Synthesis method of 3,5-dichloro-6-ethylpyrazineformamide

A technology of ethylpyrazinecarboxamide and dichloropyrazinecarboxamide is applied in the synthesis field of 3,5-dichloro-6-ethylpyrazinecarboxamide, and can solve the problems of high price and not clearly indicated, etc., To achieve the effect of short synthesis process, mild step operation and reaction conditions, easy control and industrialization

Pending Publication Date: 2020-12-11
上海鑫凯化学科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The 3,5-dichloro-6-ethylpyrazine carboxamide currently on the market not only does not clearly indicate the route of using 2,6-dichloropyrazine as a raw material to synthesize the above chemicals, but also the purchase price is expensive

Method used

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  • Synthesis method of 3,5-dichloro-6-ethylpyrazineformamide
  • Synthesis method of 3,5-dichloro-6-ethylpyrazineformamide
  • Synthesis method of 3,5-dichloro-6-ethylpyrazineformamide

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Embodiment 1

[0038] Embodiment 1: a kind of synthetic method of 3,5-dichloro-6-ethylpyrazine carboxamide comprises the following steps:

[0039] Step 1: Heat 330g of 2,6-dichloropyrazine and 1980g of formamide to 90°C, add 513g of sodium persulfate in three batches; react for 10 minutes after the addition, add 2500ml of water; cool to room temperature (ie 25°C) After each 1000ml of methylene chloride was extracted 4 times, the organic phases were combined, and the combined organic phase was washed three times with 150 ml of saturated brine, followed by drying with anhydrous sodium sulfate to remove the solvent to obtain a off-white solid, i.e. 3, 281 g of 5-dichloropyrazine carboxamide, yield 65.9%.

[0040] 3,5-Dichloropyrazine carboxamide NMR data:

[0041] CDCl 3 ,CONH(6.342,br),CONH(7.415,br),CH(8.491,s).

[0042] Step 2: Add 150 g of 3,5-dichloropyrazine carboxamide obtained in Step 1 into 200 g of phosphorus oxychloride, and heat to reflux for 4 hours. Cool and pour into 1L of ic...

Embodiment 2

[0050] Embodiment 2: a kind of synthetic method of 3,5-dichloro-6-ethylpyrazine carboxamide comprises the following steps:

[0051] Step 1: Heat 330g of 2,6-dichloropyrazine and 1950g of formamide to 95°C, add 428.6g of sodium persulfate in four batches; react for 12 minutes after the addition, add 2000ml of water; cool to room temperature (20°C) Each 1000ml of dichloromethane was extracted 4 times, the organic phases were combined, and the combined organic phase was washed three times with 200ml of saturated brine, followed by drying with anhydrous sodium sulfate to remove the solvent to obtain a off-white solid, i.e. 3,5 -Dichloropyrazine carboxamide 295g, the yield is 69.3%.

[0052] Step 2: Add 150 g of 3,5-dichloropyrazine carboxamide obtained in Step 1 to 179.3 g of phosphorus oxychloride, and heat to reflux for 4.5 hours. Cool and pour into 1L of ice water, add 500ml of dichloromethane each time for extraction, combine the organic phases, and wash the combined organic ...

Embodiment 3

[0056] Embodiment 3: a kind of synthetic method of 3,5-dichloro-6-ethylpyrazine carboxamide comprises the following steps:

[0057] Step 1: Heat 330g of 2,6-dichloropyrazine and 2340g of formamide to 100°C, add 523.8g of sodium persulfate in three batches; react for 15 minutes after the addition, add 3000ml of water; cool to room temperature (25°C) Each 1000ml of dichloromethane was extracted 4 times, the organic phases were combined, and the combined organic phase was washed three times with 250 ml of saturated brine, followed by drying with anhydrous sodium sulfate to remove the solvent to obtain a off-white solid, i.e. 3,5 -Dichloropyrazine carboxamide 310g, the yield is 72.9%.

[0058] Step 2: Add 150 g of 3,5-dichloropyrazine carboxamide obtained in Step 1 to 215.2 g of phosphorus oxychloride, and heat to reflux for 5 hours. Cool and pour into 1L of ice water, add 500ml of dichloromethane each time for extraction twice, combine the organic phases, and wash the combined o...

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Abstract

The invention discloses a synthetic method of 3,5-dichloro-6-ethylpyrazine formamide, and relates to the technical field of intermediate for synthesizing gilteritinib. The method is technically characterized by comprising the following steps: heating 2,6-dichloropyrazine and formamide to 70-130 DEG C, and carrying out free radical oxidation reaction under the action of persulfate to obtain 3,5-dichloropyrazine formamide; carrying out heating reflux on 3,5-dichloropyrazine formamide for 3-6 h under the action of a dehydrating agent, and synthesizing 3,5-dichloropyrazine formonitrile through dehydration; carrying out a Grignard reactionon the 3,5-dichloropyrazine formonitrile in an organic solvent A under the action of a methylation reagent to prepare 3,5-dichloro-2-acetylpyrazine; under theaction of an acidic catalyst and a silicon-hydrogen reducing agent, reducing the 3,5-dichloro-2-acetyl pyrazine in an organic solvent B to obtain 3,5-dichloro-2-ethyl pyrazine; and heating the 3,5-dichloro-2-ethyl pyrazine and formamide to 50-120 DEG C, and carrying out free radical oxidation reaction under the action of persulfate to obtain the 3,5-dichloro-6-ethylpyrazine formamide. According to the invention, the operation method is simple, the reaction conditions of the synthesis process are mild, the cost is reduced, and meanwhile high economic benefits can be brought.

Description

technical field [0001] The invention relates to the technical field of intermediates for synthesizing gilteritinib, more specifically, it relates to a method for synthesizing 3,5-dichloro-6-ethylpyrazine carboxamide. Background technique [0002] Gelicitinib is a small molecule drug that inhibits multiple receptor tyrosine kinases including FMS-like tyrosine kinase 3. Gelitinib b inhibits FLT3 receptor signaling and proliferation and expression in exogenous cells, including FLT33-ITD, tyrosine kinase domain mutation (TKD) FLT3-ITD-D835Y and FLT3-ITD-D835Y, thereby Induces apoptosis of leukemia cells expressing FLT3-ITD, whose chemical structural formula is [0003] Among them, 3,5-dichloro-6-ethylpyrazine carboxamide is the key intermediate for the synthesis of gilteritinib, and its CAS number is: 313340-08-8, and its molecular structure is: [0004] The 3,5-dichloro-6-ethylpyrazine carboxamide currently on the market not only does not clearly indicate the route of usi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 董金鹏张奕超李侠王小芳庄岩岩
Owner 上海鑫凯化学科技有限公司
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