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Synthesis method of 1-methyl-3-trifluoromethyl pyrazol

A technology of trifluoromethylpyrazole and a synthetic method, applied in directions such as organic chemistry, can solve the problems of high cost, inability to carry out at room temperature, large proportion of isomers, etc., to achieve improved yield and avoid excessive waste. The effect of liquid generation and reduction of volatilization

Active Publication Date: 2010-09-08
JIANGSU ZHONGDAN PHARMA RES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] (1) The reaction has certain requirements on temperature and cannot be carried out at room temperature;
[0008] (2) Using a large amount of methanol or ethanol as a solvent not only costs too much, but also is difficult to recycle, so in industrial production, it cannot be optimized;
[0009] (3) It needs to be separated from the isomers by vacuum distillation, which increases the complexity of the process
[0010] (4) The proportion of its isomers is too large, and the yield of the product is too low

Method used

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  • Synthesis method of 1-methyl-3-trifluoromethyl pyrazol
  • Synthesis method of 1-methyl-3-trifluoromethyl pyrazol
  • Synthesis method of 1-methyl-3-trifluoromethyl pyrazol

Examples

Experimental program
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Effect test

Embodiment 1

[0049] Add 7.1g of sodium hydroxide and 140mL of water into a 250mL four-neck flask, stir slowly until the solid dissolves, then add 9.9g of methylhydrazine into the flask, cool down to 0°C with an ice bath, and slowly add 30g of Tris Fluoroacetylvinyl ethyl ether, after the dropwise addition, slowly return to room temperature and react for 0.5 hours. During monitoring, use 1N HCl to adjust to PH=4~5, extract with dichloromethane, monitor by GC, ratio of 1-methyl-3-trifluoromethylpyrazole to 1-methyl-5-trifluoromethylpyrazole 13:87 (see attached image 3 ). Post-treatment, the reaction solution was extracted three times with 80 mL of dichloromethane, washed three times with 50 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent and the ethanol generated to obtain 20.85 g of 1-methyl-3-trifluoro Methylpyrazole, colorless liquid. Yield: 77.8%, Purity: 99.3% (GC).

Embodiment 2

[0051] Add 3.55g of sodium hydroxide and 140mL of water into a 250mL four-neck flask, stir slowly until the solid dissolves, then add 9.9g of methylhydrazine into the flask, cool down to 0°C with an ice bath, and slowly add 30g of trihydrazine dropwise at 0°C Fluoroacetylvinyl ethyl ether, after the dropwise addition, slowly return to room temperature and react for 0.5 hours. During monitoring, use 1N HCl to adjust to PH=4~5, extract with dichloromethane, monitor by GC, ratio of 1-methyl-3-trifluoromethylpyrazole to 1-methyl-5-trifluoromethylpyrazole It is 12:88. After treatment, the reaction solution was extracted three times with 80 mL of dichloromethane, washed three times with 50 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent and the ethanol generated to obtain 20.45 g of 1-methyl-3-trifluoro Methylpyrazole, colorless liquid. Yield: 76.4%, Purity: 99.1% (GC).

Embodiment 3

[0053]Add 10.0g of potassium hydroxide and 140mL of water into a 250mL four-neck flask, stir slowly until the solid dissolves, then add 9.9g of methylhydrazine into the flask, cool down to 0°C with an ice bath, and slowly add 30g of Fluoroacetylvinyl ethyl ether, after the dropwise addition, slowly return to room temperature and react for 0.5 hours. During monitoring, use 1N HCl to adjust to PH=4~5, extract with dichloromethane, monitor by GC, ratio of 1-methyl-3-trifluoromethylpyrazole to 1-methyl-5-trifluoromethylpyrazole It is 12:88. Post-treatment, the reaction solution was extracted three times with 80 mL of dichloromethane, washed three times with 50 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent and the ethanol generated to obtain 21.05 g of 1-methyl-3-trifluoro Methylpyrazole, colorless liquid. Yield: 78.6%, Purity: 98.9% (GC).

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Abstract

The invention discloses a synthesis method of 1-methyl-3-trifluoromethyl pyrazol. In the synthesis method, trifluoroacetyl vinyl alkyl ether is used as a main raw material to react with methylhydrazine to generate 1-methyl-3-trifluoromethyl pyrazol in the presence of the action of alkali in a medium solvent, wherein the medium solvent is water, a mixture of water and methanol or a mixture of water and alcohol, and the reaction is carried out at normal temperature. In the invention, the water or the mixture of the methanol or the alcohol with the water is used as a medium, a strong-volatility organic solvent is avoided being used, thereby reducing volatilization and avoiding the generation of excessive waste liquid, and the technological conditions of high temperature, harmful solvents, dangerous operation, special devices, and the like are also avoided. One-pot reaction is adopted in the invention, and the processes of decompression, distillation and purification are not needed. A product with higher purity can be obtained only by extracting the 1-methyl-3-trifluoromethyl pyrazol by using the solvent and then decompressing and concentrating, and the yield is improved.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and specifically relates to a synthesis method of 1-methyl-3-trifluoromethylpyrazole. Background technique [0002] 1-Methyl-3-trifluoromethylpyrazole, CAS number is CAS NO 154471-65-5, it is an important pharmaceutical intermediate, its chemical structure is as follows: [0003] [0004] The preparation of 1-methyl-3-trifluoromethylpyrazole with trifluoroacetylvinyl ether (A) as a substrate has been reported: Pavlik group (J, Heterocyclic chem., 39, 1025, 2002) reported based on Trifluoroacetylvinyl ethyl ether (A) is used as the substrate, with ethanol as the medium solvent, methylhydrazine is added dropwise at room temperature, and the reaction is refluxed. After the reaction, the ethanol is concentrated under reduced pressure, and then under high vacuum (0.1~1.0Torr) Next, 1-methyl-3-trifluoromethylpyrazole is pumped into a cold well to achieve the purpose of separating it from the interm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/12
Inventor 冯亚兵孙海波陈捷刘正季世春
Owner JIANGSU ZHONGDAN PHARMA RES
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