CN105439963B - The method that 4,6 dichloro pyrimidines are prepared under sulfuric acid catalysis - Google Patents
The method that 4,6 dichloro pyrimidines are prepared under sulfuric acid catalysis Download PDFInfo
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- CN105439963B CN105439963B CN201610062437.7A CN201610062437A CN105439963B CN 105439963 B CN105439963 B CN 105439963B CN 201610062437 A CN201610062437 A CN 201610062437A CN 105439963 B CN105439963 B CN 105439963B
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- sulfuric acid
- pyrimidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to prepare 4 under sulfuric acid catalysis, the method of 6 dichloro pyrimidines, can effectively solve 4, 6 dichloro pyrimidine yields are low, cost is high, the problem of being difficult to industrialized production, method is, in the presence of sulphuric acid, with triphosgene or surpalite and 4, 6 dihydroxy-pyrimidines react, specific method is, by 4, 6 dihydroxy-pyrimidines, sulfuric acid and N, N dimethylformamides mix, it is well mixed, it is heated to 80 100 DEG C, into mixed solution, triphosgene or surpalite are dissolved in solvent, it was slowly added dropwise in 12 hours in mixed solution, after dripping, continue insulated and stirred 3 hours, it is cooled to room temperature, pour into frozen water, separate organic solvent layer, organic solvent layer is washed, dried with anhydrous magnesium sulfate, produce 4, 6 dichloro pyrimidines；The inventive method is simple, easy to operate, and abundant raw material, cost is low, good product quality, and yield is high, and organic matter easily reclaims, and non-environmental-pollution is easy to industrialized production, and economic and social benefit is huge.
Description
Technical field
The present invention relates to chemical industry, method that 4,6- dichloro pyrimidines are prepared under particularly a kind of sulfuric acid catalysis.
Background technology
4,6- dichloro pyrimidines are important chemical intermediates, are had been widely used in agricultural chemicals and medical industry tool, such as can
With for preparing bactericide Fluoxastrobin, nucleoside analog and biologically active drug.
Its existing primary synthetic methods has：
Reacted by raw material and phosphonic chloride or thionyl chloride of 4,6- dihydroxy-pyrimidines（United States Patent (USP) 5583226,5723612,
Chinese patent 102936224 etc.）.It is substantial amounts of due to being produced after reaction although this method yield is preferable, the most frequently used in the industry
Phosphoric acid or sulfide are difficult to handle, and three waste discharge is big, seriously pollute environment, thus are gradually eliminated.
With 4,6- dihydroxy-pyrimidines for raw material, with organic amine such as triethylamine or DMA（Chinese patent
1687036,101898925, United States Patent (USP) 5750694）Or DMF is catalyst and phosgene or solid phosgene
Reaction.The main accessory substance carbon dioxide of this method, in theory with it is green the characteristics of.But organic amine price is higher,
A large amount of uses are very uneconomical, and reclaim difficult；For DMF because catalytic activity is low, reaction yield is very low, difficult
With industrialization.
The content of the invention
For the above situation, to overcome the defect of prior art, the purpose of the present invention is just to provide under a kind of sulfuric acid catalysis
The method for preparing 4,6- dichloro pyrimidines, it is low effectively to solve 4,6- dichloro pyrimidine yields, and cost is high, it is difficult to which industrialized production is asked
Topic.
The technical scheme that the present invention solves is, the present invention in the presence of sulphuric acid, with triphosgene or surpalite and 4,6- dihydroxies
Yl pyrimidines react, and specific method is to mix 4,6- dihydroxy-pyrimidines, sulfuric acid and DMF, mixing
Uniformly, 80-100 DEG C is heated to, into mixed solution, triphosgene or surpalite are dissolved in solvent, within 1-2 hours slowly
It is added dropwise in mixed solution, after dripping, continues insulated and stirred 3 hours, be cooled to room temperature, pour into frozen water, separate organic
Solvent layer, organic solvent layer washing, is dried with anhydrous magnesium sulfate, produces 4,6- dichloro pyrimidines；
Described 4,6- dihydroxy-pyrimidines and the mol ratio of triphosgene are 1 ︰ 0.5-5；4,6- dihydroxy-pyrimidines and surpalite
Mol ratio be 1 ︰ 1-10；
The mass concentration of described sulfuric acid is 90-98%, and the volume ratio of sulfuric acid and DMF is 20-40 ︰ 1；
Described 4,6- dihydroxy-pyrimidines and the mol ratio of sulfuric acid are 1 ︰ 1-100；
Described solvent is dichloro-benzenes, nitrobenzene or its mixture.
The inventive method is simple, easy to operate, and abundant raw material, cost is low, good product quality, and yield is high, and organic matter easily reclaims,
Non-environmental-pollution, is easy to industrialized production, and economic and social benefit is huge.
Embodiment
The embodiment of the present invention is elaborated with reference to embodiments.
The present invention can be provided in specific implementation by following examples.
Embodiment 1
In reaction vessel（Such as test the reaction bulb of flat bottom glass）Middle 11.2 grams of addition 4,6- dihydroxy-pyrimidines, the milli of sulfuric acid 20
Rise, 0.5 milliliter of DMF, be well mixed, be heated to 80 DEG C, it is into mixed solution, 30 grams of triphosgenes are molten
In 50 milliliters of dichloro-benzenes, it is slowly added dropwise in 1.2 hours in mixed solution, drips follow-up continuous insulated and stirred after 3 hours, it is cold
But to room temperature, pour into frozen water, separate organic solvent layer, organic solvent layer washing, then dried with anhydrous magnesium sulfate, produce 4,6-
Dichloro pyrimidine, yield 97%, mass content are more than 99%（Syrups by HPLC）；
Product is analyzed through proton nmr spectra：1HNMR（400MHz, CDCl3）δ7.51（S, 1H）, 8.89（S, 1H）；Mass spectrum
Analysis：ESI-MS, m/z:149.1 [M-H], are defined as 4,6- dichloro pyrimidines.
Embodiment 2
11 grams of 4,6- dihydroxy-pyrimidines, 10 milliliters of sulfuric acid, the milli of DMF 0.5 are added in reaction vessel
Rise, be well mixed, be heated to 90 DEG C, into mixed solution, 30 grams of triphosgenes be dissolved in 50 milliliters of nitrobenzene, 1.5 hours
Inside it is slowly added dropwise in mixed solution, drips follow-up continuous insulated and stirred after 3 hours, be cooled to room temperature, pour into frozen water, separate
Organic solvent layer, organic solvent layer washing, then dried with anhydrous magnesium sulfate, 4,6- dichloro pyrimidines are produced, yield 93%, quality contains
Amount is more than 99%（Syrups by HPLC）；
Product is analyzed through proton nmr spectra：1HNMR（400MHz, CDCl3）δ7.51（S, 1H）, 8.89（S, 1H）；Low point
Distinguish mass spectral analysis：ESI-MS, m/z:149.1 [M-H], are defined as 4,6- dichloro pyrimidines.
Embodiment 3
11 grams of 4,6- dihydroxy-pyrimidines, 12 milliliters of sulfuric acid, the milli of DMF 0.5 are added in reaction vessel
Rise, be well mixed, be heated to 98 DEG C, into mixed solution, 30 grams of triphosgenes are dissolved in the ︰ 1 of volume ratio 1 dichloro-benzenes and nitro
In 50 milliliters of the mixed liquor of benzene, it is slowly added dropwise in 2 hours in mixed solution, drips follow-up continuous insulated and stirred after 3 hours, it is cold
But to room temperature, pour into frozen water, separate organic solvent layer, organic solvent layer washing, then dried with anhydrous magnesium sulfate, produce 4,6-
Dichloro pyrimidine, yield 92%, mass content are more than 99%（Syrups by HPLC）；
Proton nmr spectra is analyzed：1HNMR（400MHz, CDCl3）δ7.51（S, 1H）, 8.89（S, 1H）；Low Resolution Mass Spectra
Analysis：ESI-MS, m/z:149.1 [M-H], are defined as 4,6- dichloro pyrimidines.
Above-described embodiment through anti-test of many times, achieve it is same or like as result, show that method is reliable and stable,
Tool has significant practical applications, effective for industrialized production.
From the foregoing, product of the present invention is analyzed through proton nmr spectra and mass spectral analysis, it is defined as 4,6- dichloro pyrimidines,
And good product quality, mass content more than 99%, preparation method is simple, and abundant raw material, cost is low, and yield is up to 97%, and existing
Technology is compared, and the present invention, as catalyst, is avoided using the expensive organic base for being difficult to reclaim using sulfuric acid cheap and easy to get（Three
Ethamine or DMA）Make catalyst（For the quotation of the technical grade concentrated sulfuric acid typically per ton below 800 yuan, triethylamine is every
Ton quotation is 1.2 ten thousand or so, and dimethylaniline quotation per ton is 1.5 ten thousand or so）, urged using DMF merely
Change, general yield is no more than 30%, well below the yield of the present invention（Yield minimum 92% of the present invention）, that is to say, that this hair
Bright yield is significantly larger than prior art, and in production practices, catalyst and solvent easily reclaim, both non-environmental-pollution, and greatly
Production cost is reduced greatly, economic and social benefit is huge.
Claims (3)
1. the method for 4,6- dichloro pyrimidines is prepared under a kind of sulfuric acid catalysis, it is characterised in that 4,6- bis- is added in reaction vessel
11.2 grams of hydroxy pyrimidine, 20 milliliters of sulfuric acid, 0.5 milliliter of DMF, it is well mixed, is heated to 80 DEG C, into
Mixed solution, 30 grams of triphosgenes are dissolved in 50 milliliters of dichloro-benzenes, is slowly added dropwise in mixed solution, drips in 1.2 hours
Follow-up continuous insulated and stirred is cooled to room temperature, poured into frozen water after 3 hours, separates organic solvent layer, and organic solvent layer is washed, then
Dried with anhydrous magnesium sulfate, produce 4,6- dichloro pyrimidines.
2. the method for 4,6- dichloro pyrimidines is prepared under a kind of sulfuric acid catalysis, it is characterised in that 4,6- bis- is added in reaction vessel
11 grams of hydroxy pyrimidine, 10 milliliters of sulfuric acid, 0.5 milliliter of DMF, it is well mixed, is heated to 90 DEG C, into mixed
Solution is closed, 30 grams of triphosgenes are dissolved in 50 milliliters of nitrobenzene, are slowly added dropwise in 1.5 hours in mixed solution, after dripping
Continue insulated and stirred after 3 hours, be cooled to room temperature, pour into frozen water, separate organic solvent layer, organic solvent layer washing, then use
Anhydrous magnesium sulfate is dried, and produces 4,6- dichloro pyrimidines.
3. the method for 4,6- dichloro pyrimidines is prepared under a kind of sulfuric acid catalysis, it is characterised in that 4,6- bis- is added in reaction vessel
11 grams of hydroxy pyrimidine, 12 milliliters of sulfuric acid, 0.5 milliliter of DMF, it is well mixed, is heated to 98 DEG C, into mixed
Solution is closed, 30 grams of triphosgenes are dissolved in the ︰ 1 of volume ratio 1 dichloro-benzenes and 50 milliliters of the mixed liquor of nitrobenzene, in 2 hours slowly
It is added dropwise in mixed solution, drips follow-up continuous insulated and stirred after 3 hours, be cooled to room temperature, pour into frozen water, separate organic molten
Oxidant layer, organic solvent layer washing, then dried with anhydrous magnesium sulfate, produce 4,6- dichloro pyrimidines.
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| CN110204495A (en) * | 2019-06-03 | 2019-09-06 | 浙江工业大学 | A kind of preparation method of chloro polyhydroxy nitrogen heteroaromatic rings compound |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1687036A (en) * | 2005-06-20 | 2005-10-26 | 江苏省激素研究所有限公司 | Method for preparing 4,6 dichloropyridine |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1687036A (en) * | 2005-06-20 | 2005-10-26 | 江苏省激素研究所有限公司 | Method for preparing 4,6 dichloropyridine |
Non-Patent Citations (1)
| Title |
|---|
| 2-丙硫基-4,6-二氯-5-氨基嘧啶的合成;吴倩倩等;《中国医药工业杂志》;20131231;第44卷(第6期);第557-559页 * |
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