Synthetic process of 2-methyl-5-carboxylic acid pyrazine

A technology of methylpyrazine and pyrazine formate, applied in the field of medicine, can solve the problems of complex purification process, low yield of oxidation and decarboxylation, and poor selectivity of oxidation

Active Publication Date: 2020-04-10
东营曜康医药科技有限公司
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Problems solved by technology

[0011] Specifically, the problem of the first method is that the process route is long, the yield of oxidation and decarboxylation is low, and potassium permanganate, which is harmful to the environment, is used, which produces a large amount of manganese-containing waste residue, and the treatment cost is high
Although the second method can avoid the use of potassium permanganate, its main raw material diaminomaleonitrile is difficult to synthesize, the cost is high, and the decarboxylation yield is low. It is reported that the yield is only 53%, which is not suitable for large-scale Production
[0015] At present, this route is a relatively commonly used synthesis method in production. The main problem of this route is that potassium permanganate is used as an oxidant, and a large amount of water needs to be added for the reaction, which will produce a large amount of manganese-containing waste residue and waste water; meanwhile, this route is due to Using 2,5-dimethylpyrazine with a symmetrical structure as a raw material, the selectivity of its oxidation is relatively poor, and a large amount of double oxidation products are produced, and the total yield is low. It is reported in the literature that the yield is only 5.8%. The purification process complex
[0016] As mentioned above, the existing synthetic methods for the preparation of 2-methyl-5-carboxylic acid pyrazine have the disadvantages of not being environmentally friendly, low yield, and difficult purification, so it is necessary to develop a more suitable synthetic process

Method used

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  • Synthetic process of 2-methyl-5-carboxylic acid pyrazine

Examples

Experimental program
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Effect test

Embodiment 1

[0065] Preparation of 3-Hydroxy-5-methylpyrazine-2-carboxamide

[0066] In a 500mL three-necked reaction flask, add 216g of 40% aqueous solution of aceglyoxal and 117g of 2-aminomalonamide in sequence, place in an ice-water bath, and cool down to about 5°C; while stirring, slowly add the prepared 100g of 40% sodium hydroxide aqueous solution, control the dropping rate, keep the internal temperature at 5°C, after 6 hours, add 10% hydrochloric acid solution dropwise to the system, adjust the pH value to about 6, a large amount of brownish yellow solid precipitates, filter, water After washing once, the filter cake was dried in an oven to obtain 120 g of crude product. LC purity 97%, yield 78%. 1 H-NMR (DMSO-d 6 ):δ=2.15(s,3H),7.41(s,1H),8.67(br,2H),15.62(br,1H).

[0067] Preparation of 3-Hydroxy-5-methylpyrazine-2-carboxylic acid

[0068] Add 120g of the crude product obtained in the previous step into a 500mL three-necked reaction flask, install a reflux condensing devi...

Embodiment 2

[0074] Preparation of 3-Hydroxy-5-methylpyrazine-2-carboxamide

[0075] In a 500mL three-necked reaction flask, add 216g of 40% aqueous solution of aceglyoxal and 117g of 2-aminomalonamide in sequence, place in an ice-water bath, and cool down to about 5°C; while stirring, slowly add 100g of the prepared solution dropwise to the system 40% sodium hydroxide aqueous solution, control the rate of addition, keep the internal temperature at 10°C, after 6 hours, add 10% hydrochloric acid solution dropwise to the system, adjust the pH value to about 6, precipitate a large amount of brownish yellow solid, filter and wash with water Once, the filter cake was dried in an oven to obtain 118g of crude product. LC purity 97%, yield 77%. 1 H-NMR (DMSO-d 6 ):δ=2.15(s,3H),7.41(s,1H),8.67(br,2H),15.62(br,1H).

[0076] Preparation of 3-Hydroxy-5-methylpyrazine-2-carboxylic acid

[0077] Add 119.23g of the crude product obtained in the previous step into a 500mL three-necked reaction fla...

Embodiment 3

[0083] Preparation of 3-bromo-5-methylpyrazine-2-carboxylic acid

[0084] 100g of 3-hydroxyl-5-methylpyrazine-2-carboxylic acid crude product prepared according to the method of Example 1 was added to a 500mL three-necked reaction flask, a reflux condenser was installed, 200mL xylene was added, 5mL DMF, Under stirring, add 129g of thionyl bromide dropwise from the constant pressure dropping funnel. After the addition, the system is heated up to 80°C for 6 hours of reaction; 200mL of water was added to the bottom solution, the mixture was extracted with 3*150mL butanone, the organic phases were combined and concentrated to obtain 93g of crude product. The crude product was recrystallized in 500 mL of water, and dried to obtain 85.2 g of a white solid product with a LC purity of 98% and a yield of 61%. 1 H-NMR (DMSO-d 6 ):δ=2.42(s,3H),8.86(s,1H),12.31(br,1H).

[0085] Preparation of 2-methyl-5-carboxylic acid pyrazine

[0086]Place 85g of the product obtained in the prev...

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Abstract

The invention provides a method for preparing 2-methyl-5-pyrazinecarboxylic acid. The method provided by the invention is characterized in that potassium permanganate which is more harmful to the environment is not used, a target compound 2-methyl-5-pyrazinecarboxylic acid can be prepared from cheap and easily available methylglyoxal and 2-amino malonamide taken as raw materials through four stepsof cyclization, hydrolysis, chlorination and reduction, the yield of the reaction route is high, the amount of byproducts is small, and products are purer.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a synthesis process of 2-methyl-5-carboxylic acid pyrazine. Background technique [0002] 2-Methyl-5-carboxylic acid pyrazine is an important pharmaceutical intermediate, which is mainly used to prepare the important hypoglycemic drug glipizide and a new generation of long-acting hypolipidemic drug acipimox. At the same time, its derivatives Methyl 2-methyl-5-pyrazinecarboxylate is also an important drug for the treatment of tuberculosis. [0003] At present, for the synthesis of this compound, there are mainly the following two types: [0004] 1) Prepared by decarboxylation of 2-methyl-5,6-dicarboxylic acid pyrazine [0005] [0006] Specifically, the preparation of 2-methyl-5,6-dicarboxylic acid pyrazine has the following two methods: [0007] A. Preparation with aceglyoxal and o-phenylenediamine as raw materials [0008] [0009] B. Prepared from maleonitrile and methylglyoxa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 高明王海卫卢朋贺军毛浙徽
Owner 东营曜康医药科技有限公司
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