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Synthesis process of 2-amino-3-bromo-6-chloropyrazine

A synthesis process, the technology of chloropyrazine, which is applied in the field of synthesis process of 2-amino-3-bromo-6-chloropyrazine, can solve the problems of difficult purification, long process steps and low yield, and achieve easy scale-up production , simple operation, high yield effect

Active Publication Date: 2021-04-30
烟台皓元生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, there are mainly two methods for synthesizing 2-amino-3-bromo-6-chloropyrazine: (1) disclosed in WO2013 / 61080A1, WO2017 / 29602, WO2016 / 142310, WO2009 / 16450A2 and US2011 / 59118A1, etc. The method is direct bromination, and the yield is very low, only 11%-31%. The preparation of 2-amino-3-bromo-6-chloropyrazine by this method can produce a main by-product which is 2-bromo-3-chloro- 5-aminopyrazine is not easy to purify; (2) the technology disclosed in CN108101857A is to be starting material by 3-aminopyrazine-2-carboxylic acid, and the processing step is very long

Method used

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  • Synthesis process of 2-amino-3-bromo-6-chloropyrazine
  • Synthesis process of 2-amino-3-bromo-6-chloropyrazine
  • Synthesis process of 2-amino-3-bromo-6-chloropyrazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Add 500 mL of chloroform and 2-amino-6-chloropyrazine (20 g, 0.154 mol) into a 1 L three-necked flask, cool down to -10 ° C, add 1 ml of HBr / AcOH, and then add liquid bromine (25.87 g) / chloroform ( 50ml), the dropwise addition was completed, reacted at 0°C for 2 hours, and detected the reaction by TLC. After the reaction was completed, sodium sulfite solution was added until the reddish-brown color faded, extracted with chloroform, washed with water, dried over anhydrous sodium sulfate, concentrated, and passed through a silica gel column (ethyl acetate / petroleum ether=1 / 5~1 / 3), petroleum ether / ethyl acetate recrystallization once, petroleum ether / tert-butyl methyl ether recrystallization once, obtain yellow solid compound 2-amino-3-bromo-6-chloropyrazine (15.7 g, yield: 49%).

[0024] 'H-NMR (300MHz, CDC1 3 ):7.70(s,1H),5.18(br,2H)

Embodiment 2

[0026] Add 500 mL of chloroform and 2-amino-6-chloropyrazine (20 g, 0.154 mol) into a 1 L three-necked flask, cool down to -10 °C, add 1 ml of HBr / H 2 After O (48% HBr aqueous solution), add liquid bromine (25.87g) / chloroform (50ml) dropwise, after the dropwise addition is complete, react at 0°C for 2 hours, and detect the reaction by TLC. Extract, wash with water, dry over anhydrous sodium sulfate, concentrate, pass through a silica gel column (ethyl acetate / petroleum ether=1 / 5~1 / 3), recrystallize once from petroleum ether / ethyl acetate, recrystallize petroleum ether / tert-butyl methyl ether After one crystallization, a yellow solid compound 2-amino-3-bromo-6-chloropyrazine (13.7 g, yield: 43%) was obtained.

[0027] 'H-NMR (300MHz, CDC1 3 ):7.70(s,1H),5.18(br,2H)

Embodiment 3

[0028] Example 3—Currently Known Methods

[0029] Add 600 mL of chloroform and 2-amino-6-chloropyrazine (20 g, 0.154 mol) into a 1 L three-necked flask, heat NBS (27.46 g, 0.154.38 mol) to reflux for 1.5 h, and detect the reaction by TLC. After the reaction is complete, add sodium sulfite The solution was removed until the reddish-brown color faded, extracted with chloroform, washed with water, dried over anhydrous sodium sulfate, concentrated, and passed through a silica gel column (ethyl acetate / petroleum ether=1 / 5~1 / 3) to obtain the yellow solid compound 2-amino-3-bromo - 6-Chloropyrazine (4.2 g, yield: 13%).

[0030] 'H-NMR (300MHz, CDC1 3 ):7.70(s,1H),5.18(br,2H)

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Abstract

The invention relates to a synthesis process of 2-amino-3-bromo-6-chloropyrazine, which comprises the following steps: 1) adding 2-amino-6-chloropyrazine into an organic solvent, cooling the system, and then adding a catalyst; (2) dropwise adding a bromination reagent, namely liquid bromine, into the system, after dropwise adding is finished, carrying out heat preservation reaction, and carrying out TLC detection and tracking reaction; and 3) adding a sodium sulfite solution into the system until reddish brown fades, extracting with chloroform, washing with water, drying with anhydrous sodium sulfate, concentrating, passing through a silicagel column roughly, and recrystallizing to obtain the yellow solid compound 2-amino-3-bromine- 6-chloropyrazine. 2-amino-3-bromine- 6-chloropyrazine is used as an initial raw material and is brominated to obtain the product, so that the method is simple to operate, short in step, easily available in raw material, simple to purify, high in yield, low in cost and easy for large-scale production.

Description

technical field [0001] The invention relates to a synthesis process of 2-amino-3-bromo-6-chloropyrazine, which belongs to the technical field of medicine synthesis. Background technique [0002] 2-Amino-3-bromo-6-chloropyrazine has important uses in medicine, and is an important intermediate in the synthesis of anti-tumor drug SHP2 inhibitors (such as: TNO155, SHP099). [0003] At present, there are mainly two methods for synthesizing 2-amino-3-bromo-6-chloropyrazine: (1) disclosed in WO2013 / 61080A1, WO2017 / 29602, WO2016 / 142310, WO2009 / 16450A2 and US2011 / 59118A1, etc. The method is direct bromination, and the yield is very low, only 11%-31%. The preparation of 2-amino-3-bromo-6-chloropyrazine by this method can produce a main by-product which is 2-bromo-3-chloro- 5-aminopyrazine is not easy to purify; (2) the technology disclosed in CN108101857A is to use 3-aminopyrazine-2-carboxylic acid as the starting material, and the process steps are very long. Contents of the inven...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/20
CPCC07D241/20
Inventor 王伟张立群崔宁宁陈锦春
Owner 烟台皓元生物医药科技有限公司
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