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Synthesis method of 2,6-dichloropyridine [3,4-B] pyrazine

A synthetic method, the technology of dichloropyridine, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of high starting raw material prices, high production costs, and many organic solvents, and achieve low cost, reduced production costs, and conditions mild effect

Inactive Publication Date: 2017-06-13
JIANGSU YUXIANG CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction solvents used in this synthesis reaction route are methanol, absolute ethanol, ethanol-water, etc., using a relatively large amount of organic solvents, and the cost is high
At the same time, a large amount of sulfuric acid and nitric acid are used in the nitrification and rearrangement reactions, resulting in a large amount of waste water; in addition, the price of starting materials is relatively high, resulting in high production costs
Therefore, there are various defects in the existing synthetic methods, or the yield is low, or there are too many organic solvents, resulting in relatively expensive costs.
The existing technical routes need to be improved in terms of environmental friendliness and cost

Method used

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  • Synthesis method of 2,6-dichloropyridine [3,4-B] pyrazine
  • Synthesis method of 2,6-dichloropyridine [3,4-B] pyrazine
  • Synthesis method of 2,6-dichloropyridine [3,4-B] pyrazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 1) In a four-neck flask equipped with mechanical stirring, a reflux condenser, and a thermometer, add 20 grams of substrate, 60 grams of methanol, stir until completely dissolved, slightly lower the temperature, add 20 grams of thionyl chloride dropwise, and stir for 20 minutes. Raise the temperature to 60-70°C and keep it warm for 10 hours. After monitoring the completion of the reaction, lower the temperature, distill off the solvent, post-process the residue, filter, wash, and dry to obtain a total of 21.15 grams of compound 1, calculated as 3-amino-4-pyridinecarboxylic acid , the yield was 96%.

[0044]2) In a four-neck flask equipped with mechanical stirring, a reflux condenser, and a thermometer, 20 grams of compound 1 was dropped into 40 grams of DMF, stirred until completely dissolved, cooled, and 19 grams of N-chlorosuccinimide was added, Stirring was continued for 60 min. Raise the temperature to 20°C, and keep the reaction at 20-30°C for 3 hours. After the c...

Embodiment 2

[0050] 1) In a four-necked flask equipped with mechanical stirring, a reflux condenser, and a thermometer, add 60 grams of methanol to 20 grams of the substrate, stir until completely dissolved, lower the temperature slightly, add 19 grams of oxalyl chloride dropwise, and stir for 20 minutes. Raise the temperature to 90-100°C and keep it warm for 8 hours. After monitoring the completion of the reaction, lower the temperature, distill off the solvent, post-process the residue, filter, wash, and dry to obtain a total of 20.9 grams of compound 1, calculated as 3-amino-4-pyridinecarboxylic acid , the yield was 95%.

[0051] 2) In a four-necked flask equipped with mechanical stirring, reflux condenser, and thermometer, put 20 grams of compound 1 into 40 grams of DMF, stir until completely dissolved, cool down, add 13.2 grams of dichlorohydantoin, and continue stirring for 60 minutes. Raise the temperature to 50°C, and keep the reaction at 50-60°C for 3 hours. After the chlorination...

Embodiment 3

[0057] 1) In a four-neck flask equipped with mechanical stirring, a reflux condenser, and a thermometer, add 20 grams of substrate, 60 grams of methanol, stir until completely dissolved, slightly lower the temperature, add 20 grams of thionyl chloride dropwise, and stir for 20 minutes. Raise the temperature to 0-10°C and keep it warm for 10 hours. After monitoring the completion of the reaction, lower the temperature, distill off the solvent, post-process the residue, filter, wash, and dry to obtain a total of 20.05 grams of compound 1, calculated as 3-amino-4-pyridinecarboxylic acid , the yield was 90.9%.

[0058] 2) In a four-neck flask equipped with mechanical stirring, a reflux condenser, and a thermometer, 20 grams of compound 1 was dropped into 40 grams of DMF, stirred until completely dissolved, cooled, and 19 grams of N-chlorosuccinimide was added, Stirring was continued for 60 min. Raise the temperature to 5°C, keep the reaction at 5-10°C for 3 hours, after the chlor...

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Abstract

The invention discloses a synthesis method of 2,6-dichloropyridine [3,4-B] pyrazine. A target compound is obtained from 3-amino-4-picolinic acid as a main starting material through esterification, chloro, aminolysis, BOC protection, hofmann rearrangement and cyclization. The route of the synthesis method is two steps longer than that of an existing route, but basically comprises amino protection and deprotection; the whole route is unit reaction basically, the operation is simple and the conditions are mild; and the target compound can be obtained through simple treatment; and the whole route is relatively high in yield. Great economic benefits and social benefits are brought for production by employing the route. In a word, the synthesis method has the characteristics of being mild in reaction condition, simple in technological operation, environment-friendly, low in cost and high in yield.

Description

technical field [0001] The invention relates to a chemical synthesis method, in particular to a synthesis method of 2,6-dichloropyridin[3,4-B]pyrazine. Background technique [0002] 2,6-Dichloropyridine[3,4-B]pyrazine is an important intermediate of new drugs for the treatment of autoimmune diseases such as rheumatoid arthritis and lupus erythematosus. Its CAS number is [1379338-74-5], and its molecular formula is as follows shown. [0003] [0004] The compound is a new type of highly selective small molecule inhibitor against the tyrosine kinase Syk (spleen tyrosine kinase) in the B cell receptor signaling pathway, and is mainly used for the treatment of autoimmune diseases such as rheumatoid arthritis and lupus erythematosus. The drug is a new type of highly selective small molecule inhibitor after MabThera, anti-TNFα drug infliximab, adalimumab and etanercept Syk (spleen tyrosine kinase), used for the treatment of rheumatoid arthritis and autoimmune diseases such as...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCY02P20/55C07D471/04
Inventor 李健新张治国黄剑程红伟
Owner JIANGSU YUXIANG CHEM
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