Preparation method of 2-methyl-3-methoxyl-4-chloropyridine

A technology of methoxyl and chloropyridine, which is applied in the field of preparation of 2-methyl-3-methoxy-4-chloropyridine, can solve the problems of high reaction temperature, increased cost, and difficulty in handling, so as to improve the reaction rate , reduced dosage, low cost effect

Inactive Publication Date: 2018-05-01
CHUZHOU UNIV +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the reaction yield is high, the excess phosphorus oxychloride is absorbed by DMF, which increases the cost, and the reaction temperature is high, with Vilsmeier by-products, which is difficult to handle

Method used

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  • Preparation method of 2-methyl-3-methoxyl-4-chloropyridine
  • Preparation method of 2-methyl-3-methoxyl-4-chloropyridine
  • Preparation method of 2-methyl-3-methoxyl-4-chloropyridine

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Experimental program
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Effect test

Embodiment 1

[0026] The preparation method of 2-methyl-3-methoxy-4-chloropyridine, see figure 2 , follow the steps below:

[0027] Step 1, adding 10kg of 2-methyl-3-methoxy-4H-pyridine into 75kg of dichloroethane, heating and dissolving to make the system solution clear;

[0028] Step 2, at 70°C, slowly add 12kg of phosphorus oxychloride to the system of step 1 under stirring, the dropping rate of phosphorus oxychloride is 4kg / h; then keep warm at 85°C for 10h to obtain a reaction solution;

[0029] Step 3: Distill the reaction liquid under reduced pressure at 85°C and 0.095Mpa, recover dichloroethane for later use, pass cooling water to cool the feed liquid after vacuum distillation to 18°C ​​(room temperature), and slowly add it to 45kg of ice water Stir evenly, stir at 40°C for 2 hours for hydrolysis;

[0030] Step 4, cool down the hydrolyzed feed liquid to 10°C, add 35-55kg of ammonia water for neutralization, make the pH of the feed liquid 7-9, pour it into a separatory funnel and ...

Embodiment 2

[0032] The preparation method of 2-methyl-3-methoxyl group-4-chloropyridine specifically carries out according to the following steps:

[0033] Step 1, adding 13kg of 2-methyl-3-methoxy-4H-pyridine into 60kg of dichloroethane, heating and dissolving to make the system solution clear;

[0034] Step 2, at 70°C, slowly add 16kg of phosphorus oxychloride to the system of step 1 under stirring, the dropping rate of phosphorus oxychloride is 3.2kg / h; then keep warm at 83°C for 11h to obtain the reaction solution ;

[0035]Step 3, distill the reaction solution under reduced pressure at 83°C and 0.095Mpa, recover dichloroethane for later use, pass cooling water to cool the feed liquid after vacuum distillation to 20°C, slowly add it to 60kg of ice water and stir evenly, Stir at 35°C for 2h for hydrolysis;

[0036] Step 4, cool down the hydrolyzed feed solution to 5°C, add 35-55kg of ammonia water for neutralization, make the pH of the feed solution 7-9, pour it into a separatory fun...

Embodiment 3

[0038] The preparation method of 2-methyl-3-methoxyl group-4-chloropyridine specifically carries out according to the following steps:

[0039] Step 1, adding 15kg of 2-methyl-3-methoxyl-4H-pyridine into 50kg of dichloroethane, heating and dissolving to make the system solution clear;

[0040] Step 2, at 70°C, slowly add 18kg of phosphorus oxychloride to the system of step 1 under stirring, the dropping rate of phosphorus oxychloride is 3kg / h; then keep it warm at 80°C for 12h to obtain a reaction solution;

[0041] Step 3, distill the reaction solution under reduced pressure at 75°C and 0.095Mpa, recover dichloroethane for later use, pass cooling water to cool down the feed liquid after reduced-pressure distillation to 22°C (room temperature), and slowly add it to 75kg of ice water Stir evenly, stir at 30°C for 2 hours for hydrolysis;

[0042] Step 4, cool down the hydrolyzed feed liquid to 0°C, add 35-55kg of ammonia water for neutralization, make the pH of the feed liquid ...

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Abstract

The invention discloses a preparation method of 2-methyl-3-methoxyl-4-chloropyridine. The preparation method comprises the following steps: adding 10 to 15 kg of 2-methyl-3-methoxyl-4H-pyridine into 50 to 75 kg of dichloroethane, and heating to dissolve the mixture; slowly adding 12 to 18 kg of phosphorus oxychloride into the solution under stirring; then performing heat preservation at 80 to 85 DEG C for 10 to 12 hours; performing reduced pressure distillation to recycle dichloroethane, cooling the material solution obtained by the reduced pressure distillation to 18 to 22 DEG C, and slowly adding the material solution into iced water for uniform stirring for hydrolysis; cooling the hydrolyzed material solution to 0 to 10 DEG C, adding an alkaline solution to adjust the pH of the materialsolution to 7 to 9, pouring the solution into a separating funnel for stewing for 1 to 2 hours, then collecting a lower-layer oily matter, extracting upper-layer liquid with an extractant, putting the extracted liquid into the collected oily matter, adding anhydrous sodium sulfate, performing drying and suction filtration, and performing reduced pressure evaporation to remove the extractant, thusobtaining the 2-methyl-3-methoxyl-4-chloropyridine. The preparation method is mild in reaction condition, convenient in technological operation, safe, reliable, high in product yield and low in cost.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and relates to a preparation method of 2-methyl-3-methoxy-4-chloropyridine. Background technique [0002] Pandoprazole has been widely used in the world in recent years for gastrointestinal diseases caused by Helicobacter pylori, and it is also a kind of proton pump inhibitor drug with better effect. It was developed by Byk GuldenR company in Germany; 2-chloromethyl-3,4- Dimethoxypyridine hydrochloride is one of the two intermediates for the synthesis of pandoprazole, and 2-methyl-3-methoxy-4-chloropyridine is the synthesis of 2-chloromethyl-3,4-dimethoxy An important intermediate of pyridine hydrochloride; [0003] In the prior art, the synthetic method of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride is to use maltol as a starting material, first methylate reaction under alkaline conditions, and then through ammoniation, Chlorination to obtain 2-methyl-3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/65
CPCC07D213/65
Inventor 葛秀涛王永贵王从春耿庆保杨志健陈永旭任淑芝王晓宇
Owner CHUZHOU UNIV
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