CN103880761B - The method of one pot process 4 (3H)-Quinazol derivative is eliminated by cyclization - Google Patents

The method of one pot process 4 (3H)-Quinazol derivative is eliminated by cyclization Download PDF

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CN103880761B
CN103880761B CN201410113565.0A CN201410113565A CN103880761B CN 103880761 B CN103880761 B CN 103880761B CN 201410113565 A CN201410113565 A CN 201410113565A CN 103880761 B CN103880761 B CN 103880761B
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CN103880761A (en
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杜云飞
程然
赵康
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Du Chuang (Shanghai) Medical Technology Co.,Ltd.
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Tianjin University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3

Abstract

The invention discloses and a kind of eliminate one pot process 4(3H by cyclization) method of-Quinazol derivative, step is: (1) with acetic acid, formic acid, trifluoroacetic acid or dichloro acetic acid for solvent, N-methoxyl group anthranilamide (II) will be replaced and react 0.3-5.0 hour with replacement aldehyde (III) at 70 ~ 100 DEG C, eliminated by cyclization, generate 4(3H)-Quinazol derivative (I), reaction formula is:

Description

The method of one pot process 4 (3H)-Quinazol derivative is eliminated by cyclization
Technical field
A kind of eliminate one pot process 4(3H by cyclization) method of-Quinazol derivative.
Background technology
4(3H)-quinazolinone and derivative thereof are the very important alkaloids of a class, and they can extract from animals and plants, microorganism widely, have a lot of pharmacology and biological activity [1], as the pegamine of extraction and isolation from Herba pegani harmalae [2](A), there is cytotoxicity feature.4(3H)-quinazolinone mother nucleus structure is also applied to some extent in medicine, such as turzolon [3](B), be a kind of sedative hypnotic being once used for the treatment of insomnia, additive and disabled due to it after 1985.Also has halofuginone hydrobromide [4], be used for the treatment of malaria, cancer, particularly in treatment coccidiosis of chicken, demonstrating good effect, is a kind of broad-spectrum anti-parasite medicine.
Pertinent literature is as follows:
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The 4(3H of current bibliographical information) the common synthetic route of-Quinazol derivative has six kinds, as follows:
(1) a method synthesizes 4(3H to replace mebenil yl-benzamide for starting raw material by heating ring)-quinazolinone mother nucleus structure [5];
(2) b method replaces benzoxazine open loop cyclization aromizing again by amination and obtains 4(3H)-quinazolinone and derivative skeleton structure thereof [6];
(3) c method is to replace anthranilamide derivatives and to replace aldehyde for raw material, by the cyclization of oxygenant or metal mediation again dehydroaromatizationof obtain 4(3H)-quinazolinone and derivative thereof [7];
(4) d method is to replace isatoic anhydride, replaces amine and replaces aldehyde, halohydrocarbon or trimethyl orthoformate and use multi-component reaction strategy to realize 4(3H under one pot of condition) structure of-quinazolinone parent nucleus [8];
(5) e method replaces anthranilamide for raw material with N-, solvent is made with tetrahydrofuran (THF) under-30 DEG C of conditions, react with diisopropylamine lithium and first generate N-and replace anthranilamide lithium reagent, then add in reaction system replace nitrile reaction and can obtain 4(3H)-quinazolinones [9];
In recent years, metal is turned as copper [10], rhodium [11], iridium [12]and palladium [13]also start to be applied to 4(3H as catalyzer) synthesis of-quinazolinone and derivative thereof.Although these methods have its feature and certain potential using value above, but not easily obtain because wherein a lot of method has raw material, severe reaction conditions, reaction times is longer, the shortcoming such as the loaded down with trivial details and product yield of post-treatment condition is not high, more importantly to use poisonous and expensive oxygenant or heavy metal, because which limit the application of these methods.
Specifically see with Publication about Document:
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[6](a)Liu,J.;Lee,J.;Dalton,A.M.;Bi,G.;Yu,L.;Baldino,C.M.;McElory,E.;Brown,M.Tetrahedron Lett.2005,46,1241-1244.(b)El-Sakka,S.S.;Hashash,M.A.;Abdel-Gawad,I.I.;Ahmed,G.E.Orient.J.Chem.2009,25,287-294.(c)Asundaria,S.T.;Patel,N.S.;Patel,K.C.Med.Chem.Res.2012,21,1199-1206.
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[8](a)Bhat,B.A.;Sahu,D.P.Synth.Commun.2004,34,2169-2176.(b)Dabiri,M.;Salehi,P.;Khajavi,M.;Mohammadi,A.Heterocycles2004,63,1417-1421.(c)Salehi,P.;Dabiri,M.;Zolfigol,M.A.;Baghbanzadeh,M.Tetrahedron Lett.2005,46,7051-7053.(d)Abiri,M.;Salehi,P.;Mohammadi,A.;Baghbanzadeh,M.Synth.Commun.2005,35,279-287.(e)Baghbanzadeh,M.;Dabiri,M.;Salehi,P.Heterocycles2008,75,2809-2815.(f)Chen,J.;Wu,D.;He,F.;Liu,M.;Wu,H.;Ding,J.;Su,W.Tetrahedron Lett.2008,49,3814-3818.(g)Dabiri,M.;Salehi,P.;Bahramnejad,M.;Alizadeh,M.Monatsh.Chem.2010,141,877-881.(h)Zeng,L.;Cai,C.J.Heterocycl.Chem.2010,47,1035-1039.(i)Mohammadi,A.;Sadat Hossini,S.S.Chin.J.Chem.2011,29,1982-1984.(j)Adib,M.;Sheikhi,E.;Bijanzadeh,H.R.Synlett2012,23,85-88.
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Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provide a kind of do not need oxygenant or heavy metal to participate in eliminate one pot process 4(3H by cyclization) method of-Quinazol derivative.
Technical scheme of the present invention is summarized as follows:
One pot process 4(3H is eliminated by cyclization) method of-Quinazol derivative (I), comprise the steps:
(1) with acetic acid, formic acid, trifluoroacetic acid or dichloro acetic acid for solvent, N-methoxyl group anthranilamide (II) will be replaced and react 0.3-5.0 hour with replacement aldehyde (III) at 70 ~ 100 DEG C, eliminated by cyclization, generate 4(3H)-Quinazol derivative (I), reaction formula is:
Wherein:
R 1=hydrogen, chlorine, bromine, fluorine, methoxyl group or methyl;
R 2=phenyl, 4-bromophenyl, 4-fluorophenyl, 3-chloro-phenyl-, o-trifluoromethyl phenyl, 4-tolyl, 4-methoxyphenyl, 4-hydroxyphenyl, 2,6-dichlorophenyl, 3,4-dimethoxy phenyl, propyl group, methyl, sec.-propyl, 2-methyl-3 phenylpropenyl or benzyloxy propyl group.
The present invention has without oxygenant and heavy metal oxidation or catalysis, and environmental protection, simple to operate, reaction raw materials and reaction reagent are easy to get, and the reaction times is shorter, and yield is advantages of higher comparatively.
Embodiment
Below in conjunction with specific embodiment, the present invention is further illustrated.
Reaction raw materials used in following each embodiment all can conveniently have been bought as replaced aldehyde (III) and solvent acetic acid etc.
Each embodiment understands the present invention better to enable those skilled in the art to below, but content of the present invention is not limited to illustrated embodiment.
Replace method synthesis (Cheng, R. that N-methoxyl group anthranilamide (II) is known report; Guo, T.; Du, Y.; Zhao, K.Synthesis2013,45,2998-3006.)
Embodiment 1
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-phenylquinazoline-4(3H)-one (I-a)) method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in acetic acid (4 milliliters), add phenyl aldehyde (III-a) (117 milligrams) more wherein, react at 100 DEG C and react completely for 1.5 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate extraction (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, removal of solvent under reduced pressure again, obtains crude material.Crude material, through silica gel column chromatogram separating purification, obtains white solid 2-phenylquinazoline-4(3H)-one (I-a) 206 milligrams, productive rate 93%.
1H NMR(600MHz,DMSO-d 6):δ12.56(br s,1H),8.21(d,J=7.9Hz,2H),8.18(dd,J=7.9Hz,J=1.2Hz,1H),7.85(t,J=8.0Hz,1H),7.76(d,J=7.9Hz,1H),7.62-7.52(m,4H)。
Embodiment 2
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-phenylquinazoline-4(3H)-one (I-a)) method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in formic acid (4 milliliters), add phenyl aldehyde (III-a) (117 milligrams) more wherein, react at 100 DEG C and react completely for 5.0 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate extraction (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, removal of solvent under reduced pressure again, obtains crude material.Crude material, through silica gel column chromatogram separating purification, obtains white solid 2-phenylquinazoline-4(3H)-one (I-a) 89 milligrams, productive rate 40%.
1H NMR(600MHz,DMSO-d 6):δ12.56(br s,1H),8.21(d,J=7.9Hz,2H),8.18(dd,J=7.9Hz,J=1.2Hz,1H),7.85(t,J=8.0Hz,1H),7.76(d,J=7.9Hz,1H),7.62-7.52(m,4H)。
Embodiment 3
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-(4-bromophenyl) quinazoline-4(3H)-one (I-b)) and method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in trifluoroacetic acid (4 milliliters), add p-bromobenzaldehyde (III-b) (204 milligrams) more wherein, react at 70 DEG C and react completely for 1.0 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate extraction (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, removal of solvent under reduced pressure again, obtains crude material.Crude material, through silica gel column chromatogram separating purification, obtains white solid 2-(4-bromophenyl) quinazoline-4(3H)-one (I-b) 245 milligrams, productive rate 82%.
1H NMR(600MHz,DMSO-d 6):δ12.61(br s,1H),8.16(dd,J=7.9,1.1Hz,1H),8.13(d,J=8.6Hz,2H),7.87-7.83(m,1H),7.78-7.74(m,3H),7.56-7.52(m,1H).
Embodiment 4
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-(4-fluorophenyl) quinazoline-4(3H)-one (I-c)) and method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in dichloro acetic acid (4 milliliters), add p-Fluorobenzenecarboxaldehyde (III-c) (136 milligrams) more wherein, react at 90 DEG C and react completely for 1.0 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate extraction (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, removal of solvent under reduced pressure again, obtains crude material.Crude material, through silica gel column chromatogram separating purification, obtains white solid 2-(4-fluorophenyl) quinazoline-4(3H)-one (I-c) 204 milligrams, productive rate 85%.
1H NMR(600MHz,DMSO-d 6):δ12.58(br s,1H),8.26(dd,J=8.8,5.5Hz,2H),8.16(d,J=7.8Hz,1H),7.85(t,J=7.0Hz,1H),7.74(d,J=8.1Hz,1H),7.53(t,J=7.5Hz,1H),7.40(t,J=8.8Hz,2H)。
Embodiment 5
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-(3-chloro-phenyl-) quinazoline-4(3H)-one (I-d)) and method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in acetic acid (4 milliliters), add m chlorobenzaldehyde (III-d) (155 milligrams) more wherein, react at 100 DEG C and react completely for 0.3 hour, be cooled to room temperature, poured into by reaction mixture in frozen water, the precipitation water of separating out and ethyl acetate/petroleum ether (1:5) washing, filter cake is dry in air dry oven, obtain 2-(3-chloro-phenyl-) quinazoline-4(3H)-one (I-d) 210 milligrams, productive rate 82%.
1H NMR(600MHz,DMSO-d 6)δ12.63(br s,1H),8.25(s,1H),8.16(t,J=6.5Hz,2H),7.86(t,J=8.3Hz,1H),7.77(d,J=8.1Hz,1H),7.67(d,J=7.9Hz,1H),7.59(t,J=7.9Hz,1H),7.55(t,J=7.4Hz,1H).
Embodiment 6
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-(2-(trifluoromethyl) phenyl) quinazoline-4(3H)-one (I-e)) method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in acetic acid (4 milliliters), add 2-(Trifluoromethyl) benzaldehyde (III-e) (191 milligrams) more wherein, react at 100 DEG C and react completely for 4.5 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate extraction (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, removal of solvent under reduced pressure again, obtains crude material.Crude material, through silica gel column chromatogram separating purification, obtains white solid 2-(2-(trifluoromethyl) phenyl) quinazoline-4(3H)-one (I-e) 234 milligrams, productive rate 81%.
1H NMR(600MHz,CDCl 3):δ10.48(s,1H),8.24(d,J=7.9Hz,1H),7.88-7.78(m,3H),7.77-7.67(m,3H),7.54(t,J=7.2Hz,1H); 13C NMR(150MHz,CDCl 3)δ163.2,151.6,148.7,135.0,132.8,132.1,130.58,130.56,128.8(q,J C-F=31.5Hz),127.9,127.3,127.0(q,J C-F=4.8Hz),126.3,123.6(q,J C-F=272.1Hz),120.7
Embodiment 7
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-(4-aminomethyl phenyl) quinazoline-4(3H)-one (I-f)) and method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in acetic acid (4 milliliters), add p-tolyl aldehyde (III-f) (132 milligrams) more wherein, react at 80 DEG C and react completely for 1.0 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate extraction (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, removal of solvent under reduced pressure again, obtains crude material.Crude material, through silica gel column chromatogram separating purification, obtains white solid 2-(4-aminomethyl phenyl) quinazoline-4(3H)-one (I-f) 205 milligrams, productive rate 87%.
1H NMR(600MHz,DMSO-d 6):δ12.47(br s,1H),8.15(dd,J=7.9,1.1Hz,1H),8.11(d,J=8.2Hz,2H),7.83(t,J=8.4Hz,1H),7.73(d,J=7.9Hz,1H),7.51(t,J=7.9Hz,1H),7.36(d,J=8.0Hz,2H),2.40(s,3H).
Embodiment 8
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-(4-p-methoxy-phenyl) quinazoline-4(3H)-one (I-g)) and method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in acetic acid (4 milliliters), add aubepine (III-g) (150 milligrams) more wherein, react at 100 DEG C and react completely for 1.0 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, removal of solvent under reduced pressure again, obtains crude material.Crude material, through silica gel column chromatogram separating purification, obtains white solid 2-(4-p-methoxy-phenyl) quinazoline-4(3H)-one (I-g) 183 milligrams, productive rate 73%.
1H NMR(600MHz,DMSO-d 6):δ12.42(br s,1H),8.20(d,J=8.8Hz,2H),8.14(d,J=7.6Hz,1H),7.82(t,J=8.2Hz,1H),7.71(d,J=8.1Hz,1H),7.49(t,J=7.5Hz,1H),7.10(d,J=8.8Hz,2H),3.86(s,3H).
Embodiment 9
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-(4-hydroxy phenyl) quinazoline-4(3H)-one (I-h)) and method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in acetic acid (4 milliliters), add p-Hydroxybenzaldehyde (III-h) (134 milligrams) more wherein, react at 100 DEG C and react completely for 2.0 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, removal of solvent under reduced pressure again, obtains crude material.Crude material, through silica gel column chromatogram separating purification, obtains light yellow solid 2-(4-hydroxy phenyl) quinazoline-4(3H)-one (I-h) 218 milligrams, productive rate 92%.
1H NMR(600MHz,DMSO-d 6):δ12.29(br s,1H),10.25(br s,1H),8.12(dd,J=7.9,1.3Hz,1H),8.09(d,J=8.8Hz,2H),7.80(t,J=8.4Hz,1H),7.68(d,J=8.0Hz,1H),7.47(t,J=7.9Hz,1H),6.91(d,J=8.8Hz,2H).
Embodiment 10
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-(2,6-dichlorophenyl) quinazoline-4(3H)-one (I-i)) and method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in acetic acid (4 milliliters), add 2 wherein again, 6-dichlorobenzaldehyde (III-i) (193 milligrams), react at 100 DEG C and react completely for 2.0 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, then removal of solvent under reduced pressure, obtain crude material.Crude material, through silica gel column chromatogram separating purification, obtains white solid 2-(2,6-dichlorophenyl) quinazoline-4(3H)-one (I-i) 275 milligrams, productive rate 95%.
1H NMR(600MHz,DMSO-d 6):δ12.80(br s,1H),8.20(d,J=7.9Hz,1H),7.88(t,J=7.6Hz,1H),7.74(d,J=8.1Hz,1H),7.66(d,J=8.4Hz,2H),7.63-7.56(m,2H); 13C NMR(150MHz,DMSO-d 6)δ161.4,149.8,148.4,134.8,133.2,132.8,132.3,128.3,127.54,127.48,125.9,121.4.
Embodiment 11
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-(3,4-Dimethoxyphenyl) quinazoline-4(3H)-one (I-j)) and method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in acetic acid (4 milliliters), add 3 wherein again, 4-dimethoxy benzaldehyde (III-j) (183 milligrams), react at 100 DEG C and react completely for 1.0 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, then removal of solvent under reduced pressure, obtain crude material.Crude material, through silica gel column chromatogram separating purification, obtains white solid 2-(3,4-Dimethoxyphenyl) quinazoline-4(3H)-one (I-j) 275 milligrams, productive rate 98%.
1H NMR(600MHz,DMSO-d 6):δ12.44(br s,1H),8.15(dd,J=7.9,1.2Hz,1H),7.89(dd,J=8.5,2.2Hz,1H),7.84-7.80(m,2H),7.73(d,J=8.0Hz,1H),7.49(t,J=8.0Hz,1H),7.12(d,J=8.6Hz,1H),3.90(s,3H),3.86(s,3H).
Embodiment 12
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (the bromo-2-phenylquinazoline of 6--4(3H)-one (I-k)) method, comprise the steps:
Bromo-for 2-amino-5-N-methoxy benzamide (II-b) (245 milligrams) is dissolved in acetic acid (4 milliliters), add phenyl aldehyde (III-a) (117 milligrams) more wherein, react at 100 DEG C and react completely for 0.3 hour, be cooled to room temperature, reaction mixture is poured in frozen water, the precipitation water separated out and ethyl acetate/petroleum ether (1:5) washing, filter cake is dry in air dry oven, obtain the bromo-2-phenylquinazoline of white solid 6--4(3H)-one (I-k) 280 milligrams, productive rate 93%.
1H NMR(600MHz,DMSO-d 6):δ12.72(br s,1H),8.23(d,J=1.9Hz,1H),8.18(d,J=7.4Hz,2H),7.98(dd,J=8.6,2.2Hz,1H),7.70(d,J=8.7Hz,1H),7.61(t,J=7.2Hz,1H),7.56(t,J=7.4Hz,2H).
Embodiment 13
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (8-methyl-2-phenylquinazoline-4(3H)-one (I-l)) method, comprise the steps:
2-amino-N-methoxy-3-methyl benzamide (II-c) (180 milligrams) is dissolved in acetic acid (4 milliliters), add phenyl aldehyde (III-a) (117 milligrams) more wherein, react at 100 DEG C and react completely for 0.5 hour, be cooled to room temperature, reaction mixture is poured in frozen water, the precipitation water separated out and ethyl acetate/petroleum ether (1:5) washing, filter cake is dry in air dry oven, obtain white solid 8-methyl-2-phenylquinazoline-4(3H)-one (I-l) 188 milligrams, productive rate 80%.
1H NMR(600MHz,DMSO-d 6):δ12.54(br s,1H),8.24(d,J=6.9Hz,2H),8.00(d,J=7.5Hz,1H),7.70(d,J=7.2Hz,1H),7.61-7.55(m,3H),7.41(t,J=7.6Hz,1H),2.63(s,3H).
Embodiment 14
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (7-methoxyl group-2-phenylquinazoline-4(3H)-one (I-m)) method, comprise the steps:
By 2-amino-N, 4-dimethoxybenzarnide (II-d) (196 milligrams) is dissolved in acetic acid (4 milliliters), add phenyl aldehyde (III-a) (117 milligrams) more wherein, react at 100 DEG C and react completely for 0.5 hour, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, then removal of solvent under reduced pressure, obtain crude material.Crude material, through silica gel column chromatogram separating purification, obtains light yellow solid 7-methoxyl group-2-phenylquinazoline-4(3H)-one (I-m) 248 milligrams, productive rate 98%.
1H NMR(600MHz,DMSO-d 6): 1H NMR(600MHz,DMSO-d 6)δ12.47(br s,1H),8.25(d,J=7.6Hz,2H),8.12(d,J=8.7Hz,1H),7.68-7.60(m,3H),7.26(d,J=1.5Hz,1H),7.17(dd,J=8.7,1.7Hz,1H),3.99(s,3H).
Embodiment 15
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-propyl group quinazoline-4(3H)-one (I-n)) method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in acetic acid (4 milliliters), add butyraldehyde-n (III-k) (80 milligrams) more wherein, react at 100 DEG C and react completely for 1.0 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, removal of solvent under reduced pressure again, obtains crude material.Crude material, through silica gel column chromatogram separating purification, obtains white solid 2-propyl group quinazoline-4(3H)-one (I-n) 148 milligrams, productive rate 79%.
1H NMR(600MHz,DMSO-d 6): 1H NMR(600MHz,DMSO-d 6)δ12.16(br s,1H),8.08(dd,J=7.9,1.0Hz,1H),7.77(t,J=8.4Hz,1H),7.59(d,J=8.1Hz,1H),7.46(t,J=7.2Hz,1H),2.58(t,J=7.6Hz,2H),1.78-1.71(m,2H),0.94(t,J=7.4Hz,3H).
Embodiment 16
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (5-chloro-2-propyl group quinazoline-4(3H)-one (I-o)) method, comprise the steps:
Chloro-for 2-amino-6-N-methoxy benzamide (II-e) (200 milligrams) is dissolved in acetic acid (4 milliliters), add butyraldehyde-n (III-k) (80 milligrams) more wherein, react at 100 DEG C and react completely for 1.0 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, removal of solvent under reduced pressure again, obtains crude material.Crude material, through silica gel column chromatogram separating purification, obtains white solid 5-chloro-2-propyl group quinazoline-4(3H)-one (I-o) 167 milligrams, productive rate 75%.
1H NMR(600MHz,CDCl 3):δ11.94(s,1H),7.61-7.58(m,2H),7.46-7.43(m,1H),2.76(t,J=7.7Hz,2H),1.97-1.88(m,2H),1.08(t,J=7.4Hz,3H); 13C NMR(150MHz,CDCl 3)δ162.9,157.8,152.0,134.1,134.0,129.0,126.5,117.8,37.5,20.9,13.8;IR(KBr):3034,2360,1681,1623,1599,1459cm -1.
Embodiment 17
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (the fluoro-2-methylquinazolin of 7--4(3H)-one (I-p)) method, comprise the steps:
Fluoro-for 2-amino-4-N-methoxy benzamide (II-f) (184 milligrams) is dissolved in acetic acid (4 milliliters), add acetaldehyde 40wt.%(III-l wherein again) (330 milligrams), react at 100 DEG C and react completely for 5.0 hours, be cooled to room temperature, add ethyl acetate (20 milliliters) dilution wherein, add saturated sodium bicarbonate solution (20 milliliters) neutralization again, aqueous phase is extracted with ethyl acetate (3 × 20 milliliters), the organic phase saturated common salt water washing merged, anhydrous sodium sulfate drying, removal of solvent under reduced pressure again, obtains crude material.Crude material, through silica gel column chromatogram separating purification, obtains the fluoro-2-methylquinazolin of white solid 7--4(3H)-one (I-p) 169 milligrams, productive rate 95%.
1H NMR(600MHz,DMSO-d 6)δ12.29(br s,1H),8.13(t,J=7.6Hz,1H),7.35-7.29(m,2H),2.35(s,3H); 13C NMR(150MHz,DMSO-d 6)δ165.6(d,J C-F=248.7Hz),160.9,155.9,151.1,128.7(d,J C-F=10.4Hz),117.6(d,J C-F=22.2Hz),114.3,111.5(d,J C-F=22.7Hz),21.4.
Embodiment 18
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative (2-sec.-propyl-7-methoxyquinazoline hydrochloride-4(3H)-one (I-q)) method, comprise the steps:
By 2-amino-N, 4-dimethoxybenzarnide (II-d) (180 milligrams) is dissolved in acetic acid (4 milliliters), add isobutyric aldehyde (III-m) (216 milligrams) more wherein, react at 100 DEG C and react completely for 3.0 hours, be cooled to room temperature, reaction mixture is poured in frozen water, the precipitation water separated out and ethyl acetate/petroleum ether (1:5) washing, filter cake is dry in air dry oven, obtain white solid 2-sec.-propyl-7-methoxyquinazoline hydrochloride-4(3H)-one (I-q) 175 milligrams, productive rate 80%.
1H NMR(600MHz,CDCl 3)δ12.07(br s,1H),8.19(d,J=8.8Hz,1H),7.11(d,J=2.4Hz,1H),7.03(dd,J=8.8,2.4Hz,1H),3.93(s,3H),3.10-3.02(m,1H),1.45(d,J=7.0Hz,6H); 13CNMR(150MHz,CDCl 3)δ164.9,164.0,162.0,151.9,127.7,116.7,114.2,107.8,55.7,34.9,20.4.
Embodiment 19
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative ((E)-2-(1-phenyl third-1-alkene-2-base) quinazoline-4(3H)-one (I-r)) and method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) is dissolved in acetic acid (4 milliliters), add α-methylcinnamaldehyde (III-n) (161 milligrams) more wherein, react at 100 DEG C and react completely for 3.0 hours, be cooled to room temperature, reaction mixture is poured in frozen water, the precipitation water separated out and ethyl acetate/petroleum ether (1:5) washing, filter cake is dry in air dry oven, obtain white solid (E)-2-(1-phenyl third-1-alkene-2-base) quinazoline-4(3H)-one (I-r) 215 milligrams, productive rate 82%.
1H NMR(600MHz,DMSO-d 6)δ12.22(br s,1H),8.14(dd,J=7.9,1.0Hz,1H),7.82(t,J=8.3Hz,1H),7.70(d,J=8.0Hz,1H),7.56(s,1H),7.53-7.49(m,3H),7.46(t,J=7.6Hz,2H),7.36(t,J=7.3Hz,1H),2.31(d,J=0.8Hz,3H); 13C NMR(150MHz,DMSO-d 6)δ162.0,154.6,148.5,136.1,134.5,134.1,130.6,129.4,128.4,127.9,127.4,126.5,125.8,121.0,15.1.
Embodiment 20
A kind of eliminate one pot process 4(3H by cyclization)-Quinazol derivative ((1) 2-(3-(benzyloxy) propyl group) quinazoline-4(3H)-one (I-s)) method, comprise the steps:
2-amino-N-methoxy benzamide (II-a) (166 milligrams) being dissolved in acetic acid (4 milliliters), then adding 4-(benzyloxy wherein) butyraldehyde (III-o) is (by the synthesis of report method: Kiddie, J.; Green, D.C.; Thompson, C.Tetrahedron1995,51,2851-2864.) (196 milligrams), react at 100 DEG C and react completely for 5.0 hours, be cooled to room temperature, poured into by reaction mixture in frozen water, the precipitation water of separating out and ethyl acetate/petroleum ether (1:5) washing, filter cake is dry in air dry oven, obtain white solid 2-(3-(benzyloxy) propyl group) quinazoline-4(3H)-one (I-s) 253 milligrams, productive rate 86%.
1H NMR(600MHz,CDCl 3)δ11.71(br s,1H),8.25(d,J=7.8Hz,1H),7.75(t,J=7.1Hz,1H),7.68(d,J=8.1Hz,1H),7.43(t,J=7.5Hz,1H),7.35-7.28(m,4H),7.27-7.24(m,1H),4.56(s,2H),3.65(t,J=6.0Hz,2H),2.92(t,J=7.3Hz,2H),2.22-2.17(m,2H); 13C NMR(150MHz,CDCl 3)δ163.8,156.5,152.5,138.1,134.7,128.4,127.7,127.7,127.2,126.4,126.3,120.7,73.0,69.3,32.9,27.1.
(2) preparation of pegamine (I-t)
Under hydrogen environment (balloon), to 2-(3-(benzyloxy) propyl group) quinazoline-4(3H) and-one (I-s) (147 milligrams) methyl alcohol (1.5 milliliters) solution in add 5% palladium/carbon (74.0 milligrams), reflux has been reacted for 6.0 hours, be cooled to room temperature, paving suction filtered through kieselguhr, removal of solvent under reduced pressure again, obtains crude material.Crude material, through silica gel column chromatogram separating purification, obtains white solid pegamine (I-t) 88 milligrams, productive rate 86%.
1H NMR(600MHz,DMSO-d 6)δ12.19(br s,1H),8.08(d,J=7.8Hz,1H),7.77(t,J=7.5Hz,1H),7.60(d,J=8.1Hz,1H),7.46(t,J=7.4Hz,1H),4.59(s,1H),3.50-3.46(m,2H),2.66(t,J=7.6Hz,2H),1.92-1.85(m,2H).
Below be only section Example of the present invention, not do any pro forma restriction to the present invention, every any simple amendment done above-described embodiment according to technical spirit of the present invention, equivalent variations and modification, all belong to technical solution of the present invention scope.

Claims (1)

1. the method for one pot process 4 (3H)-Quinazol derivative (I) is eliminated by cyclization, it is characterized in that comprising the steps: with acetic acid, formic acid, trifluoroacetic acid or dichloro acetic acid as solvent, N-methoxyl group anthranilamide (II) will be replaced and react 0.3-5.0 hour with replacement aldehyde (III) at 70 ~ 100 DEG C, eliminated by cyclization, generate 4 (3H)-Quinazol derivatives (I), reaction formula is:
Wherein:
R 1=hydrogen, chlorine, bromine, fluorine, methoxyl group or methyl;
R 2=phenyl, 4-bromophenyl, 4-fluorophenyl, 3-chloro-phenyl-, o-trifluoromethyl phenyl, 4-tolyl, 4-methoxyphenyl, 4-hydroxyphenyl, 2,6-dichlorophenyl, 3,4-dimethoxy phenyl, propyl group, methyl, sec.-propyl, 2-methyl-3 phenylpropenyl or benzyloxy propyl group.
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