6-fluorine-3-hydroxy-2-pyrazinamide synthetic method

A synthetic method, the technology of pyrazinamide, applied in the direction of organic chemistry, etc., can solve the problems of long synthetic route steps, high activity of fluorine atoms, low total yield of the process, etc., and achieve simple method, short synthetic route and mild reaction conditions Effect

Active Publication Date: 2016-11-09
SHANDONG BESTCOMM PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0027] The synthesis route of this method is tedious, and the fluorine atom in the intermediate 5-fluoro-isoxazolo[4,5-b]pyrazine-3-carboxylate has high activity and is easily re-hydrolyzed into hydroxyl during the hydrolysis process. The total yield of the process is relatively low

Method used

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  • 6-fluorine-3-hydroxy-2-pyrazinamide synthetic method
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  • 6-fluorine-3-hydroxy-2-pyrazinamide synthetic method

Examples

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Embodiment 1

[0055] Embodiment 1: Preparation of 3,6-dibromo-2-pyrazinecarboxylic acid methyl ester

[0056] In 600ml N,N-dimethylformamide, add 120g (0.52mol) methyl 6-bromo-3-aminopyrazinecarboxylate, 181g copper bromide (0.78mol), stir and mix at room temperature, add 90.87 g (0.78mol) of isoamyl nitrite, after the dropwise addition, the temperature was raised to 65°C for 2-3 hours. After completion of the reaction, cool down to room temperature, add 200ml of water and 1L of ethyl acetate for extraction, separate the layers, wash the organic phase with saturated brine and saturated sodium bicarbonate solution successively, dry, decolorize, and distill under reduced pressure to obtain 150.3g of brown oily liquid. The oil was slurried with petroleum ether to obtain 124 g of off-white solid. Yield: 81.5%. MS:295 [M+H]

[0057] The following table compounds were prepared in the same way:

[0058]

Embodiment 2

[0059] Embodiment 2: Preparation of 3,6-dibromo-2-pyrazinamide

[0060] In 850ml of methanol, add 85g (0.29mol) of methyl 3,6-dibromo-2-pyrazinecarboxylate, add 1.7L of ammonia water, and stir at room temperature for 2 to 3 hours. Filter, rinse the filter cake with methanol, and dry to obtain 75 g of light yellow solid. Yield: 92%. MS:280 [M+H]

[0061] The following table compounds were prepared in the same way:

[0062]

Embodiment 3

[0063] Example 3: Preparation method 1 of 3,6-difluoro-2-pyrazinamide

[0064] In 50ml dimethyl sulfoxide, add 5g (17.8mmol) 3,6-dibromo-2-pyrazinamide, 6.2g (106.8mmol) potassium fluoride, 1.2g (3.56mmol) tetrabutylammonium bromide , heated to 150 ° C for 3 h. The reaction was completed, lowered to room temperature, added 50ml of water and 150ml of ethyl acetate for extraction, separated, the organic phase was washed with saturated brine, dried, decolorized, concentrated under reduced pressure to obtain an oily crude product, and recrystallized with isopropanol to obtain 1.2g of Yellow target product. Yield: 43%. MS:160 [M+H]

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Abstract

The invention relates to a compound 6-fluorine-3-hydroxy-2-pyrazinamide synthetic method. The method comprises the following steps that a compound of a formula (IV) is used for preparing a compound of a formula (III) through amine ester exchange, the compound of the formula (III) is used for preparing a compound of a formula (II) through a fluorization reaction, and reaction equations are specified in the description, wherein the substituent group R is C1-4 alkoxy groups, X and Y are Cl or Br, and substituent groups X and Y can be identical or different. The preparation method for synthesizing a starting material 6-bromine (chlorin)-3-amino pyrazine formic ether is simple and low in cost; the synthetic line is simple and short, the method is simple, and key products can be obtained only through four-step reactions; reaction conditions of each step are mild, strong-corrosion and high-toxicity reagents are prevented from being adopted, and environmental pollution is reduced.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a synthesis method of 6-fluoro-3-hydroxyl-2-pyrazinamide. Background technique [0002] Favipiravir (Favipiravir) is an influenza treatment drug developed by Toyama Chemical Industry Co., Ltd. in Japan. It was approved for manufacturing and sales in Japan in 2014 as a new anti-influenza drug. Its mechanism of action is different from that of many anti-influenza drugs. Drugs such as Tamiflu prevent the aggravation of infection by preventing the proliferating virus from drilling out of the cell, while Favipiravir inhibits the proliferation of the virus itself by hindering gene replication in the cell. Its chemical name is 6-fluoro-3-hydroxy-2-pyrazinamide, and its chemical structure is as follows: [0003] [0004] At present, related patent documents on the synthesis method of favipiravir in the prior art include CN99809897.3, WO2010087117A1, CN201110316778.X, CN...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 张志强甄宜战于阳赵巧丽
Owner SHANDONG BESTCOMM PHARMA CO LTD
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