Preparation method of avanafil

A technology of avanafil and compounds, applied in the field of medicinal chemistry, can solve the problems of low reaction yield, many impurities, difficult to remove impurities, etc., and achieve the effect of simple reaction operation

Active Publication Date: 2015-05-27
SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In this route, the price of raw material 4-chloro-2-methylthiopyrimidine-5-carboxylate ethyl ester (III) is more expensive, and oxidizing 4-(3-chloro-4- Methoxybenzylamino)-2-methylthiopyrimidine-5-carboxylate ethyl ester (IV) is prone to impurity that is difficult to remove, and 4-(3-chloro-4-methoxybenzylamino)- The yield of the reaction between ethyl 2-methylsulfonylpyrimidine-5-carboxylate (V) and L-prolinol (VI) is too low
[0008] Because the above-mentioned preparation method has the disadvantages of high cost, low yield, many impurities and difficult separation, it is necessary to find an economical, practical, environmentally friendly, stable, reasonable and feasible new route to improve process stability, reduce costs, and improve product quality. quality

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1 Preparation of ethyl 2,4-dichloro-5-pyrimidinecarboxylate

[0059]

[0060] Into a 100ml three-neck flask, add ethyl uracil-5-carboxylate (2.2g, 11.95mmol) and N,N-dimethylaniline (2g, 16.50mmol). Phosphorus oxychloride (9.2 g, 60 mmol) was gradually added under ice-cooling, and stirred continuously. After the dropwise addition was completed, stir for 10 minutes, gradually raise the temperature to 110° C., and keep the temperature for 3 hours to react. The reaction solution was slowly poured into an ice-water mixture (100ml) to quench, and kept stirring to keep the temperature below 5°C. Extracted twice with ethyl acetate (200ml). The organic phases were combined, washed with saturated brine, dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography to obtain 1.8 g of solid, with a yield of 68%.

[0061] 1 H NMR (DMSO-d 6 ,400MHz): δ9.13(s,1H), 4.37(q,2H), 1.32(t,3H).

Embodiment 2

[0062] Example 2 Preparation of tert-butyl 2,4-dichloro-5-pyrimidinecarboxylate

[0063]

[0064] Into a 100ml three-necked flask, add uracil-5-carboxylate tert-butyl ester (2.5g, 11.95mmol), N,N-dimethylaniline (2g, 16.50mmol). Phosphorus oxychloride (9.2 g, 60 mmol) was gradually added under ice-cooling, and stirred continuously. After the dropwise addition was completed, stir for 10 minutes, gradually raise the temperature to 110° C., and keep the temperature for 3 hours to react. Concentrate to dryness, add saturated sodium bicarbonate solution (100ml), keep the temperature below 5°C. Extracted twice with ethyl acetate (200ml). The organic phases were combined, washed with saturated brine, dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography to obtain 1.9 g of solid, with a yield of 65%.

[0065] 1 H NMR (DMSO-d 6 ,400MHz): δ9.13(s,1H),1.43(s,9H). MS (m / z): 250 (MH + ).

Embodiment 3

[0066] Example 3 Preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-[(S)-2-hydroxymethylpyrrolidinyl-1-]-5-pyrimidinecarboxylate

[0067]

[0068] To a 25ml three-neck flask, add ethyl 2,4-dichloro-5-pyrimidinecarboxylate (150mg, 0.679mmol), triethylamine (270mg, 2.668mmol), dichloromethane (2ml) in sequence, and gradually stir until dissolved , cooled in an ice bath to below 0°C, 3-chloro-4-methoxybenzylamine hydrochloride (145 mg, 0.697 mmol) was added in batches to the reaction solution, and the reaction was kept for two hours after the addition was complete. Then, L-prolinol (105 mg, 1.038 mmol) was added dropwise to the reaction solution, and after the addition was completed, the reaction was continued to stir for 2 hours. The reaction liquid was added to water (30 ml), and extracted with dichloromethane. The organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the organic phase was conce...

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Abstract

The invention relates to a preparation method of avanafil and a new compound provided in a preparation process. According to the method, 5-uracil carboxylic acid or an ester thereof is taken as the raw material, and the avanafil meeting the clinical requirements can be synthesized at a relatively cost; besides, the preparation method is simple and convenient to operate, mild in reaction conditions, high in yield, low in cost, environmentally friendly and suitable for industrial large-scale production of the avanafil.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular, relates to a preparation method of avanafil (avanafil), which is a PDE5 inhibitor, i.e. a type 5 phosphodiesterase inhibitor, and also relates to a new method provided during the preparation process. compound. Background technique [0002] Avanafil (avanafil) is a highly selective phosphodiesterase-5 (PDE-5) inhibitor for the treatment of male erectile dysfunction (ED) developed by Vivus, an American company authorized by Tanabe Mitsubishi Pharmaceutical Co., Ltd. On April 27, 2012, it was approved by the US FDA to go on the market in the United States under the trade name of Stendra. The drug has the same mechanism of action as other PDE-5 inhibitors, but has unique pharmacokinetic and pharmacodynamic properties. Its advantage lies in faster oral absorption, and many ED patients can succeed within 0.5 hours after using this product Having sex, it is equivalent or superior ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14C07D239/557C07D239/30C07D239/42
CPCC07D239/30C07D239/42C07D239/557C07D403/14
Inventor 田广辉李军奇
Owner SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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