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Novel method for preparing Sildenafil intermediate 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide

A technology of n-propyl pyrazole 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: 2013-04-17
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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  • Novel method for preparing Sildenafil intermediate 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide
  • Novel method for preparing Sildenafil intermediate 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide
  • Novel method for preparing Sildenafil intermediate 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide

Examples

Experimental program
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Effect test

Embodiment 1

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

[0023] Add 2500ml of dichloromethane and 196.1g of ethyl 1-methyl-3-n-propylpyrazole-5-carboxylate (1.0mol) into a 5000ml three-necked flask equipped with mechanical stirring, and control the reaction temperature below 10°C 239.8g (1.5mol) of liquid bromine was slowly added dropwise under dark conditions, and the dropwise addition was completed in about 1 hour, and the temperature was raised to room temperature for reaction, followed by TLC until the raw material point disappeared. Then slowly add 1000ml of 15% sodium carbonate solution dropwise, stir for 1h after the dropwise addition, let the layers stand, discard the water layer, dry the organic phase with anhydrous sodium sulfate, filter, evaporate the solvent, and wash the residue with ethyl acetate 261.4 g of the product was obtained by recrystallization, with a yield of 95.4%.

Embodiment 2

[0024] Embodiment 2: the preparation of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (I)

[0025] Add 200g of ethyl 4-bromo-1-methyl-3-n-propylpyrazole-5-carboxylate (0.73mol) and 1800ml of concentrated ammonia water into a 3000ml autoclave, close it, start stirring, and heat up to 60°C The reaction was followed by TLC until the raw material spots disappeared. After cooling down 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] Embodiment 3: the preparation of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (I)

[0027] In a 3000ml autoclave, add 200g of 4-bromo-1-methyl-3-n-propylpyrazole-5-ethyl carboxylate (0.73mol), 1800ml of saturated ammonia ethanol solution and 57.7g of pyridine (0.73mol ), airtight, start stirring, heat up to 80°C for reaction, TLC tracking, until the raw material point disappears. After cooling down to room temperature, concentrate under reduced pressure to remove the solvent, dissolve the residue with 1500ml of dichloromethane, wash with 1N hydrochloric acid (600ml×3) and water (500ml×2) respectively, and recrystallize the residue 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, belonging to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Sildenafil, the 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 used clinically, the trade name is Viagra, developed by Pfizer, for the treatment of Erectile dysfunction in men. The chemical structure of sildenafil is shown below: [0003] [0004] The main synthetic route of sildenafil is based on 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 ring closure reaction, chlorosulfonylation and condensation with methylpiperazine. The raw mate...

Claims

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Application Information

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Patent Type & Authority Applications(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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