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Preparation method of 6-bromine-2-pyridine methyl formate

A technology of methyl picolinate and picolinic acid, which is applied in the field of preparation of methyl 6-bromo-2-picolinate, can solve the problems of not being suitable for large-scale industrial production, insufficient product purity, troublesome post-processing, etc. The effect of preparation yield, less process pollution and easy separation

Active Publication Date: 2015-06-17
BEIJING GREENCHEM TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The reaction conditions of this route are easy to control, and the reaction is relatively stable, but the last step of the esterification reaction is catalyzed by concentrated sulfuric acid. Because concentrated sulfuric acid is highly corrosive, there are many side reactions in the esterification reaction process, resulting in very troublesome post-treatment. , the product is not pure enough and extremely difficult to purify, which eventually leads to low yield, high preparation cost, difficult separation and other disadvantages, so it is not suitable for large-scale industrial production

Method used

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  • Preparation method of 6-bromine-2-pyridine methyl formate
  • Preparation method of 6-bromine-2-pyridine methyl formate
  • Preparation method of 6-bromine-2-pyridine methyl formate

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preparation example Construction

[0025] The preparation method of 6-bromo-2-picolinic acid methyl ester provided by the invention comprises:

[0026] Add anhydrous methanol, 6-bromo-2-pyridinecarboxylic acid and p-toluenesulfonic acid into the reaction vessel, wherein the molar ratio of 6-bromo-2-pyridinecarboxylic acid to anhydrous methanol is 1:40-60, 6-bromo-2-pyridinecarboxylic acid - The molar ratio of 2-pyridinecarboxylic acid to p-toluenesulfonic acid is 1:0.06-0.2, preferably 1:0.1-0.16, heated to reflux under stirring for 2-8 hours, preferably refluxed for 4-6 hours, stop heating after the reaction is completed, continue Stir to cool to room temperature.

[0027] After the reaction system is spin-dried, the solid is dissolved in organic solvents such as ethyl acetate, dichloromethane or ether, washed with saturated sodium bicarbonate or sodium carbonate solution, and then washed with water for 2-3 times, and dried with a desiccant such as anhydrous Magnesium sulfate, sodium sulfate, calcium sulfate,...

Embodiment 1

[0041] (1) Preparation of 6-bromo-2-methylpyridine

[0042] Add 46mL of hydrobromic acid with a concentration of 48% and 10.8g of analytically pure 2-amino-6-picoline into the reaction flask, slowly add 6.2mL of liquid bromine dropwise at -10°C, complete the dropwise addition for 0.5h, and react for 1.5h; At -10°C-0°C, 22.8 mL of aqueous sodium nitrite solution with a concentration of 25% by mass was added dropwise. After the dropwise addition was completed, the reaction was carried out at 15°C for 0.5 h; Reacted for 1 h, left to stand and separated, the aqueous phase was extracted 3 times with 200 mL of dichloromethane, the organic phases were combined, washed with water, the organic phase was concentrated, and distilled under reduced pressure to obtain 15.8 g of light yellow liquid with a calculated yield of 92%. The purity of 6-bromo-2-picoline product obtained by phase chromatography is 99.3%.

[0043] (2) Preparation of 6-bromo-2-pyridinecarboxylic acid

[0044] Add 15....

Embodiment 2-5

[0048] Embodiment 2-5 differs from Example 1 in that the molar ratio of p-toluenesulfonic acid and 6-bromo-2-pyridinecarboxylic acid is shown in Table 1 below, and other steps and conditions are the same as in Example 1, and the yield obtained They are listed in Table 1 respectively.

[0049] Table 1

[0050]

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Abstract

The invention relates to a preparation method of 6-bromine-2-pyridine methyl formate. The preparation method comprises the step of catalyzing esterification reaction of 6-bromine-2-pyridine carboxylic acid by taking p-toluenesulfonic acid as a catalyst, to be specific, heating and fluxing absolute methanol, the 6-bromine-2-pyridine carboxylic acid and the p-toluenesulfonic acid for 2-8 hours under stirring, cooling to a room temperature after reaction is ended, rotary drying a reaction system, dissolving solids in an organic solvent, washing, drying, filtering, concentrating, recrystallizing a concentrated product by a mixed solvent to obtain the 6-bromine-2-pyridine methyl formate, wherein a preferable molar ratio of the 6-bromine-2-pyridine carboxylic acid and the p-toluenesulfonic acid is 1: (0.1-0.16). According to one embodiment of the invention, the 6-bromine-2-pyridine carboxylic acid is obtained through diazotization, bromination and oxidation of 6-amino-2-methylpyridine. The preparation method is few in side reaction and simple in aftertreatment and is suitable for industrial production; and the product is easy to separate and has high yield, high purity and good quality.

Description

technical field [0001] The invention relates to a preparation method of methyl 6-bromo-2-picolinate, belonging to the technical field of organic synthesis. Background technique [0002] Methyl 6-bromo-2-pyridinecarboxylate is an important organic intermediate and plays an irreplaceable role in the chemical and pharmaceutical fields. It is an important raw material for the synthesis of 11-beta hydroxysteroid dehydrogenase inhibitors and related compounds for the treatment of diabetes and obesity; it is also an important precursor for the synthesis of chemokine receptors for the treatment of AIDS and other diseases. [0003] It has been reported in the literature that 2,6-dibromopyridine was used as a raw material to obtain the product 6-bromo-2-pyridinecarboxylic acid methyl ester through lithium halogen exchange, addition of lithium compound and carbon dioxide, and esterification. The reaction conditions of this route are easy to control, and the reaction is relatively stab...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/79C07D213/803
Inventor 宫宁瑞
Owner BEIJING GREENCHEM TECH
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