Preparation method of sildenafil

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

Active Publication Date: 2014-11-05
HANGZHOU ADAMERCK PHARMLABS INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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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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Effect test

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 to the dry reaction flask, stir to dissolve. Dissolve 2-ethoxybenzoic acid (4.99g, 30.0mmol) and N-hydroxysuccinimide (NHS) (3.80g, 33.0mmol) in 25ml of dry dioxane and add dropwise to In the above DCC solution. After the addition was completed, the reaction was stirred at room temperature for 1 h. After the reaction, 1.0 ml of water was added dropwise to the reaction solution, and stirring was continued for 1 hour. After filtering, the filtrate was concentrated to dryness to obtain a viscous liquid. The viscous liquid was dissolved in 30 ml of dichloromethane to obtain solution ①; the filter cake obtained by filtration was washed with dichloromethane (10 ml×3) to obtain washing liquid ②. Combine solution ① and lotion ②, wash with saturated brine (20ml×1), and wash with water (20ml×2). The organic phase ...

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 to a dry three-neck 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 hour, and heated to reflux for 24 hours. After the reaction, the reaction solution was naturally cooled to room temperature, diluted with 15ml of dichloromethane, adjusted to neutral with 0.5mol / L dilute hydrochloric acid, separated the organic layer, and washed with saturated brine (20ml×2), Wash with water (20ml×2). Dry with anhydrous magnesium sulfate, concentrate to near dryness, filter, and wash the filter cake with dichloromethane (6ml×2). The filter cake was vacuum dried to obtain 4.85 g of yel...

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 to a dry three-necked flask. Under the protection of nitrogen, the mixed solution of phosphorus pentachloride and phosphorus oxychloride was added dropwise with stirring, and the temperature was about 2°C. After dripping, the temperature was raised to 90°C and reacted for 4h. After finishing the reaction, the reaction solution was cooled to room temperature and then added dropwise to crushed ice under stirring. A yellow solid was formed. Add dichloromethane to extract (40ml×3) the above solids, combine the extracted dichloromethane solutions, wash with saturated brine (40ml×4), and dry with 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 seen in the Chinese patent "Preparation method of pyrazolopyrimidinone anti-angina pectoris agent" (CN1057464), Chinese patent application "Method for preparing cibolone" (patent number 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 cumbersome, and finally requires crystallization and purification to obtain the product. [0004] The key step for preparing sildenafil in CN1168376 is the final ring-closure reaction. Under appropriate conditions, the product obtained by the ring-closure reaction does not require further purification treatmen...

Claims

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Application Information

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Patent Type & Authority Patents(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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