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Preparation method of 3, 6-dichloropyrazine-2-formonitrile

A technology of pyridazine and toluene, applied in the field of medicine and chemical synthesis

Pending Publication Date: 2021-12-03
NANJING CHEMPION BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The invention provides a method for the preparation of 3,6-dichloropyrazine-2-formonitrile (I) by-product 3-bromo-6-chloropyrazine-2-formyl cyanide (III) and 3 -Chloro-6-bromopyrazine-2-methyl cyanide (IV) more problems, looking for a better process plan to reduce by-products

Method used

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  • Preparation method of 3, 6-dichloropyrazine-2-formonitrile
  • Preparation method of 3, 6-dichloropyrazine-2-formonitrile
  • Preparation method of 3, 6-dichloropyrazine-2-formonitrile

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Embodiment 1

[0031] Embodiment 1: the synthesis of 3,6-dichloropyrazine-2-formonitrile

[0032]

[0033] Compound 3-hydroxyl-6-bromopyrazine-2-amide (10g), lithium chloride (1.94g) and phosphorus oxychloride (28g) were mixed and stirred and heated to 50°C, followed by diisopropylethyl Amine (17.78g) was added to the reaction system, and the system was heated to 80°C and then stirred for 1 hour. Then, the system was cooled to about 30°C, and the system was slowly quenched by adding ice water, followed by filtration. The filter cake was slurried by adding isopropanol (15mL) to obtain the product 3,6-dichloropyrazine-2-carbonitrile (6.6g, pale yellow solid)

Embodiment 2

[0034] Example 2: Synthesis of 3,6-difluoropyrazine-2-carbonitrile

[0035]

[0036] Compound 3,6-dichloropyrazine-2-carbonitrile (10 g) was added into DMF (60 mL), followed by TBAF (catalytic amount) and potassium fluoride (20 g), and the system was heated to 60° C. for 12 hours. After the reaction, the system was cooled to room temperature, quenched by adding water, the aqueous phase was extracted three times with methyl tert-butyl ether (50 mL), and the organic phases were combined. The organic phase was washed with water (50 mL), then dried and concentrated to give 3,6-difluoropyrazine-2-carbonitrile (the crude product was directly carried on to subsequent reactions without further purification)

Embodiment 3

[0037] Example 3: Synthesis of 3-hydroxyl-6-fluoropyridazine-2-cyano

[0038]

[0039] The compound 3,6-difluoropyrazine-2-carbonitrile (crude product, 7g) was added to DMF (30mL), and then the system was cooled in an ice-water bath, and acetic acid (6g) and triethylamine (10g) were added to the reaction system in sequence, After the addition was complete, the system was returned to temperature and stirred overnight. After the reaction, the first was added to ice water, then the pH was adjusted to 3-4, extracted with methyl tert-butyl ether (100 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was then extracted with n-heptyl Slurry with alkane to give: 3-hydroxy-6-fluoropyridazine-2-cyano (6 g brownish yellow solid).

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Abstract

The invention provides a preparation method of a pyrazine compound as shown in a formula (I). According to the invention, 3-hydroxy-6-bromopyrazine-2-amide is taken as a starting material, and brominated impurities are greatly reduced by adding inorganic chloride under the conditions of phosphorus oxychloride and DIEA, so that high-purity 3, 6-dichloropyrazine-2-formonitrile is obtained. The 3, 6-dichloropyrazine-2-formonitrile obtained by the method has the advantages of high purity and low production cost, is suitable for industrial amplification, and is greatly helpful for subsequent production of piravir API.

Description

technical field [0001] The invention relates to a preparation method of pyridazine compounds, belonging to the fields of medicine and chemical synthesis. Background technique [0002] Favipiravir is a compound that shows excellent effects on various viruses, especially influenza viruses, and studies have shown that it has good therapeutic activity on the new coronavirus sars-cov-2. Its structural formula is as follows: [0003] [0004] The main route for the synthesis of Favipiravir is to use 3,6-dichloropyrazine-2-carbonitrile as the starting material, followed by fluorination and subsequent hydrolysis. Therefore, how to obtain the intermediate 3,6-dichloropyrazine-2-carbonitrile with low cost and excellent quality has become a major problem. There are mainly two routes for the synthesis of 3,6-dichloropyrazine-2-carbonitrile currently known, and the routes are as follows. [0005] Route 1: [0006] [0007] Route 2 (CN 102307865B): [0008] [0009] Consider...

Claims

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Application Information

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IPC IPC(8): C07D241/24
CPCC07D241/24A61P31/12A61K31/4965C07D241/10
Inventor 陈剑卞永江李耀强
Owner NANJING CHEMPION BIOTECHNOLOGY CO LTD