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: 2012-10-10
SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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  • 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

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Embodiment 1

[0034] Compound V (2-methyl-4-nitropyridine-N-oxide) is a commercially available product. The same applies to the following examples.

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

[0036] 15.4g (0.10mol) 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 completion, 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 11.7 g of 4-chloro-2-methyl-pyridine-N- Oxide, the purity determined by HPLC (High Performance Liquid Chromatography, HPLC for short) is 98.7%, the discounted purity is 11.55 g, and the yield is 80.4%.

[0037] (2) Preparation of 4-chloro-2-methylpyridine (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....

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 to the autoclave, heated to 250°C, and reacted for 8 hours. After the completion, adjust the pH to 6-7 with NaOH, extract with chloroform, and distill under reduced pressure to obtain 4-chloro-2-methylpyridine-N-oxide, to obtain 5.8g of 4-chloro-2-methyl-pyridine-N- Oxide (HPLC purity 97.6%), equivalent to 5.66 g, yield 39.4%.

[0052] (2) Preparation of 4-chloro-2-methylpyridine (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-methylpyridine-N-oxide in a three-necked flask, dissolve it in 43ml of dichloromethane, cool to -10°C, and add 10.5ml (0.12 mol) Phosphorus trichloride. The temperature was raised to 40°C for 6 hours. Cool to room temperatur...

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 to the autoclave, heated to 120°C, and reacted for 30 hours. After completion, 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%), equivalent to 4.96 g, yield 34.5%.

[0067] (2) Preparation of 4-chloro-2-methylpyridine (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 a three-necked flask, dissolve it in 129ml carbon tetrachloride, cool to 10℃, and add dropwise within 1 hour 21.0ml (0.24mol) phosphorus trichloride. The temperature was ra...

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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 pharmaceutical and pesticide intermediates, and specifically relates to the preparation of methyl 4-chloro-2-picolinate hydrochloride. Background technique [0002] Methyl 4-chloro-2-picolinate hydrochloride is an important pharmaceutical and pesticide intermediate, specifically related to an important intermediate of sorafenib. [0003] Journal de Pharmacie de Belgique, 35(1), 5-11, 1980 reported a one-step synthesis of 4-chloro-2-picolinic acid methyl ester from 4-chloro-2-picolinic acid and diazomethane, and the yield reached 90%. However, this method is difficult to achieve due to the source of diazomethane raw materials used, and it is difficult to ensure safety, and it has no practical significance in industrial production. [0004] Synthetic Communications, 27(5), 861-870, 1997, WO 2005075425, WO 2005004864, WO2005058832, US 2006189617, WO 2005123680, WO 2007070826, WO 2008030448 reported that DMF was used as...

Claims

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Application Information

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Patent Type & Authority Patents(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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