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New green synthesis process of sildenafil intermediate compound 4-amino-1-methyl-3-n-propyl pyrazole-5-formamide

A technology of n-propylpyrazole and formamide, which is applied in the field of preparation of drugs for treating male erectile dysfunction and drug intermediates, can solve the problems of unsatisfactory separation and purification, and achieve easier control of reactions, less heat release, The effect of little environmental pollution

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

At the same time, the use of flammable catalysts and explosive hydrogen often brings many safety disadvantages to production.
However, the use of reducing agents such as tin dichloride and sodium borohydride for reduction often requires acid-base destruction at the end of the reaction, which easily produces a large amount of waste residue, and separation and purification are often unsatisfactory.

Method used

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  • New green synthesis process of sildenafil intermediate compound 4-amino-1-methyl-3-n-propyl pyrazole-5-formamide
  • New green synthesis process of sildenafil intermediate compound 4-amino-1-methyl-3-n-propyl pyrazole-5-formamide
  • New green synthesis process of sildenafil intermediate compound 4-amino-1-methyl-3-n-propyl pyrazole-5-formamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Preparation of 4-nitro-1-methyl-3-n-propylpyrazole-5-carboxamide (III)

[0028] Add 16.7 g of 1-methyl-3-n-propylpyrazole-5-carboxamide into 50 mL of dichloromethane, control the temperature below 15° C., and add fuming nitric acid (12 g) dropwise. Stir the reaction at 20-25° C. and track it by TLC until the raw material point disappears. Then the reaction solution was poured into ice water, stirred, separated, the organic phase was washed with water (20mL×2), dried, filtered, and concentrated dichloromethane to dryness to obtain 4-nitro-1-methyl-3-n-propyl Pyrazole-5-carboxamide 19.3g, yield 91%, HPLC purity 95.6%.

Embodiment 2

[0029] Example 2: Preparation of 4-nitro-1-methyl-3-n-propylpyrazole-5-carboxamide (III)

[0030] 16.7g of 1-methyl-3-n-propylpyrazole-5-carboxamide was added to 50mL of dichloromethane, the temperature was controlled below 15°C, 25g of concentrated nitric acid was added dropwise, and after stirring for 40 minutes, the temperature was controlled at 5g of concentrated sulfuric acid was added dropwise below 15°C. Stir the reaction at 20-25° C. and track it by TLC until the raw material point disappears. Then the reaction solution was poured into ice water, stirred, separated, the organic phase was washed with water (20mL×2), dried, filtered, and concentrated dichloromethane to dryness to obtain 4-nitro-1-methyl-3-n-propyl Pyrazole-5-carboxamide 20.1 g, yield 95%, HPLC purity 96.8%.

Embodiment 3

[0031] Embodiment 3: the preparation of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (I)

[0032] 21.2g of 4-nitro-1-methyl-3-n-propylpyrazole-5-carboxamide, [bmim][BF 4 ] 100mL, 13g of zinc particles, 10mL of water and 9.5g of ammonium formate were mixed, stirred rapidly at room temperature, followed by TLC until the raw materials disappeared. Add diethyl ether for extraction (150mL×3), combine the diethyl ether phases, and concentrate to dryness to obtain 16.2 g of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide, with a yield of 89%, HPLC purity was 95.1%.

[0033] The ionic liquid layer was dissolved in 100 mL of dichloromethane, dried by adding anhydrous sodium sulfate, filtered off the desiccant, and concentrated to dryness under reduced pressure to obtain 92 mL of reusable ionic liquid.

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Abstract

The invention discloses a new green process of a medicament for treating male erectile dysfunction, namely a sildenafil citrate key intermediate compound 4-amino-1-methyl-3-n-propyl pyrazole-5-formamide. According to the method provided by the process, the safety is high, the reaction is easy to control, less pollution is caused to the environment, and solvent can be recovered and repeatedly used, thereby lowering the cost, reducing the emission, and ensuring that the process is greener and more environment-friendly.

Description

technical field [0001] The present invention relates to a preparation method of a drug intermediate, more specifically to a drug sildenafil citrate key intermediate 4-amino-1-methyl-3-n-propyl for treating male erectile dysfunction The new green process of pyrazole-5-carboxamide belongs to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Sildenafil citrate was developed by Pfizer Pharmaceuticals of the United States and entered clinical research as a 5-phosphodiesterase inhibitor for the treatment of cardiovascular diseases. In April 1991, the clinical study was declared a failure, but a side effect reported by subjects that resulted in erections caught the attention of researchers. So the researchers launched a study on the effect of sildenafil on the smooth muscle of the cavernous body of the penis, and on March 27, 1998, it was approved by the US Federal Food and Drug Administration for the treatment of male erectile dysfunction...

Claims

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Application Information

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IPC IPC(8): C07D231/38
Inventor 陈再新夏正君张明光王明林林送马堰启吉小龙
Owner CHANGZHOU YABANG PHARMA
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