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Preparation method of 6-fluoro-3-hydroxy-2-pyrazinamide

The technology of pyrazinamide and hydroxyl group is applied in the field of preparation of 6-fluoro-3-hydroxy-2-pyrazinamide, which can solve the problems of low yield of multi-step reaction, complicated operation steps, harsh reaction conditions, etc. The effect of easy control of conditions, high yield and mild process conditions

Active Publication Date: 2012-11-14
SHANDONG QIDU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] 1. The process route is long and the operation steps are cumbersome,
[0009] 2. The yield of multi-step reaction is low, such as the introduction of methoxy in diazotization, and the two-step reaction yield of methyl protecting group demethoxy is 35% and 15% respectively
[0010] 3. The reaction conditions are very harsh, requiring absolute anhydrous solvents and reagents, and some reactions are based on reversed-phase chromatographic column separation

Method used

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  • Preparation method of 6-fluoro-3-hydroxy-2-pyrazinamide
  • Preparation method of 6-fluoro-3-hydroxy-2-pyrazinamide

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Experimental program
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Effect test

Embodiment 1

[0073] CDCl 3 : deuterated chloroform

Embodiment 1－1

[0075]

[0076] Under nitrogen protection, 14g (100.7mmol, 1.0eq) of [1] was dissolved in 300ml of 1M hydrochloric acid, and 8.3g (200.8mmol, 1.2eq) of NaNO was added under stirring. 2 , stirred in an ice bath for 3 h, TLC detected that the reaction was complete, and the reaction was stopped. Then the reaction solution was poured into 5 times the volume of water to precipitate a solid, filtered, and the filter cake was vacuum-dried at room temperature to obtain 12.7 g of [2] with a yield of 90%. 1 H-NMR (CDCl 3 ,400MHz) δ value: 8.50(1H,d,pyrazine H,J=12Hz),8.53(1H,d,pyrazine H,J=12Hz),11.45(1H,s,OH),11.53(1H,s,COOH ).

Embodiment 1－2

[0078]

[0079] Under the protection of nitrogen, 12.7g (90.7mmol) of [2] was dissolved in 150ml of anhydrous methanol, and concentrated sulfuric acid (15ml) was added dropwise with stirring, and the reaction system was stirred at 40°C for 5h. TLC detected that the reaction was complete and stopped. reaction. Finally, 8 times the volume of water / ethyl acetate (5 / 3) was added, stirred for 5 min, separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to obtain 12.8 g of [3]. The yield was 92%. 1 H-NMR (CDCl 3 ,400MHz) δ value: 4.09 (3H,s,CH 3 ), 8.50 (1H, d, pyrazine H, J=12Hz), 8.53 (1H, d, pyrazine H, J=12Hz), 11.44 (1H, s, OH).

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Abstract

The invention relates to a preparation method of 6-fluoro-3-hydroxy-2-pyrazinamide, which is characterized by comprising the following steps: by using methyl 3-amino-2-pyrazinecarboxylate as the initial raw material, hydroxylating, esterifying, aminating, nitrifying, reducing and fluorizing to obtain the 6-fluoro-3-hydroxy-2-pyrazinamide. The preparation method of 6-fluoro-3-hydroxy-2-pyrazinamide has the advantages of easily purchased initial raw material, mild reaction conditions and high yield, is simple to operate, and is suitable for industrial production. The technical route is short, the operation is simple, and the technical conditions are easy to control. The yields of all the six reaction steps are high. The technical conditions are mild and easy to control. The invention is suitable for an industrial production device, and can operate stably.

Description

technical field [0001] The invention is a preparation method of 6-fluoro-3-hydroxyl-2-pyrazinamide. Background technique [0002] 6-Fluoro-3-hydroxy-2-pyrazinamide (hereinafter referred to as QD-Z0212) is a compound used for the prevention and treatment of viral infectious diseases, especially influenza virus infection. Its structural formula is as follows: [0003] [0004] There are mainly three types of QD-Z0212 and synthesis techniques in the prior art. WO0010569 is prepared by multi-step reaction of methyl 6-bromo-3-amino-2-pyrazinecarboxylate. Conference report 2, International Electronic Conference on Synthetic Organic Chemistry, 13th, Nov.1-30, 2009, prepared from 3-hydroxy-2-pyrazinamide by multi-step reaction after nitration, and WO2010087117A1 prepared from 3-hydroxy-2 -Pyrazinamide is prepared by multi-step reaction after bromination. [0005] It is prepared from 6-bromo-3-amino-2-pyrazinecarboxylic acid methyl ester, which needs to be substituted with meth...

Claims

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Application Information

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IPC IPC(8): C07D241/24
Inventor 郑家晴张涛刘昌铭冯波李宗涛
Owner SHANDONG QIDU PHARMA
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