CN102898385B - Synthesis of 4(3H)-quinazolone through catalysis of recyclable copper oxide - Google Patents
Synthesis of 4(3H)-quinazolone through catalysis of recyclable copper oxide Download PDFInfo
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- quinazolone
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Abstract
The invention provides a process for synthesizing 4(3H)-quinazolone (that is, 2-aryl-4(3H)-quinazolone, shorten in the application: 2-aryl-quinazolone) through the catalysis of recyclable copper oxide. In the process, copper oxide is used as a catalyst, air is used as an oxidizer, and o-aminoaryl amide and aldehydes are subjected to one-pot reaction to obtain 4(3H)-quinazolone compounds. The method is low in toxicity and cost; the recyclable copper oxide is used as the catalyst, and the consumption of the catalyst is low; and the raw materials are accessible and stable, the cost is low, the process is environment-friendly, and the requirements for atom economy are met. Thus, the invention is suitable for industrial big production.
Description
Technical field
This patent relates to the research field of organic synthesis, organic chemical industry, pharmaceutical synthesis, concretely, is exactly the synthesis of 2-arylquinazolinethione.
Background technology
2-aryl-quinazoline ketone compound has good biological activity, in antitumor, hypertension, anti-inflammatory, pain relieving, sterilization etc., show good pharmacologically active.
The 2-arylquinazolinethione with multiple important use has multiple synthetic method.
L mono-aryl 1 dimethylin 1 phenyl one 1,3 one phenodiazine one 1,3 one divinyl and the phenylisocyanate such as Croce obtain 2 one phenyl substituted quinazoline ketone in reflux in toluene under nitrogen protection; productive rate 70%-88%(Heterocycles; 1997,45,1309).One of method raw material of Croce needs multistep to synthesize.
The logical HCl gas in the methanol solution of aromatic nitriles such as Connolly reacts, and obtain imines methyl ester hydrochloride, the latter is obtained by reacting 2-arylquinazolinethione with anthranilic acid again, yield 42%-70%(Synlett, 2001, (11), 1707).
Couture and co-worker thereof seize the proton on the amino of anthranoyl diethylamide at highly basic LDA at-30 DEG C, then 2-arylquinazolinethione is obtained by reacting with fragrant nitrile or fatty nitrile, productive rate 15% ~ 75%(Synthesis, 1991, (11), 1609).
The people such as Su are with Ga (OTf) 3 catalysis isatoic anhydride, ammonium acetate or amine and aldehyde three components synthesizing dihydro quinazolinone in ethanol, then be oxidized dihydroquinazoline ketone with DMSO and obtain 2-arylquinazolinethione (Tetrahedron Letters, 2008,49,3814).
One section of paper of more relevant to this patent is Tetrahedron Letters in 2004, this section of paper adopts the method for two steps to synthesize, the first step anthranilamide and phenyl aldehyde react and generate imine intermediate, and second step needs the CuCl using imine intermediate 3 times of molar weights
2carry out iminoxy intermediate and obtain target product 2-arylalkyl quinazolinone (Tetrahedron Letters 2004,45,3475).
These methods all need through polystep reaction to synthesize 2-arylalkyl quinazolinone above.Document below just can complete the reaction of synthesis 2-arylalkyl quinazolinone in one pot.
2010, Wang etc. used catalysis of iodine anthranilamide and phenyl aldehyde at ionic liquid [bmim
+] [BF4
-] middle one pot reaction synthesis 2-arylalkyl quinazolinone (Synthetic Communications, 2010,40,2633).But the consumption that this paper does not mention iodine is from start to finish specifically how many.With reference to the bibliographical information of some other catalysis of iodine organic reaction, iodine consumption general 10 (mol) % or more.In addition, although ionic liquid can by reclaiming, removal process is cumbersome, and ionic liquid cost is high, expensive.
2011, one pot reaction synthesized 2-arylalkyl quinazolinone under air, in dimethylsulfoxide solvent with the adjacent iodine aryl carboxamides of 10% cupric bromide catalysis and benzylamine for Fu and co-worker thereof.The iodo reagent of the adjacent iodine virtue methane amide that the method uses and so on, expensive, in addition, in reaction process, generate hydrogen iodide, also need to add acid binding agent salt of wormwood.
A few days ago, we find that 1 (mol) % vanadic salts can catalyze and synthesize 2-aryl-quinazoline ketone compounds (number of patent application 201110365727.6) effectively in atmosphere.In view of the toxicity of vanadic salts, we do and further study discovery, and cupric oxide that is heterogeneous, that can be recycled also may be used for the synthesis of 2-aryl-quinazoline ketone compounds.
Summary of the invention
The object of this invention is to provide a kind of new synthetic method of 2-aryl-quinazoline ketone compounds.
The present invention take air as oxygenant, with the cupric oxide of capable of circulation, 3 (mol) % for catalyzer, and one pot of synthesis completing 2-aryl-quinazoline ketone compounds.
The laboratory operating procedures of this synthetic method: 1mmol anthranilamide, 1mmol aromatic aldehyde, 0.03 mmol cupric oxide, a certain amount of solvent add in test tube successively, heated and stirred reaction certain hour.After cooling, add certain water gaging, with a certain amount of extraction into ethyl acetate 3 times, organic phases washed with water twice, then with the mixed solvent of sherwood oil and ethyl acetate for eluent, with silica gel column chromatography separating purification, or pass through recrystallization in ethanol, obtain product 2-aryl-quinazoline ketone compounds.
Table 1 investigates various reaction conditions to the impact of this reaction.
Table 2 synthesizes various 2-with optimal conditions to replace and 2,3-disubstituted quinazoline ketone compounds.
table 3 is investigated catalyst oxidation copper and is recycled impact on this reaction.
Embodiment
Set forth the present invention further below by embodiment, therefore do not limit the present invention among described scope of embodiments.In the patent being characterized in before us of compound, majority provides (number of patent application 201110365727.6), no longer repeats at this.
embodiment 1
Cupric oxide, 3 milliliters of N, N-diethyl acetamide solvents of the anthranilamide of 1 mmole, the phenyl aldehyde of 1 mmole, 0.03 mmole added in test tube successively, 120 DEG C of stirring reactions 24 hours.After cooling, add 10 ml waters, with 10 milliliters of extraction into ethyl acetate 3 times, organic phases washed with water twice, then with the mixed solvent of sherwood oil and ethyl acetate for eluent, with silica gel column chromatography separating purification obtain 2-phenylquinazoline ketone (
3a), productive rate 96.66%.
embodiment 2
With the phenyl aldehyde in the n-hexyl aldehyde alternative embodiment 1 of 1 mmole, other condition is identical, obtain productive rate 58.52% 2-n-pentyl quinazolinone (
3l).Mp. 152-154
oC.
1 H NMR (300 MHz, DMSO-
d 6 ) , δ(ppm): 12.15 (s , 1H ) , 8.07 (d ,
J=7.89Hz , 1H ) , 7.72-7.78 (m , 1H ) , 7.58 (d ,
J=8.10Hz , 1H ) , 7.41-7.46 (m , 1H ) , 2.49-2.60 (m , 2H.) , 1.67-1.72 (m , 2H) , 1.29 (d ,
J=7.14Hz , 4H) , 0.85 (d ,
J=6.66Hz , 3H) .
13C NMR (75 MHz, DMSO-
d 6 ) δ (ppm): 162.0 , 157.7 , 149.0 , 134.4 , 126.8 , 126.0 , 125.8 , 120.8 . IR(KBr) , ν (cm
-1)：3846, 3696, 3121, 2925, 1845, 1675, 1614, 1564, 1470, 1380, 1324, 1254, 1027, 976, 737, 647.
embodiment 3
Cupric oxide, 3 milliliters of N, N-diethyl acetamides of the anthranilamide of 1 mmole, the phenyl aldehyde of 1 mmole, 0.05 mmole added in test tube successively, 120 DEG C of stirring reactions 24 hours.After cooling, add 10 milliliters of ethyl acetate, the static cupric oxide that allows is deposited to bottom, gently with the extremely remaining a little lower floor's solution containing cupric oxide of glue head dropper sucking-off supernatant layer, add 10 milliliters of ethyl acetate again, then use glue head dropper sucking-off supernatant liquor gently, totally three times so repeatedly.Upper solution carries out normal aftertreatment by embodiment 1, obtain after column chromatography separating purification 2-phenylquinazoline ketone (
3a), productive rate 97.53%.Lower floor containing cupric oxide a little solution decompression removing ethyl acetate solvent, then added reaction raw materials, that is, anthranilamide, the phenyl aldehyde of 1 mmole, 3 milliliters of N, N-diethyl acetamides of 1 mmole, 120 DEG C of stirring reactions 24 hours.Aftertreatment separation and purification according to a conventional method, cupric oxide recycles 1 time, and the productive rate of reaction is 95.22%.Recycle copper oxide catalyst by similar approach, for the second time, for the third time, the reaction yield of the 4th time is respectively: 95.06%, 92.92%, 90.78%.
Claims (1)
1. the synthetic method of a 2-arylquinazolinethione, it is characterized in that: the cupric oxide of the anthranilamide of 1 mmole, the phenyl aldehyde of 1 mmole, 0.03 mmole, 3 milliliters of N, N-diethyl acetamide solvent added in test tube successively, 120 DEG C of stirring reactions 24 hours; After cooling, add 10 ml waters, with 10 milliliters of extraction into ethyl acetate 3 times, organic phases washed with water twice, then with the mixed solvent of sherwood oil and ethyl acetate for eluent, obtain 2-phenylquinazoline ketone with silica gel column chromatography separating purification, productive rate 96.66%.
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| CN103613550A (en) * | 2013-11-29 | 2014-03-05 | 成都理工大学 | Environment-friendly synthesis method for 4(3H)-quinazolinone |
| CN103864702B (en) * | 2014-02-27 | 2016-05-11 | 福建医科大学 | A kind of in water microwave catalysis prepare the method for Quinazolinone compounds |
| CN105272926B (en) * | 2014-07-24 | 2018-09-25 | 中国科学院大连化学物理研究所 | A kind of method that alcohol and 2- amino-benzylamines are synthetically prepared quinazoline derivant |
| CN105732520A (en) * | 2014-12-11 | 2016-07-06 | 中国科学院大连化学物理研究所 | Method of synthesizing quinazolinone-structured compound |
| CN115028588B (en) * | 2022-06-24 | 2023-08-11 | 徐州医科大学 | Green synthesis method of heterocyclic compound |
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| CN102432551A (en) * | 2011-11-18 | 2012-05-02 | 成都理工大学 | Method for synthesizing 2-arylquinazolinethione |
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Non-Patent Citations (3)
| Title |
|---|
| A novel and efficient methodology for construction of quinazolines based on supported copper oxide nanoparticles;Jintang Zhang等;《Chemical Communications》;20100624;第46卷(第29期);第5245页 * |
| A Simple and Efficient Approach to Quinazolinones under Mild Copper-Catalyzed Conditions;Xiaowei Liu等;《Angewandte Chemie International Edition》;20081203;第48卷(第2期);全文 * |
| Copper-Catalyzed Synthesis of N-Heterocyclic Compounds;Tao Liu等;《Synthesis》;20120813;第44卷(第18期);全文 * |
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