CN1155581C - Process for preparing 5-methyl pyrazine-2-carboxylic acid - Google Patents
Process for preparing 5-methyl pyrazine-2-carboxylic acid Download PDFInfo
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- CN1155581C CN1155581C CNB021379874A CN02137987A CN1155581C CN 1155581 C CN1155581 C CN 1155581C CN B021379874 A CNB021379874 A CN B021379874A CN 02137987 A CN02137987 A CN 02137987A CN 1155581 C CN1155581 C CN 1155581C
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- carboxylic acid
- methylpyrazine
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- butanone
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Abstract
The present invention relates to a method for preparing 5-methylpyrazine-2-carboxylic acid. In the method, methylglyoxal and o-phenylenediamine are used as basic raw materials, 5-methylpyrazine-2-carboxylic acid having a melting point at the temperature of 164 to 172 DEG C can be obtained under the cyclization of catalysts through oxidation with inorganic oxidizers, acidification with sulfuric acid, decarboxylation, extraction and separation with butanone at the pH value of 1.5 to 4.0, crystallization, drying, baking and pulverization. The 5-methylpyrazine-2-carboxylic acid can be used as a midbody for synthesizing a third generation medicine (glipizide) for treating diabetes and medicines (acipimox or olbetam) for lowering blood fat. The raw materials utilized in the method can be easily obtained, synthesis technology is simple, and production scale is flexible; the price of products is lower than that of imported products, and the quality of the products conforms to the requirements for the medicinal midbody.
Description
Technical field
The present invention relates to the preparation method of a kind of 5-methylpyrazine-2-carboxylic acid, belong to the preparation of medicine intermediate.
Background technology
Along with the raising day by day of people's living standard, the sickness rate of diabetes and high fat of blood increases day by day.The pharmaceutical requirements amount for the treatment of this type of disease also increases thereupon.5-methylpyrazine-2-carboxylic acid is one of intermediate of this similar drug of preparation.Prior preparation method mainly contains three kinds: the first is the synthesis method of raw material with two amido succinonitrile.Though this method operational path is simple, transformation efficiency is higher, synthetic high temperature, high pressure and the raw material severe toxicity of needing of two amido butyronitrile itself, and synthetic route is longer, the processing condition harshness, no manufacturer production in the native land, import price is high again.Even abroad, suitability for industrialized production does not adopt this method yet; It two is 2,5-dimethylpyrazine electrolytic oxidation.This method is ripe, but 2,5-dimethylpyrazine itself synthetic, and existence conditions is still had any problem at home, and import price is high, so can't adopt from the production cost consideration; It three is fermentation methods.Though this method technology is ripe, be subjected to the seasonal restriction of raw material, each amount of fermentation is bigger, is difficult to produce at any time according to the market requirement, in addition, product impurity more (fusing point is 160～172 ℃).
Summary of the invention
The objective of the invention is to, the preparation method of a kind of 5-methylpyrazine-2-carboxylic acid is provided.This method is raw materials used to be easy to get, easy and simple to handle, industrial scale flexibly, product purity increases.
Realize the technical scheme of the object of the invention: the preparation method of a kind of 5-methylpyrazine-2-carboxylic acid is a basic raw material with pyruvic aldehyde and O-Phenylene Diamine, makes through following step:
1. cyclization: pyruvic aldehyde and O-Phenylene Diamine in 30～90 ℃ of reaction 0.5～2h, are finished ring-closure reaction in the presence of the catalyzer Sodium Pyrosulfite, through neutralization, processing industry salt, dewater, rectifying obtains 3-methyl benzopyrazines;
2. oxidation: use inorganic oxidizer, with the 1. 3-methyl benzopyrazines of step gained, in 60～105 ℃ of reaction 1～4h, finish oxidizing reaction, through cooling, the filtrate behind the separating solid residue is evaporated to 115 ± 3 ℃, and cooling obtains 5-methylpyrazine-2,3-carboxylic acid potassium;
3. acidifying and decarboxylation: 2. step gained 5-methylpyrazine-2,3-carboxylic acid potassium at 30～130 ℃, carries out acidifying and decarboxylation with sulfuric acid, sulfuric acid and 5-methylpyrazine-2, the mol ratio of 3-carboxylic acid potassium is 1.5～3.0: 1;
4. extracting and separating: the decarboxylation post neutralization to pH be 1.5～4.0, with butanone extraction 5-methylpyrazine-2-carboxylic acid, remove butanone with ordinary method, crystallization, drying, oven dry and pulverizing are finished product 5-methylpyrazine-2-carboxylic acid, its content 〉=99%, structural formula is as follows:
Among the above-mentioned preparation method, 2. the used inorganic oxidizer of step is potassium permanganate, perhaps potassium bichromate.These two kinds of oxygenants are easy to get, price is low, dangerous little in using, particularly potassium permanganate is all the more so.
Among the above-mentioned preparation method, 1. the rectifying described in the step be-0.092MPa～-vacuum tightness of 0.1MPa under rectifying, collect 95～130 ℃ 3-methyl benzopyrazines fraction.The purity of the 3-methyl benzopyrazines that obtains under this condition improves, and more helps the reaction in following each step, also more helps the raising of the finished product purity.
Among the above-mentioned preparation method, 2. the solid residue described in the step can directly utilize after reclaiming, and also can further process the back again and use.4. the mother liquor after the extraction can reach emission standard in the step after alkali neutralization and biochemical treatment, and the butanone that removes can return again and be used for extraction.Environmentally safe also can reduce cost.
Among the above-mentioned preparation method, 3. the acidifying of step and decarboxylation and 4. the extraction of step can in same equipment, finish.Can reduce facility investment like this and reduce floor space.
Technique effect of the present invention: basic raw material pyruvic aldehyde and O-Phenylene Diamine selected in the technical solution of the present invention are domestic common chemical raw materials, and the source is abundant, price is lower.In preparation process, no matter be cyclization, oxidation, acidifying and operations such as decarboxylation, extraction, do not need harsh processing condition or specific installation such as high temperature, pressurization, therefore, the preparation method is easy to grasp, production-scale size can be decided according to the market requirement, even utilizes breadboard equipment also can produce.Few and process butanone extracting and separating and crystallization of side reaction makes product content 〉=99%, fusing point reach 164～172 ℃ in each preparation process, the product (160～172 ℃ of fusing points) of existing fermentation method, and purity increases.
Description of drawings
Fig. 1, preparation method's of the present invention technological process block-diagram, oxygenant adopts KMnO
4
Embodiment
Below in conjunction with drawings and Examples, preparation method of the present invention is further described in detail, but is not limited to this.
Embodiment
(1) main chemical reactions that relates among the preparation method
1. cyclization:
2. oxidation:
3. acidifying:
Decarboxylation:
(2) main raw material, specification and consumption
| Material name | Specification | Consumption (kg/kg) |
| Pyruvic aldehyde CH 3COCHO O-Phenylene Diamine C 6H 4(NH 2) 2Sodium Pyrosulfite Na 2S 2O 5Potassium permanganate KMnO 4Industrial Salt NaCl sulfuric acid H 2SO 4Liquid caustic soda NaOH butanone CH 3COCH 2CH 3 | Industrial goods (by 100%) industrial goods, 98% industrial goods, 98% industrial goods, 98% industrial goods, 98% industrial goods, 98% industrial goods, 40% industrial goods | 7.00 8.50 6.75 38.00 35.00 31.00 an amount of 100 |
(3) preparation process
1. cyclization
In the 200L reactor, add Sodium Pyrosulfite 6.75kg and water 13kg, stirring and dissolving 0.5h, add pyruvic aldehyde 7.00kg and stirring, in advance O-Phenylene Diamine 8.50kg and 17kg water are added ℃ dissolving of 100L header tank internal heating to 80, splash into then in the above-mentioned 200L reactor.Stir down, finish ring-closure reaction at 60～80 ℃ of reaction 0.5h, be cooled to 30～40 ℃, dropwise liquid adds Industrial Salt 35.00kg after transferring the DH value to be 7.0～7.5, is warming up to 50 ℃ of dissolvings again, leave standstill the back branch vibration layer, organic layer is sent in the 100L rectifying still, adds thermal rectification in vacuum tightness under-the 0.092MPa, and the about 6.00kg of fraction that collects 95～130 ℃ of scopes is 3-methyl benzopyrazines;
2. oxidation
To 1. step gained 6.00kg3-methyl benzopyrazines, drop in the 500L oxidizing reactor, stir down and add 3kg water and be warming up to 80 ℃, in advance in the 200L header tank, add 38kg potassium permanganate and 110kg water wiring solution-forming, splash in the above-mentioned oxidizing reactor, temperature is controlled at 100～103 ℃, and the carbonic acid gas emptying at any time that oxidizing reaction generates dropwises and is incubated 0.5h again, cold filtration separates, solid manganese dioxide reclaims, and filtrate is sent into 500L container internal heating and dewatered, steam to temperature in the kettle be 115 ± 3 ℃ of blowings, cooling is oxidation products 5-methylpyrazine-2,3-carboxylic acid potassium;
3. acidifying and decarboxylation
2. the 5-methylpyrazine-2 that step is obtained, 3-carboxylic acid potassium all drops in 200L acidifying and the decarboxylic reaction still, splashes into 10kg sulfuric acid and is controlled in 80 ℃ with jacket water (J.W.) cooling, finishes acidifying and becomes 5-methylpyrazine-2, the 3-carboxylic acid, continue subsequently to drip 21kg sulfuric acid fast in reactor, temperature is controlled at 115 ± 10 ℃, finishes and is incubated the 1h postcooling again, decarboxylation is finished, wherein, used sulfuric acid of acidifying and decarboxylation and 5-methylpyrazine-2, the mol ratio of 3-carboxylic acid potassium is 2.5 ± 0.1;
4. extracting and separating
In the reactor of 3. step, add 20kg water.Transferring to pH at 50 ℃ of dropwise liquids (40%) is 1.5～4.0 scope, adds the 100kg butanone, stirs the about 0.5h of extraction, isolates the butanone solution that contains 5-methylpyrazine-2-carboxylic acid, send into remove butanone in the common vacuum distilling apparatus after.With 3kg water flushing blowing, crystallisation by cooling, drying, oven dry and pulverizing promptly obtain 5-methylpyrazine-2-carboxylic acid, measure fusing point at 164～172 ℃, content 99.5% (HPLC mensuration);
The mother liquor of extracting and separating, behind alkali neutralization sulfuric acid wherein, separate solid can discharge, and liquid portion carries out biochemical treatment and reaches emission standard and discharge, and the butanone that steams can return and remake extraction solvent and use.
5-methylpyrazine-2-the carboxylic acid that adopts aforesaid method to make, its content 〉=99% (HPLC mensuration) is suitable as medicine intermediate fully.Particularly suitable is made the intermediate of synthetic third generation treatment Rezulin (Glipizide) and hypolipidemic (Olbetam or olbetam), and price is lower than imported product, and production process is pollution-free.
Claims (6)
1, the preparation method of 5-methylpyrazine-2-carboxylic acid is characterized in that, is basic raw material with pyruvic aldehyde and O-Phenylene Diamine, makes through following step:
1. cyclization: pyruvic aldehyde and O-Phenylene Diamine in 30～90 ℃ of reaction 0.5～2h, are finished ring-closure reaction in the presence of the catalyzer Sodium Pyrosulfite, through neutralization, processing industry salt, dewater, rectifying obtains 3-methyl benzopyrazines;
2. oxidation: use inorganic oxidizer, with the 1. 3-methyl benzopyrazines of step gained, in 60～105 ℃ of reaction 1～4h, finish oxidizing reaction, through cooling, the filtrate behind the separating solid residue is evaporated to 115 ± 3 ℃, and cooling obtains 5-methylpyrazine-2,3-carboxylic acid potassium;
3. acidifying and decarboxylation: 2. step gained 5-methylpyrazine-2,3-carboxylic acid potassium at 30～130 ℃, carries out acidifying and decarboxylation with sulfuric acid, sulfuric acid and 5-methylpyrazine-2, the mol ratio of 3-carboxylic acid potassium is 1.5～3.0: 1;
4. extracting and separating: the decarboxylation post neutralization to pH be 1.5～4.0, with butanone extraction 5-methylpyrazine-2-carboxylic acid, remove butanone with ordinary method, crystallization, drying, oven dry and pulverizing are finished product 5-methylpyrazine-2-carboxylic acid, its content 〉=99%, structural formula is as follows:
2, preparation method according to claim 1 is characterized in that, 2. the used inorganic oxidizer of step is potassium permanganate, perhaps potassium bichromate.
3, preparation method according to claim 1 and 2 is characterized in that, 1. the rectifying described in the step be-0.092MPa～-vacuum tightness of 0.1MPa under rectifying, collect 95～130 ℃ 3-methyl benzopyrazines fraction.
4, preparation method according to claim 1 and 2 is characterized in that, 2. the solid residue described in the step reclaims directly utilization of back, or further processes the back again and use.
5, preparation method according to claim 1 and 2 is characterized in that, 4. the mother liquor after the extraction reaches emission standard in the step after alkali neutralization and biochemical treatment, and the butanone that removes returns and is used for extraction.
6, preparation method according to claim 1 and 2 is characterized in that, 3. the acidifying of step and decarboxylation and 4. the butanone extraction of step in same equipment, finish.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB021379874A CN1155581C (en) | 2002-07-17 | 2002-07-17 | Process for preparing 5-methyl pyrazine-2-carboxylic acid |
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| CNB021379874A CN1155581C (en) | 2002-07-17 | 2002-07-17 | Process for preparing 5-methyl pyrazine-2-carboxylic acid |
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| CN1155581C true CN1155581C (en) | 2004-06-30 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101519379B (en) * | 2009-04-14 | 2011-02-02 | 凯莱英生命科学技术(天津)有限公司 | Method for preparing 5-methylprazine-2-carboxylic acid |
| CN101899012B (en) * | 2009-05-30 | 2012-05-30 | 鲁南制药集团股份有限公司 | Method for improving synthesis process of Acipimox |
| CN103420927A (en) * | 2013-06-07 | 2013-12-04 | 华中农业大学 | Synthetic method of quinoxaline-2-carboxylic acid |
| CN103664805B (en) * | 2013-12-05 | 2016-05-11 | 华北水利水电大学 | A kind of method of preparing Acipimox |
| CN108059621A (en) * | 2018-01-26 | 2018-05-22 | 常州工程职业技术学院 | A kind of process for purification of high-purity 5-Methylpyrazine-2-carboxylic acid |
| CN112010846A (en) * | 2019-05-30 | 2020-12-01 | 四川大学华西医院 | Pyridine derivative and preparation method and application thereof |
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