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Synthesis method of 7-bromothieno [2, 3-B] pyrazine

A synthetic method, 3-B technology, applied in the direction of organic chemistry, etc., can solve the problems of low yield, unsuitable for scale-up, high cost of raw materials, etc., and achieve the effects of high yield, easy scale-up production, and high selectivity

Inactive Publication Date: 2020-09-01
凯美克(上海)医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The purpose of the present invention is to provide a low-cost, high-purity and high-yield 7-bromothieno[2,3-B]pyrazine synthesis method to solve the problem of high raw material cost and low yield in the prior art. Problems that should not be enlarged

Method used

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  • Synthesis method of 7-bromothieno [2, 3-B] pyrazine
  • Synthesis method of 7-bromothieno [2, 3-B] pyrazine
  • Synthesis method of 7-bromothieno [2, 3-B] pyrazine

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Effect test

Embodiment 1

[0048] 1) Synthetic compound (2) 2-methyl-4-(3-chloropyrazine)-3-butyn-2-ol

[0049]

[0050] Add 2,3-dichloropyrazine (100g, 0.676mol, 1eq), cuprous iodide (12.8g, 0.067mol, 0.1eq), Pd(PPh 3 ) 4 (15.6g, 0.0135mol, 0.02eq), 1L triethylamine and 1L acetonitrile, under nitrogen protection, 2-methyl-3-butyn-2-ol (62g, 0.737mol, 1.1eq) was added dropwise at room temperature, After the addition was completed, stir at room temperature for 15 h. After the reaction was complete, the reaction solution was directly concentrated and subjected to column chromatography to obtain compound (2) 2-methyl-4-(3-chloropyrazine)-3-butyne-2 -Alcohol 120g, yield 91.1%.

[0051] 2) Synthetic compound (3) 2-chloro-3-ethynylpyrazine

[0052]

[0053] Add compound (2) 2-methyl-4-(3-chloropyrazine)-3-butyn-2-alcohol (120g, 0.612mol, 1eq) and 1.2L toluene in the reaction flask, then add sodium hydroxide (29.4g, 0.734mol, 1.2eq), heated to 110°C and reacted for 0.5h. After the reaction was comple...

Embodiment 2

[0061] 1) Synthetic compound (2) 2-methyl-4-(3-chloropyrazine)-3-butyn-2-ol

[0062] Add 2,3-dichloropyrazine (10g, 67.6mmol, 1eq), cuprous iodide (1.28g, 67mol, 0.1eq), Pd(DBA) into the reaction flask 3 (1.24g, 1.35mol, 0.02eq), 100mL triethylamine and 100mL acetonitrile, under nitrogen protection, 2-methyl-3-butyn-2-ol (6.2g, 73.7mmol, 1.1eq) was added dropwise at room temperature , the addition was completed, stirred at room temperature for 15h, after the reaction was complete, the reaction solution was directly concentrated and subjected to column chromatography to obtain compound (2) 2-methyl-4-(3-chloropyrazine)-3-butyne- 2-alcohol 9.5g, yield 72.1%.

[0063] 2) Synthetic compound (3) 2-chloro-3-ethynylpyrazine

[0064] Add compound (2) 2-methyl-4-(3-chloropyrazine)-3-butyn-2-alcohol (12g, 61.2mmol, 1eq) and 120mL toluene in reaction flask, then add sodium hydroxide ( 3.67g, 91.8mmol, 1.5eq), heated to 110°C and reacted for 0.5h. After the reaction was complete, the r...

Embodiment 3

[0070] 1) Synthetic compound (2) 2-methyl-4-(3-chloropyrazine)-3-butyn-2-ol

[0071] Add 2,3-dichloropyrazine (10g, 67.6mmol, 1eq), cuprous iodide (1.28g, 67mol, 0.1eq), Pd(PPh 3 ) 4 (0.78g, 0.676mmol, 0.01eq), 100mL triethylamine and 100mL acetonitrile, under nitrogen protection, 2-methyl-3-butyn-2-ol (6.2g, 73.7mmol, 1.1eq) was added dropwise at room temperature , the addition was completed, stirred at room temperature for 15h, after the reaction was complete, the reaction solution was directly concentrated and subjected to column chromatography to obtain compound (2) 2-methyl-4-(3-chloropyrazine)-3-butyne- 10.5 g of 2-alcohol, yield 79.2%.

[0072] 2) Synthetic compound (3) 2-chloro-3-ethynylpyrazine

[0073] Add compound (2) 2-methyl-4-(3-chloropyrazine)-3-butyn-2-alcohol (10g, 51mmol, 1eq) and 100mL toluene in the reaction flask, then add sodium hydroxide (2.24 g, 56.1mmol, 1.1eq), heated to 110°C for 0.5h, after the reaction was complete, the reaction solution was co...

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Abstract

The invention provides a preparation method of 7-bromothieno [2, 3-b] [1, 2, 4] thiadiazole. The invention discloses a synthetic method of 2, 3-B] pyrazine. Relating to the organic synthesis field, the preparation method comprises the following steps: reacting 2, 3-dichloropyrazine with 2-methyl-3-butyne-2-ol, cuprous iodide and triethylamine under the catalytic action of tetrakis (triphenylphosphine) palladium to generate 2-methyl-4-(3-chloropyrazine)-3-butyne-2-ol; 2-methyl-4-(3-chloropyrazine)-3-butyne-2-ol reacts with alkali to obtain 2-chloro-3-ethynylpyrazine, 2-chloro-3-ethynylpyrazinereacts with sodium sulfide nonahydrate to generate thieno [2, 3-B] pyrazine, and thieno [2, 3-B] pyrazine further reacts with N-bromosuccinimide to generate 7-bromothieno [2, 3-. The synthesis methodprovided by the invention has the advantages of easily available raw materials, mild reaction conditions, high selectivity, good operability of post-treatment, high yield and easiness in large-scale production.

Description

technical field [0001] The invention relates to the field of organic synthesis of chemical intermediates, in particular to a method for synthesizing 7-bromothieno[2,3-B]pyrazine. Background technique [0002] 7-Bromothieno[2,3-B]pyrazine is a 7-substituted thieno[2,3-B]pyrazine compound, which is an extremely important class of pharmaceutical intermediates with broad application prospects. Such as the preparation of B-Raf inhibitors; as inhibitors of IRAK4 activity; its derivatives as acetyl-CoA carboxylase inhibitors, etc. [0003] Although there have been reports on the synthesis of 7-bromothieno[2,3-B]pyrazine as an intermediate synthetic drug, the raw material cost of the synthetic route is relatively high. [0004] For the preparation of 7-bromothieno[2,3-B]pyrazine, the relevant methods reported in the literature are as follows: [0005] [0006] Wherein, condition a is ethyl thioglycolate (Ethyl thioglycolate), sodium ethoxide (EtONa), ethanol (EtOH); condition b...

Claims

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Application Information

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IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 郦荣浩杨龙沛
Owner 凯美克(上海)医药科技有限公司
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