CN1130350C - Process for preparing 4,6-dichloro-2-methiopyrimidine - Google Patents
Process for preparing 4,6-dichloro-2-methiopyrimidine Download PDFInfo
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- CN1130350C CN1130350C CN 00128918 CN00128918A CN1130350C CN 1130350 C CN1130350 C CN 1130350C CN 00128918 CN00128918 CN 00128918 CN 00128918 A CN00128918 A CN 00128918A CN 1130350 C CN1130350 C CN 1130350C
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- methylthiopyrimidines
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Abstract
The present invention relates to a method for synthesizing 4, 6-dichloro-2-methiopyrimidine which is the intermediate of agricultural chemicals and dye. The method is characterized in that the method uses thiourea as initial raw materials, the thiourea is condensed with malonic acid ester, the thiourea reacts with dimethyl sulfate in a methylation reaction mode, finally a reaction product is chlorinated by phosphorus oxychloride or phosphorus trichloride, and 4, 6-dichloro-2-methiopyrimidine is prepared. The total yield is greater than 52%.
Description
The background of invention
4,6-two chloro-2-methylthiopyrimidines are important intermediate of synthesizing new, efficient, low-toxin farm chemicals and reactive dyestuffs, and it is raw material that its synthetic method mainly contains with the 2-thiobarbituric acid, make through sulfomethylation, chlorination.
For example, patent US4199583 makes sulfomethylation reagent with methyl iodide, and the cost height is difficult to suitability for industrialized production; And patent US5149357 adopts monobromethane to make methylating reagent, because the monobromethane boiling point is low, need to adopt reaction under high pressure, and cost is than higher.
The description of invention
The objective of the invention is to seek a kind of not only economy but also feasible the synthetic 4 of suitability for industrialized production, the method for 6-two chloro-2-methylthiopyrimidines of being applicable to.
The present invention adopts and can supply in a large number, cheap thiocarbamide and malonic ester is starting raw material, through condensation, methylate, chlorination and make 4,6-two chloro-2-methylthiopyrimidines.It is methylating reagent that its characteristics are to adopt methyl-sulfate, and raw material is easy to get, and price is low, and the yield height is simple to operate, is fit to large-scale industrial production.
Condensation reaction under the effect of alkali, can take place in thiocarbamide and malonic ester in suitable organic solvent, generate the 2-thiobarbituric acid.The 2-thiobarbituric acid is an organic heterocyclic strongly-acid compound, becomes to salt out in the strong basicity reaction medium, and then impels reaction to carry out to the right.Malonic ester can be dimethyl malonate, diethyl malonate etc.Multiple organic solvent can be made reaction solvent, as methyl alcohol, ethanol, benzene, toluene, chloroform etc.Alkali can be organic bases, also can use mineral alkali, as sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood etc.20 ℃～100 ℃ of temperature of reaction, general 40 ℃～80 ℃, optimum 50 ℃～70 ℃; Reactant molar ratio is a thiocarbamide: malonic ester: alkali=1: (1～1.2): (3～3.5), optimum are 1: 1.1: 3.25; 2～6 hours reaction times, optimum 3～4 hours.
The sodium salt of 2-thiobarbituric acid is insoluble in the organic solvent, and is soluble in water, so its methylation reaction carries out in the aqueous solution.During reaction, should control the consumption of methylating reagent methyl-sulfate and the temperature of reaction, so that methylation reaction is only taken place on sulphur atom, if the methyl-sulfate consumption is too big, temperature of reaction is too high, and the methylated side reaction of Sauerstoffatom then can take place.Reactant molar ratio: 2-thiobarbituric acid sodium salt: methyl-sulfate=1: (1～1.5), optimum are 1: 1.25.Temperature of reaction-10 ℃～60 ℃, general 0 ℃～40 ℃, best 20 ℃～30 ℃; 1～6 hour reaction times, optimum 4 hours.
4,6-dihydroxyl-2-methylthiopyrimidine under the effect of phosphorus oxychloride, 4, the hydroxyl of 6-position replaces by chlorine and generate 4,6-two chloro-2-methylthiopyrimidines, chlorination reagent can be with phosphorus oxychloride or phosphorus trichloride.The mol ratio of reactant: 4,6-dihydroxyl-2-methylthiopyrimidine: phosphorus oxychloride (or phosphorus trichloride)=1: (3～6.9), optimum are 1: (4～5).60 ℃～100 ℃ of temperature of reaction, optimum is 70 ℃; 2～6 hours reaction times, best 4 hours.
Working of an invention example 1:
In a 500ml there-necked flask, add 38g thiocarbamide (0.5mol), the sodium methylate of 306g28.5% (1.615mol), stirring is warming up to 65 ℃, drips 88g diethyl malonate (0.550mol) in 30 minutes, after adding, insulation reaction is 4 hours between 60 ℃～65 ℃, after being cooled to room temperature, suction filtration, filter cake washs with small amount of methanol sodium, dry the 102.9g white solid, yield 98%.Example 2:
Charging capacity, operation are with example 1.After reaction was finished, methyl alcohol, ethanol were removed in underpressure distillation, added 600ml water, were directly used in next step methylation reaction.Example 3:
In a 1000ml there-necked flask, add 102.9g 2-thiobarbituric acid sodium salt (0.490mol), 600ml water, stirring and dissolving.About 25 ℃, 80g methyl-sulfate (0.635mol) is splashed into 1 hour dropping time.After adding, continued stirring reactions 4 hours at 25 ℃, reaction finishes, and with hydrochloric acid reaction solution is transferred PH to 5～6, suction filtration, water is washed till neutrality with filter cake, dry 60g4,6-dihydroxyl-2-methylthiopyrimidine, m.p＞300 ℃, yield 75.9%.Example 4:
Charging capacity, operation are with example 3.The 2-thiobarbituric acid sodium-salt aqueous solution of example 2 gained is methylated with methyl-sulfate, and the result gets product 61.6g, and m.p＞300 ℃ are 78% with the thiocarbamide rate of collecting.Example 5:
In there-necked flask, add 50g4,6-dihydroxyl-2-methylthiopyrimidine, 230g phosphorus oxychloride (1.50mol) is warming up to 70 ℃, insulation reaction 4 hours.Reaction boils off excessive phosphorus oxychloride after finishing, and under agitation drips 300ml water, and product is separated out, and suction filtration washes with water to neutrality, and vacuum-drying gets 43.2g4,6-two chloro-2-methylthiopyrimidines, m.p.40 ℃～42 ℃, yield 70%.
Claims (4)
1, a kind of 4, the synthetic method of 6-two chloro-2-methylthiopyrimidines is characterized in that with thiocarbamide, malonic ester be raw material, makes 4 through condensation, sulfomethylation, chlorination reaction, 6-two chloro-2-methylthiopyrimidines.
2, synthesize 4 according to claim 1 is described, the method for 6-two chloro-2-methylthiopyrimidines is characterized in that condensation reaction is raw material with the thiocarbamide, generates 2-thiobarbituric acid sodium salt with the malonic ester reaction under the effect of sodium methylate.
3, described synthetic 4 according to claim 1, the method for 6-two chloro-2-methylthiopyrimidines is characterized in that the sulfomethylation reaction makes methylating reagent with methyl-sulfate.
4, described synthetic 4 according to claim 1, the method for 6-two chloro-2-methylthiopyrimidines, the chlorination reagent that it is characterized in that chlorination reaction is with phosphorus oxychloride or phosphorus trichloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00128918 CN1130350C (en) | 2000-09-15 | 2000-09-15 | Process for preparing 4,6-dichloro-2-methiopyrimidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00128918 CN1130350C (en) | 2000-09-15 | 2000-09-15 | Process for preparing 4,6-dichloro-2-methiopyrimidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1343665A CN1343665A (en) | 2002-04-10 |
| CN1130350C true CN1130350C (en) | 2003-12-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 00128918 Expired - Fee Related CN1130350C (en) | 2000-09-15 | 2000-09-15 | Process for preparing 4,6-dichloro-2-methiopyrimidine |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321004A (en) * | 2011-06-04 | 2012-01-18 | 山西大学 | The compound method of a kind of L-(+)-selenomethionine |
| CN103910683A (en) * | 2014-03-10 | 2014-07-09 | 常熟市南湖实业化工有限公司 | Preparation method of 5-methoxy-4,6-dichloropyrimidine |
| CN108101853A (en) * | 2018-01-16 | 2018-06-01 | 吴江信凯医药科技有限公司 | A kind of synthetic method of the chloro- 2- methylthiopyrimidines -5- carboxylic acid, ethyl esters of high-purity 4- |
| CN109824602B (en) * | 2019-02-25 | 2023-10-27 | 南京哈柏医药科技有限公司 | Synthesis method of 4-chloro-2-methylthiopyrimidine |
| CN112552244A (en) * | 2020-12-22 | 2021-03-26 | 内蒙古科硕新材料科技有限公司 | Production process of 4, 6-dimethoxy-2-methylsulfonyl pyrimidine |
| CN112920126A (en) * | 2021-01-13 | 2021-06-08 | 新沂大江化工有限公司 | Preparation method and preparation device of bispyribac-sodium intermediate 2-methylsulfonyl 4, 6-dimethoxypyrimidine |
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2000
- 2000-09-15 CN CN 00128918 patent/CN1130350C/en not_active Expired - Fee Related
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| CN1343665A (en) | 2002-04-10 |
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