CN101475537A - Preparation of 2,4-dichloroquinazoline - Google Patents
Preparation of 2,4-dichloroquinazoline Download PDFInfo
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- CN101475537A CN101475537A CNA2009100291665A CN200910029166A CN101475537A CN 101475537 A CN101475537 A CN 101475537A CN A2009100291665 A CNA2009100291665 A CN A2009100291665A CN 200910029166 A CN200910029166 A CN 200910029166A CN 101475537 A CN101475537 A CN 101475537A
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Abstract
The invention relates to a method for preparing 2,4-dichloroquinazoline. The method comprises the following steps that: (1) ortho-aminobenzoic acid reacts with potassium cyanate to generate 2,4-quinazoline diones; and (2) the 2,4-quinazoline diones and a chlorinating agent undergo a chlorination reaction to generate the 2,4-dichloroquinazoline. Particularly, in step (1), the mass ratio of the ortho-aminobenzoic acid to the potassium cyanate is 1:1-3, the reaction uses water as a solvent, and is performed at a temperature of between 20 and 100 DEG C with pH of between 9 and 12; and in step (2), the chlorination reaction uses fatty amine as a solvent. The method uses non-toxic solvent and accessible raw materials, has high reaction yield, and is applicable to industrial production.
Description
Technical field
The present invention relates to a kind of 2, the preparation method of 4-two chloro-quinazolines.
Background technology
2,4-two chloro-quinazolines are a kind of important organic intermediates, are mainly used in fields such as medicine, agricultural chemicals, dyestuff and organic synthesis.In recent years, along with 2, the application of 4-two chloro-quinazoline derived product, the increase of demand, its market outlook are boundless.
In the prior art, 2,4-two chloro-quinazolines synthetic mainly contains following two kinds of synthetic routes:
Route 1: aniline/carbobenzoxy isocyanic ester method, reaction equation is as follows:
In US 04/02885 patent, on the books to this synthetic route, the total recovery that adopts this synthetic route is about 58%.
Route 2: anthranilic acid/potassium cyanate method, equation is as follows:
Anthranilic acid reacts with potassium cyanate in acetate system and generates 2, the 4-quinazoline diones, and 2, the chlorination in xylidine of 4-quinazoline diones obtains 2,4-two chloro-quinazolines, the total recovery of this method is about 43%.
Route 1 raw material is difficult to obtain, and is unsuitable for suitability for industrialized production; Though route 2 raw materials are easy to get, reaction yield is low, the production cost height, and xylidine toxicity is bigger.
Summary of the invention
Technical problem to be solved by this invention is in order to overcome the deficiencies in the prior art, provides a kind of 2, the preparation method of 4-two chloro-quinazolines, and this method yield height, production cost are low.
For solving above technical problem, the present invention takes following technical scheme:
A kind of 2, the preparation method of 4-two chloro-quinazolines comprises the steps:
(1), anthranilic acid and potassium cyanate reaction generate 2, the 4-quinazoline diones;
(2), 2, it is described 2 that 4-quinazoline diones and chlorizating agent generation chlorination reaction generate, 4-two chloro-quinazolines, particularly, in the step (1), anthranilic acid is 1:1～3 with the ratio of the amount of substance of potassium cyanate, reaction is solvent with water, 20～100 ℃ of temperature, carries out under pH9～12 conditions; In the step (2), described chlorination reaction is solvent with the aliphatic amide.
In the step (1), the temperature of reaction is preferably 40～90 ℃, and the reaction times is 2～8h.
Step (1) can further be implemented in the following manner: the mixture that at first makes anthranilic acid and water, stir, the potassium cyanate drips of solution is added in the said mixture, stir, dropping sodium solution makes pH between 9～12 then, stirs and be incubated 1～12 hour, below the cooling reaction solution to 10 ℃, add hydrochloric acid and regulate pH solid is separated out, filter and dry gained solid be described 2, the 4-quinazoline diones.
Described chlorizating agent can be any in phosphorus trichloride, phosphorus pentachloride, sulfur oxychloride, thionyl chloride and the phosphorus oxychloride, is preferably phosphorus oxychloride.
Because the technique scheme utilization, the present invention compared with prior art has following advantage:
The ring-closure reaction of anthranilic acid and potassium cyanate is carried out in aqueous systems, and this step reaction molar yield is more than 85%; Chlorination reaction is a solvent with the aliphatic amide, and not only solvent toxicity is little, and makes reaction have higher yields (more than 73%).The inventive method overall yield height (greater than 60%), production cost is low, is applicable to suitability for industrialized production.
Embodiment
Below the specific embodiment of the present invention is described, but be not limited to these embodiment.
Embodiment 1
A kind of 2, the preparation method of 4-two chloro-quinazolines in turn includes the following steps:
(1), anthranilic acid and potassium cyanate react and generate 2, the 4-quinazoline diones
Get exsiccant 500ml four-hole boiling flask, load onto temperature and take into account cooling tube, add 41g (0.3mol) anthranilic acid and 100ml water composition mixture, the 200ml aqueous solution of Dropwise 5 5g (0.68mol) potassium cyanate then drips 36g 0.5mol/L aqueous sodium hydroxide solution after stirring half an hour, and solution temperature is controlled in 40 ℃, stir half an hour, heat temperature raising to 85 ℃ is incubated 2 hours, is cooled to 0 ℃, add 30% hcl acidifying, regulate pH2～3, temperature remains on about 0 ℃, and filtration drying gets 42g 2, the 4-quinazoline diones, with 2,4-quinazoline diones meter, molar yield are 86.3%.
(2), 2, the chlorination of 4-quinazoline diones obtains 2,4-two chloro-quinazolines
Get 500ml exsiccant four-hole boiling flask, add 96g 2,4-quinazoline diones, 200ml phosphorus oxychloride and 100ml triethylamine, mixture heating up backflow 10h, reaction mixture concentrate oily matter, dissolve oily matter with toluene, and with careful the joining in the frozen water of oily matter, organic layer separates, water layer extracts with toluene, merge organic layer, water, hydrochloric acid, water, the soda ash aqueous solution, water washing successively, anhydrous sodium sulfate drying, concentrate, reclaim solvent and get 2,4-two chloro-quinazoline 86g, calculating molar yield is 73%.
Embodiment 2
A kind of 2, the preparation method of 4-two chloro-quinazolines in turn includes the following steps:
(1), anthranilic acid and potassium cyanate react and generate 2, the 4-quinazoline diones
Get exsiccant 500ml four-hole boiling flask, load onto temperature and take into account cooling tube, add 41g (0.3mol) anthranilic acid and 100ml water composition mixture, drip the 200ml aqueous solution of 60g (0.74mol) potassium cyanate then, stirring drips 60g 0.3mol/L aqueous sodium hydroxide solution after half an hour, solution temperature is controlled in 40 ℃, stir half an hour, heat temperature raising to 90 ℃ is incubated 2.5 hours, is cooled to 0 ℃, add 30% hcl acidifying, regulate pH2～3, temperature remains on about 0 ℃, and filtration drying gets 45g 2, the 4-quinazoline diones, with 2,4-quinazoline diones meter, its molar yield are 92.5%.
(2), 2, the chlorination of 4-quinazoline diones obtains 2,4-two chloro-quinazolines
Get 500ml exsiccant four-hole boiling flask, add 96g 2,4-quinazoline diones, 200ml phosphorus oxychloride and 120ml Trimethylamine 99, mixture heating up backflow 12h, reaction mixture concentrate oily matter, dissolve oily matter with chloroform, and with careful the joining in the frozen water of oily matter, organic layer separates, the water layer chloroform extraction, merge organic layer, water, hydrochloric acid, water, the soda ash aqueous solution, water washing successively, anhydrous sodium sulfate drying, concentrate, reclaim solvent and get 2,4-two chloro-quinazoline 94g, calculating molar yield is 79%.
Claims (4)
1, a kind of 2, the preparation method of 4-two chloro-quinazolines comprises the steps:
(1), anthranilic acid and potassium cyanate reaction generate 2, the 4-quinazoline diones;
(2), 2, it is described 2 that 4-quinazoline diones and chlorizating agent generation chlorination reaction generate, 4-two chloro-quinazolines is characterized in that:
In the step (1), anthranilic acid is 1:1～3 with the ratio of the amount of substance of potassium cyanate, and reaction is a solvent with water, 20～100 ℃ of temperature, carries out under pH9～12 conditions;
In the step (2), the solvent of described chlorination reaction is an aliphatic amide.
2, according to claim 1 a kind of 2, the preparation method of 4-two chloro-quinazolines is characterized in that: in the step (1), the temperature of reaction is 40～90 ℃, and the reaction times is 2～8h.
3, according to claim 1 a kind of 2, the preparation method of 4-two chloro-quinazolines, it is characterized in that: step (1) is specially: the mixture that at first makes anthranilic acid and water, stir, the potassium cyanate drips of solution is added in the said mixture, stir, dropping sodium solution makes pH between 9～12 then, stirring also is incubated 1～12 hour, below the cooling reaction solution to 10 ℃, add hydrochloric acid and regulate pH solid is separated out, filter and dry gained solid be described 2,4-dichloro quinazoline diones.
4, according to claim 1 a kind of 2, the preparation method of 4-two chloro-quinazolines is characterized in that: described chlorizating agent is a kind of in phosphorus trichloride, phosphorus pentachloride, sulfur oxychloride, thionyl chloride and the phosphorus oxychloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNA2009100291665A CN101475537A (en) | 2009-01-07 | 2009-01-07 | Preparation of 2,4-dichloroquinazoline |
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| CNA2009100291665A CN101475537A (en) | 2009-01-07 | 2009-01-07 | Preparation of 2,4-dichloroquinazoline |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584721A (en) * | 2011-12-29 | 2012-07-18 | 浙江工业大学 | Synthetic method of 2,4-dichloroquinazoline derivative |
| CN109153652A (en) * | 2016-04-01 | 2019-01-04 | 上海瑛派药业有限公司 | The preparation process of 1- (aryl methyl) quinazoline -2,4 (1H, 3H)-diketone |
-
2009
- 2009-01-07 CN CNA2009100291665A patent/CN101475537A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584721A (en) * | 2011-12-29 | 2012-07-18 | 浙江工业大学 | Synthetic method of 2,4-dichloroquinazoline derivative |
| CN102584721B (en) * | 2011-12-29 | 2014-07-02 | 浙江工业大学 | Synthetic method of 2,4-dichloroquinazoline derivative |
| CN109153652A (en) * | 2016-04-01 | 2019-01-04 | 上海瑛派药业有限公司 | The preparation process of 1- (aryl methyl) quinazoline -2,4 (1H, 3H)-diketone |
| CN109153652B (en) * | 2016-04-01 | 2021-07-27 | 上海瑛派药业有限公司 | Process for preparing 1- (arylmethyl) quinazoline-2, 4(1H,3H) -diketone |
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Open date: 20090708 |