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Synthesizing method of 2-trifluoromethyl-3-fluoropyridin

A technology of trifluoromethylation and synthesis method, which is applied in the field of synthesis of 2-trifluoromethyl-3-fluoropyridine, can solve the problems of trifluoromethylation reagent toxicity, complex reaction, expensive, etc., and achieve low cost of raw materials , simple and easy to operate, and the effect of low production equipment requirements

Active Publication Date: 2013-03-20
HANGZHOU ALLSINO CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In order to solve the problems that the trifluoromethylation reagent is highly toxic or expensive, the reaction is complicated, and the conversion rate is low in the synthesis reaction of trifluoromethylation similar compounds, the invention provides a 2-trifluoromethyl-3-fluoro The synthetic method of pyridine, the raw material cost of this method is low, easy to obtain, post-treatment is simple and convenient, suitable for small-scale preparation in the laboratory and suitable for large-scale industrial production

Method used

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  • Synthesizing method of 2-trifluoromethyl-3-fluoropyridin

Examples

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Effect test

Embodiment 1

[0020] (1) Dissolve ethyl 2-trifluoromethylnicotinate (47.5 g, 0.217 mol) in 475 mL of methanol, add 85% hydrazine hydrate (128 g, 2.17 mol) and heat to 65°C, keep the reaction for 10 hours Afterwards, the reaction solution was concentrated to dryness (desolvation) to obtain 42 g of 2-trifluoromethylnicotinic acid hydrazide, with a yield of 94%.

[0021] 2-Trifluoromethylnicotinic acid hydrazide (42 g, 0.2 mol) was dissolved in 210 mL of 2 N HCl aqueous solution, and the reaction solution was cooled to -5°C. Slowly add sodium nitrite aqueous solution (16.87 g, 0.244 mol) dropwise to the reaction solution, keep the temperature of the reaction solution at -5°C, and keep it warm for 1 hour, then filter the reaction solution, and rinse the filter cake with 50 mL of water to obtain a white solid. For the intermediate, put the white solid into 450 mL of acetic acid aqueous solution (acetic acid: water = 1:1 (volume ratio)) to dissolve, heat to 90°C, and keep the reaction for 4 hours...

Embodiment 2

[0025] (1) Dissolve ethyl 2-trifluoromethylnicotinate (2.19 g, 10 mmol) in 22 mL of methanol, add ammonium chloride (0.53 g, 10 mmol) and 15 mL of 25% ammonia water (150 mmol) and tetrabutylammonium bromide (0.32 g, 1 mmol). The reaction solution was heated to 65~70°C for reflux reaction. After reflux reaction for 24 hours, the reaction solution was concentrated (precipitated) to obtain a crude product, which was then rinsed with 2 mL of water and methanol to obtain 0.95 g of 2-trifluoromethylnicotinamide. The yield was 50%.

[0026] Dissolve 9.8 g (240 mmol) of sodium hydroxide in 104 mL of water, cool down to 0°C and add 12.5 g (78 mmol) of liquid bromine, stir for 10 minutes and then dissolve 2-trifluoromethylnicotinamide (12.16 g, 64 mmol ) was added to the above reaction solution at one time, after stirring at 0°C for 15 minutes, the temperature of the reaction solution was raised to 75°C, and the reaction was kept for 90 minutes, then the reaction was cooled to room tem...

Embodiment 3

[0030] (1) Dissolve ethyl 2-trifluoromethylnicotinate (21.9 g, 0.1 mol) in 219 mL of tetrahydrofuran, add 80% hydrazine hydrate (50.1 g, 0.8 mol) and heat to 70°C, keep the reaction for 24 hours . After the reaction was completed, the reaction solution was concentrated to dryness (desolvation) to obtain 18.2 g of 2-trifluoromethylnicotinic acid hydrazide, with a yield of 88.7%.

[0031] Put 2-trifluoromethyl nicotinic acid hydrazide (18.2 g, 88.7 mmol) into 91 mL of 1 N HCl aqueous solution to dissolve, then cool the reaction solution to 0 °C, and slowly add sodium nitrite aqueous solution (6.12 g, 88.7 mmol), keep the temperature of the reaction solution at 0°C, keep the temperature for 2 hours, filter the reaction solution, rinse the filter cake with 20 mL of water to obtain a white solid intermediate, put the white solid into 200 mL volume concentration of 40 % of acetic acid aqueous solution, and heated to 100 ° C, heat preservation reaction for 6 hours. The reaction sol...

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Abstract

The invention relates to the field of medicine and chemical industry. Aims at solving problems of high trifluoromethylation reagent toxicity, or high cost, complicated reaction, and low conversion rate existing in synthesizing reactions of trifluoromethylation similar compounds, the invention provides a synthesizing method of 2-trifluoromethyl-3-fluoropyridin. The method comprises the steps that: (2) with 2-trifluoromethyl ethyl nicotinate as a raw material, 2-trifluoromethyl-3-aminopyridine is produced through a reaction; and (2) the product obtained in the step (1) is subjected to a reaction with fluoboric acid, such that 2-trifluoromethyl-3-fluoropyridin is obtained. According to the invention, the raw materials have low cost, and are easy to obtain. Also, post treatment is simple. The method is suitable for laboratory small-scale preparation, and is suitable for large-scale industrialized production.

Description

Technical field: [0001] The invention relates to the field of medicine and chemical industry, in particular to a synthesis method of 2-trifluoromethyl-3-fluoropyridine. Background technique: [0002] Because fluorine-containing heterocyclic compounds have a wide range of physiological activities and broad application prospects, the synthesis methods and medicinal properties of these compounds have always been paid attention to, and the research on the synthesis methodology of fluorine-containing heterocyclic compounds has always been the focus of organic fluorine. One of the research directions of chemistry. 2-Trifluoromethyl-3-fluoropyridine is an important intermediate that can be used to produce high value-added fine chemical products. It has broad prospects in the pharmaceutical, pesticide and chemical industries, and has a huge market potential (see WO2011112662, WO2010102778, WO2012068450, WO2007046809, US2007093498, etc.). But for the synthesis of 2-trifluoromethyl-...

Claims

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Application Information

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IPC IPC(8): C07D213/61
Inventor 闻建明章中平徐国庆
Owner HANGZHOU ALLSINO CHEM
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