CN105439963A - Method for preparing 4,6-dichloropyrimidine under sulfuric acid catalysis - Google Patents
Method for preparing 4,6-dichloropyrimidine under sulfuric acid catalysis Download PDFInfo
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- CN105439963A CN105439963A CN201610062437.7A CN201610062437A CN105439963A CN 105439963 A CN105439963 A CN 105439963A CN 201610062437 A CN201610062437 A CN 201610062437A CN 105439963 A CN105439963 A CN 105439963A
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- sulfuric acid
- pyrimidine
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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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Abstract
The invention relates to a method for preparing 4,6-dichloropyrimidine under sulfuric acid catalysis. By the adoption of the method, the problems that the yield of 4,6-dichloropyrimidine is low, cost is high, and industrial production is hard to achieve can be effectively solved. According to the method, in the presence of sulfuric acid, triphosgene or diphosgene reacts with 4,6-dihydroxypyrimidine; specifically, 4,6-dihydroxypyrimidine, sulfuric acid and N,N-dimethyl formamide are mixed evenly and heated to 80-100 DEG C to form a mixed solution, triphosgene or diphosgene is dissolved in a solvent and added into the mixed solution within 1-2 h dropwise slowly, heat insulation and stirring are continued for 3 h, temperature is reduced to room temperature, then the product is poured into ice water, and an organic solvent layer is separated out, washed, and dried with anhydrous magnesium sulfate to generate the 4,6-dichloropyrimidine. The method is simple, operation is easy, raw materials are rich, cost is low, product quality is high, the yield is high, organic matter is easy to recycle, environment pollution is avoided, industrial production is facilitated, and economic and social benefits are great.
Description
Technical field
The present invention relates to chemical industry, particularly under a kind of sulfuric acid catalysis, prepare the method for 4,6-dichloro pyrimidine.
Background technology
4,6-dichloro pyrimidine is important chemical intermediate, has been widely used at agricultural chemicals and medicine industry tool, such as, can be used for preparing sterilant Azoxystrobin, nucleoside analog and biologically active drug.
Its existing primary synthetic methods has:
Be that raw material and phosphonyl chloride or thionyl chloride react (United States Patent (USP) 5583226,5723612, Chinese patent 102936224 etc.) with 4,6-dihydroxy-pyrimidine.Although the method yield is better, the most frequently used in the industry, owing to reacting a large amount of phosphoric acid of rear generation or sulfide is difficult to process, three waste discharge is large, and serious environment pollution, is thus eliminated gradually.
With 4,6-dihydroxy-pyrimidine for raw material, with organic amine if triethylamine or DMA (Chinese patent 1687036,101898925, United States Patent (USP) 5750694) or DMF are that catalyzer and phosgene or solid phosgene react.The by product carbonic acid gas that the method is main, has the feature of environmental protection in theory.But organic amine price is higher, a large amount of use is very uneconomical, and reclaims difficulty; DMF due to catalytic activity low, reaction yield is very low, is difficult to industrialization.
Summary of the invention
For above-mentioned situation, for overcoming the defect of prior art, the object of the present invention is just to provide the method for preparation 4,6-dichloro pyrimidine under a kind of sulfuric acid catalysis, and effectively can solve 4,6-dichloro pyrimidine yield low, cost is high, is difficult to the problem of suitability for industrialized production.
The technical scheme that the present invention solves is, the inventive method reaction formula as shown in Figure 1, in the presence of sulphuric acid, by triphosgene or trichloromethylchloroformate and 4, 6-dihydroxy-pyrimidine reacts, concrete grammar is, by 4, 6-dihydroxy-pyrimidine, sulfuric acid and N, dinethylformamide mixes, mix, be heated to 80-100 DEG C, become mixing solutions, triphosgene or trichloromethylchloroformate are dissolved in solvent, slowly be added dropwise in mixing solutions in 1-2 hour, after dripping, continue insulated and stirred 3 hours, be cooled to room temperature again, pour in frozen water, separate organic solvent layer, organic solvent layer is washed, with anhydrous magnesium sulfate drying, obtain 4, 6-dichloro pyrimidine,
4,6-described dihydroxy-pyrimidines and the mol ratio of triphosgene are 1 ︰ 0.5-5; The mol ratio of 4,6-dihydroxy-pyrimidine and trichloromethylchloroformate is 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;
4,6-described dihydroxy-pyrimidines and the mol ratio of sulfuric acid are 1 ︰ 1-100;
Described solvent is dichlorobenzene, oil of mirbane or its mixture.
The inventive method is simple, and easy to operate, abundant raw material, cost is low, good product quality, and yield is high, and organism easily reclaims, and non-environmental-pollution is easy to suitability for industrialized production, and economic and social benefit is huge.
Accompanying drawing explanation
Fig. 1 is structural response formula figure of the present invention.
Embodiment
Below in conjunction with embodiment, the specific embodiment of the present invention is elaborated.
The present invention, in concrete enforcement, can be provided by following examples.
Embodiment 1
4 are added in reaction vessel (as tested the reaction flask of flat bottom glass), 6-dihydroxy-pyrimidine 11.2 grams, 20 milliliters, sulfuric acid, N, dinethylformamide 0.5 milliliter, mix, be heated to 80 DEG C, become mixing solutions, 30 grams of triphosgene are dissolved in dichlorobenzene 50 milliliters, slowly be added dropwise in mixing solutions in 1.2 hours, drip follow-up continuous insulated and stirred after 3 hours, be cooled to room temperature, pour in frozen water, separate organic solvent layer, organic solvent layer is washed, use anhydrous magnesium sulfate drying again, obtain 4, 6-dichloro pyrimidine, yield 97%, mass content is greater than 99%(Syrups by HPLC),
Product is through hydrogen nuclear magnetic resonance spectrum analysis:
1hNMR(400MHz, CDCl
3) δ 7.51(s, 1H), 8.89(s, 1H); Mass spectroscopy: ESI-MS, m/z:149.1 [M-H], be defined as 4,6-dichloro pyrimidine.
Embodiment 2
4 are added in reaction vessel, 6-dihydroxy-pyrimidine 11 grams, 10 milliliters, sulfuric acid, N, dinethylformamide 0.5 milliliter, mix, be heated to 90 DEG C, become mixing solutions, 30 grams of triphosgene are dissolved in 50 milliliters, oil of mirbane, slowly be added dropwise in mixing solutions in 1.5 hours, drip follow-up continuous insulated and stirred after 3 hours, be cooled to room temperature, pour in frozen water, separate organic solvent layer, organic solvent layer is washed, then uses anhydrous magnesium sulfate drying, obtain 4,6-dichloro pyrimidine, yield 93%, mass content is greater than 99%(Syrups by HPLC);
Product is through hydrogen nuclear magnetic resonance spectrum analysis:
1hNMR(400MHz, CDCl
3) δ 7.51(s, 1H), 8.89(s, 1H); Low Resolution Mass Spectra is analyzed: ESI-MS, m/z:149.1 [M-H], be defined as 4,6-dichloro pyrimidine.
Embodiment 3
4 are added in reaction vessel, 6-dihydroxy-pyrimidine 11 grams, 12 milliliters, sulfuric acid, N, dinethylformamide 0.5 milliliter, mix, be heated to 98 DEG C, become mixing solutions, 30 grams of triphosgene are dissolved in the dichlorobenzene of volume ratio 1 ︰ 1 and the mixed solution 50 milliliters of oil of mirbane, slowly be added dropwise in mixing solutions in 2 hours, drip follow-up continuous insulated and stirred after 3 hours, be cooled to room temperature, pour in frozen water, separate organic solvent layer, organic solvent layer is washed, use anhydrous magnesium sulfate drying again, obtain 4, 6-dichloro pyrimidine, yield 92%, mass content is greater than 99%(Syrups by HPLC),
Hydrogen nuclear magnetic resonance spectrum analysis:
1hNMR(400MHz, CDCl
3) δ 7.51(s, 1H), 8.89(s, 1H); Low Resolution Mass Spectra is analyzed: ESI-MS, m/z:149.1 [M-H], be defined as 4,6-dichloro pyrimidine.
Above-described embodiment obtains test of many times through anti-, and all achieve identical or akin result, show that method is reliable and stable, tool has significant practical applications, and is effective to suitability for industrialized production.
From the above, product of the present invention is through hydrogen nuclear magnetic resonance spectrum analysis and mass spectroscopy, be defined as 4, 6-dichloro pyrimidine, and good product quality, mass content more than 99%, preparation method is simple, abundant raw material, cost is low, yield is up to 97%, compared with prior art, the present invention adopts sulfuric acid cheap and easy to get as catalyzer, avoid and use the expensive organic bases (triethylamine or the N that are difficult to reclaim, accelerine) do catalyzer (quotation of the technical grade vitriol oil general per ton below 800 yuan, triethylamine quotation per ton is about 1.2 ten thousand, xylidine quotation per ton is about 1.5 ten thousand), simple use N, dinethylformamide catalysis, general yield is no more than 30%, well below yield of the present invention (yield of the present invention is minimum is 92%), that is, yield of the present invention is far away higher than prior art, and in production practice, catalyzer and solvent easily reclaim, both non-environmental-pollution, greatly reduce production cost again, economic and social benefit is huge.
Claims (4)
1. prepare 4 under a sulfuric acid catalysis, the method of 6-dichloro pyrimidine, is characterized in that, by 4,6-dihydroxy-pyrimidine, sulfuric acid and N, dinethylformamide mixes, and mixes, and is heated to 80-100 DEG C, become mixing solutions, triphosgene or trichloromethylchloroformate are dissolved in solvent, were slowly added dropwise in mixing solutions in 1-2 hour, after dripping, continue insulated and stirred 3 hours, be cooled to room temperature again, pour in frozen water, separate organic solvent layer, organic solvent layer is washed, with anhydrous magnesium sulfate drying, obtain 4,6-dichloro pyrimidine;
4,6-described dihydroxy-pyrimidines and the mol ratio of triphosgene are 1 ︰ 0.5-5; The mol ratio of 4,6-dihydroxy-pyrimidine and trichloromethylchloroformate is 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;
4,6-described dihydroxy-pyrimidines and the mol ratio of sulfuric acid are 1 ︰ 1-100;
Described solvent is dichlorobenzene, oil of mirbane or its mixture.
2. prepare 4 under sulfuric acid catalysis according to claim 1, the method of 6-dichloro pyrimidine, it is characterized in that, 4 are added in reaction vessel, 6-dihydroxy-pyrimidine 11.2 grams, 20 milliliters, sulfuric acid, N, dinethylformamide 0.5 milliliter, mix, be heated to 80 DEG C, become mixing solutions, 30 grams of triphosgene are dissolved in dichlorobenzene 50 milliliters, slowly be added dropwise in mixing solutions in 1.2 hours, drip follow-up continuous insulated and stirred after 3 hours, be cooled to room temperature, pour in frozen water, separate organic solvent layer, organic solvent layer is washed, use anhydrous magnesium sulfate drying again, obtain 4, 6-dichloro pyrimidine.
3. prepare 4 under sulfuric acid catalysis according to claim 1, the method of 6-dichloro pyrimidine, it is characterized in that, 4 are added in reaction vessel, 6-dihydroxy-pyrimidine 11 grams, 10 milliliters, sulfuric acid, N, dinethylformamide 0.5 milliliter, mix, be heated to 90 DEG C, become mixing solutions, 30 grams of triphosgene are dissolved in 50 milliliters, oil of mirbane, slowly be added dropwise in mixing solutions in 1.5 hours, drip follow-up continuous insulated and stirred after 3 hours, be cooled to room temperature, pour in frozen water, separate organic solvent layer, organic solvent layer is washed, use anhydrous magnesium sulfate drying again, obtain 4, 6-dichloro pyrimidine.
4. prepare 4 under sulfuric acid catalysis according to claim 1, the method of 6-dichloro pyrimidine, it is characterized in that, 4 are added in reaction vessel, 6-dihydroxy-pyrimidine 11 grams, 12 milliliters, sulfuric acid, N, dinethylformamide 0.5 milliliter, mix, be heated to 98 DEG C, become mixing solutions, 30 grams of triphosgene are dissolved in the dichlorobenzene of volume ratio 1 ︰ 1 and the mixed solution 50 milliliters of oil of mirbane, slowly be added dropwise in mixing solutions in 2 hours, drip follow-up continuous insulated and stirred after 3 hours, be cooled to room temperature, pour in frozen water, separate organic solvent layer, organic solvent layer is washed, use anhydrous magnesium sulfate drying again, obtain 4, 6-dichloro pyrimidine.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
|---|
| 吴倩倩等: "2-丙硫基-4,6-二氯-5-氨基嘧啶的合成", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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