Preparation method of sildenafil

A technology for sildenafil and compounds, applied in the field of preparation of sildenafil, can solve problems such as difficult removal of by-products, no relevant reports, unstable intermediates, etc., achieve easy control of reaction conditions, simple and convenient purification process, The effect of low production cost

Active Publication Date: 2012-09-26
HANGZHOU ADAMERCK PHARMLABS INC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in this technology, compounds containing acid chlorides react with ammonium salts to form compounds containing sulfonamides. It is generally believed that it is very difficult for this type of reaction to be successful, and there is no relevant report at present.
[0005] CN101429166 also discloses the method for preparing sildenafil, but the intermediate in this route is unstable, and the chlorine on the pyrimidine ring is easily hydrolyzed, and can react with N-methylpiperazine, and the side reactions are many and the by-products of the reaction are difficult to remove

Method used

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Examples

Experimental program
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Embodiment 1

[0026] Example 1 Synthesis of N-(2-ethoxybenzoyl)succinimide (compound II)

[0027] Add N,N'-dicyclohexylcarbodiimide (DCC) (7.74g, 37.5mmol) and 30ml of dry dioxane solution into the dry reaction flask, and stir to dissolve. 2-Ethoxybenzoic acid (4.99g, 30.0mmol) and N-hydroxysuccinimide (NHS) (3.80g, 33.0mmol) were dissolved in 25ml of dry dioxane, and added dropwise to In the above DCC solution. After the dropwise addition, the reaction was stirred at room temperature for 1 h. After the reaction was completed, 1.0 ml of water was added dropwise to the reaction liquid, and stirring was continued for 1 h. Filtrate, concentrate the filtrate to nearly dryness to obtain a viscous solution, dissolve the viscous solution with 30ml of dichloromethane to obtain solution ①; wash the filtered cake with dichloromethane (10ml×3) to obtain lotion ②. Combine solution ① and lotion ②, wash with saturated brine (20ml×1), and wash with water (20ml×2). The organic phase was dried with anhy...

Embodiment 2

[0030] Example 2 Synthesis of 4-(2-ethoxybenzamide)-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (compound III)

[0031] Add 1-methyl-3-propyl-4-aminopyrazole-5-carboxamide hydrochloride (4.59g, 21.0mmol) hydrochloride into the three-necked flask, add 45ml of dry dichloromethane, and stir 30min. Add 4-dimethylaminopyridine (DMAP) (7.69 g, 63.0 mmol), stir at room temperature for 20 min, and then add compound II (6.90 g, 26.2 mmol). The reaction was stirred at room temperature for 1 h, and heated to reflux for 24 h. After the reaction, the reaction solution was naturally cooled to room temperature, diluted with 15ml of dichloromethane, adjusted to neutrality with 0.5mol / L dilute hydrochloric acid, separated the organic layer, and washed the organic layer with saturated brine (20ml×2), Wash with water (20ml×2). Dry over anhydrous magnesium sulfate, concentrate to near dryness, filter, and wash the filter cake with dichloromethane (6ml×2). The filter cake was vacuum-dried to o...

Embodiment 3

[0035] Example 3 1-methyl-3-n-propyl-5-(2-ethoxyphenyl)-7-methoxy-1,6-dihydro-7H-pyrazolo[4,3-d] Synthesis of Pyrimidine (Compound IV)

[0036]Weigh phosphorus pentachloride (6.04g, 29.0mmol), and add it to 24.0ml of phosphorus oxychloride. Compound III (4.78 g, 14.5 mmol) was added into a dry three-necked flask. Under the protection of nitrogen, add the mixed solution of phosphorus pentachloride and phosphorus oxychloride dropwise under stirring, and the dropping temperature is about 2°C. After dropping, the temperature was raised to 90°C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and added dropwise to crushed ice with stirring, and a yellow solid was formed. Add dichloromethane to extract (40ml×3) the above solid, combine the extracted dichloromethane solution, wash with saturated brine (40ml×4), and dry over anhydrous magnesium sulfate for 2h. Filter, collect the filtrate, and concentrate under reduced pressure at...

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Abstract

The invention provides a preparation method of sildenafil, which comprises the following steps: carrying out condensation reaction on initial raw materials 2-ethoxybenzoic acid and N-hydroxysuccinimide to obtain a compound II, and reacting with 1-methyl-3-propyl-4-aminopyrazolyl-5-formamide hydrochloride to obtain a compound III; after cyclizing and chlorinating the compound III, carrying out nucleophilic substitution reaction with alcohol to obtain a compound IV; reacting the compound IV with chlorosulfonic acid to obtain a compound V; reacting the compound V with N-methylpiperazine to obtain a compound VI; and carrying out hydrolysis reaction to obtain the target compound sildenafil. The invention has the advantages of accessible raw material, stable intermediate, high product yield, low production cost and mild reaction conditions, is simple to operate, and can easily control the reaction conditions of the intermediate; compared with the existing method, the invention has fewer side reactions, and enhances the yield and purity of the product; and the product contains fewer impurities, the purification treatment process is simple and convenient, and thus, the invention has high industrial applicability. The reaction route is as follows.

Description

technical field [0001] The invention belongs to the field of medicine and relates to a preparation method of sildenafil. Background technique [0002] Sildenafil as a medicinal compound is found in the Chinese patent "Preparation method of pyrazolopyrimidinone anti-angina pectoris" (CN1057464), Chinese patent application "Method for preparing siberdone" (Patent No. CN1168376), and Chinese patent application "Method for preparing sildenafil" (Patent Publication No. CN1246478). [0003] CN1057464 discloses the preparation method of sildenafil and its derivatives. Among them, the reaction time for synthesizing sildenafil is four days, and the reaction treatment process is more loaded down with trivial details, and crystallization and purification are needed finally to obtain the product. [0004] The key step for preparing sildenafil in CN1168376 is the final ring-closing reaction. Under proper conditions, the product obtained by the ring-closing reaction does not need furthe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 漆又毛赵玉荣漆莹贝
Owner HANGZHOU ADAMERCK PHARMLABS INC
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