CN102417485A - Synthetic method of 2,5-dimethyl-3-chloropyrazine - Google Patents
Synthetic method of 2,5-dimethyl-3-chloropyrazine Download PDFInfo
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- CN102417485A CN102417485A CN2011101366878A CN201110136687A CN102417485A CN 102417485 A CN102417485 A CN 102417485A CN 2011101366878 A CN2011101366878 A CN 2011101366878A CN 201110136687 A CN201110136687 A CN 201110136687A CN 102417485 A CN102417485 A CN 102417485A
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Abstract
The invention provides a synthetic method of 2,5-dimethyl-3-chloropyrazine, comprising the following steps: step A, adding water and 2,5-dimethyl pyrazine in a reactor, using monoperoxy diphenyl acid as a catalyst, at room temperature, adding hydrogen peroxide dropwisely, letting the system automatically heat up, carrying out reaction at the temperature of 60-80 DEG C, after reacting for 6 h, cooling, filtering and drying to obtain a step-A product with a purity of more than 98 % and a yield of 90 %; and step B, adding toluene, phosphorous oxychloride and the step-A product in the reactor at room temperature, heating up to 70 DEG C, releasing heat by the system automatically until reflux, after 30 min stopping the reaction, drying the solvent by distillation, pouring the obtained product into crushed ice, stirring for about 1 h, separating the liquid, and drying by distillation to obtain a crude product, and carrying out simply distillation to obtain a colorless watery liquid as the product. The method has the advantages of easy obtainment of raw materials, simple synthetic route, and no generation of large amount of by-products, and is easy to industrial production.
Description
Technical field
The present invention relates to a kind of 2, the compound method of 5-dimethyl--3-chloropyrazine.
Background technology
Document (ioorganic and Medicinal Chemistry Letters; 2007; 17,6250) clearly speak of 2 in, 5-dimethyl--3-chloropyrazine is as the important intermediate of anxiety and depression and field medicine CRF1 receptor antagonists such as irritable bowel syndrome, pain and neuroprotective.See formula 6
Has vast market prospect.
2,5-dimethyl--3-chloropyrazine plays important effect in the process of synthetic drugs.2 of present bibliographical information, the synthetic route of 5-dimethyl--3-chloropyrazine is:
2, though the synthetic of 5-dimethyl--3-chloropyrazine has more document to report, all there are the problem of some each side in these routes and method, cause this product never to realize suitability for industrialized production.Through the Synthetic 2 to present report, the document of 5-dimethyl--3-chloropyrazine is analyzed and researched, and mainly contains following three synthetic routes:
Article one, route is the present route that we adopt, and with 2, the 5-dimethylpyrazine is a starting raw material, and through the N-oxidation, chlorination is synthesized.But there is following defective in the document of report at present: 1, use a large amount of organic solvents in the bibliographical information, like acetate, methylene dichloride, acetone etc., cost is higher, pollutes big; 2, the reaction of acetate and ydrogen peroxide 50 generates the Peracetic Acid midbody in the first step reaction process, remove after reaction finishes cumbersome, the residual danger that sets off an explosion easily; 3, product is with a large amount of dichloromethane extraction gained, and cost increases, and the three wastes are more; 4, reaction is violent, wayward.
The second route is through the propanedioic acid cyclization, and two steps of chlorination obtain product.Severe reaction conditions, yield is lower, and cost is higher, and amplification production difficulty is bigger.See formula 4
Article three, route methylates through the glyoxal ethyline quinoline, and ring expansion obtains product.Reaction conditions requires high, and a large amount of hypertoxic solvents are dangerous higher, are difficult to carry out industrial amplification production.See formula 5
Comprehensive above three routes, though there has been more document that title product is synthesized, because such-and-such deficiency never has a kind of proper method up till now and is applicable to production and scale amplification.So how this product is accomplished scale production, find a cost low, be applicable to the route that production operation and mass-producing are amplified, most important for the widespread use of this product.In view of the situation, we have carried out repeated screening and optimization for this product synthetic method and route, have developed present this operational path at last.
Summary of the invention
In view of this, the present invention proposes a kind of new 2, the compound method of 5-dimethyl--3-chloropyrazine, this method starting raw material is easy to get, synthetic route is simple, does not have a large amount of by products to produce, and is easy to suitability for industrialized production.
Of the present invention 2, the compound method of 5-dimethyl--3-chloropyrazine is carried out according to the following steps:
(1) the first step adds entry, 2 in the reactor drum, 5-dimethylpyrazine, single peroxide two benzoic acids be as catalyzer, room temperature; Drip ydrogen peroxide 50, system heats up automatically, and temperature of reaction 60-80 ℃, after reacting 6 hours; Cooling, the suction filtration oven dry step product of promptly winning, purity be more than 98%, yield about 90%;
Second step added toluene, POCl3, the first step product in the room temperature downhill reaction device, be warming up to 70 ℃; The automatic heat release of system is to refluxing stopped reaction after 30 minutes, solvent evaporated; Gains are poured in the trash ice, stir separatory about one hour; Evaporate to dryness gets bullion, and it is product that simple distillation promptly gets colourless aqueous liquid;
The present invention and compared with techniques in the past have the following advantages: (1) the first step water, be system, and pollution-free, select 30-80 ℃ of temperature of reaction dropwise operation for use; Mild condition is easy to control, and safety system is high; Aftertreatment cooling back directly suction filtration obtains product, and mother liquor can be applied mechanically repeatedly, and energy consumption is low; Low-carbon environment-friendly is fit to industrial production and amplifies good process repeatability; (2) second steps replaced pure POCl3 system with toluene, POCl3 system, reduced the POCl3 consumption, reduced production costs; Reaction temperature is lacked with polluting, and the direct separatory of aftertreatment, distillation can get product, and be easy and simple to handle; Being easy to amplify the production other features and advantages of the present invention will set forth in specification sheets subsequently; And, partly from specification sheets, become obvious, perhaps understand through embodiment of the present invention.
Embodiment
Following embodiments of the invention describe, and should be appreciated that embodiment described herein only is used for explanation and explains the present invention, and are not used in qualification the present invention.
Describe in the face of embodiments of the invention down.
Embodiment 1
2, the compound method of 5-dimethyl--3-chloropyrazine is carried out according to the following steps:
(1) the first step adds entry, 2 in the reactor drum, 5-dimethylpyrazine, single peroxide two benzoic acids be as catalyzer, room temperature; Drip ydrogen peroxide 50, system heats up automatically, and temperature of reaction 60-80 ℃, after reacting 6 hours; Cooling, the suction filtration oven dry step product of promptly winning, purity be more than 98%, yield about 90%;
(2) second steps added toluene, POCl3, the first step product in the room temperature downhill reaction device, be warming up to 70 ℃; The automatic heat release of system is to refluxing stopped reaction after 30 minutes, solvent evaporated; Gains are poured in the trash ice, stir separatory about one hour; Evaporate to dryness gets bullion, and it is product that simple distillation promptly gets colourless aqueous liquid.This method starting raw material is easy to get, and synthetic route is simple, does not have a large amount of by products to produce, and is easy to suitability for industrialized production.
The above is merely the preferred embodiments of the present invention, is not limited to the present invention, and for a person skilled in the art, the present invention can have various changes and variation.All within spirit of the present invention and principle, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (1)
1. one kind 2,5-dimethyl--3-chloropyrazine compound method is characterized in that: carry out according to the following steps:
(1) the first step adds entry, 2 in the reactor drum, 5-dimethylpyrazine, single peroxide two benzoic acids be as catalyzer, room temperature; Drip ydrogen peroxide 50, system heats up automatically, and temperature of reaction 60-80 ℃, after reacting 6 hours; Cooling, the suction filtration oven dry step product of promptly winning, purity be more than 98%, yield about 90%;
(2) second steps added toluene, POCl3, the first step product in the room temperature downhill reaction device, be warming up to 70 ℃; The automatic heat release of system is to refluxing stopped reaction after 30 minutes, solvent evaporated; Gains are poured in the trash ice, stir separatory about one hour; Evaporate to dryness gets bullion, and it is product that simple distillation promptly gets colourless aqueous liquid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2011101366878A CN102417485A (en) | 2011-05-25 | 2011-05-25 | Synthetic method of 2,5-dimethyl-3-chloropyrazine |
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| CN2011101366878A CN102417485A (en) | 2011-05-25 | 2011-05-25 | Synthetic method of 2,5-dimethyl-3-chloropyrazine |
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| CN102417485A true CN102417485A (en) | 2012-04-18 |
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| CN2011101366878A Pending CN102417485A (en) | 2011-05-25 | 2011-05-25 | Synthetic method of 2,5-dimethyl-3-chloropyrazine |
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Cited By (1)
| 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 |
-
2011
- 2011-05-25 CN CN2011101366878A patent/CN102417485A/en active Pending
Cited By (2)
| 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 |
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Application publication date: 20120418 |