectile dysfunction. For the medicine obtained by the total synthesis method, due to the use of various intermediates and the use of many reaction reagents, when the desired final active pharmaceutical ingredient (API) is obtained, pharmaceutical impurities will be mixed in the API. These impurities can have a significant impact on the effectiveness and safety of the final product. According to the general guidelines on impurities in drug substances recommended by the International Conference on Harmonization (ICH), any impurity greater than 0.10% in the drug substance should b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 袁金桥陈永孙允凯赵梦梦喻芳芳李海龙田娟妮
Owner HARVEST PHARMA HUNAN CO LTD
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