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Preparation process of high-purity 4-chloro-2-pyridinecarboxylate hydrochloride

A technology for the preparation of methyl picolinate and a preparation process, which is applied in the field of preparation of intermediates of medicines and pesticides, can solve the problems of low product purity and inconvenient source of 4-chloropyridine raw materials, and achieve high product yield, easy industrial production, and raw materials Source Rich Effects

Active Publication Date: 2011-04-13
SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Organic Preparations and Procedures International, 29(1), 117-122, 1997, WO 2005012320, US 2005043248, US 2005215488, US 2006148722, WO2 008060568, WO 2008070014 reported using sodium bromide or 2-hydrogen bromide as a catalyst, A process for the one-step synthesis of 4-chloro-2-picolinic acid methyl ester hydrochloride from picolinic acid and thionyl chloride, but this process also has the defect of low purity of the synthesized product
[0006] Chinese Invention Patent Application Publication Specification CN101302193 discloses a method for preparing 4-chloro-2-pyridinecarboxylic acid methyl ester hydrochloride from 4-chloropyridine. The shortcoming of this method is that the raw material source of 4-chloropyridine is inconvenient

Method used

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  • Preparation process of high-purity 4-chloro-2-pyridinecarboxylate hydrochloride
  • Preparation process of high-purity 4-chloro-2-pyridinecarboxylate hydrochloride

Examples

Experimental program
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Embodiment 1

[0034] Compound V (2-methyl-4-nitropyridine-N-oxide), commercially available, the following examples are the same.

[0035] (1) Preparation of 4-chloro-2-methyl-pyridine-N-oxide (compound IV)

[0036] 15.4g (0.10mol) of 2-methyl-4-nitropyridine-N-oxide (compound V) (and 180ml of concentrated hydrochloric acid were added to the autoclave, heated to 180°C, and reacted for 24 hours. After the end, use NaOH Adjust the pH to 6-7, extract with chloroform, and distill under reduced pressure to obtain 4-chloro-2-methylpyridine-N-oxide (compound IV) to obtain 11.7g 4-chloro-2-methyl-pyridine-N- Oxides, HPLC (high performance liquid chromatography, High Performance Liquid Chromatography, referred to as HPLC) measured purity 98.7%, reduced pure 11.55g, yield 80.4%.

[0037] (2) Preparation of 4-chloro-2-picoline (compound III)

[0038] Mass / volume ratio compound VI: organic solvent = 1: 6.96

[0039] Molar ratio compound VI: phosphorus trichloride=1:2.13

[0040] Add 11.5g (0.08mol) ...

Embodiment 2

[0050] (1) Preparation of 4-chloro-2-methyl-pyridine-N-oxide (compound IV)

[0051] 15.4g (0.10mol) of 2-methyl-4-nitropyridine-N-oxide (compound V) and 180ml of concentrated hydrochloric acid were added into the autoclave, heated to 250°C, and reacted for 8 hours. After the end, adjust the pH to 6-7 with NaOH, extract with chloroform, and distill under reduced pressure to obtain 4-chloro-2-methylpyridine-N-oxide, and obtain 5.8g of 4-chloro-2-methyl-pyridine-N- Oxide (HPLC purity 97.6%), pure 5.66g, yield 39.4%.

[0052] (2) Preparation of 4-chloro-2-picoline (compound III)

[0053] Mass / volume ratio: compound VI: organic solvent = 1: 3.74

[0054] Molar ratio compound VI: phosphorus trichloride=1:1.5

[0055] Add 11.5g (0.08mol) 4-chloro-2-picoline-N-oxide into the three-necked flask, dissolve it in 43ml of dichloromethane, cool down to -10°C, add 10.5ml (0.12 mol) phosphorus trichloride. The temperature was raised to 40° C. for 6 hours. Cool down to room temperature, ...

Embodiment 3

[0065] (1) Preparation of 4-chloro-2-methyl-pyridine-N-oxide (compound IV)

[0066] 15.4g (0.10mol) of 2-methyl-4-nitropyridine-N-oxide (compound V) and 180ml of concentrated hydrochloric acid were added into the autoclave, heated to 120°C, and reacted for 30 hours. After the end, adjust the pH to 6-7 with NaOH, extract with chloroform, and distill under reduced pressure to obtain 4-chloro-2-methylpyridine-N-oxide (compound IV) to obtain 5.0 g of 4-chloro-2-methyl -Pyridine-N-oxide (HPLC purity 99.1%), pure 4.96g, yield 34.5%.

[0067] (2) Preparation of 4-chloro-2-picoline (compound III)

[0068] Mass / volume ratio: compound VI: organic solvent = 1: 11.22

[0069] Molar ratio compound VI: phosphorus trichloride=1:3

[0070] Add 11.5g (0.08mol) 4-chloro-2-methylpyridine-N-oxide (compound IV) into the three-necked flask, dissolve it in 129ml carbon tetrachloride, cool down to 10°C, add dropwise within 1 hour 21.0ml (0.24mol) phosphorus trichloride. Raise the temperature to ...

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Abstract

The invention relates to a preparation process of high-purity 4-chloro-2-pyridinecarboxylate hydrochloride, which comprises the following steps of reacting 2-methyl-4-nitropyridine-N-oxide taken as a starting raw material with hydrochloric acid to obtain 4-chloro-2-methyl-pyridine-N-oxide; then dripping phosphorus trichloride into an organic solvent, carrying out reaction for generating 4-chloro-2-methylpyridine, further adding potassium permanganate into water for carrying out oxidation reaction, thus obtaining 4-chloro-2-picolinate; and mixing the 4-chloro-2-picolinate with the catalytic amount of DMF (dimethyfumarate), dripping thionyl chloride, and finally carrying out esterification reaction with methanol so as to obtain the 4-chloro-2-pyridinecarboxylate hydrochloride. The total yield can be up to 36.8%, and the purity can be 99.8% according to the HPLC (high performance liquid chromatography) detection. The process has the advantages of being rich in raw material resources, small in whole process pollution, conductive to controlling three wastes and easy for realizing industrial production.

Description

technical field [0001] The invention belongs to the preparation of medicine and pesticide intermediates, in particular to the preparation of 4-chloro-2-pyridinecarboxylic acid methyl ester hydrochloride. Background technique [0002] 4-Chloro-2-pyridinecarboxylic acid methyl ester hydrochloride is an important medicine and pesticide intermediate, and specifically relates to an important intermediate of sorafenib. [0003] Journal de Pharmacie de Belgique, 35 (1), 5-11, 1980 reported the method for the one-step synthesis of 4-chloro-2-pyridinecarboxylic acid methyl ester by 4-chloro-2-pyridinecarboxylic acid and diazomethane, and yield reached 90%. But this method is difficult to realize because of the diazomethane raw material source used, safety is difficult to guarantee, and has no practical significance in industrialized production. [0004] Synthetic Communications, 27(5), 861-870, 1997, WO 2005075425, WO 2005004864, WO2005058832, US 2006189617, WO 2005123680, WO 20070...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/803
Inventor 李湛江赵叶青刘刚徐立臣刘承平孙艳丽
Owner SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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