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A Scalable Process for the Preparation of 2-Amino-3-Bromo-6-Chloropyrazine

A technology of chloropyrazine and amino group, applied in the field of pyrazine compound synthesis, can solve the problems of difficult separation, low yield, unsuitable for scale-up production, etc., and achieves the effect of simple purification method and low production cost

Active Publication Date: 2021-09-03
ACCELA CHEMBIO CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this method, because of the activation of the amino group, the bromine is mainly positioned at the para-position of the amino group, and the by-product 2-bromo-3-chloro-5-aminopyrazine and part of the dibromo-by-product 2-amino-3,5-di Bromo-6-chloropyrazine, the product 2-amino-3-bromo-6-chloro is less, the yield is low (column chromatography separation yield is 25% to 31%), and column chromatography purification is required, and the separation is difficult , not suitable for scale-up production (WO2013 / 61080A1, WO2009 / 16460A2 and US2011 / 59118A1)

Method used

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  • A Scalable Process for the Preparation of 2-Amino-3-Bromo-6-Chloropyrazine
  • A Scalable Process for the Preparation of 2-Amino-3-Bromo-6-Chloropyrazine
  • A Scalable Process for the Preparation of 2-Amino-3-Bromo-6-Chloropyrazine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 Synthesis of 2-amino-3-bromo-6-chloropyrazine

[0032] step 1):

[0033]

[0034] Add 500 mL of acetonitrile, compound 1 (100 g, 0.653 mol) and NCS (87.2 g, 0.653 mol) into a 1 L three-necked flask, heat to 82 ° C for 12 hours, and the reaction is complete. Concentrate to remove acetonitrile, and recrystallize from petroleum ether / ethyl acetate to obtain bright green crystal compound 2 (112.7 g, 92%). 1 H-NMR (300MHz, CDCl 3 ): 8.24 (s, 1H), 6.49 (br, 2H), 4.00 (s, 3H).

[0035] Step (2):

[0036]

[0037] Add 100mL of acetic acid and compound 2 (20g, 0.11mol) to a 500ml three-necked flask, add 100mL of 40% aqueous hydrogen bromide solution dropwise at 0°C, react for 30min after dropping, and add sodium nitrite (20.7g, 0.33 mol) of 50ml aqueous solution. The dropwise reaction was completed for 30 minutes, and the reaction was complete. It was quenched by adding 30ml of 10% sodium bisulfite solution dropwise, extracted with ethyl acetate (200ml×2), d...

Embodiment 22

[0048] The synthesis of embodiment 22-amino-3-bromo-6-chloropyrazine

[0049] step 1):

[0050]

[0051] Add 500 mL of acetonitrile, compound 7 (109 g, 0.65 mol) and NCS (87.2 g, 0.65 mol) into a 1 L three-necked flask, heat to 82 ° C for 12 hours, and the reaction is complete. Concentrate to remove acetonitrile, recrystallize from petroleum ether / ethyl acetate to obtain bright green crystal compound 8 (117.5 g, yield 90%), and the H NMR data are: 1 H-NMR (300MHz, CDCl 3 ): 8.23 ​​(s, 1H), 6.40 (br, 2H), 4.20 (q, 2H), 1.31 (t, 3H).

[0052] Step (2):

[0053]

[0054] Add 100 mL of acetic acid and compound 8 (20.1 g, 0.10 mol) into a 500 ml three-necked flask, add 100 mL of 40% hydrogen bromide aqueous solution dropwise at 0°C, and react for 30 minutes after dropping, then add sodium nitrite (20.7 g, 0.3mol) in 50ml of aqueous solution. The reaction was completed after 30 minutes of dripping, quenched by adding 30ml of 10% sodium bisulfite solution dropwise, extract...

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Abstract

A scalable process for preparing 2-amino-3-bromo-6-chloropyrazine, using 3-aminopyrazine-2-carboxylate as raw material, through chlorination, diazotization bromination, and ester group hydrolysis , carboxyl rearrangement and de-tert-butoxycarbonyl steps to obtain products. The process provided by the invention has high yield, simple purification, easy scale-up production, effective and low-cost production.

Description

technical field [0001] The invention relates to a method for synthesizing pyrazine compounds, in particular to a cyclic chiral amino compound containing a ureido group, which can be scaled up and is easy for industrial production. Background technique [0002] 2-Amino-3-bromo-6-chloropyrazine has important uses in the pharmaceutical industry and is an important intermediate for the synthesis of a class of antineoplastic drug SHP2 inhibitors (Journal of Medicinal Chemistry, 2016, vol.59, #17 , p.7773-7782, WO2015 / 107495A1). [0003] At present, in terms of the process for preparing 2-amino-3-bromo-6-chloropyrazine, the one-step bromination reaction of 2-amino-6-chloropyrazine is mainly used. In this method, because of the activation of the amino group, the bromine is mainly positioned at the para-position of the amino group, and the by-product 2-bromo-3-chloro-5-aminopyrazine and part of the dibromo-by-product 2-amino-3,5-di Bromo-6-chloropyrazine, the product 2-amino-3-bro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/20
CPCC07D241/20
Inventor 魏渊博郭涛吴勇
Owner ACCELA CHEMBIO CO LTD
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