Synthesis method of 4-3 (H) quinazolinone and derivative thereof

A quinazolinone and a synthesis method technology, applied in the field of biomedicine, can solve the problems of high toxicity of isocyanate, many reaction steps, easy carbonization and blackening of reactants, etc., and achieve the effects of good functional group tolerance and short reaction time.

Active Publication Date: 2022-03-25
CHONGQING MEDICAL UNIVERSITY
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

The traditional 4-(3H) quinazolinone synthesis mainly includes: use phosphinimine and isocyanate, substituted phenol (or other nucleophile) to synthesize 4-(3H) quinazolinone core by Aza-Wittig reaction, the The method has mild conditions and high yield, but isocyanate is highly toxic; 4-(3H)quinazolinone is synthesized by using 4H-3,1-benzoxazin-4-one as an intermediate, and the method is simple to separate and purify. However, there are many reaction steps; 4(3H)-quinazolinone is synthesized in one pot with anthranilic acid and formamide. This method has few steps, but the temperature is too high, the reactants are easily carbonized and blackened, and the product is difficult to separate and purify, resulting in the production of The efficiency is reduced; there are also bibliographic reports on the synthesis of 4(3H)-quinazolinones with organic metals as catalysts. This type of method has simple raw materials, but there are disadvantages such as catalysts that are harmful to the environment and are expensive; the newly reported solid-phase method is used to synthesize quinazolinones. The mother nucleus of oxazolinone, this method can be used for the synthesis of large combinatorial library, and product purity is high, but reaction steps is many, and total yield is low, therefore, develops a kind of new simple synthesis method environmentally friendly and low toxicity to construct quinone The mother nucleus of oxazolinone is of great significance

Method used

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  • Synthesis method of 4-3 (H) quinazolinone and derivative thereof
  • Synthesis method of 4-3 (H) quinazolinone and derivative thereof
  • Synthesis method of 4-3 (H) quinazolinone and derivative thereof

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Embodiment 1

[0050] The general preparation steps that the present invention obtains are:

[0051] In a 10ml three-necked flask, add the compound of formula I, the compound of formula II and imidazole hydrochloride as a reaction catalyst, place the reaction in an oil bath at 150°C for heating, monitor the reaction process by TLC, add 30ml of distilled water after the reaction, and mix the obtained The mixture was extracted three times with 30ml ethyl acetate, and the combined layers were washed with H 2 O (50ml) wash, then brine (50ml), then anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether and ethyl acetate = 25:1 solvent), and recrystallized from ethyl acetate and n-hexane to obtain the target product.

[0052] In the initial experiment, the inventors carried out the reaction of cyclization of 2-amino-3-methylbenzoic acid (1b) and DMF (2a) to synthesize 4-(3H) quinazolinone ...

specific Embodiment

[0067] Embodiment 1 Synthetic 2, the general method (3a-3f) of 3-disubstituted quinazolinone derivatives

[0068] Into a 10ml three-necked flask were added 1a (0.41g, 3.0mmol, 1eq), imidazole hydrochloride (0.16g, 1.5mmol, 0.5eq) and N,N-dimethylformamide (2ml). The resulting solution was warmed to 150° C. and stirred at this temperature for 10 h, followed by TLC plate monitoring. When the reaction was complete, 30 ml of water was added, and the resulting mixture was extracted three times with 30 ml of ethyl acetate. with H 2 O (50ml) washed, then brine (50ml), then anhydrous Na 2 SO 4 After drying, filtering and concentrating under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from n-hexane and ethyl acetate to obtain the target product.

[0069] General method for the synthesis of 2,3-disubstituted quinazolinone derivatives (3g-3r)

[0070] A mixture of 1b (0.45g, 3.0mmol, 1eq), imidazole hydrochloride (0.16g, 1.5mmol, ...

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Abstract

The invention provides a synthesis method of 4-(3H) quinazolinone and a derivative thereof (formula III), which is characterized in that imidazole hydrochloride is used as a catalyst, and 2, 3-disubstituted quinazolinone and the derivative thereof are synthesized from anthranilic acid and a derivative thereof and a DMF (Dimethyl Formamide) derivative by a one-pot method in the absence of other catalysts or additives. The synthesis method disclosed by the invention has good functional group tolerance, and 4-(3H) quinazolinone and derivatives thereof can be synthesized for research in medicines or other fields. According to the synthetic method, dichloromethane, corrosive concentrated hydrochloric acid and a metal catalyst are not used, harsh reaction conditions, gas protection and an autoclave are not needed, the reaction time is short, and the synthetic method has certain value in industrial production.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a synthesis method of 4-(3H) quinazolinone and derivatives thereof. Background technique [0002] 4-(3H)quinazolinone is a class of important nitrogen-containing heterocyclic compounds with a benzopyrimidinone skeleton, which exists in many natural bases such as ethosine, cameline, and citrine. Quinazolinone compounds have a wide range of application potentials because their quinazolinone skeletons are easily modified by multiple functional genes, especially in the field of medicine. Substances containing quinazolinone structures have been found to have a variety of biopharmacological activities. Including antibacterial, antiviral, antitumor, antihypertensive, antiallergic, anti-inflammatory and analgesic, enzyme inhibition, etc. For example, the recently approved new drug Idelalisib, as a 4-(3H) quinazolinone-based P13K inhibitor, is used to treat some hematolog...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/91
CPCC07D239/91
Inventor 袁建勇王印王雪桐徐平张修宇
Owner CHONGQING MEDICAL UNIVERSITY
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