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A kind of preparation method of 2-chloromethyl-3-trifluoromethylpyridine

A technology of trifluoromethylpyridine and chloromethyl, which is applied in the field of preparation of 2-chloromethyl-3-trifluoromethylpyridine, can solve the problems of cumbersome operation, low total yield and many steps, and achieve the reaction The effect of controllable process, short synthetic route and mild reaction process

Active Publication Date: 2022-03-08
江苏美迪克化学品有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] There are only a small number of literature reports on the synthesis process of 2-chloromethyl-3-trifluoromethylpyridine, for example: using 2-methyl-3-trifluoromethylpyridine as raw material through nitrogen oxidation, hydroxylation and chlorination reactions Generate the final 2-chloromethyl-3-trifluoromethylpyridine (PCT Int.Appl., 2008144266). The process route of this method is relatively stable, but there are many steps, low overall yield, cumbersome operation and high cost;

Method used

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  • A kind of preparation method of 2-chloromethyl-3-trifluoromethylpyridine
  • A kind of preparation method of 2-chloromethyl-3-trifluoromethylpyridine
  • A kind of preparation method of 2-chloromethyl-3-trifluoromethylpyridine

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Embodiment 1

[0023] Example 1 Preparation of 2-chloromethyl-3-trifluoromethylpyridine

[0024] N-chlorosuccinimide 10mmol (1.33g), azobisisobutyronitrile (AIBN) 0.1mmol (16mg), 2-methyl-3-trifluoromethylpyridine 30mmol (4.83g), N- 1 mmol (163 mg) of hydroxysuccinimide was dissolved in 40 mL of acetonitrile, and stirred at room temperature for 5 min. Then the temperature was raised to 80°C to continue the reaction for 4h. After the reaction was completed, the acetonitrile was removed by rotary evaporation, and the final 2-chloromethyl-3-fluoromethylpyridine was purified by silica gel column chromatography, 4.23g, with a yield of 72% and a purity of 96.6%. Measured: 1 HNMR (500MHz, CDCl 3 )δ: 4.79 (s, 2H), 7.37-7.40 (m, 1H), 7.96 (d, J=7.9Hz, 1H), 8.80 (d, J=4.5Hz, 1H).

Embodiment 2

[0025] Example 2 Preparation of 2-chloromethyl-3-trifluoromethylpyridine

[0026] N-chlorosuccinimide 10mmol (1.33g), azobisisobutyronitrile (AIBN) 0.1mmol (16mg), 2-methyl-3-trifluoromethylpyridine 30mmol (4.83g), N- 1 mmol (163 mg) of hydroxysuccinimide was dissolved in 40 mL of dichloromethane, and stirred at room temperature for 5 min. Then the temperature was raised to 50°C to continue the reaction for 4h. After the reaction was completed, dichloromethane was removed by rotary evaporation, and the final 2-chloromethyl-3-fluoromethylpyridine was obtained by silica gel column chromatography purification, 2.82g, with a yield of 48% and a purity of 95.8%.

Embodiment 3

[0027] Example 3 Preparation of 2-chloromethyl-3-trifluoromethylpyridine

[0028] N-chloroisoindole-1,3-dione 10mmol (1.33g), azobisisobutyronitrile (AIBN) 0.1mmol (16mg), 2-methyl-3-trifluoromethylpyridine 30mmol (4.83g ), N-hydroxysuccinimide 1mmol (163mg) was dissolved in 40mL dichloroethane, stirred at room temperature for 5min. Then the temperature was raised to 80°C to continue the reaction for 4h. After the reaction was completed, acetonitrile was removed by rotary evaporation, and the final 2-chloromethyl-3-fluoromethylpyridine was obtained by silica gel column chromatography purification, 4.40 g, with a yield of 75% and a purity of 97.0%.

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Abstract

The invention discloses a preparation method of 2-chloromethyl-3-trifluoromethylpyridine, comprising the following steps: making an electrophilic chlorination reagent, 2-methyl-3-trifluoromethylpyridine, free radicals The nitroxide radical precursor reacts in an organic solvent to generate 2-chloromethyl-3-trifluoromethylpyridine; wherein the nitroxide radical precursor is selected from N-hydroxysuccinimide, N- A combination of one or more of hydroxyisoindole-1,3-dione and 1-hydroxy-benzotriazole; the method not only has a short reaction route, but also has good selectivity, mild reaction conditions, and short reaction time Short, easy to implement, and conducive to industrialized mass production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of 2-chloromethyl-3-trifluoromethylpyridine. Background technique [0002] 2-Chloromethyl-3-trifluoromethylpyridine is an important pharmaceutical intermediate, which is an important raw material for the synthesis of C5a receptor modulators, the receptor (C5a anaphylatoxin chemotactic receptor 1, also known as CD88) plays a key role in the innate immune response (PCT Int.Appl., 2019141808), and can also be used to synthesize ion channel regulators (PCT Int.Appl., 2013006485, PCT Int.Appl., 2010045251), It can also be used to synthesize hNaV1.7 blockers (Medicinal Chemistry Research, 2013, 22, 1825) and psychotropic drugs (PCT Int. Appl., 2015012400), etc. [0003] There are only a small number of literature reports on the synthesis process of 2-chloromethyl-3-trifluoromethylpyridine, for example: using 2-methyl-3-trifluoromethylpyridine as raw ma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/26
CPCC07D213/26
Inventor 杨盟徐肖洁景亚婷陆国刚
Owner 江苏美迪克化学品有限公司