CN102675222A - Method for preparing multi-substituted quinazoline and heterocyclic pyrimidine derivative - Google Patents
Method for preparing multi-substituted quinazoline and heterocyclic pyrimidine derivative Download PDFInfo
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- CN102675222A CN102675222A CN2012101323523A CN201210132352A CN102675222A CN 102675222 A CN102675222 A CN 102675222A CN 2012101323523 A CN2012101323523 A CN 2012101323523A CN 201210132352 A CN201210132352 A CN 201210132352A CN 102675222 A CN102675222 A CN 102675222A
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Abstract
The invention discloses a method for preparing a multi-substituted quinazoline and heterocyclic pyrimidine derivative. The method comprises the following step of: performing cyclization reaction on substituted o-halogenated aromatic aldehyde/ ketone shown as a formula II and alcohol shown as a formula III in the presence of aqueous ammonia, oxidant and catalyst to obtain a compound shown as a formula I, wherein the catalyst is a copper salt, and the substituted o-halogenated aromatic aldehyde/ ketone shown as the formula II is single-substituted or multi-substituted o-halogenated aromatic aldehyde/ ketone. The method for synthesizing the multi-substituted quinazoline and heterocyclic pyrimidine derivative shown as the formula I is a one-step synthesizing method, and the method has the following characteristics that (1) the catalyst is cheap and readily available, the reaction operation is simple, and the method is suitable for large-scale production; (2) the catalyst system has extremely high chemical reaction property and selectivity, and the multi-substituted quinazoline and heterocyclic pyrimidine derivative can be synthesized with high yield; and (3) the catalyst system has strong universality to substrates, and the substrates containing various functional groups can efficiently react.
Description
Technical field
The present invention relates to the preparation method of a kind of polysubstituted quinazoline and heterocycle and pyrimidine derivatives, belong to fine chemical product catalytic synthetic techniques field.
Background technology
Quinazoline and heterocycle and pyrimidine derivatives are very important compounds, extensively are present in natural product and the drug molecule.They have antibiotic [Selected papers: (a) Bedi, P.M.S.; Kumar, V.; Mahajan, M.P.Bioorg.Med.Chem.Lett.2004,14,5211. (b) Purohit, D.M.; Shah, V.H.Indian J.Heterocycl.Chem.1999,8,213.], antiviral [Selected papers: (a) Chien, T.C.; Chen, C.S.; Yu, F.H.; Chern, J.W.Chem.Pharm.Bull.2004,52,1422. (b) Herget, T.; Freitag, M.; Morbitzer, M.; Kupfer, R.; Stamminger, T.; Marschall, M.Antimicrob.Agents Chemother.2004,48,4154.], tuberculosis [Selected papers: (a) Waisser, K.; Gregor, J.; Dostal, H.; Kunes, J.; Kubicova, L.; Klimesova, V.; Kaustova, J.Farmaco 2001,56,803. (b) Kunes, J.; Bazant, J.; Pour, M.; Waisser, K.; Slosarek, M.; Janota, J.Farmaco 2000,55,725.], anticancer [Selected papers: (a) Doyle, L.A.; Ross, D.D.Oncogene 2003,22,7340. (b) Henderson, E.A.; Bavetsias, V.; Theti, D.S.; Wilson, S.C.; Clauss, R.; Jackman, A.L.Bioorg.Med.Chem.2006,14,5020. (c) Foster, A.; Coffrey, H.A.; Morin, M.J.; Johnson & Johnson's thing, medicinal activity such as Rastinejad, F.Science 1999,286,2507.], so the novel synthesis of quinazoline and heterocycle and pyrimidine derivatives has actual application value, receives showing great attention to of association area researcher.
Classical synthesis method such as reining in the cyclisation synthesis method than executing, has been widely used in quinazoline and heterocycle miazines compound synthetic; But often the substrate suitability is limited for these methods; Starting raw material is difficult for synthetic, and reactions step is miscellaneous sometimes, and reaction conditions is harsh.In recent years, scientists is devoted to utilize transition metal-catalyzed, gentle, the effective quinazoline of development of new and heterocycle and pyrimidine derivatives method.For example, Truong [Truong, V.L.; Morrow, M.Tetrahedron Lett.2010,51,758.], Huang [Huang, C.; Fu, Y.; Fu, H.; Jiang, Y.; Zhao, Y.Chem.Commun.2008,6333.] reported that the adjacent halobenzene formaldehyde of copper catalysis, the condensation of amidine hydrochloride generate the method for quinazoline derivant; Wang [Wang, C.; Li, S.; Liu, H.; Jiang, Y.; Fu, H.J.Org.Chem.2010,75,7936.] reported under the dioxygen oxidation condition method of adjacent bretylium of copper catalysis and amide condensed generation quinazoline derivant.But these methods need be starting raw material with complicated nitrogenous compound all, limit the suitability of reaction, therefore, develop and new have better substrate flexibility and more green synthesis method is a significant problem.
Summary of the invention
The purpose of this invention is to provide the method that a kind of single stage method prepares polysubstituted quinazoline and heterocycle and pyrimidine derivatives.
Polysubstituted quinazoline provided by the present invention and heterocycle and pyrimidine derivatives are the preparation method of compound shown in the formula I, comprise the steps: that alcohol shown in adjacent halogen aromatic aldehyde/ketone of replacement shown in the formula II and the formula III carries out cyclization and promptly gets compound shown in the formula I under the condition that ammoniacal liquor, oxygenant and catalyzer exist;
Said catalyzer is a mantoquita; Replacing adjacent halogen aromatic aldehyde/ketone shown in the formula II is single the replacement or polysubstituted adjacent halogen aromatic aldehyde/ketone;
Formula I formula II formula III
In the formula, R
1It for hydrogen or carbonatoms 1～10 alkyl; R
2For hydrogen, carbonatoms 1～10 alkyl or substituted aryl; R
3For hydrogen, halogen, carbonatoms are that 1～10 alkoxyl group, nitro or carbonatoms are 1～10 alkyl; X is fluorine, chlorine or bromine.
Among the above-mentioned preparation method, R
1Can be hydrogen or methyl; R
2Can be hydrogen, phenyl, rubigan, p-methylphenyl or p-methoxyphenyl; R
3Can be hydrogen or fluorine.
Among the above-mentioned preparation method, the aromatic ring that replaces in adjacent halogen aromatic aldehyde/ketone shown in the formula II can be phenyl ring or thiphene ring.
Among the above-mentioned preparation method, the quality percentage composition of said ammoniacal liquor can be 25%～28%, as 25%; Said oxygenant can be air, oxygen, ydrogen peroxide 50, di-t-butyl peroxide (DTBP) or peroxy tert-butyl alcohol; Said mantoquita can be selected from least a in cuprous chloride, cuprous bromide, cuprous iodide, Red copper oxide, venus crystals, copper sulfate, cupric chloride, cupric bromide, cupric nitrate and the copper trifluoromethanesulfcomposite.
Among the above-mentioned preparation method, the molfraction ratio that replaces adjacent halogen aromatic aldehyde/ketone and alcohol shown in the formula III shown in the formula II can be 1: (1～5) specifically can be 1: 1,1: 3 or 1: 5; Said oxygenant can be (1～5) with the molfraction ratio that replaces adjacent halogen aromatic aldehyde/ketone shown in the formula II: 1, specifically can be 1: 1,2.5: 1 or 5: 1; Said catalyzer can be (0.05～0.3) with the molfraction ratio that replaces adjacent halogen aromatic aldehyde/ketone shown in the formula II: 1, specifically can be 0.05: 1,0.1: 1 or 0.3: 1; Said ammoniacal liquor can be (5～30) with the molfraction ratio that replaces adjacent halogen aromatic aldehyde/ketone shown in the formula II: 1, and wherein, the amount of ammoniacal liquor is in its ammoniated amount, specifically can be 5: 1,14: 1 or 30: 1.
Among the above-mentioned preparation method, the temperature of said cyclization is 60 ℃～140 ℃, specifically can be 80 ℃, 120 ℃ or 140 ℃, and the time is 3h～12h, specifically can be 3h, 6h or 12h.
Among the above-mentioned preparation method, said cyclization can carry out in the reaction unit of sealing, as in the glass tube sealing, carrying out.
The method of polysubstituted quinazoline and heterocycle and pyrimidine derivatives is one-step synthesis shown in the synthesis type I provided by the invention, and this method has following characteristics: (1) catalyzer is cheap and easy to get, and operation is simple, is fit to scale operation; (2) catalyst system has high chemical reactivity and selectivity, synthetic polysubstituted quinazoline and heterocycle and pyrimidine derivatives that can high yield; (3) catalystsystem is strong to the universality of substrate, and the substrate that contains various functional groups can both react efficiently.
Description of drawings
Fig. 1 is the hydrogen spectrogram of embodiment 1 gained title product.
Fig. 2 is the carbon spectrogram of embodiment 1 gained title product.
Fig. 3 is the hydrogen spectrogram of embodiment 7 gained title products.
Fig. 4 is the carbon spectrogram of embodiment 7 gained title products.
Fig. 5 is the hydrogen spectrogram of embodiment 9 gained title products.
Fig. 6 is the carbon spectrogram of embodiment 9 gained title products.
Fig. 7 is the hydrogen spectrogram of embodiment 10 gained title products.
Fig. 8 is the carbon spectrogram of embodiment 10 gained title products.
Fig. 9 is the hydrogen spectrogram of embodiment 16 gained title products.
Figure 10 is the carbon spectrogram of embodiment 16 gained title products.
Embodiment
Employed experimental technique is ordinary method like no specified otherwise among the following embodiment.
Used material, reagent etc. like no specified otherwise, all can obtain from commercial sources among the following embodiment.
The content of the ammoniacal liquor in following embodiment and the Comparative Examples is the quality percentage composition.
Take by weighing CuCl 10mg (0.1mmol) respectively, adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol); 25% ammoniacal liquor 1mL; DTBP 365mg (2.5mmol) joins in the 50mL glass reaction tube with cover, and sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then; Stirring, insulation reaction 6h postcooling obtain title product 2-phenyl provided by the invention-4-methyl quinazoline to room temperature.
Reaction result: isolating title product 2-phenyl-4-methyl quinazoline is weighed, and the isolated yield that calculates this product is 65%.
Fig. 1 and Fig. 2 are respectively hydrogen spectrum and the carbon spectrum that this embodiment prepares gained title product 2-phenyl-4-methyl quinazoline, can know that by figure this compound structure is correct.
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), methyl alcohol 100mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 4-methyl quinazoline provided by the invention to room temperature.
Reaction result: isolating title product 4-methyl quinazoline is weighed, and the isolated yield that calculates this product is 17%.
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), p-methoxybenzyl alcohol 415mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 2-p-methoxyphenyl provided by the invention-4-methyl quinazoline to room temperature.
Reaction result: isolating title product 2-p-methoxyphenyl-4-methyl quinazoline is weighed, and the isolated yield that calculates this product is 55%.
Embodiment 4, preparation 2-rubigan-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), to chlorobenzene methanol 425mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 2-rubigan provided by the invention-4-methyl quinazoline to room temperature.
Reaction result: isolating title product 2-rubigan-4-methyl quinazoline is weighed, and the isolated yield that calculates this product is 81%.
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), to fluorophenyl methanol 378mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 2-provided by the invention to fluorophenyl-4-methyl quinazoline to room temperature.
Reaction result: isolating title product 2-is weighed to fluorophenyl-4-methyl quinazoline, and the isolated yield that calculates this product is 61%.
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), to methylbenzyl alcohol 366mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 2-p-methylphenyl provided by the invention-4-methyl quinazoline to room temperature.
Reaction result: isolating title product 2-p-methylphenyl-4-methyl quinazoline is weighed, and the isolated yield that calculates this product is 62%.
Embodiment 7, preparation 2,4-dimethyl-quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively, adjacent bromoacetophenone 199mg (1mmol), ethanol 140mg (3mmol); 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature; Obtain title product 2 provided by the invention, 4-dimethyl-quinazoline.
Reaction result: with isolating title product 2,4-dimethyl-quinazoline is weighed, and the isolated yield that calculates this product is 55%.
Fig. 3 and Fig. 4 are respectively this embodiment and prepare gained title product 2, and the hydrogen spectrum of 4-dimethyl-quinazoline and carbon spectrum can know that by figure this compound structure is correct.
Embodiment 8, preparation 2-ethyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), propyl alcohol 180mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 2-ethyl provided by the invention-4-methyl quinazoline to room temperature.
Reaction result: isolating title product 2-ethyl-4-methyl quinazoline is weighed, and the isolated yield that calculates this product is 51%.
Embodiment 9, preparation 2-n-hexyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), n-Heptyl alcohol 350mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 2-n-hexyl provided by the invention-4-methyl quinazoline to room temperature.
Reaction result: isolating title product 2-n-hexyl-4-methyl quinazoline is weighed, and the isolated yield that calculates this product is 58%.
Fig. 5 and Fig. 6 are respectively hydrogen spectrum and the carbon spectrum that this embodiment prepares gained title product 2-n-hexyl-4-methyl quinazoline, can know that by figure this compound structure is correct.
Take by weighing CuCl 10mg (0.1mmol) respectively; 2-bromo-4-fluoro acetophenone 216mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 7-fluoro-4-methyl provided by the invention-2-phenylquinazoline to room temperature.
Reaction result: isolating title product 7-fluoro-4-methyl-2-phenylquinazoline is weighed, and the isolated yield that calculates this product is 57%.
Fig. 7 and Fig. 8 are respectively hydrogen spectrum and the carbon spectrum that this embodiment prepares gained title product 7-fluoro-4-methyl-2-phenylquinazoline, can know that by figure this compound structure is correct.
Embodiment 11, preparation 7-fluoro-4-methyl-2-rubigan quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; 2-bromo-4-fluoro acetophenone 216mg (1mmol), to chlorobenzene methanol 425mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 7-fluoro-4-methyl provided by the invention-2-rubigan quinazoline to room temperature.
Reaction result: isolating title product 7-fluoro-4-methyl-2-rubigan quinazoline is weighed, and the isolated yield that calculates this product is 67%.
Embodiment 12, preparation 7-fluoro-4-methyl-2-p-methoxyphenyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; 2-bromo-4-fluoro acetophenone 216mg (1mmol), p-methoxybenzyl alcohol 415mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 7-fluoro-4-methyl provided by the invention-2-p-methoxyphenyl quinazoline to room temperature.
Reaction result: isolating title product 7-fluoro-4-methyl-2-p-methoxyphenyl quinazoline is weighed, and the isolated yield that calculates this product is 52%.
Embodiment 13, preparation 7-fluoro-4-methyl-2-p-methylphenyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; 2-bromo-4-fluoro acetophenone 216mg (1mmol), to methylbenzyl alcohol 366mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 7-fluoro-4-methyl provided by the invention-2-p-methylphenyl quinazoline to room temperature.
Reaction result: isolating title product 7-fluoro-4-methyl-2-p-methylphenyl quinazoline is weighed, and the isolated yield that calculates this product is 62%.
Embodiment 14, preparation 7-fluoro-4-methyl-2-are to the fluorophenyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; 2-bromo-4-fluoro acetophenone 216mg (1mmol), to fluorophenyl methanol 378mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50-mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 7-fluoro-4-methyl-2-provided by the invention to the fluorophenyl quinazoline to room temperature.
Reaction result: isolating title product 7-fluoro-4-methyl-2-fluorophenyl quinazoline is weighed, and the isolated yield that calculates this product is 60%.
Take by weighing CuCl 10mg (0.1mmol) respectively; 2-bromo-4-fluoro acetophenone 216mg (1mmol), n-Heptyl alcohol 350mg (3mmol) (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 7-fluoro-4-methyl provided by the invention-2-n-hexyl quinazoline to room temperature.
Reaction result: isolating title product 7-fluoro-4-methyl-2-n-hexyl quinazoline is weighed, and the isolated yield that calculates this product is 53%.
Embodiment 16, preparation 2-rubigan quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromobenzaldehyde 186mg (1mmol), to chlorobenzene methanol 425mg (3mmol), 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube then; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling obtain title product 2-rubigan quinazoline provided by the invention to room temperature.
Reaction result: isolating title product 2-rubigan quinazoline is weighed, and the isolated yield that calculates this product is 33%.
Fig. 9 and Figure 10 are respectively hydrogen spectrum and the carbon spectrum that this embodiment prepares gained title product 2-rubigan quinazoline, can know that by figure this compound structure is correct.
Take by weighing CuCl 10mg (0.1mmol) respectively, 2-ethanoyl-3 bromo thiophene 205mg (1mmol) is to chlorobenzene methanol 425mg (3mmol); 25% ammoniacal liquor 1mL and DTBP 365mg (2.5mmol) join in the 50mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature; Obtain title product 2-rubigan provided by the invention-4-thiotolene [3,3-d] and pyrimidine.
Reaction result: isolating title product 2-rubigan-4-thiotolene [3,2-d] and pyrimidine are weighed, and the isolated yield that calculates this product is 41%.
Embodiment 18, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuBr 14mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 1mL; DTBP 365mg (2.5mmol) joins in the 50mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 60%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 19, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuI 18mg (0.1mmol) respectively, adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol); 25% ammoniacal liquor 1mL; DTBP 365mg (2.5mmol) joins in the 50mL glass reaction tube with cover, is full of air atmosphere in the reaction tubes, then sealed reaction tube; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 61%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 20, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively, adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 1mL, 30%H
2O
2283mg (2.5mmol) joins in the 50mL glass reaction tube with cover, and sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 53%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 21, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively, adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol); 25% ammoniacal liquor 1mL; Join in the 50mL glass reaction tube with cover, be full of air atmosphere in the reaction tubes, then sealed reaction tube; Put reaction tubes and in oil bath, be heated to 120 ℃, stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 25%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 22, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 1mL; Peroxy tert-butyl alcohol 225mg (2.5mmol) joins in the 50-mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 37%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 23, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 5mg (0.05mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 1mL; DTBP 365mg (2.5mmol) joins in the 50-mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 45%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 24, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 30mg (0.3mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 1mL; DTBP 365mg (2.5mmol) joins in the 50mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 65%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 25, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 108mg (1mmol), 25% ammoniacal liquor 1mL; DTBP 365mg (2.5mmol) joins in the 50mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 28%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 26, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 550mg (5mmol), 25% ammoniacal liquor 1mL; DTBP 365mg (2.5mmol) joins in the 50mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 65%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 27, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 0.3mL; DTBP 365mg (2.5mmol) joins in the 50-mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 33%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 28, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 2mL; DTBP 365mg (2.5mmol) joins in the 50mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 65%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 29, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 1mL; DTBP 146mg (1mmol) joins in the 50mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 30%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 30, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 1mL; DTBP 730mg (5mmol) joins in the 50-mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 65%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 31, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 1mL; DTBP 365mg (2.5mmol) joins in the 50mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 80 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 19%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 32, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 1mL; DTBP 365mg (2.5mmol) joins in the 50-mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 140 ℃ then, and stirring, insulation reaction 6h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 59%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 33, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 1mL; DTBP 365mg (2.5mmol) joins in the 50mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 3h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, raw material has residue, title product 2-phenyl-4-methyl quinazoline 38%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Embodiment 34, preparation 2-phenyl-4-methyl quinazoline
Take by weighing CuCl 10mg (0.1mmol) respectively; Adjacent bromoacetophenone 199mg (1mmol), phenylcarbinol 325mg (3mmol), 25% ammoniacal liquor 1mL; DTBP 365mg (2.5mmol) joins in the 50mL glass reaction tube with cover; Sealed reaction tube is put reaction tubes and in oil bath, is heated to 120 ℃ then, and stirring, insulation reaction 12h postcooling are to room temperature.
Reaction result: with gc and this catalystic converter system of mass spectroscopy, title product 2-phenyl-4-methyl quinazoline 66%.
The hydrogen spectrum and the carbon spectrum of the prepared title product that obtains are similar with Fig. 1 and Fig. 2 respectively.
Claims (7)
1. the preparation method of compound shown in the formula I comprises the steps:
Alcohol shown in adjacent halogen aromatic aldehyde/ketone of replacement and the formula III shown in the formula II carries out cyclization and promptly gets compound shown in the formula I under the condition that ammoniacal liquor, oxygenant and catalyzer exist;
Said catalyzer is a mantoquita; Replacing adjacent halogen aromatic aldehyde/ketone shown in the formula II is single the replacement or polysubstituted adjacent halogen aromatic aldehyde/ketone;
Formula I formula II formula III
In the formula, R
1It for hydrogen or carbonatoms 1～10 alkyl; R
2For hydrogen, carbonatoms 1～10 alkyl or substituted aryl; R
3For hydrogen, halogen, carbonatoms are that 1～10 alkoxyl group, nitro or carbonatoms are 1～10 alkyl; X is fluorine, chlorine or bromine.
2. preparation method according to claim 1 is characterized in that: R
1Be hydrogen or methyl; R
2Be hydrogen, phenyl, rubigan, p-methylphenyl or p-methoxyphenyl; R
3Be hydrogen or fluorine.
3. preparation method according to claim 1 and 2 is characterized in that: the aromatic ring that replaces in adjacent halogen aromatic aldehyde/ketone shown in the formula II is phenyl ring or thiphene ring.
4. according to arbitrary described preparation method among the claim 1-3, it is characterized in that: the quality percentage composition of said ammoniacal liquor is 25%～28%; Said oxygenant is air, oxygen, ydrogen peroxide 50, di-t-butyl peroxide or peroxy tert-butyl alcohol; Said mantoquita is selected from cuprous chloride, cuprous bromide, cuprous iodide, Red copper oxide, venus crystals, copper sulfate, cupric chloride, cupric bromide, cupric nitrate and the copper trifluoromethanesulfcomposite at least a.
5. according to arbitrary described preparation method among the claim 1-4, it is characterized in that: replacing adjacent halogen aromatic aldehyde/ketone shown in the formula II is 1 with molfraction ratio pure shown in the formula III: (1～5); Said oxygenant is (1～5) with the molfraction ratio that replaces adjacent halogen aromatic aldehyde/ketone shown in the formula II: 1; Said catalyzer is (0.05～0.3) with the molfraction ratio that replaces adjacent halogen aromatic aldehyde/ketone shown in the formula II: 1; Said ammoniacal liquor is (5～30) with the molfraction ratio that replaces adjacent halogen aromatic aldehyde/ketone shown in the formula II: 1, and wherein, the amount of ammoniacal liquor is in its ammoniated amount.
6. according to arbitrary described preparation method among the claim 1-5, it is characterized in that: the temperature of said cyclization is 60 ℃～140 ℃, and the time is 3h～12h.
7. according to arbitrary described preparation method among the claim 1-6, it is characterized in that: said cyclization carries out in the reaction unit of sealing.
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| CN103275016A (en) * | 2013-06-04 | 2013-09-04 | 温州医学院附属第二医院 | Synthetic method of 2-subsituted quinazoline compounds |
| CN105418516A (en) * | 2015-12-21 | 2016-03-23 | 信阳师范学院 | Quinazoline compounds and preparation method thereof |
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Cited By (4)
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| CN103275016A (en) * | 2013-06-04 | 2013-09-04 | 温州医学院附属第二医院 | Synthetic method of 2-subsituted quinazoline compounds |
| CN103275016B (en) * | 2013-06-04 | 2015-03-11 | 温州医科大学附属第二医院 | Synthetic method of 2-subsituted quinazoline compounds |
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| CN105418516B (en) * | 2015-12-21 | 2018-03-02 | 信阳师范学院 | A kind of quinazoline compounds and preparation method thereof |
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