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New method for preparing sildenafil intermediate 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide

A technology of n-propylpyrazole and formamide, which is applied in the field of pharmaceutical intermediate synthesis, can solve the problems of serious corrosion, a large amount of acid water, environmental protection pressure, etc., and achieves the effects of improving yield, avoiding strong corrosion and easier control of operation process.

Active Publication Date: 2017-09-15
CHANGZHOU YABANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, thionyl chloride is very corrosive to equipment and produces a large amount of acid water, which puts a lot of pressure on environmental protection.

Method used

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  • New method for preparing sildenafil intermediate 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide
  • New method for preparing sildenafil intermediate 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide
  • New method for preparing sildenafil intermediate 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1: Preparation of 4-bromo-1-methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester (III)

[0023] 2500ml of dichloromethane and 196.1g of ethyl 1-methyl-3-n-propylpyrazole-5-carboxylate (1.0mol) were added to a 5000ml there-necked flask equipped with mechanical stirring, and the reaction temperature was controlled below 10°C , 239.8 g (1.5 mol) of liquid bromine was slowly added dropwise under the dark condition, the dropwise addition was completed for about 1 h, the temperature was raised to room temperature and the reaction was followed by TLC until the starting point disappeared. Then 1000ml of 15% sodium carbonate solution was slowly added dropwise, stirred for 1 h after the dropwise addition, left to stand for layers, the aqueous layer was discarded, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was washed with ethyl acetate. After recrystallization, 261.4 g of product was obtained, and the...

Embodiment 2

[0024] Example 2: Preparation of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (I)

[0025] In a 3000ml autoclave, add 200g of 4-bromo-1-methyl-3-n-propylpyrazole-5-ethyl carboxylate (0.73mol) and 1800ml of concentrated ammonia, airtight, open stirring, and be warming up to 60°C The reaction was followed by TLC until the starting point disappeared. After cooling to room temperature, it was concentrated to dryness under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 140.8 g of the product with a yield of 91%.

Embodiment 3

[0026] Example 3: Preparation of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (I)

[0027] In a 3000ml autoclave, add 200g of ethyl 4-bromo-1-methyl-3-n-propylpyrazole-5-carboxylate (0.73mol), 1800ml of saturated ammonia in ethanol and 57.7g of pyridine (0.73mol ), closed, turned on stirring, heated to 80°C for reaction, followed by TLC until the starting point disappeared. After cooling to room temperature, the solvent was evaporated under reduced pressure, the residue was dissolved in 1500ml of dichloromethane, washed with 1N hydrochloric acid (600ml×3) and water (500ml×2) respectively, and the residue was recrystallized with ethyl acetate to obtain the product 135.6g, yield 87.6%.

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Abstract

The invention discloses a novel method for preparing Sildenafil intermediate 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide. According to the method, the 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide is prepared from 1-methyl-3-n-propyl-pyrazole-5-ethyl formate through bromation and ammoniation. The novel method disclosed by the invention is safe, efficient and environment-friendly and is suitable for industrial production.

Description

technical field [0001] The invention relates to a new preparation method of sildenafil intermediate 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide, and belongs to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Sildenafil, chemical name is 1-methyl-3-n-propyl-5-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]- 1,6-Dihydro-7H-pyrazolo[4,2-d]pyrimidin-7-one, its citrate salt is clinically used under the trade name Viagra, developed by Pfizer for the treatment of Male erectile dysfunction. The chemical structure of sildenafil is shown below: [0003] [0004] The main synthetic route of sildenafil is 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (formula I) and 2-ethoxybenzoic acid or 2-ethoxy Benzoyl chloride is used as the starting material, and sildenafil is obtained through condensation reaction, pyrimidinone cyclization reaction, chlorosulfonylation and condensation with methylpiperazine. The raw materials of this...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/38
Inventor 陈再新张明光夏正君王明林林送马堰启吉小龙
Owner CHANGZHOU YABANG PHARMA
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