CN100999502A - Process of selective synthesizing 5-methyl pyrazine-2-carboxylic acid using 2,5-dimethyl pyrazine - Google Patents
Process of selective synthesizing 5-methyl pyrazine-2-carboxylic acid using 2,5-dimethyl pyrazine Download PDFInfo
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- CN100999502A CN100999502A CN 200610172182 CN200610172182A CN100999502A CN 100999502 A CN100999502 A CN 100999502A CN 200610172182 CN200610172182 CN 200610172182 CN 200610172182 A CN200610172182 A CN 200610172182A CN 100999502 A CN100999502 A CN 100999502A
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Abstract
This invention use 2,5- dimethyl pyrazine as raw materials, selectively synthesize 5-methyl pyrazine-2-carboxylic acid. Its technology is use 2,5 - dimethyl pyrazine as raw material, through oxidation of nitrogen and hydrogen peroxide, acetic anhydride acid oxidation, hydrolysis and oxidation process, gain 5-methyl pyrazine-2-carboxylic acid. HPLC analysis of their content is over 99%, with 0.1 mol / L of sodium hydroxide titration, content is not less 98%, melting point is not less than of 163 deg, the quality of medicine to meet glipizide, Acipimox requirements. The process is scheme simple, high-yield, low cost and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of usefulness 2, the 5-dimethylpyrazine is a raw material, and single selective synthesizes the method for 5-methylpyrazine-2-carboxylic acid, belongs to technical field of organic synthesis.
Background technology
5-methylpyrazine-2-carboxylic acid is the key intermediate of synthetic third generation treatment Rezulin Glipizide and hypolipidemic acipimox, and its existing synthetic method mainly contains microorganism synthesis method, electrochemical oxidation process and chemical synthesis.Electrochemical process needs to use earlier chemical method Synthetic 2-methyl-5-methylol pyrazine, adopts electrochemical process Synthetic 2-methylpyrazine-5-carboxylic acid (EP0316945,1989) then; Biological synthesis process is with 2, and the 5-dimethylpyrazine is a raw material, in the mash-back of 30 ℃ of PH=7.0 and room temperatures, cultivates pseudomonas with p-Xylol as the unique carbon source and the energy, and pseudomonas plays oxygenizement, and yield can reach 95% (US5213973,1993); Adopt the technology of preparing of chemical method to have: with 2, the 5-dimethylpyrazine is a raw material, through the chlorination of N-succinate chloride imines, again through esterification, alkaline hydrolysis, synthetic 5-methylpyrazine of four steps of oxidation-2-carboxylic acid, yield 47% (Org.Prep.Proced, Int., 1985,34 (2), 188-190); Be feedstock production 5-methylpyrazine-2-carboxylic acid with O-Phenylene Diamine and pyruvic aldehyde among the CN1392143; Directly with 2, the 5-dimethylpyrazine is a raw material among the CN1365974, adopt to add inhibitor potassium permanganate direct oxidation 2, and 5-dimethylpyrazine one-step synthesis 5-methylpyrazine-2-carboxylic acid, reaction yield can reach more than 60%.
The electrochemical process investment is big in the above technology, power consumption is high, product cost is high; Fermentation method yield height, but cultivate oxidation bacterial classification difficulty, and this technology is subjected to seasonal restriction; Prepare 5-methylpyrazine-2-carboxylic acid with O-Phenylene Diamine and pyruvic aldehyde among the CN1392143, need to consume a large amount of potassium permanganate and sulfuric acid, produce a large amount of wastes; Adopt the potassium permanganate direct oxidation 2 that has added inhibitor among the CN1365974,5-dimethylpyrazine one-step synthesis 5-methylpyrazine-2-carboxylic acid, the existence of inhibitor is in order to prevent that potassium permanganate from continuing oxidation 5-methylpyrazine-2-carboxylic acid, therefore the existence of inhibitor has reduced by 2 simultaneously, the transformation efficiency of 5-dimethylpyrazine, improved the consumption of potassium permanganate, by product pyrazine-2,5-dicarboxylic acid are difficult for separating from product.
Summary of the invention
The invention provides the preparation method of a kind of 5-methylpyrazine-2-carboxylic acid.This method technological process is simple, and product cost is low, and good product quality is fit to industrialized production.
With 2, the 5-methylpyrazine is a raw material, and substep is selected synthetic 5-methylpyrazine-2-carboxylic acid.Its operational path is as follows:
Technical scheme of the present invention:
1., with 2, the 5-dimethylpyrazine is a raw material, adds the suitable quantity of water dissolving, adds the appropriate amount of acid catalyzer, the hydrogen peroxide of Dropwise 5 %-40% is an oxygenant, reaction 2-10h, 2,5-dimethylpyrazine-1-oxide compound;
2., will 1. get product and acetic anhydride backflow 2-15h and obtain 2-acetyl-o-methyl-5-methylpyrazine;
3., after the solvent distillation reclaims in will be 2., add suitable quantity of water and alkali, controlled temperature drips potassium permanganate at 15-45 ℃; After having reacted, steam portion water, regulate PH=1.0-4.0, be cooled to 0-25 ℃, separate out crystallization, obtain 5-methylpyrazine-2-carboxylic acid with mineral acid.
Above-mentioned acid catalyst is: inorganic acid catalyst is sulfuric acid, phosphoric acid; Solid acid comprises wolframic acid, with many wolframic acids, assorted many wolframic acids, molybdic acid, isopolymolybdic acid, heteropolymolybdic acid and basic salt thereof;
Above-mentioned alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus;
Above-mentioned potassium permanganate can be that solid adds, and also can be that the aqueous solution adds;
The mineral acid of above-mentioned adjusting PH is hydrochloric acid, sulfuric acid, phosphoric acid;
Above-mentioned when adding potassium permanganate solution temperature of reaction be controlled at 15-45 ℃, optimum temperature range is at 15-20 ℃;
The invention has the advantages that product technology is simple, cost is low, 5-methylpyrazine-2-carboxylic acid yield can reach 66%.
Embodiment
1, single nitrogen oxidation
In the 1000ml reaction flask, add 108g2,5-dimethylpyrazine and 450ml water, 2.0g sodium wolframate, 2ml sulfuric acid dripped 30% hydrogen peroxide 114g with 2 hours in the time of 70 ℃, keep 70 ℃ and continue reaction 6 hours, get 2,5-dimethylpyrazine-1-oxide compound 115.3g, yield 93%.
2, the preparation of 2-acetyl-o-methyl-5-methylpyrazine
In the 500ml flask, add 24.8g2,5-dimethylpyrazine-1-oxide compound adds acetic anhydride 250ml, and behind the reflux 10h, the acetic acid of reclaim under reduced pressure acetic anhydride and generation gets residual oily matter 2-acetyl-o-methyl-5-methylpyrazine 28.5g, yield 86%.
3, hydrolysis oxidation
In the 500ml flask, add 16.6g2-acetyl-o-methyl-5-methylpyrazine, add 50ml and 0.5g sodium hydroxide, controlled temperature 20-25 ℃, dropping contains the 300ml aqueous solution of potassium permanganate 15.8g, drips off back insulation reaction 4 hours, removes by filter Manganse Dioxide, water liquid is concentrated into 40ml, transfer PH=1.0 with 6mol/L hydrochloric acid, be placed on refrigerator and be chilled to 3-5 ℃, filter 5-methylpyrazine-2-carboxylic acid 11.4g, yield 82.5% is with 0.1mol/L sodium hydroxide titration content 98.6%.
Claims (7)
1, the preparation method of a kind of 5-methylpyrazine-2-carboxylic acid, it is characterized in that: processing step is as follows:
With 2, the 5-dimethylpyrazine is a raw material, adopts the synthetic 5-methylpyrazine of method of fractional steps selectivity-2-carboxylic acid, its concrete route:
1. with 2, the selective oxidation of 5-dimethylpyrazine becomes single oxynitride, in 20-95 ℃ of scope, adopt water or acetic acid to make solvent, mineral acid or solid acid are catalyzer, and the hydrogen peroxide of 5%-40% is an oxygenant, reaction 2-24h steams solvent and promptly gets 2,5-dimethylpyrazine-1-oxide compound;
2. will 1. get product and acetic anhydride backflow 2-15h and obtain 2-acetyl-o-methyl-5-methylpyrazine;
3. will 2. get the product water dissolution, and add appropriate bases, stirring and dissolving drips potassium permanganate solution then, controlled temperature after reacting completely, steams portion water at 15-45 ℃, regulates PH=1.0-4.0 with mineral acid, be cooled to 0-25 ℃, separate out crystallization, obtain 5-methylpyrazine-2-carboxylic acid.
2, preparation method according to claim 1 is characterized in that: the inorganic acid catalyst that 1. step adopts is sulfuric acid, phosphoric acid; Solid acid comprises wolframic acid, with many wolframic acids, assorted many wolframic acids, molybdic acid, isopolymolybdic acid, heteropolymolybdic acid and basic salt thereof.
3, preparation method according to claim 3 is characterized in that: the 1. middle hydrogen peroxide concentration that adopts of step is 20%-30% preferably, and temperature range is preferably in 60-70 ℃, best 8-12h of reaction times.
4, according to right 1 requirement, it is characterized in that: the 3. middle alkali of step can be sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus.
5, according to right 1 requirement, it is characterized in that: the 3. middle accent PH mineral acid that adopts of step can be hydrochloric acid, sulfuric acid, phosphoric acid.
6, according to right 1 requirement, it is characterized in that: the PH scope is preferably in 1.0-3.0.
7, according to claim 1, it is characterized in that: the 3. middle cooling temperature of step is preferably in the 3-5 ℃ of scope.
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| CN100999502B CN100999502B (en) | 2011-02-23 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664805A (en) * | 2013-12-05 | 2014-03-26 | 华北水利水电大学 | Method for preparing acipimox |
| CN103694181A (en) * | 2013-11-29 | 2014-04-02 | 西安近代化学研究所 | Synthetic method of 2, 6-diamino-3, 5-binitropyrazine-1-oxide |
| CN104111279A (en) * | 2014-08-08 | 2014-10-22 | 广东东阳光药业有限公司 | Method for measuring content of 2-pyrazinecarboxylic acid |
| CN108017586A (en) * | 2018-01-26 | 2018-05-11 | 常州工程职业技术学院 | A kind of preparation method of 5-Methylpyrazine-2-carboxylic acid |
| CN109369544A (en) * | 2018-12-05 | 2019-02-22 | 兰州大学 | A kind of method that catalysis oxidation prepares 5-Methylpyrazine-2-carboxylic acid |
| CN116217499A (en) * | 2023-03-10 | 2023-06-06 | 常州大学 | Continuous preparation method and reaction system of 5-methylpyrazine-2-carboxylic acid |
-
2006
- 2006-12-31 CN CN2006101721826A patent/CN100999502B/en not_active Expired - Fee Related
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103694181A (en) * | 2013-11-29 | 2014-04-02 | 西安近代化学研究所 | Synthetic method of 2, 6-diamino-3, 5-binitropyrazine-1-oxide |
| CN103694181B (en) * | 2013-11-29 | 2015-03-25 | 西安近代化学研究所 | Synthetic method of 2, 6-diamino-3, 5-binitropyrazine-1-oxide |
| CN103664805A (en) * | 2013-12-05 | 2014-03-26 | 华北水利水电大学 | Method for preparing acipimox |
| CN103664805B (en) * | 2013-12-05 | 2016-05-11 | 华北水利水电大学 | A kind of method of preparing Acipimox |
| CN104111279A (en) * | 2014-08-08 | 2014-10-22 | 广东东阳光药业有限公司 | Method for measuring content of 2-pyrazinecarboxylic acid |
| CN108017586A (en) * | 2018-01-26 | 2018-05-11 | 常州工程职业技术学院 | A kind of preparation method of 5-Methylpyrazine-2-carboxylic acid |
| CN108017586B (en) * | 2018-01-26 | 2021-04-23 | 常州工程职业技术学院 | Preparation method of 5-methylpyrazine-2-carboxylic acid |
| CN109369544A (en) * | 2018-12-05 | 2019-02-22 | 兰州大学 | A kind of method that catalysis oxidation prepares 5-Methylpyrazine-2-carboxylic acid |
| CN109369544B (en) * | 2018-12-05 | 2022-06-03 | 兰州大学 | Method for preparing 5-methylpyrazine-2-carboxylic acid by catalytic oxidation |
| CN116217499A (en) * | 2023-03-10 | 2023-06-06 | 常州大学 | Continuous preparation method and reaction system of 5-methylpyrazine-2-carboxylic acid |
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