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Preparation method of 2-trifluoromethyl-3-fluoro-4-picolinic acid and derivatives thereof

A technology of sodium trifluoromethyl sulfinate and picolinic acid, which is applied in the field of medicine and chemical industry, can solve the problems of high price of Meiben reagent, insufficient atom economy, positional selectivity, etc., and achieve high selectivity, high conversion rate, and raw material Easy to get effect

Pending Publication Date: 2020-04-03
AQFLUOROTECH +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, for the trifluoromethyl structure substituted by the ortho position of pyridine, this method needs to introduce a halogen atom first, the operation is more complicated, and it also faces the problem of position selectivity in the process of introducing the halogen atom
In addition, the Meiben reagent used in this method is expensive, and there will be a large number of by-products, and the atom economy is insufficient.

Method used

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  • Preparation method of 2-trifluoromethyl-3-fluoro-4-picolinic acid and derivatives thereof
  • Preparation method of 2-trifluoromethyl-3-fluoro-4-picolinic acid and derivatives thereof
  • Preparation method of 2-trifluoromethyl-3-fluoro-4-picolinic acid and derivatives thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 1. Preparation of methyl 2-trifluoromethyl-3-fluoro-4-pyridinecarboxylate (VI), as shown in Reaction Formula 4.

[0040]

[0041] In a 5L three-necked reaction flask, add 1.25L of dichloromethane, 500mL of water and the compound 3-fluoro-4-pyridinecarboxylic acid methyl ester (250g, 1.0eq) represented by formula (V) and stir evenly, then add 250mL of tert-butanol peroxide and 360 g of sodium trifluoromethylsulfinate (5.0 eq). The mixture was stirred at room temperature for 12 hours and monitored for completion.

[0042] The dichloromethane solvent was carefully removed at room temperature, and the residue was carefully added to crushed ice, stirred evenly, and extracted twice with diethyl ether. After the combined organic phases were washed three times with ice water, the organic phases were dried and concentrated at low temperature, and the obtained product (VI) was directly put into the next reaction.

Embodiment 2

[0044] 1. Preparation of methyl 3-trifluoromethyl-4-pyridinecarboxylate (V), as shown in Reaction Formula 3.

[0045]

[0046] In a 100L reactor, add 20L of methanol and the compound 3-fluoropyridine-4-carboxylic acid (2.0kg, 14.18mol, 1.0eq), stir to dissolve evenly, and then add concentrated sulfuric acid. The mixture was warmed to 70°C and stirred overnight to check for completion.

[0047]After the mixture was brought to room temperature, it was concentrated to remove the solvent, and the concentrated solution was cooled to 0° C. and adjusted to pH=9 with saturated sodium bicarbonate solution. After extraction with ethyl acetate, the combined organic phases were dried, filtered and concentrated to obtain the product as a yellow oil (2.06kg, 94% yield): H NMR (400MHz, CDCl3): δ8.62 (d, J=Hz, 1H), 8.54(d, J=4.8Hz, 1H), 7.77(t, J=4.8Hz, 1H), 3.98(s, 3H); MS-ESI: Theoretical value (M): 155.0; Actual value: 178.1(M+ Na + ).

[0048] 2. Preparation of methyl 2-trifluorome...

Embodiment 3

[0058] 1. Preparation of methyl 2-trifluoromethyl-3-fluoro-4-pyridinecarboxylate (VI), as shown in Reaction Formula 4.

[0059]

[0060] In a 500L reactor, add 120L dichloromethane, 50L water and the compound 3-fluoro-4-pyridinecarboxylic acid methyl ester (25.0kg, 1.0eq) shown in formula (V) and stir evenly, then add 25.0L peroxy tert-butanol and 72 kg sodium trifluoromethylsulfinate (4.0 eq). The mixture was stirred at room temperature for 24 hours and monitored for completion.

[0061] The dichloromethane solvent was carefully removed at zero degrees Celsius, and the residue was carefully added to crushed ice, stirred evenly, and extracted twice with diethyl ether. After the combined organic phases were washed three times with ice water, the organic phases were dried and concentrated at low temperature, and the obtained product (VI) was directly put into the next reaction.

[0062] 2. Preparation of 2-trifluoromethyl-3-fluoro-4-pyridinecarboxylic acid and its derivativ...

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Abstract

The invention discloses a preparation method of 2-trifluoromethyl-3-fluoro-4-picolinic acid and derivatives thereof, and is characterized in that provided is the preparation method of 2-trifluoromethyl-3-fluoro-4-picolinic acid and the derivatives thereof by a method of introducing trifluoromethyl into 2-site of a polysubstituted pyridine ring through a free radical mechanism, wherein the preparation method is suitable for large-scale application. The method for directly carrying out trifluoromethylation reaction on the 2-site of 3-fluoro-4-pyridine carboxylic acid alkyl ester is reported forthe first time, and is simple and convenient in process, easily available in raw materials, high in conversion rate and simple in reaction post-treatment operation. Meanwhile, the selectivity of the method in introducing trifluoromethyl into the 2-site of pyridine is quite high, and a single product with trifluoromethyl substituted at the 2-site can be obtained only through simple recrystallization.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a preparation method of 2-trifluoromethyl-3-fluoro-4-pyridinecarboxylic acid and derivatives thereof. Background technique [0002] In the field of medicinal chemistry, trifluoromethyl group is an important chemical group, because of its high fat solubility, good metabolic stability, high electronegativity and bioavailability, it has a wide range of bioactive molecules. Applications (Tomashenko, O.A.; Grushin, V.V. Chem. Rev. 2011, 111, 4475-4521). As early as 1928, Lehmann et al. published their observations on the biological activities of some simple trifluoromethyl organic compounds. In this document, researchers found that different substituted trifluoromethylbenzenes could cause central nervous system damage. Influence (Lehmann, F., Arch. Exptl. Path. Pharmakol., 130, 250 (1928); C.A., 22, 2993 (1928)). [0003] According to statistics, there are ne...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/79C07D213/803
CPCC07D213/79C07D213/803
Inventor 于峰王忠吴香梅晏飞军卢艺卢寿福
Owner AQFLUOROTECH
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