CN103059001B - Quinazolinone Schiff base containing triazole and preparation method thereof - Google Patents
Quinazolinone Schiff base containing triazole and preparation method thereof Download PDFInfo
- Publication number
- CN103059001B CN103059001B CN201210469118.XA CN201210469118A CN103059001B CN 103059001 B CN103059001 B CN 103059001B CN 201210469118 A CN201210469118 A CN 201210469118A CN 103059001 B CN103059001 B CN 103059001B
- Authority
- CN
- China
- Prior art keywords
- triazole
- methyl
- quinazolinone
- reaction
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- IIWGNJVRQPJLBP-UHFFFAOYSA-N O=Cc(cc1)ccc1-[n]1nnc(CCl)c1 Chemical compound O=Cc(cc1)ccc1-[n]1nnc(CCl)c1 IIWGNJVRQPJLBP-UHFFFAOYSA-N 0.000 description 2
- 0 *c1ccc(C=O)cc1 Chemical compound *c1ccc(C=O)cc1 0.000 description 1
- VWDUFDUVETWRPN-LSHDLFTRSA-N CC(N1/N=C/c(cc2)ccc2-[n]2nnc(CCl)c2)=Nc2cc(F)ccc2C1=O Chemical compound CC(N1/N=C/c(cc2)ccc2-[n]2nnc(CCl)c2)=Nc2cc(F)ccc2C1=O VWDUFDUVETWRPN-LSHDLFTRSA-N 0.000 description 1
- PQIUQRJPSAGBOL-UHFFFAOYSA-N CC(N1N)=Nc2cc(F)ccc2C1=O Chemical compound CC(N1N)=Nc2cc(F)ccc2C1=O PQIUQRJPSAGBOL-UHFFFAOYSA-N 0.000 description 1
- XLNMYFOERWONOV-UHFFFAOYSA-N CC(O1)=Nc2cc(F)ccc2C1=O Chemical compound CC(O1)=Nc2cc(F)ccc2C1=O XLNMYFOERWONOV-UHFFFAOYSA-N 0.000 description 1
- LGPVTNAJFDUWLF-UHFFFAOYSA-N Nc1cc(F)ccc1C(O)=O Chemical compound Nc1cc(F)ccc1C(O)=O LGPVTNAJFDUWLF-UHFFFAOYSA-N 0.000 description 1
- BXRFQSNOROATLV-UHFFFAOYSA-N [O-][N+](c1ccc(C=O)cc1)=O Chemical compound [O-][N+](c1ccc(C=O)cc1)=O BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to the technical field of drug synthesis, and specifically relates to a quinazolinone Schiff base containing triazole and a preparation method thereof. The chemical structure is 3-(4-((4-chloromethyl)-1H-1, 2, 3- triazole) benzal methylamino-2- methyl-7- fluorine-4 (3H)-quinazolinone. The preparation method comprises the following steps of: synthesizing the quinazolinone from 2- amino-4-fluorobenzoic acid, synthesizing triazole from 4-nitrobenzaldehyde, then, generating the 3-(4-((4-chloromethyl)-1H-1, 2, 3- triazole) benzal methylamino-2- methyl-7- fluorine-4 (3H)- quinazolinone by reaction between aldehyde and amine. The quinazolinone Schiff base compound containing 1, 2, 3-triazole synthesized by the method organically and orderly combines quinazolinone, triazole and triazole functional group and has very important application foreground in the fields such as biomedicine and medicine; in the method provided by the invention, the synthetic route is novel in conception, the raw materials are easy to get, operations are simple and cost is low, so that the method has good application foreground and is easy for industrial production.
Description
Technical field
The invention provides a kind of quinazolinone Schiff's base and preparation method thereof, belong to technical field of organic synthesis.
Background technology
Quinazoline (ketone) compounds is the nitrogen-containing heterocycle compound that a class has good biological activity, and it is antibacterial
[1], anti-inflammatory
[2], hypertension
[3]with anticancer
[4]etc. aspect all demonstrate good activity.This type of structural compounds has excellent pharmacologically active, has caused medical research personnel's very big interest.To becoming focus take quianzolinones as basic derivative research, particularly contain the quinazolinone analog derivative of other heterocycle fragments, because the mutability of its structure and its derivative have the biological activity of wide spectrum, at medicine and pesticide field, have a wide range of applications.Some has entered clinical operational phase, as the treatment antifol Raltitrexed (raltitrexed) for late period knot, the rectum cancer of classics
[5-6]in just contain quinazolinone structure fragment.
1,2,3-3-triazole compounds is the very important compound of a class, there is stability and the good bio-compatibility of aromatic nucleus, it is a molecule that the pharmacophore of different substrates is connected into by triazole loop chain, its product can be used for improving and the binding ability of biological targets by hydrogen bond and dipole, and has the toxicity lower than imidazoles
[7].This compounds is widely used in fields such as biological medicine, agricultural chemicals, material, catalysis.Existing numerous triazole derivatives are as antibacterial
[8], antitumor
[9], anti-inflammatory
[10], hypertension
[11]deng medicine, be widely used in clinical.Schiff's base is also a kind of special physiologically active pharmacophoric group that has, as antibacterial, sterilization, the aspect such as antitumor, antiviral all have unique medicinal effect.The quinazolinone Schiff bases compound containing 1,2,3-triazole that present method is synthetic, by organic ordered three combining, has very important application prospect in fields such as organic chemistry, Materials science, biomedicine, medicine and pesticide intermediates.
Reference:
[1]Pereira?M?F,Chevrot?R,Rosenfeld?E?et?al.J.Enzym.Inhib.Med.Chem.2007,22,577.
[2]Brumas?B?V,Fiallo?M?M?L,Berthon?G.Inorg.Biochem.2006,100,362.
[3]Ram?V?J,Farhanu?Uah,Tfipathi?B?K,et?a1.Bioorg.Med.Chem.2003,11,2439.
[4]Berman?E?M,Werbel?L?M.J.Med.Chem.1991,34,479.
[5]Marsham?P?R,Hughes?L?R,Jackman?A?L,et?al.J.Med.Chem.1991,34,1594.
[6]Cunninghanl?D,Zalcberg?J,Maroun?J,et?a1.Eur.J.Cancer.2002,38,478.
[7]Best,M.Biochem.2009,48,6571.
[8]Pandeya?S?N,Sriram?D,Nath?G,et?a1.Pham.Acta.Helv.1999,74,11.
[9]Bennan?E?M,Werbel?L?M.J.Med.Chem.1991,34,479.
[10]Santagati?N?A,Bousquet?E,Spadaro?A?et?al.Farmaco.1999,54,780.
[11]Ram?V?J,Farhanullah,Tripathi?B?K?et?al.Bioorg.Med.Chem.2003,11,2439.
Summary of the invention
The object of the invention is to provide a kind of quinazolinone Schiff's base containing triazole and preparation method thereof, its structure is 3-(4-((4-chloromethyl)-1H-1,2,3-triazole) fluoro-4 (the 3H)-quinazolinones of benzene methylene amido-2-methyl-7-.
Its synthetic route is as follows:
The present invention propose 3-(preparation method of 4-((4-chloromethyl)-1H-1,2,3-triazole) fluoro-4 (the 3H)-quinazolinones (Compound I) of benzene methylene amido-2-methyl-7-, comprises the following steps:
(1) the fluoro-2-of 7-methyl-4 (3H)-3, the preparation of 1-benzoxazinone (Compound I I)
By 2-amino-4-fluorobenzoic acid and diacetyl oxide, under agitation condition, react, be cooled to after room temperature, the cooling solid of separating out, suction filtration, sherwood oil or normal hexane making beating for gained solid, be dried to obtain the fluoro-2-of 7-methyl-4 (3H)-3,1-benzoxazinone (Compound I I); The mol ratio of described 2-amino-4-fluorobenzoic acid and diacetyl oxide is preferably 1:10～1:15; Temperature of reaction is preferably 100～140 ℃; Reaction times is preferably 0.5～1.5 hour;
(2) preparation of fluoro-4 (the 3H)-quinazolinones (compound III) of 2-methyl-3-amino-7-
By the fluoro-2-of 7-methyl-4 (3H)-3 of step (1) gained, 1-benzoxazinone (Compound I I) joins in reactor, take ethanol as solvent, add hydrazine hydrate, react, reaction solution returns to room temperature, separate out after solid, suction filtration, gained solid ethyl alcohol recrystallization, is dried to obtain fluoro-4 (the 3H)-quinazolinones (compound III) of 2-methyl-3-amino-7-; Temperature of reaction is preferably 60～80 ℃; Reaction times is preferably 2～4 hours; The fluoro-2-of described 7-methyl-4 (3H)-3, the reaction raw materials mol ratio of 1-benzoxazinone and hydrazine hydrate is 1:3～1:5; The fluoro-2-of 7-methyl-4 (3H)-3, preferably 1:50～1:100 of the mol ratio of 1-benzoxazinone and solvent;
(3) preparation of 4-triazobenzene formaldehyde (compound IV)
4-nitrobenzaldehyde is joined in reactor, add solvent, add sodium azide, react, again reaction solution is returned to room temperature, add ether, wash with water, then wash with saturated nacl aqueous solution, separate organic phase, after organic phase is dried and dewaters, ether is removed in evaporation, obtains 4-triazobenzene formaldehyde (compound IV); The mol ratio of 4-nitrobenzaldehyde and sodium azide is preferably 1:2～1:4; The mol ratio of 4-nitrobenzaldehyde and solvent is preferably 1:10～1:20; Preferably 25～80 ℃ of temperature of reaction; Preferably 8～24 hours reaction times;
Solvent can adopt any in HMPA, DMF or methyl-sulphoxide;
(4) preparation of 4-((4-chloromethyl)-1H-1,2,3-triazole) phenyl aldehyde (compound V)
The 4-triazobenzene formaldehyde (compound IV) of step (3) gained is joined in the reactor that fills solvent, add successively 3-chloroallylene, sodium ascorbate, catalyzer, reaction is reacted under nitrogen protection, then suction filtration is removed insolubles; Resistates acetic acid ethyl dissolution, washing, use again saturated common salt water washing, separate organic phase, organic phase is dry dewater after, ethyl acetate is removed in evaporation, gained solid is by recrystallization or column chromatography 4-((4-the chloromethyl)-1H-1 that purifies to obtain, 2,3-triazole) phenyl aldehyde (compound V); Wherein, the mol ratio of described 4-triazobenzene formaldehyde and 3-chloroallylene is preferably 1:1～1:1.2; The mol ratio of 4-triazobenzene formaldehyde and sodium ascorbate is preferably 1:0.1～1:0.5; The mol ratio of 4-triazobenzene formaldehyde and catalyzer is preferably 1:0.1～1:0.5; Described catalyzer is cuprous iodide or cupric sulfate pentahydrate; The mol ratio of 4-triazobenzene formaldehyde and solvent is preferably 1:25～1:100; Temperature of reaction is room temperature preferably; Preferably 3～5 hours reaction times; Solvent can adopt any in acetonitrile, the trimethyl carbinol, HMPA, DMF or methyl-sulphoxide;
(5) 3-(preparation of 4-((4-chloromethyl)-1H-1,2,3-triazole) fluoro-4 (the 3H)-quinazolinones (Compound I) of benzene methylene amido-2-methyl-7-
By the 4-of step (4) gained ((4-chloromethyl)-1H-1,2,3-triazole) phenyl aldehyde (compound V) joins in the reactor that fills solvent, add fluoro-4 (the 3H)-quinazolinones (compound III) of 2-methyl-3-amino-7-of step (2) gained, react, evaporation is except after desolventizing again, the solid obtaining is purified and obtained 3-(4-((4-chloromethyl)-1H-1 by column chromatography or ethyl alcohol recrystallization, 2,3-triazole) fluoro-4 (the 3H)-quinazolinones (Compound I) of benzene methylene amido-2-methyl-7-, described 4-((4-chloromethyl)-1H-1,2,3-triazole) mole the caing be compared to most for 1:1～1:1.2 of phenyl aldehyde (compound V) and fluoro-4 (the 3H)-quinazolinones (compound III) of 2-methyl-3-amino-7-, 4-((4-chloromethyl)-1H-1,2,3-triazole) phenyl aldehyde (compound V) is preferably 1:50～100 with the mol ratio of solvent, preferably 60～160 ℃ of temperature of reaction, preferably 5～8 hours reaction times, solvent can adopt any in methyl alcohol, ethanol, DMF, acetonitrile or toluene.
The present invention is take 2-amino-4-fluorobenzoic acid cheap and easy to get, 4-nitrobenzaldehyde as raw material, through series reaction, obtained 3-(4-((4-chloromethyl)-1H-1,2,3-triazole) fluoro-4 (the 3H)-quinazolinones of benzene methylene amido-2-methyl-7-, this synthetic route have raw material be easy to get, easy and simple to handle, save solvent, reduce the advantage such as pollution, be convenient to suitability for industrialized production.
The quinazolinone Schiff bases compound containing 1,2,3-triazole that present method is synthetic, quinazolinone, triazole, three kinds of groups of Schiff's base organically combine, and have antitumous effect.
Embodiment
Followingly by embodiment, further illustrate the present invention, but can not limit content of the present invention.
Embodiment 1:
(1) the fluoro-2-of 7-methyl-4 (3H)-3, the preparation of 1-benzoxazinone (Compound I I)
By 2-amino-4-fluorobenzoic acid 1.55g(0.01mmol) join in round-bottomed flask, add 10.2mL(0.1mmol) diacetyl oxide, and after stirring, stirring reaction 1 hour under 140 ℃ of conditions.After TLC detection reaction, be cooled to room temperature, be placed in 0 ° of C cooling, separate out solid, suction filtration.Gained solid is pulled an oar with sherwood oil, and suction filtration obtains the fluoro-2-of off-white color solid 7-methyl-4 (3H)-3,1-benzoxazinone (Compound I I) 1.71g, yield 95.2% after the vacuum-drying of gained solid.
Data characterization is as follows:
.mp:195.4-195.7 ° of C. of off-white color solid
1hNMR (300MHz, CDCl
3): δ 2.46 (3H, s), 7.17-7.21 (2H, m), 8.20 (1H, dd, J=6.0,9.0Hz) .MS (ESI): m/z 180 (M+H)
+.
(2) preparation of fluoro-4 (the 3H)-quinazolinones (compound III) of 2-methyl-3-amino-7-
By the fluoro-2-of 7-methyl-4 (3H)-3 of step (1) gained, 1-benzoxazinone 895mg (5mmol) joins in round-bottomed flask, add 15mL ethanol to make solvent, add 750mg(15mmol) hydrazine hydrate, reaction is reacted 2 hours under 80 ℃ of conditions.After TLC detection reaction completes, solution returns to room temperature, separates out light brown solid, suction filtration, gained solid ethyl alcohol recrystallization, vacuum-drying obtains fluoro-4 (3H)-quinazolinone (compound III) 930mg of off-white color solid 2-methyl-3-amino-7-, yield 96.4%.Data characterization is as follows:
Off-white color solid .mp:153.1-153.7 ℃.
1h NMR (300MHz, CDCl
3): δ 2.68 (s, 3H), 4.87 (s, 2H), 7.13-7.29 (m, 2H), 8.24 (1H, dd, J=6.0,9.0Hz) .MS (ESI): m/z 194 (M+H)
+.
(3) preparation of 4-triazobenzene formaldehyde (compound IV)
By 4-nitrobenzaldehyde 3.02g(20mmol) join in round-bottomed flask, add 35mL HMPA to make solvent, add 2.6g(40mmol) sodium azide, reaction was 25 ° of C reactions 24 hours.After TLC detection reaction completes, in reaction solution, add 200mL ether, wash with water after (100mL × 2 time) again with saturated nacl aqueous solution 100mL washing 1 time, separate organic phase, organic phase anhydrous sodium sulfate drying.Suction filtration is removed siccative, and rotary evaporation obtains brown oil 4-triazobenzene formaldehyde (compound IV) 2.78g, yield 94.5%.
In this step, solvent can adopt equimolar N, and any in N-METHYLFORMAMIDE or methyl-sulphoxide replaces, and can realize this preparation process.
Data characterization is as follows:
Brown liquid .IR (KBr): 3301,3288,2117,1698cm
-1.
1h NMR (CDCl
3, 300MHz): δ 7.18 (d, J=9.0Hz, 2H), 7.91 (d, J=10.5Hz, 2H), 9.97 (s, 1H) .MS (ESI): m/z 148 (M+H)
+.
(4) preparation of 4-((4-chloromethyl)-1H-1,2,3-triazole) phenyl aldehyde (compound V)
By 4-triazobenzene formaldehyde (compound IV) 1.47g(10mmol of step (3) gained) join in the round-bottomed flask that fills 50mL acetonitrile, add successively 3-chloroallylene 0.75g(10mmol), sodium ascorbate 198mg(1mmol), cuprous iodide 191mg(1mmol), stir.Reaction stirring at room 3 hours under nitrogen protection, after TLC detection reaction, suction filtration is removed insolubles, and rotary evaporation is except desolventizing.Resistates 200mL acetic acid ethyl dissolution, washing (100mL × 2 time), then with saturated aqueous common salt 100mL washing 1 time, separate organic phase, organic phase anhydrous sodium sulfate drying.Suction filtration is removed siccative, rotary evaporation is removed ethyl acetate, and gained solid is by silica gel column chromatography purify to obtain yellow solid 4-((4-chloromethyl)-1H-1,2,3-triazole) phenyl aldehyde (compound V) 2.03g, yield 91.7%.
In this step, solvent can adopt any replacement in the equimolar trimethyl carbinol, HMPA, DMF or methyl-sulphoxide, can realize the preparation method of this step.
Data characterization is as follows:
Yellow solid .mp:119.5-120.3 ° C.
1h NMR (CDCl
3, 300MHz): δ 4.80 (s, 2H), 7.96 (d, J=8.4Hz, 2H), 8.07 (d, J=8.4Hz, 2H), 8.14 (s, 1H), 10.08 (s, 1H) .MS (ESI): m/z 244 (M+Na)
+.
(5) 3-(preparation of 4-((4-chloromethyl)-1H-1,2,3-triazole) fluoro-4 (the 3H)-quinazolinones (Compound I) of benzene methylene amido-2-methyl-7-
By the 4-of step (4) gained ((4-chloromethyl)-1H-1,2,3-triazole) phenyl aldehyde (compound V) 221mg(1mmol) join in the round-bottomed flask that fills 25mL toluene, add fluoro-4 (3H)-quinazolinone (compound III) 193mg(1mmol of 2-methyl-3-amino-7-of step (2) gained), be warming up to 110 ℃ of backflows, stirring reaction 5 hours.After TLC detection reaction, rotary evaporation is removed toluene, gained solid is by ethyl alcohol recrystallization brown ceramic powder 3-(4-((4-the chloromethyl)-1H-1 that purifies to obtain, 2,3-triazole) fluoro-4 (3H)-quinazolinone (Compound I) 354mg of benzene methylene amido-2-methyl-7-, yield 89.5%.
In this step, solvent can replace with any in equimolar methyl alcohol, ethanol, DMF, acetonitrile, can realize the preparation method of this step.
Structural characterization:
Brown solid .mp:208.5-209.1 ℃.
1h NMR (DMSO-d
6, 300MHz): δ 2.56 (s, 3H), 4.96 (s, 2H), 7.39-7.48 (m, 2H), 8.13-8.25 (m, 5H), 9.05 (s, 1H), 9.09 (s, 1H) .MS (ESI): m/z 397 (M+H)
+.
Total recovery: 71.2%.
Embodiment 2
(1) the fluoro-2-of 7-methyl-4 (3H)-3, the preparation of 1-benzoxazinone (Compound I I)
By 2-amino-4-fluorobenzoic acid 1.55g(0.01mmol) join in round-bottomed flask, add 15.3mL(0.15mmol) diacetyl oxide, and after stirring, stirring reaction 1 hour under 100 ℃ of conditions.After TLC detection reaction, be cooled to room temperature, be placed in-5 ℃ cooling, separate out solid, suction filtration.Gained solid is pulled an oar with normal hexane, and suction filtration obtains the fluoro-2-of off-white color solid 7-methyl-4 (3H)-3,1-benzoxazinone (Compound I I) 1.68g, yield 93.8% after the vacuum-drying of gained solid.
(2) preparation of fluoro-4 (the 3H)-quinazolinones of 2-methyl-3-amino-7-
By the fluoro-2-of 7-methyl-4 (3H)-3 of step (1) gained, 1-benzoxazinone (Compound I I) 895mg (5mmol) joins in round-bottomed flask, add 20mL ethanol to make solvent, add 1.25g(25mmol) hydrazine hydrate, reaction is reacted 4 hours under 60 ℃ of conditions.After TLC detection reaction completes, solution returns to room temperature, separates out light brown solid, suction filtration, gained solid ethyl alcohol recrystallization, vacuum-drying obtains fluoro-4 (3H)-quinazolinone (compound III) 914mg of off-white color solid 2-methyl-3-amino-7-, yield 94.7%.
The preparation of (3) 4 – triazobenzene formaldehyde (compound IV)
By 4-nitrobenzaldehyde 3.02g(20mmol) join in round-bottomed flask, add 30mL N, N-METHYLFORMAMIDE is made solvent, adds 5.2g(80mmol) sodium azide, reaction was 80 ℃ of reactions 8 hours.After TLC detection reaction completes, in reaction solution, add 200mL ether, wash with water after (100mL × 2 time) again with saturated nacl aqueous solution 100mL washing 1 time, separate organic phase, organic phase anhydrous sodium sulfate drying.Suction filtration is removed siccative, and rotary evaporation obtains brown oil 4-triazobenzene formaldehyde (compound IV) 2.43g, yield 82.7%.
(4) preparation of 4-((4-chloromethyl)-1H-1,2,3-triazole) phenyl aldehyde (compound V)
By 4-triazobenzene formaldehyde (compound IV) 1.47g(10mmol of step (3) gained) join in the round-bottomed flask that fills 20mL HMPA, add successively 3-chloroallylene 0.90g(12mmol), sodium ascorbate 990mg(5mmol), cupric sulfate pentahydrate 1.25g(5mmol), stir.Reaction stirring at room 5 hours under nitrogen protection, after TLC detection reaction, suction filtration is removed insolubles; add 200mL ethyl acetate, washing (100mL × 2 time), then with saturated aqueous common salt 100mL wash 1 time; separate organic phase, organic phase anhydrous sodium sulfate drying.Suction filtration is removed siccative, rotary evaporation is removed ethyl acetate, and gained solid is by recrystallization from ethyl acetate/petroleum ether purify to obtain yellow solid 4-((4-chloromethyl)-1H-1,2,3-triazole) phenyl aldehyde (compound V) 2.08g, yield 94.2%.
(5) 3-(preparation of 4-((4-chloromethyl)-1H-1,2,3-triazole) fluoro-4 (the 3H)-quinazolinones (Compound I) of benzene methylene amido-2-methyl-7-
By the 4-of step (4) gained ((4-chloromethyl)-1H-1,2,3-triazole) phenyl aldehyde (compound V) 221mg(1mmol) join and fill 25mL N, in the round-bottomed flask of dinethylformamide, add fluoro-4 (3H)-quinazolinone (compound III) 231mg(1.2mmol of 2-methyl-3-amino-7-of step (2) gained), be warming up to 78 ℃ of backflows, stirring reaction 8 hours.After TLC detection reaction, rotary evaporation is removed N, dinethylformamide, gained solid is by ethyl alcohol recrystallization brown ceramic powder 3-(4-((4-the chloromethyl)-1H-1 that purifies to obtain, 2,3-triazole) fluoro-4 (3H)-quinazolinone (Compound I) 338mg of benzene methylene amido-2-methyl-7-, yield 85.6%.
Total recovery 59.2%.
Embodiment 3
Be with the difference of embodiment 1:
In step (1), the charging capacity of diacetyl oxide is 0.12mmol, and temperature of reaction is 110 ℃, and the reaction times is 0.5 hour;
In step (2), the reaction times is 3 hours, and temperature of reaction is 70 ℃, and the charging capacity of hydrazine hydrate is 20mmol;
In step (3), the reaction times is 16 hours, and temperature of reaction is 50 ℃, and the charging capacity of sodium azide is 60mmol;
In step (4), the reaction times is 4 hours, and the charging capacity of 3-chloroallylene is 11mmol, and the charging capacity of sodium ascorbate is 3mmol, and the charging capacity of cuprous iodide is 3mmol;
In step (5), the reaction times is 7 hours, and temperature of reaction is 120 ℃, and the charging capacity of fluoro-4 (the 3H)-quinazolinones of 2-methyl-3-amino-7-is 1.1mmol;
Also can prepare 3-provided by the invention (fluoro-4 (the 3H)-quinazolinones of 4-((4-chloromethyl)-1H-1,2,3-triazole) benzene methylene amido-2-methyl-7-.
Embodiment 4
3-(the antitumor action experiment of 4-((4-chloromethyl)-1H-1,2,3-triazole) fluoro-4 (the 3H)-quinazolinones of benzene methylene amido-2-methyl-7-:
A-549 lung carcinoma cell is seeded in 96 orifice plates, with calf serum (PAA) nutrient solution containing 10%, is placed in 5%CO
2in incubator, 37 ℃ are cultured to cell attachment, discard nutrient solution, add containing medicine 3-(4-((4-chloromethyl)-1H-1,2,3-triazole)) the nutrient solution 200mL of fluoro-4 (the 3H)-quinazolinones of benzene methylene amido-2-methyl-7-, establish six concentration gradients, each concentration is established three multiple holes, each concentration joins respectively in corresponding aperture, 5%CO
2in 37 ℃ of incubators, cultivate 72 hours, add the 5mg/mLMTT of 20mL.Hatch after 3 hours for 37 ℃, supernatant is abandoned in suction, add the DMSO of 100mL to dissolve, select 450nm, use enzyme-linked immunosorbent assay instrument to survey each hole absorbance value, obtain as calculated the half growth inhibitory concentration IC of 3-(4-((4-chloromethyl)-1H-1,2,3-triazole)) fluoro-4 (the 3H)-quinazolinones of benzene methylene amido-2-methyl-7-
50value is 20mmol/L.Can find out, the quinolinone Schiff's base containing triazole provided by the invention is inhibited for lung carcinoma cell.
Claims (6)
1. prepare a method for the quinazolinone Schiff's base containing triazole as shown in the formula (I),
It is characterized in that, comprise the steps:
Step (1): the fluoro-2-of 7-methyl-4 (3H)-3, the preparation of 1-benzoxazinone
By 2-amino-4-fluorobenzoic acid and diacetyl oxide, under agitation condition, react, be cooled to after room temperature, the cooling solid of separating out, suction filtration, sherwood oil or normal hexane making beating for gained solid, be dried to obtain the fluoro-2-of 7-methyl-4 (3H)-3,1-benzoxazinone;
Step (2): the preparation of fluoro-4 (the 3H)-quinazolinones of 2-methyl-3-amino-7-
By the fluoro-2-of 7-methyl-4 (3H)-3 of step (1) gained, 1-benzoxazinone joins in reactor, take ethanol as solvent, add hydrazine hydrate, react, reaction solution returns to room temperature, separate out after solid, suction filtration, gained solid ethyl alcohol recrystallization, is dried to obtain fluoro-4 (the 3H)-quinazolinones of 2-methyl-3-amino-7-;
Step (3): the preparation of 4-triazobenzene formaldehyde
4-nitrobenzaldehyde is joined in reactor, add solvent, add sodium azide, react, reaction solution returns to room temperature, adds ether, washes with water, then washs with saturated nacl aqueous solution, separate organic phase, after organic phase is dried and dewaters, ether is removed in evaporation, obtains 4-triazobenzene formaldehyde;
The preparation of step (4): 4-((4-chloromethyl)-1H-1,2,3-triazole) phenyl aldehyde
The 4-triazobenzene formaldehyde of step (3) gained is joined in the reactor that fills solvent, add successively 3-chloroallylene, sodium ascorbate, catalyzer, reaction is reacted under nitrogen protection, then suction filtration is removed insolubles; Resistates acetic acid ethyl dissolution, washing, then use saturated common salt water washing, separate organic phase, after organic phase is dried and dewaters, ethyl acetate is removed in evaporation, gained solid is by recrystallization or column chromatography 4-((4-chloromethyl)-1H-1,2, the 3-triazole) phenyl aldehyde of purifying to obtain; Described catalyzer is cuprous iodide or cupric sulfate pentahydrate;
Step (5): the 3-(preparation of 4-((4-chloromethyl)-1H-1,2,3-triazole) fluoro-4 (the 3H)-quinazolinones of benzene methylene amido-2-methyl-7-
By the 4-of step (4) gained ((4-chloromethyl)-1H-1,2,3-triazole) phenyl aldehyde joins in the reactor that fills solvent, add fluoro-4 (the 3H)-quinazolinones of 2-methyl-3-amino-7-of step (2) gained, react, evaporation is except after desolventizing again, the solid obtaining is purified and obtained 3-(4-((4-chloromethyl)-1H-1 by column chromatography or ethyl alcohol recrystallization, 2,3-triazole) fluoro-4 (the 3H)-quinazolinones of benzene methylene amido-2-methyl-7-.
2. preparation formula according to claim 1 (I), containing the method for the quinazolinone Schiff's base of triazole, is characterized in that: in described step (1), the mol ratio of described 2-amino-4-fluorobenzoic acid and diacetyl oxide is 1:10～1:15; Temperature of reaction is 100～140 ℃; Reaction times is 0.5～1.5 hour.
3. preparation formula according to claim 1 (I), containing the method for the quinazolinone Schiff's base of triazole, is characterized in that: in described step (2), temperature of reaction is 60～80 ℃; Reaction times is 2～4 hours; The fluoro-2-of described 7-methyl-4 (3H)-3, the reaction raw materials mol ratio of 1-benzoxazinone and hydrazine hydrate is 1:3～1:5.
4. preparation formula according to claim 1 (I), containing the method for the quinazolinone Schiff's base of triazole, is characterized in that: in described step (3), the mol ratio of 4-nitrobenzaldehyde and sodium azide is 1:2～1:4; Temperature of reaction is 25～80 ℃; Reaction times is 8～24 hours; Solvent is any in HMPA, DMF or methyl-sulphoxide.
5. preparation formula according to claim 1 (I), containing the method for the quinazolinone Schiff's base of triazole, is characterized in that: in described step (4), the mol ratio of described 4-triazobenzene formaldehyde and 3-chloroallylene is 1:1～1:1.2; The mol ratio of 4-triazobenzene formaldehyde and sodium ascorbate is 1:0.1～1:0.5; The mol ratio of 4-triazobenzene formaldehyde and catalyzer is 1:0.1～1:0.5; Temperature of reaction is room temperature; Reaction times is 3～5 hours; Solvent is any in acetonitrile, the trimethyl carbinol, HMPA, DMF or methyl-sulphoxide;
6. preparation formula according to claim 1 (I) is containing the method for the quinazolinone Schiff's base of triazole, it is characterized in that: in described step (5), described 4-((4-chloromethyl)-1H-1,2,3-triazole) mol ratio of phenyl aldehyde and fluoro-4 (the 3H)-quinazolinones of 2-methyl-3-amino-7-is 1:1～1:1.2; Temperature of reaction is 60～160 ℃; Reaction times is 5～8 hours; Solvent is any in methyl alcohol, ethanol, DMF, acetonitrile or toluene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210469118.XA CN103059001B (en) | 2012-11-19 | 2012-11-19 | Quinazolinone Schiff base containing triazole and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210469118.XA CN103059001B (en) | 2012-11-19 | 2012-11-19 | Quinazolinone Schiff base containing triazole and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103059001A CN103059001A (en) | 2013-04-24 |
| CN103059001B true CN103059001B (en) | 2014-04-16 |
Family
ID=48101930
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210469118.XA Active CN103059001B (en) | 2012-11-19 | 2012-11-19 | Quinazolinone Schiff base containing triazole and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103059001B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892630B (en) * | 2015-05-22 | 2017-01-25 | 河南科技大学第一附属医院 | 1,4-benzoxazine-1,2,3-triazole compound as well as synthesis method and application thereof |
-
2012
- 2012-11-19 CN CN201210469118.XA patent/CN103059001B/en active Active
Non-Patent Citations (3)
| Title |
|---|
| Choi, Yongmun等.Identification of Bioactive Molecules by Adipogenesis Profiling of Organic.《Journal of Biological Chemistry》.2003,第278卷(第9期),7320-7324. |
| Identification of Bioactive Molecules by Adipogenesis Profiling of Organic;Choi, Yongmun等;《Journal of Biological Chemistry》;20031231;第278卷(第9期);7320-7324 * |
| 王颖.201210469118.《STN检索记录》.2013, * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103059001A (en) | 2013-04-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Moafi et al. | New HA 14-1 analogues: synthesis of 2-amino-4-cyano-4H-chromenes | |
| CN105017259A (en) | Trifluoromethyl containing quinazoline derivative and preparation method and application thereof | |
| CN103664785A (en) | Synthesis of novel dihydro-pyrazole sulfonamide derivative and application of novel dihydro-pyrazole sulfonamide derivative in anti-cancer drug | |
| CN106967003A (en) | A kind of method for synthesizing the assimilation compound of 1,3 benzoxazine 4 | |
| CN103880822B (en) | Containing 2,4,6-trisubstituted pyrimidine compounds of 1,2,3-triazole, preparation method and application thereof | |
| CN104072493A (en) | Naphthalimide compound containing 2-mercaptobenzothiazole and triazole heterocycle, preparation method and application thereof | |
| Li et al. | A novel and green synthesis of kojic acid derivatives in ionic liquid [bmim] BF4 | |
| CN102816150B (en) | Indole with bacteriostatic activity and derivatives thereof-triazole compounds, and preparation method thereof | |
| CN104529895A (en) | Synthetic method of nitrogen-containing heterocyclic compound | |
| CN103059001B (en) | Quinazolinone Schiff base containing triazole and preparation method thereof | |
| CN110204464B (en) | Synthesis method of aryl tertiary sulfonamide compound | |
| CN103664786A (en) | Synthesis method of dihydro-pyrazole sulfonamide derivatives of salicylaldehydes and application of dihydro-pyrazole sulfonamide derivatives to preparation of anticancer drugs | |
| CN103755659A (en) | 6-cinnamon acyl-2H-benzo [b] [1, 4] oxazine-3 (4H)-ketone compound and application thereof | |
| CN110437156A (en) | Paeonol dihydro-pyrimidin ketones derivant and its preparation method and application | |
| CN106045980A (en) | Quinazoline derivative and preparation method thereof | |
| CN105399644A (en) | Molecular tweezer compounds with (1S,2S)-1,2-cyclohexanediamine as spacer group and isosteviol as chiral arm, and preparation method and application thereof | |
| CN105622507A (en) | Naphthalimide derivative and preparing method and application thereof | |
| CN102838515A (en) | Cinnamoyl sulfonamide compound preparation and applications of cinnamoyl sulfonamide compounds in anti-tumor treatment drugs | |
| CN108033913A (en) | A kind of pyrazoline quinoline derivant and its preparation method and application | |
| CN104119319B (en) | Containing the pyrimidine derivatives and its production and use of 1,2,3-triazole and urea structure uint | |
| CN105732521B (en) | A kind of preparation method of dihydroquinazoline ketone derivatives | |
| CN108976214A (en) | Pyruvate dehydrogenase system inhibitor and its preparation method and application | |
| Chandralekha et al. | Efficient atom-economical solvent-free one-pot multicomponent synthesis of 2-amino-4 H-benzo [b] pyrans catalyzed by solid base SiO 2-OK as a reusable catalyst | |
| Su et al. | The supramolecular assemblies of 7-amino-2, 4-dimethylquinolinium salts and the effect of a variety of anions on their luminescent properties | |
| CN102268003B (en) | Unsymmetrical poly-substituted porphyrin gold (III) type anticancer compound and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |