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Synthesis method of avanafil

A technology of avanafil and synthetic method, which is applied in the field of organic chemical synthesis, can solve the problems of cumbersome operation, high cost, unfavorable industrial production, etc., and achieve the effect of high product purity, low cost and easy operation

Inactive Publication Date: 2014-08-27
HEBEI KANGTAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The above method has many advantages. However, the post-treatment of the oxidation reaction step is cumbersome, time-consuming and labor-intensive, and wastes solvents, which is unfavorable for industrial production.
In the last step, under the action of the dehydrating agent EDC·HCl, the obtained product is an oily substance containing more impurities, which needs to be separated and purified by column chromatography, which has the disadvantages of cumbersome operation, high cost, and unfavorable industrial production

Method used

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  • Synthesis method of avanafil
  • Synthesis method of avanafil
  • Synthesis method of avanafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] A kind of synthetic method of avanafil comprises the steps:

[0035] 1. Synthesis of 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (structure 3)

[0036] At room temperature, in a 50mL round bottom flask, add 3-chloro-p-methoxybenzylamine hydrochloride (0.68g, 3.3mol), N,N-dimethylformamide (4mL), triethylamine (1mL) , 4-Chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (0.66 g, 2.8 mmol). Reaction at room temperature, electromagnetic stirring for 1 hour.

[0037] Crude product purification: add distilled water (15mL) to the crude product, extract with ethyl acetate (20mL×3), collect the organic layer and concentrate to 20mL, then add distilled water to wash (20mL), collect the organic phase, anhydrous Na 2 SO 4 After drying and rotary evaporation under reduced pressure, a white solid was obtained, which was recrystallized from ethyl acetate and petroleum ether, and finally 1.00 g of powdery white crystal was obtained, with a yield of 86% and...

Embodiment 2

[0052] A kind of synthetic method of avanafil comprises the steps:

[0053] 1. Synthesis of 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (structure 3)

[0054] At room temperature, in a 100mL round bottom flask, add 3-chloro-p-methoxybenzylamine hydrochloride (2.00g, 9.70mol), N,N-dimethylformamide (6mL), triethylamine (6mL) , 4-Chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (1.94 g, 8.24 mmol). Reaction at room temperature, electromagnetic stirring for 1 hour.

[0055] Crude product purification: add distilled water (20mL) to the crude product, extract with ethyl acetate (20mL×3), collect the organic layer and concentrate to 20mL, then add distilled water to wash (20mL), collect the organic phase, anhydrous Na 2 SO 4 After drying and rotary evaporation under reduced pressure, a white solid was obtained, which was recrystallized from ethyl acetate and petroleum ether, and finally 2.91 g of powdery white crystals were obtained, with a yield of 85...

Embodiment 3

[0069] A synthetic method of avanafil, comprising the following steps:

[0070] (1) Add 3-chloro-p-methoxybenzylamine hydrochloride, N,N-dimethylformamide, triethylamine, 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine to the container Carry out nucleophilic substitution reaction to obtain 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine, the reaction temperature of the nucleophilic substitution reaction is 0-40 °C, the reaction time is 1-2 hours.

[0071] (2) Add m-CPBA, 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine to obtain 4-(3-chloro-4 -methoxybenzylamino)-5-ethoxycarbonyl-2-methylsulfonylpyrimidine; the reaction temperature of the oxidation reaction is 10-40° C., and the reaction time is 1-3 hours.

[0072] (3) adding triethylamine, 4-(3-chloro-4-methoxybenzyl amino)-5-ethoxycarbonyl-2-methylsulfonyl pyrimidine and L-prolinol carry out nucleophilic reaction to obtain ( S)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxyc...

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Abstract

The invention relates to the field of the organic chemistry synthesis and in particular relates to a synthesis method of avanafil. The method comprises the following steps: carrying out nucleophilic substitution on raw materials which are 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine and 3-chloro-p-methoxy benzyl amine hydrochloride to obtain 4-(3-chloro-4-methoxy benzyl amine hydrochloride)-5-ethoxycarbonyl-2-methylthiopyrimidine, then sequentially carrying out oxidation reaction, nucleophilic reaction with L-prolinol, esterolysis and dehydration synthesis to finally obtain avanafil. The method has the advantages that the used raw materials are cheap and easily available; the cost is low; the operation is simple and convenient; the prepared final product has few impurities and is of a solid state. The final product can be directly re-crystallized to obtain a pure product; the product is high in purity and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of organic chemical synthesis, in particular to a synthesis method of avanafil. Background technique [0002] Avanafil (trade name Stendra, Avanafil), chemical name (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-hydroxymethyl-1-pyrrolidinyl)- N-(2-pyrimidinemethyl)-5-pyrimidinecarboxamide, its structural formula is as follows: [0003] [0004] Avanafil is a phosphodiesterase type Ⅴ (PDE-5) inhibitor, which is a product authorized by Vivus Company of the United States from Mitsubish Tanabe Pharma Corporation of Japan. On April 27, 2012, Vivus was approved by the FDA to market avanafil in the United States for the treatment of male ED (Erectile Dysfunction). At present, the first-line ED treatment drugs in the market are sildenafil, vardenafil and tadalafil, among which sildenafil and vardenafil have inhibitory effect on PDE-5, and also have a certain effect on PDE-6. The inhibitory effect of PDE-6 affects retinal fu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 童瑶李金岭姜申德
Owner HEBEI KANGTAI PHARMA
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