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Preparation method for 6-fluoro-3-hydroxyl-2-pyrazinamide

The technology of pyrazinamide and hydroxyl group is applied in the field of preparation of 6-fluoro-3-hydroxy-2-pyrazinamide, can solve the problems of complicated steps, low yield and the like, and achieves simple and convenient preparation method, high yield and easy The effect of preparation

Inactive Publication Date: 2016-07-06
QINGDAO HUANGDAO HOSPITAL OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This process route is long and cumbersome, many places need column purification, and the yield of the multi-step reaction is low. In the diazotization, the methyl protecting group of methoxy and demethoxy is introduced, and the yield of the two-step reaction is respectively 35% and 15%

Method used

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  • Preparation method for 6-fluoro-3-hydroxyl-2-pyrazinamide
  • Preparation method for 6-fluoro-3-hydroxyl-2-pyrazinamide
  • Preparation method for 6-fluoro-3-hydroxyl-2-pyrazinamide

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Effect test

Embodiment 1

[0023] (1) Under nitrogen protection, dissolve 14g (64.5mmol, 1eq) of 6-bromo-3-amino-2-pyrazinamide in 200ml of N,N-dimethylformamide, and add 21g ( 96.75mmol, 1.5eq) Boc 2 O and 3.1g (129mmol, 2eq) of NaH were stirred at 25°C for 3h, the reaction was detected by TLC as complete, and the reaction was stopped. Then 5 times the volume of water was added under ice bath to quench the excess NaH, and at the same time, solids were precipitated in the system, filtered, and the filter cake was vacuum-dried at 25°C to obtain 16.6g of 6-bromo-3-carbamate tert-butyl ester-2- Pyrazinamide, the yield was 81%. The NMR index of 6-bromo-3-tert-butyl carbamate-2-pyrazinamide is as follows:

[0024] 1 H-NMR (DMSO-d6, 600MHz) δ value: 1.39 (9H, s, Boc), 7.72 (1H, s, NH 2 ),7.98(1H,s,NH 2 ), 8.47 (1H, s, pyrazine H), 9.82 (1H, s, NH).

[0025] (2) Under nitrogen protection, dissolve 2g (6mmol) of tert-butyl 6-bromo-3-carbamate-2-pyrazinamide in 20ml of dimethyl sulfoxide, and add 0.87g (15...

Embodiment 2

[0032](1) Under nitrogen protection, dissolve 0.50g (2.31mmol, 1eq) of 6-bromo-3-amino-2-pyrazinamide in 5ml of N,N-dimethylformamide, and add 0.76 Boc of g (3.47mmol, 1.5eq) 2 O and 0.11 g (4.62 mmol, 2 eq) of NaH were stirred at 30° C. for 3 h, and the reaction was detected to be complete by TLC, so the reaction was stopped. Then 5 times the volume of water was added under ice bath to quench the excess NaH, and at the same time, solids were precipitated in the system, filtered, and the filter cake was vacuum-dried at 30°C to obtain 0.57g of 6-bromo-3-carbamic acid tert-butyl ester- 2-Pyrazinamide, yield 78%. The NMR index of 6-bromo-3-tert-butyl carbamate-2-pyrazinamide is as follows:

[0033] 1 H-NMR (DMSO-d6, 600MHz) δ value: 1.37 (9H, s, Boc), 7.69 (1H, s, NH 2 ),7.94(1H,s,NH 2 ),8.43(1H,s,pyrazineH),9.80(1H,s,NH)

[0034] (2) Under nitrogen protection, dissolve 0.2g (0.63mmol) of 6-bromo-3-carbamic acid tert-butyl ester-2-pyrazinamide in 5ml of dimethyl sulfoxide, ...

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Abstract

The invention belongs to the field of chemical synthesis, and specifically relates to a preparation method for 6-fluoro-3-hydroxyl-2-pyrazinamide. According to the invention, 6-fluoro-3-hydroxyl-2-pyrazinamide is prepared by using 6-bromo-3-amino-2-pyrazinamide as a raw material through four reaction steps of amino protection, halogen replacement, deprotection and azidation. The invention has the following advantages: procurement or preparation of the raw material is convenient; the preparation method is simple and convenient to operate; and the prepared 6-fluoro-3-hydroxyl-2-pyrazinamide has high yield and is applicable to industrial production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and specifically relates to a preparation method of 6-fluoro-3-hydroxyl-2-pyrazinamide. Background technique [0002] The 6-fluoro-3-hydroxyl-2-pyrazinamide of the present invention is a compound used for preventing and treating viral infectious diseases, especially influenza virus infection. Its structural formula is as follows: [0003] [0004] Currently known 6-fluoro-3-hydroxyl-2-pyrazinamide synthesis process mainly contains three kinds: (1) patent document WO0010569 discloses a kind of 6-bromo-3-amino-2-pyrazine carboxylate methyl ester It is prepared by multi-step reaction; (2) It is prepared by multi-step reaction after nitration of 3-hydroxy-2-pyrazinamide (conference report 2, International Electronic Conference on Synthetic Organic Chemistry, 13th, Nov.1-30, 2009,); (3) Patent Document WO2010087117A1 discloses a multi-step reaction preparation of 3-hydroxy-2-pyrazinamide after b...

Claims

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Application Information

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IPC IPC(8): C07D241/24
Inventor 卢彦敏
Owner QINGDAO HUANGDAO HOSPITAL OF TRADITIONAL CHINESE MEDICINE
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