Synthesis method of 2-aminopyrazinyl-5-formic acid

The technology of an aminopyrazine and a synthesis method is applied in the new synthesis process field of 2-aminopyrazine-5-carboxylic acid, and can solve the problems of difficult preparation of starting materials, unsuitable for scale-up production, high temperature required for the reaction, etc. The effect of shortening the production process, less impurities and easy purification

Inactive Publication Date: 2013-06-19
苏州科捷生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Comparing the above three routes comprehensively, it is found that the reagents used are highly toxic or highly oxidizing, causing great environmental pollution, requiring high temperature for the reaction, difficult to control, difficult to prepare starting materials, and need to use precious metals, etc. The cost is high and it is not suitable for scale-up production

Method used

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  • Synthesis method of 2-aminopyrazinyl-5-formic acid
  • Synthesis method of 2-aminopyrazinyl-5-formic acid
  • Synthesis method of 2-aminopyrazinyl-5-formic acid

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Effect test

Embodiment 1

[0026] Embodiment 1: Synthesis of ethyl 2-formate-5-formylhydrazine pyrazine (compound 2)

[0027] 2,5-ethyl pyrazine dicarboxylate (85g, 0.38 mol) was dissolved in absolute ethanol (1500 ml), and under ice-bath conditions, 85% hydrazine hydrate (22.3g, 0.38 mol) was slowly added dropwise, and the addition was completed Stir overnight at room temperature, filter with suction, wash with absolute ethanol (100 ml), and dry in vacuo to obtain 60 g of white solid compound (2), yield: 75.3%. mp: 142-143°C

[0028] HNMR (DMSO-d6, 400MHz): δ9.47(1H, s), 9.23(1H, s), 8.84(1H, s), 4.55(2H, m), 4.16(2H, m), 1.47(3H, t).

Embodiment 2

[0029] Embodiment 2: Synthesis of ethyl 2-formate-5-formyl azidopyrazine (compound 3)

[0030] 2-Ethyl formate-5-formylhydrazine pyrazine (37g, 0.18 moles), was added dichloromethane (600 milliliters), water (600 milliliters), sodium nitrite (60g, 0.87 moles), under ice water cooling, 6N HCl (250 ml) was added dropwise. After the addition, the aqueous phase was extracted with dichloromethane (200 ml x 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness with a water pump at room temperature to obtain off-white Solid compound (3) 33g, yield: 82.9%.

Embodiment 3

[0031] Embodiment 3: Synthesis of ethyl 2-formate-5-Boc-amino-pyrazine (compound 4)

[0032] 2-Ethyl formate-5-formylazide pyrazine (100g, 0.45 mol), add toluene (600ml) and t-BuOH (100ml), heat to reflux, react for 1 hour, cool to room temperature, and filter with suction , washed with toluene (50 ml), and dried to obtain 110 g of white solid compound (4), yield: 91.6%. mp: 162-163°C

[0033] HNMR (DMSO-d6, 400MHz): δ9.40(1H, s), 8.95(1H, s), 4.49(2H, m), 1.57(9H, s), 1.44(3H, t).

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Abstract

The invention discloses a novel synthesis method of 2-aminopyrazinyl-5-formic acid, which comprises the following steps: carrying out hydrazinolysis reaction on accessible 2,5-ethyl diformate pyrazine to hydrazinolyze the monoester, reacting with a sodium nitrate solution, refluxing in toluene and tert-butyl alcohol to obtain a key intermediate 2-ethyl formate-5-Boc-amino-pyrazine, and refluxing in hydrochloric acid to obtain the 2-aminopyrazinyl-5-formic acid. The method has the advantages of mild and simple reaction conditions, low cost and high yield, is simple to operate and suitable for industrial production, and has great economic significance.

Description

technical field [0001] The invention relates to a new synthesis process of 2-aminopyrazine-5-carboxylic acid, which belongs to the technical fields of medicine and chemical industry. Background technique [0002] Pyrazine and its derivatives are important intermediates connecting the chemical industry and the pharmaceutical industry, and are widely used in the fields of medicine, pesticides, dyes, surfactants, rubber vulcanization accelerators, antioxidants, and preservatives. [0003] 2-Aminopyrazine-5-carboxylic acid is a kind of pyrazine derivative, which can be used to synthesize drugs for the treatment of diabetes (JMC2012, 55, 1318-1333); it can also be used to synthesize drugs for the treatment of allergies, inflammation and cardiovascular diseases. Drugs (WO2012027322). [0004] The synthetic methods reported in the literature are as follows: [0005] Route A (JACS1949, 71, 2798-2800) [0006] [0007] Route B (Helvetica Chimica Acta 1964, 47, 873-6) [0008] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/28
Inventor 邵东黄传满
Owner 苏州科捷生物医药有限公司
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