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Preparation method of 6-bromine-3-hydroxyl-2-pyrazinamide

A technology of pyrazinamide and hydroxyl group is applied in the field of preparation of 6-bromo-3-hydroxy-2-pyrazinamide, and can solve the problems of complex synthesis, high purchase cost, low yield and the like

Active Publication Date: 2015-02-04
SHANDONG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
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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 market purchase cost is very high, the synthesis is relatively complicated, and it needs to use some unstable raw materials or no domestic suppliers. Raw materials are prepared, the process is loaded down with trivial details, and yield is low (referring to Journal of Heterocyclic Chemistry, 16 (1), 193-4; 1979); (2) N, N-dimethylformamide with high boiling point needs to be used for reaction Solvent, it will be difficult to remove when the solvent remains; (3) the total yield is low

Method used

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  • Preparation method of 6-bromine-3-hydroxyl-2-pyrazinamide

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Effect test

Embodiment 1

[0020] (1) Add 458g (3mol, 1eq) of 3-hydroxyl-2-pyrazinecarboxylate methyl ester and 532g (3mol, 1eq) of N-bromosuccinimide successively into 5L of acetonitrile, at 25°C Stir for 12 hours, after TLC detects that the reaction is complete, stop the reaction, filter, and the filter cake is vacuum-dried at normal temperature to obtain 554g of product 6-bromo-3-hydroxyl-2-pyrazinecarboxylic acid methyl ester (including its tautomer 6 -Bromo-3-oxo-3,4-dihydro-2-pyrazinecarboxylic acid methyl ester), the yield was 85%. The nuclear magnetic resonance of 6-bromo-3-hydroxyl-2-pyrazinecarboxylate methyl ester and mass spectrometry detection index are as follows:

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

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

[0023] (2) Dissolve 21g (0.14mol) of 6-bromo-3-hydroxyl-2-pyrazinecarboxylic acid methyl ester in 450mL of tetrahydrofuran, add 257ml of concentrated ammonia (mass fraction 25%) ...

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 for one hour at 27°C, 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-hydroxyl-2-pyrazinecarboxylic acid methyl Esters (including its tautomer methyl 6-bromo-3-oxo-3,4-dihydro-2-pyrazinecarboxylate) in 65% yield. The nuclear magnetic resonance of 6-bromo-3-hydroxyl-2-pyrazinecarboxylate methyl ester and mass spectrometry detection index are as follows:

[0028] 1 H-NMR (CDCl 3 , 600MHz) δ value: 4.09 (3H, s, CH 3 ), 8.53 (1H, s, pyrazine H), 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 6-bromo-3...

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Abstract

The invention belongs to the field of chemical synthesis and particularly relates to a reparation method of 6-bromine-3-hydroxyl-2-pyrazinamide. The method comprises the steps of converting 3-hydroxyl-2-pyrazinecarboxylic acid methyl ester which is taken as an initial material into 6-bromine-3-hydroxyl-2-pyrazinecarboxylic acid methyl ester, and then carrying out ammonolysis, so that the 6-bromine-3-hydroxyl-2-pyrazinamide can be prepared with high yield by simple and convenient operations. The preparation method has the advantages that the 3-hydroxyl-2-pyrazinecarboxylic acid methyl ester which is cheap in price, and convenient to purchase in markets is taken as the initial material, the method is simple and convenient and easy to implement, the selected solvent range is wide, a solvent is easy to remove, the yield is high, and the method can be applicable to 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-hydroxy-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 known at present: (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 market pu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/24
Inventor 张涛张建礼崔美兰刘新泳刘昌铭李宗涛刘文坤王鑫翟海民刘杰于海云
Owner SHANDONG UNIV
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