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Novel intermediate used for preparation of avanafil and preparation method thereof

A technology of avanafil and intermediates, which is applied in the field of key intermediates of avanafil, can solve the problems of cumbersome post-processing, etc., and achieve the effect of being beneficial to purification, easy to purify, and reducing the use of column chromatography

Active Publication Date: 2014-09-24
REGENEX PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The present invention aims at the deficiencies in the prior art that require column chromatography purification, cumbersome post-treatment, etc., further researches on the preparation method of avanafil, and invents a method using 4-(3-chloro-4-methoxybenzyl Amino)-2-R base-N-(2-pyrimidinylmethyl)pyrimidine-5-carboxamide is a new route for the preparation of avanafil as the key intermediate. The post-reaction treatment process is simpler and the intermediate is easier to purify. The product has higher purity, is suitable for large-scale industrial production, and has high economic value

Method used

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  • Novel intermediate used for preparation of avanafil and preparation method thereof
  • Novel intermediate used for preparation of avanafil and preparation method thereof
  • Novel intermediate used for preparation of avanafil and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] (1) Preparation of 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (Ⅵ):

[0036]

[0037] Add 15g of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine and 18ml of triethylamine to dissolve in 130ml of tetrahydrofuran respectively, cool down to 0°C, and add 13.5g of 3-chloro-4-methoxy Benzylamine, react at 0-5°C for 30 minutes, then react at 20-30°C, and detect the end point of the reaction by HPLC. The reactant was concentrated under reduced pressure, and 120 ml of ethyl acetate and citric acid aqueous solution were added for washing. The organic phase was washed with water and brine, dried, filtered, and concentrated under reduced pressure to obtain 22 g of crude product. Finally, dissolve the crude product with absolute ethanol at 55-60°C, stir and crystallize overnight, filter, and dry to obtain 15 g of the product. 1 H NMR: 8.78 (t, J =6.0Hz, 1H), 8.55(s, 1H), 7.43(s, 1H), 7.29(d, J =8.4Hz, 1H), 7.10 (d, J =8.4Hz, 1H), 4.62 (d, J =6....

Embodiment 2

[0053] (1) Preparation of 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (Ⅵ):

[0054]

[0055] Add 15g of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine and 18ml of triethylamine to dissolve in 130ml of tetrahydrofuran respectively, cool down to 0°C, and add 13.5g of 3-chloro-4-methoxy in batches Benzylamine, react at 0-5°C for 30 minutes, then react at 20-30°C, and detect the end point of the reaction by HPLC. The reactant was concentrated under reduced pressure, and 120 ml of ethyl acetate and citric acid aqueous solution were added for washing. The organic phase was washed with water and brine, dried, filtered, and concentrated under reduced pressure to obtain 22 g of crude product. Finally, dissolve the crude product with absolute ethanol at 55-60°C, stir and crystallize overnight, filter, and dry to obtain 15 g of the product.

[0056] (2) Preparation of 4-(3-chloro-4-methoxybenzylamino-2-(methylthio)pyrimidine-5-carboxylic acid (VII):

...

Embodiment 3

[0069] (1) Preparation of 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (Ⅵ):

[0070]

[0071] Add 2.32g of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine and 3.06ml of triethylamine to dissolve in 30ml of ethyl acetate respectively, cool down to 0~5℃, add 2.28g of 3-chloro-4 -Methoxybenzylamine, react at 0~5°C for 30min, then react at 20~30°C, and detect the end point of the reaction by HPLC. The reactant was concentrated under reduced pressure, washed by adding 120 ml each of ethyl acetate and citric acid aqueous solution, and the organic phase was washed with water and brine, dried, filtered, and concentrated under reduced pressure to obtain 3.1 g of crude product. Finally, dissolve the crude product with absolute ethanol at 55-60°C, stir and crystallize overnight, filter, and dry to obtain 2.0 g of the product.

[0072] (2) Preparation of 4-(3-chloro-4-methoxybenzylamino-2-(methylthio)pyrimidine-5-carboxylic acid (VII):

[0073]

[007...

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Abstract

The invention provides a novel intermediate IV which is used for preparation of avanafil. The intermediate has a general formula IV as described in the specification; and in the general formula IV, R represents a C1-20 alkylsulfinyl group or a C1-20 alkylsulfonyl group. The intermediate has high purity, is suitable for industrial production and can be subjected to a one-step chemical reaction to prepare avanafil. The invention also provides a preparation method for the intermediate and a method for preparing avanafil from the intermediate.

Description

technical field [0001] The present invention relates to the key intermediate of avanafil, namely 4-(3-chloro-4-methoxybenzylamino)-2-Ryl-N-(2-pyrimidinylmethyl)pyrimidine-5-carboxamide The preparation method and its application in the preparation of avanafil belong to the field of medicinal chemistry. Background technique [0002] Avanafil, the chemical name is ( S )-4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)- 5-pyrimidinecarboxamide, structural formula such as formula V: [0003] [0004] Avanafil is a new drug for the treatment of erectile dysfunction produced by Vivus. It was approved by the FDA on April 27, 2012. It is compatible with Sildenafil (Pfizer), Tadalafil ( Tadalafil (Eli Lilly) and Vardenafil (Vardenafil, Bayer) have the same mechanism of action and are 5-phosphodiesterase (PED-5) inhibitors. Studies have shown that the onset time of the drug is only 15 minutes, far shorter than the 30-60 minutes rep...

Claims

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Application Information

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IPC IPC(8): C07D239/47C07D403/14
CPCC07D239/47C07D403/14
Inventor 陈与华卢平平莫恩青左联卢智俊彭贵子袁永玲
Owner REGENEX PHARMA LTD
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