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Synthetic method of quinazoline-2,4(1H, 3H)-dione and derivatives thereof

A synthesis method and quinazoline technology are applied in the field of synthesis of quinazoline-2,4-dione and derivatives thereof, which can solve the problems of industrial application limitation of reaction conditions, harsh reaction conditions, complicated processes, etc. The method is simple and controllable, with low cost and good selectivity.

Active Publication Date: 2017-07-14
EAST CHINA NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

6,7-dimethoxy-quinazoline-2,4(1H,3H)-dione is an important intermediate in the production of antihypertensive drugs, and its traditional synthesis method is mainly anthranilic acid and urea or cyanic acid Potassium reaction, the reaction of anthranilamide with phosgene and the reaction of anthranilate with isocyanate, in which the use of toxic reagents such as phosgene, potassium cyanate and isocyanate and harsh reaction conditions make it more and more popular in industrial applications limit
[0004] The quinazoline-2,4(1H,3H)-dione and its derivatives prepared by the prior art are complicated in process, and the reaction conditions are harsh. Toxic reagents such as phosgene, potassium cyanate and isocyanate are used, and the environmental pollution is relatively serious.

Method used

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  • Synthetic method of quinazoline-2,4(1H, 3H)-dione and derivatives thereof
  • Synthetic method of quinazoline-2,4(1H, 3H)-dione and derivatives thereof
  • Synthetic method of quinazoline-2,4(1H, 3H)-dione and derivatives thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0019] Weigh 0.59g (5mmol) of o-aminobenzonitrile and place it in the polytetrafluoroethylene lining of a stainless steel reaction kettle, add 3mL of an aqueous solution of diethanolamine with a concentration of 1mol / L, stir for 2 minutes and mix well, then introduce carbon dioxide and heat up To 100° C., adjust the carbon dioxide pressure to 1 MPa to carry out the carboxycyclization reaction under stable conditions, and the reaction time is 12 hours. After the reaction, cool the reaction system to room temperature, slowly release unreacted carbon dioxide, add 10 mL of deionized water and stir to disperse the product, filter the precipitate and wash it with a small amount of distilled water, then wash it three times with 15 mL of methyl tert-butyl ether each time, After drying at 100°C, the product was quinazoline-2,4(1H,3H)-dione with a yield of 94%.

Embodiment 2

[0021] Weigh 0.68g (5mmol) of 2-amino-5-fluorobenzonitrile and place it in the polytetrafluoroethylene lining of a stainless steel reaction kettle, add 3mL of a diethanolamine aqueous solution with a concentration of 0.33mol / L, stir for 2 minutes and mix well , feed carbon dioxide and raise the temperature to 100° C., adjust the pressure of carbon dioxide to 1 MPa to carry out carboxycyclization reaction under stable conditions, and the reaction time is 12 hours. After the reaction, cool the reaction system to room temperature, slowly release unreacted carbon dioxide, add 10 mL of deionized water and stir to disperse the product, filter the precipitate and wash it with a small amount of distilled water, then wash it three times with 15 mL of methyl tert-butyl ether each time, The product was dried at 100° C. to obtain 6-fluoroquinazoline-2,4(1H,3H)-dione with a yield of 94%.

Embodiment 3

[0023] Weigh 0.763g (5mmol) of 2-amino-5-chlorobenzonitrile and place it in the polytetrafluoroethylene lining of the stainless steel reaction kettle, add 3mL of diethanolamine aqueous solution with a concentration of 1.33mol / L, stir for 2 minutes and mix well , feed carbon dioxide and raise the temperature to 100° C., adjust the pressure of carbon dioxide to 1 MPa to carry out carboxycyclization reaction under stable conditions, and the reaction time is 12 hours. After the reaction, cool the reaction system to room temperature, slowly release unreacted carbon dioxide, add 10 mL of deionized water and stir to disperse the product, filter the precipitate and wash it with a small amount of distilled water, then wash it three times with 15 mL of methyl tert-butyl ether each time, The product 6-chloroquinazoline-2,4(1H,3H)-dione was dried at 100° C. with a yield of 93%.

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Abstract

The invention discloses a synthetic method of quinazoline-2,4(1H, 3H)-dione and derivatives thereof. The method comprises the following steps: carrying out a carboxy cyclization on a substrate o-aminobenzontrile or 4,5-position substituted derivatives thereof in carbon dioxide with a diethanolamine-water solution as a catalyst, and filtering, washing and drying the obtained reaction solution to obtain the product quinazoline-2,4(1H, 3H)-dione and the derivatives thereof, wherein a molar ratio of the substrate to the diethanolamine-water solution is (3-8):(1-3); the reaction temperature of the carboxy cyclization is 60-140 DEG C, and the reaction time is 6-18 h; and the pressure of the carbon dioxide is 0.5-2 MPa. Compared with the prior art, the synthetic method has the advantages of low cost of the catalyst, high product yield and good selectivity, and is an environmentally-friendly method for homogeneous catalytic synthesis of the quinazoline-2,4(1H, 3H)-dione and the derivatives thereof.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical intermediates, in particular to a synthesis method of quinazoline-2,4(1H,3H)-dione and derivatives thereof. Background technique [0002] Quinazoline-2,4(1H,3H)-dione is an important pharmaceutical intermediate with excellent biopharmaceutical activity, 7-chloro-quinazole as the intermediate raw material of diabetes drug FK366 and heart disease drug KF31327 Phenyl-2,4(1H,3H)-dione is one of its derivatives. 6,7-dimethoxy-quinazoline-2,4(1H,3H)-dione is an important intermediate in the production of antihypertensive drugs, and its traditional synthesis method is mainly anthranilic acid and urea or cyanic acid Potassium reaction, the reaction of anthranilamide with phosgene and the reaction of anthranilate with isocyanate, in which the use of toxic reagents such as phosgene, potassium cyanate and isocyanate and harsh reaction conditions make it more and more popular in industrial application...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/96
CPCC07D239/96
Inventor 吴海虹盛治政吴鹏
Owner EAST CHINA NORMAL UNIV
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