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A preparing method of 6-bromo-3-hydroxy-2-pyrazinamide

A technology of pyrazinamide and hydroxyl, which is applied in the field of preparation of 6-bromo-3-hydroxy-2-pyrazinamide, can solve the problems of low total yield, difficult removal of solvent, cumbersome process, etc., and achieve convenient market procurement, The effect of a wide range of solvents and low prices

Inactive Publication Date: 2016-07-06
QINGDAO HUANGDAO HOSPITAL OF TRADITIONAL CHINESE MEDICINE
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Problems solved by technology

[0004] However, these known preparation methods have the following disadvantages: (1) the intermediate 3-hydroxyl-2-pyrazinamide has a high market purchase cost, and the synthesis is relatively complicated, requiring the use of some unstable raw materials or those without domestic suppliers. raw materials, the process is cumbersome, and the yield is low (see Journal of Heterocyclic Chemistry, 16(1), 193-4; 1979); (2) the reaction needs to use N,N-dimethylformamide with a high boiling point as a solvent, and the solvent It will be difficult to remove when remaining; (3) the total yield is low

Method used

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  • A preparing method of 6-bromo-3-hydroxy-2-pyrazinamide

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Effect test

Embodiment 1

[0020] (1) Add 458g (3mol, 1eq) of methyl 3-hydroxy-2-pyrazinecarboxylate and 532g (3mol, 1eq) of N-bromosuccinimide to 5L of acetonitrile in sequence, at 25°C Stir for 12 hours, after the TLC detection reaction is complete, stop the reaction, filter, filter cake room temperature vacuum drying, obtain the product 6-bromo-3-hydroxyl-2-pyrazinecarboxylic acid methyl ester of 554g (comprising its tautomer 6 -Bromo-3-oxo-3,4-dihydro-2-pyrazinecarboxylate) with a yield of 85%. 6-Bromo-3-hydroxyl-2-pyrazinecarboxylate Methyl NMR and mass spectrometry indicators are as follows:

[0021] 1 H-NMR (CDCl 3 ,600MHz) δ value: 4.09 (3H,s,CH 3 ),8.53(1H,s,pyrazineH)

[0022] MS(ESI)m / z:233.1[M+H] + ,235.2[M+2+H] +

[0023] (2) Dissolve 21g (0.14mol) of methyl 6-bromo-3-hydroxy-2-pyrazinecarboxylate in 450mL of tetrahydrofuran, add 257ml of concentrated ammonia water (mass fraction 25%) under stirring, at 25°C After 7 hours of reaction, TLC detected that the reaction was complete, and...

Embodiment 2

[0027] (1) Add 308g (2mol, 1eq) of methyl 3-hydroxy-2-pyrazinecarboxylate and 956g (6mol, 3eq) of liquid bromine into 4L of acetonitrile, stir at 27°C for one hour, and TLC detects that the reaction is complete , the reaction solution was poured into 4L of water, the excess liquid bromine was removed with a saturated aqueous solution of sodium sulfite, left to filter, and the filter cake was vacuum-dried at room temperature to obtain 300 g of the product 6-bromo-3-hydroxy-2-pyrazinecarboxylic acid methyl Esters (including its tautomer 6-bromo-3-oxo-3,4-dihydro-2-pyrazinecarboxylate methyl ester) in a yield of 65%. 6-Bromo-3-hydroxyl-2-pyrazinecarboxylate Methyl NMR and mass spectrometry indicators are as follows:

[0028] 1 H-NMR (CDCl 3 ,600MHz) δ value: 4.09 (3H,s,CH 3 ),8.53(1H,s,pyrazineH),11.45(1H,s,OH)

[0029] MS(ESI)m / z:233.1[M+H] + ,235.2[M+2H] (2+) ,255.1[M+Na] +

[0030] (2) Dissolve 10g (0.04mol) of methyl 6-bromo-3-hydroxy-2-pyrazinecarboxylate in 200mL of...

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Abstract

The invention belongs to the field of chemical synthesis and particularly relates to a preparing method of 6-bromo-3-hydroxy-2-pyrazinamide. The method adopts methyl 3-hydroxy-2-pyrazinecarboxylate as an initial raw material and includes converting the raw material into methyl 6-bromo-3-hydroxy-2-pyrazinecarboxylate, and performing aminolysis, so that the 6-bromo-3-hydroxy-2-pyrazinamide is prepared with a high yield through simple and convenient operation. The method is advantageous in that the methyl 3-hydroxy-2-pyrazinecarboxylate which is low in price and convenient to purchase in the market is adopted as the initial raw material, the preparing method is simple, convenient and feasible, adopted solvents are wide in range and easily removable, the yield is high, and the method can be used for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a preparation method of 6-bromo-3-hydroxyl-2-pyrazinamide. Background technique [0002] 6-fluoro-3-hydroxyl-2-pyrazinamide is a compound used for preventing and treating viral infectious diseases, especially influenza virus infectious diseases. It is currently known to prepare 6-fluoro-3-hydroxy-2-pyrazinamide from 6-bromo-3-hydroxy-2-pyrazinamide. [0003] For the preparation method of 6-bromo-3-hydroxyl-2-pyrazinamide, the following methods are currently known: (1) patent document JP2010077089A discloses a method using 3-hydroxyl-2-pyrazinamide and tribromo-n-butyl method of ammonium reaction. (2) Patent document JP2010077082A discloses a method using 3-hydroxy-2-pyrazinamide and 1,3-dibromo-5,5-dimethylhydantoin reaction. [0004] However, these known preparation methods have the following disadvantages: (1) the intermediate 3-hydroxyl-2-pyrazinamide has a hig...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/24
Inventor 卢彦敏
Owner QINGDAO HUANGDAO HOSPITAL OF TRADITIONAL CHINESE MEDICINE
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