CN110156789A - A kind of synthetic method of azacyclo- and quinazoline compounds - Google Patents
A kind of synthetic method of azacyclo- and quinazoline compounds Download PDFInfo
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- CN110156789A CN110156789A CN201910425623.6A CN201910425623A CN110156789A CN 110156789 A CN110156789 A CN 110156789A CN 201910425623 A CN201910425623 A CN 201910425623A CN 110156789 A CN110156789 A CN 110156789A
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses the synthetic methods of a kind of azacyclo- and quinazoline compounds, this method includes: by the benzaldehyde with the structure as shown in formula A and having the aromatic amine as shown in formula B in methanol aqueous solution or methanol solution, and the molar ratio of the benzaldehyde and aromatic amine is more than or equal to 2:1, under the catalytic action of hog gastric mucosa protease, constant temperature stirs at 40~65 DEG C, and reaction obtains azacyclo- and quinazoline compounds with the structure as shown in formula C；Wherein, R1 and R2 constitutes azacyclo-.Method reaction condition of the invention is mild, and catalyst is biodegradable, and step is simple, and cost is relatively low, entire synthesis path be easy carry out and it is economic and environment-friendly, yield is preferable, reach 41%~95%, have popularizing value.
Description
Technical field
The invention belongs to organic synthesis fields, and in particular to the synthesis side of a kind of azacyclo- and quinazoline compounds
Method.
Background technique
Quinazoline derivant is that one kind has the active nitrogen-containing heterocycle compound of good biological, the work in many natural products
Quinazoline skeleton can be also found in property substance.Quinazoline compounds are widely used in medicine and pesticide industry, can be applied to resist
The fields such as cancer, antimalarial, anti-hypertension and mite killing, sterilization.Market commercialisation or progress has been put into some quinazoline derivatives
Medical clinical test, such as anticancer drug Gefitinib and fungicide the third oxygen quinoline.Therefore, the synthesis of quinazoline compounds by
The giving more sustained attention of scientists.
The method of conventional synthesis quinazoline compounds is usually with o-Aminobenzaldehyde, ortho-aminobenzoic acid, adjacent amino
This formamide or o-amino benzoyl cyanogen etc. are starting material, withAcid, Lewis acid, transition metal or ionic liquid etc.
As the catalyst to synthesis, although there are also more green catalyst to be reported here, these synthetic methods with
Environment-friendly organic synthesis is compared to still there is some shortcomings, and if operating process is many and diverse, catalyst is not recyclable or degrades, cost is excessively high,
The substrate scope of application is small etc..Therefore, exploiting economy is environmentally friendly and the wider array of environment-friendly preparation method thereof of the scope of application has positive effect.
The features such as efficient, less toxic, mild and selective based on biocatalysis, grinds in industry, agricultural, medical treatment and new drug
Hair etc. has far-reaching influence, is one of the important trend of Green Chemistry and green chemical industry development.Enzyme is a kind of common
Bioactivity catalyst has consequence in organic synthesis field, with efficient, single-minded, degradable, pollution-free and
The advantages that environmental protection and economy.
The technical matters that prior art synthesizes [1,2-a] quinazoline compounds is more many and diverse, and energy consumption is higher, to environment dirt
Contaminate it is larger, so develop Enzyme catalyzed synthesis [1,2-a] quinazoline compounds method be of great significance.
Summary of the invention
The object of the present invention is to provide the synthetic methods of a kind of azacyclo- and quinazoline compounds, solve existing
The larger problem of technique environmental pollution, reaction condition is mild, and catalyst is biodegradable, and step is simple, and cost is relatively low, entirely
Synthesis path be easy carry out and it is economic and environment-friendly, have popularizing value.
In order to achieve the above object, the present invention provides the synthetic methods of a kind of azacyclo- and quinazoline compounds, should
Method includes:
By the benzaldehyde with the structure as shown in formula A and have the aromatic amine as shown in formula B in methanol aqueous solution or methanol
In solution, and the molar ratio of the benzaldehyde and aromatic amine is more than or equal to 2:1, in the catalytic action of hog gastric mucosa protease
Under, it is vibrated at 40~65 DEG C, reaction obtains azacyclo- and quinazoline compounds with the structure as shown in formula C；Wherein, R1
And R2Connect and compose azacyclo-.
Method of the invention, when temperature is 40 DEG C, the yield of azacyclo- and quinazoline compounds can reach 38%；?
When temperature is 45 DEG C, the yield of azacyclo- and quinazoline compounds reaches 51%；When temperature is 50 DEG C, azacyclo- and quinoline azoles
The yield of quinoline class compound reaches 61%；When temperature is 55 DEG C, the yield of azacyclo- and quinazoline compounds reaches 71%；
When temperature is 60 DEG C, the yield of azacyclo- and quinazoline compounds reaches 75%；When temperature is 65 DEG C, azacyclo- and quinoline
The yield of oxazoline compound reaches 74%.Therefore, temperature range is preferably 55~60 DEG C, to improve azacyclo- and quinazoline ditosylate salt
The yield of compound.
Method of the invention, when making catalyst using hog gastric mucosa protease, the production of azacyclo- and quinazoline compounds
Rate is fine, does not have product generation when catalyst is not added.Therefore, reaction of the invention must be added to hog gastric mucosa protease and be catalyzed
Agent is to greatly improve yield.
Preferably, the volume ratio of methanol and water is 1:2~2:1 in the methanol aqueous solution.
Preferably, the revolving speed of the oscillation is 150~250rpm.
Preferably, the reaction time is not less than 36h.It is highly preferred that the reaction time is 36~48h.With reaction
Time extends, and yield is improved, but the reaction time, after 48h, yield decreases instead.
Preferably, the quality molar ratio of the hog gastric mucosa protease and aromatic amine is 75mg:1mmol~150mg:
1mmol；The Molar of the methanol aqueous solution and aromatic amine ratio is 5mL:1mmol~10mL:1mmol.
Preferably, it is described after reaction, using column chromatography separating purification.
Preferably, the eluant, eluent that the pillar layer separation uses is ethyl acetate-light petrol or methylene chloride-n-hexane.
It is highly preferred that eluant, eluent uses volume ratio for the methylene chloride and n-hexane of the ethyl acetate of 1:15 and petroleum ether or 1:1.
Preferably, R1And R2Include :-CH2-(CH2)n-CH2, n=1~6；OrN=0~4, D are carbocyclic ring
Or heterocycle.More specifically, R1And R2The N heterocycle of composition includes:
More specifically, the carbocyclic ring or heterocycle include five yuan or more of carbocyclic ring or heterocycle, such as five yuan of carbocyclic rings or heterocycle, six-membered carbon ring or miscellaneous
Ring, seven-element carbon ring or heterocycle, carbocyclic eight-membered ring or heterocycle.
Preferably, D is aromatic rings, more specifically comprising phenyl ring, R1And R2The N heterocycle of composition includes:
Preferably, the aromatic amine has the structure as shown in formula E or F:
Wherein, R3And R4It is each independently H or electron donating group or electron-withdrawing substituent；G be carbocyclic ring or heterocycle,
It can be saturated carbon ring or heterocycle, or unsaturated carbocyclic ring or heterocycle.Wherein, electron donating group is not influence fragrance
The electron donating group of amino and benzaldehyde reacted in amine, does not include: amino, hydroxyl.More specifically, unsaturated carbocyclic ring
Or heterocycle or saturated carbon ring or heterocycle all can be five yuan, hexatomic ring, unsaturated carbocyclic ring includes phenyl ring.
Preferably, any one of the electron donating group in methyl, ethyl, methoxyl group and ethyoxyl；It is described
Any one of electron-withdrawing substituent in halogen, trifluoromethyl, nitro and cyano.
The synthetic method of azacyclo- and quinazoline compounds of the invention, solves existing prior art environmental pollution
Larger problem, has the advantage that
Method of the invention, reaction condition is mild, and catalyst is biodegradable, and step is simple, and cost is relatively low, entire to synthesize
Path be easy carry out and it is economic and environment-friendly, yield is preferable, reach 41%~95%, have popularizing value.
Specific embodiment
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation
Example is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common
Technical staff's every other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
Embodiment 1
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route are as follows:
Specifically includes the following steps:
1) in 10mL tool plug test tube, 0.4mmol 2- (1- pyrrolidinyl) benzaldehyde, 0.2mmol aniline, 30mg is added
The methanol aqueous solution of hog gastric mucosa protease and 2mL50%；
2) test tube in step 1) is put into 60 DEG C of constant temperature oil baths, 36h is reacted under magnetic agitation and obtains crude product；
3) crude product obtained in step 2) is subjected to pillar layer separation, eluant, eluent uses ethyl acetate and petroleum ether, body
Product is than being 1:10, and azacyclo- and quinazoline compounds are prepared in dry 3~4h at 40 DEG C.
The azacyclo- and quinazoline compounds being prepared are 4- phenyl -1,2,3,3a, 4,5- hexahydropyrrolo simultaneously [1,2-
A] quinazoline, yield 75%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.32 (dd, J=10.6,5.1Hz, 2H), 7.20-
7.11 (m, 4H), 6.97 (d, J=7.4Hz, 1H), 6.65 (t, J=7.4Hz, 1H), 6.54 (d, J=8.1Hz, 1H), 4.64
(dd, J=8.3,5.3Hz, 1H), 4.39 (d, J=14.9Hz, 1H), 4.13-4.11 (m, 1H), 3.46 (td, J=8.7,
3.0Hz, 1H), 3.38 (dd, J=16.5,8.2Hz, 1H), 2.08 (dd, J=8.6,3.6Hz, 1H), 1.98 (ddd, J=9.9,
5.3,2.3Hz, 1H), 1.95-1.87 (m, 1H), 1.73 (ddd, J=16.5,10.1,5.5Hz, 1H).13C NMR(126MHz,
CDCl3)δ150.28,143.47,128.99,127.82,125.97,125.22,124.81,120.84,116.18,111.36,
76.72,57.37,47.10,32.00,22.29。
Embodiment 2
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
Essentially identical, difference is the aromatic amine used for 4- methylaniline, and the azacyclo- and quinazoline compounds being prepared are
4- (p-methylphenyl) -1,2,3,3a, 4,5- hexahydropyrrolos simultaneously [1,2-a] quinazoline, yield 66%, white solid.
Nuclear-magnetism characterize data are as follows:1HNMR(500MHz,CDCl3) δ 7.17-7.05 (m, 5H), 6.95 (d, J=7.3Hz,
1H), 6.63 (t, J=7.3Hz, 1H), 6.52 (d, J=8.0Hz, 1H), 4.60 (dd, J=8.3,5.2Hz, 1H), 4.35 (d, J
=14.9Hz, 1H), 4.06 (d, J=14.9Hz, 1H), 3.52-3.29 (m, 2H), 2.32 (s, 3H), 2.04-1.87 (m, 3H),
1.71 (ddd, J=11.5,9.9,5.7Hz, 1H).13C NMR(126MHz,CDCl3)δ147.70,143.42,134.62,
129.65,127.81,126.03,125.26,120.84,116.08,111.29,76.93,57.62,47.14,32.09,
22.34,20.96。
Embodiment 3
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
Essentially identical, difference is the aromatic amine used for 3- methylaniline, and the azacyclo- and quinazoline compounds being prepared are
4- (tolyl) -1,2,3,3a, 4,5- hexahydropyrrolos simultaneously [1,2-a] quinazoline, yield 68%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.20 (t, J=7.7Hz, 1H), 7.13 (t, J=
7.6Hz, 1H), 7.10-6.88 (m, 4H), 6.64 (t, J=7.4Hz, 1H), 6.53 (d, J=8.0Hz, 1H), 4.61 (dd, J=
8.3,5.2Hz, 1H), 4.34 (d, J=14.8Hz, 1H), 4.10 (d, J=14.8Hz, 1H), 3.53-3.33 (m, 2H), 2.34
(s, 3H), 2.11-1.84 (m, 3H), 1.73 (tt, J=11.5,8.2Hz, 1H).13C NMR(126MHz,CDCl3)δ150.26,
143.33,138.72,128.75,127.76,125.94,125.85,125.61,121.87,120.83,116.07,111.30,
76.69,57.47,47.12,32.10,22.28,21.50。
Embodiment 4
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
Essentially identical, difference is the aromatic amine used for 2-aminotoluene, and the azacyclo- and quinazoline compounds being prepared are
4- (o-tolyl) -1,2,3,3a, 4,5- hexahydropyrrolos simultaneously [1,2-a] quinazoline, yield 55%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.27-7.19 (m, 1H), 7.15 (t, J=7.9Hz,
2H), 7.08 (t, J=7.1Hz, 2H), 6.94 (d, J=7.3Hz, 1H), 6.64 (t, J=7.3Hz, 1H), 6.58 (d, J=
8.0Hz, 1H), 4.74 (t, J=14.4Hz, 1H), 4.14 (s, 1H), 3.89 (d, J=15.0Hz, 1H), 3.52 (t, J=
7.2Hz, 1H), 3.37 (dd, J=16.2,8.6Hz, 1H), 2.34 (d, J=12.1Hz, 3H), 2.05-1.81 (m, 3H), 1.51
(tt, J=11.6,8.1Hz, 1H).13C NMR(126MHz,CDCl3)δ146.08,143.76,136.74,130.55,
127.56,126.66,125.95,125.06,115.87,111.76,109.69,99.93,76.35,56.67,47.65,
32.69,22.54,17.97。
Embodiment 5
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
It is essentially identical, difference be the aromatic amine used for 4- aminoanisole, the azacyclo- being prepared simultaneously quinazoline compounds
For 4- (4- methoxyphenyl) -1,2,3,3a, 4,5- hexahydropyrrolos simultaneously [1,2-a] quinazoline, yield 50%, white solid.
Nuclear-magnetism characterize data are as follows:1HNMR(500MHz,CDCl3) δ 7.16-7.08 (m, 3H), 6.95 (d, J=7.3Hz,
1H), 6.88-6.82 (m, 2H), 6.63 (t, J=7.2Hz, 1H), 6.52 (d, J=8.0Hz, 1H), 4.57 (dd, J=8.3,
5.0Hz, 1H), 4.36 (d, J=14.9Hz, 1H), 4.01 (d, J=14.9Hz, 1H), 3.79 (s, 3H), 3.46 (td, J=
8.6,2.6Hz, 1H), 3.36 (dd, J=15.9,8.6Hz, 1H), 2.01-1.82 (m, 3H), 1.69 (ddd, J=11.2,8.3,
3.6Hz,1H)。13C NMR(126MHz,CDCl3)δ157.13,143.39,143.09,127.80,126.80,126.07,
120.82,116.02,114.18,111.23,77.27,57.63,55.44,47.13,32.01,22.33。
Embodiment 6
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
Essentially identical, difference is the aromatic amine used for 4- fluoroaniline, and simultaneously quinazoline compounds are 4- to the azacyclo- being prepared
(4- fluorophenyl) -1,2,3,3a, 4,5- hexahydropyrrolos simultaneously [1,2-a] quinazoline, yield 60%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.53 (d, J=8.5Hz, 2H), 7.16 (d, J=
8.4Hz, 3H), 6.99 (d, J=7.3Hz, 1H), 6.70 (t, J=7.4Hz, 1H), 6.57 (d, J=8.0Hz, 1H), 4.65
(dd, J=8.3,5.4Hz, 1H), 4.42 (d, J=15.0Hz, 1H), 4.21 (d, J=15.0Hz, 1H), 3.48-3.32 (m,
2H), 2.22 (tdd, J=7.7,5.5,2.7Hz, 1H), 2.08-1.87 (m, 2H), 1.74 (ddd, J=18.9,12.0,
8.6Hz,1H)。13C NMR(126MHz,CDCl3)δ153.01,143.78,128.07,126.14,126.05,125.86,
123.24,120.93,116.99,111.73,75.88,55.69,46.75,31.62,22.01。
Embodiment 7
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
Essentially identical, difference is the aromatic amine used for 4- chloroaniline, and simultaneously quinazoline compounds are 4- to the azacyclo- being prepared
(4- chlorphenyl) -1,2,3,3a, 4,5- hexahydropyrrolos simultaneously [1,2-a] quinazoline, yield 61%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.25 (dd, J=9.5,2.7Hz, 2H), 7.14 (t, J
=7.7Hz, 1H), 7.11-7.03 (m, 2H), 6.96 (d, J=7.3Hz, 1H), 6.65 (t, J=7.3Hz, 1H), 6.53 (d, J
=8.0Hz, 1H), 4.60 (dd, J=8.3,5.3Hz, 1H), 4.37 (d, J=15.0Hz, 1H), 4.07 (d, J=15.0Hz,
1H), 3.49-3.28 (m, 2H), 2.13-1.81 (m, 3H), 1.68 (tt, J=11.2,8.3Hz, 1H)13C NMR(126MHz,
CDCl3)δ148.69,143.44,130.07,129.06,127.96,126.59,125.98,120.46,116.36,111.41,
76.62,57.19,47.02,31.78,22.24。
Embodiment 8
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
Essentially identical, difference is the aromatic amine used for 4- bromaniline, and simultaneously quinazoline compounds are 4- to the azacyclo- being prepared
(4- bromophenyl) -1,2,3,3a, 4,5- hexahydropyrrolos simultaneously [1,2-a] quinazoline, yield 52%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.41 (d, J=8.6Hz, 2H), 7.14 (t, J=
7.6Hz, 1H), 7.03 (d, J=8.6Hz, 2H), 6.96 (d, J=7.3Hz, 1H), 6.66 (t, J=7.3Hz, 1H), 6.53 (d,
J=8.0Hz, 1H), 4.61 (dd, J=8.2,5.4Hz, 1H), 4.37 (d, J=15.0Hz, 1H), 4.08 (d, J=15.0Hz,
1H), 3.54-3.38 (m, 1H), 3.38-3.29 (m, 1H), 2.11-1.88 (m, 3H), 1.69 (ddd, J=20.0,11.3,
8.4Hz,1H)。13C NMR(126MHz,CDCl3)δ148.98,143.38,132.03,127.98,126.89,125.98,
120.34,117.91,116.44,111.46,76.56,57.05,47.01,31.70,22.21。
Embodiment 9
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
Essentially identical, difference is the aromatic amine used for 4- Iodoaniline, and simultaneously quinazoline compounds are 4- to the azacyclo- being prepared
(4- iodophenyl) -1,2,3,3a, 4,5- hexahydropyrrolos simultaneously [1,2-a] quinazoline, yield 43%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.60 (d, J=8.6Hz, 2H), 7.14 (t, J=
7.6Hz, 1H), 6.93 (dd, J=28.0,8.0Hz, 3H), 6.66 (t, J=7.3Hz, 1H), 6.53 (d, J=8.0Hz, 1H),
(4.61 dd, J=8.3,5.3Hz, 1H), 4.37 (d, J=15.0Hz, 1H), 4.09 (d, J=15.0Hz, 1H), 3.49-3.28
(m, 2H), 2.14-2.03 (m, 1H), 2.02-1.84 (m, 2H), 1.70 (tt, J=11.1,8.4Hz, 1H).13C NMR
(126MHz,CDCl3)δ149.89,143.47,137.98,127.96,127.13,125.94,120.47,116.43,
111.44,88.56,76.38,56.95,46.97,31.74,22.21。
Embodiment 10
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
Essentially identical, difference is the aromatic amine used for 4- aminobenzonitrile, and the azacyclo- and quinazoline compounds being prepared are
4- (4- cyano-phenyl) -1,2,3,3a, 4,5- hexahydropyrrolos simultaneously [1,2-a] quinazoline, yield 49%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.53 (d, J=8.8Hz, 2H), 7.20 (t, J=
7.4Hz, 1H), 7.02 (dd, J=17.1,8.1Hz, 3H), 6.77 (t, J=7.4Hz, 1H), 6.64 (d, J=8.0Hz, 1H),
4.58 (dd, J=8.3,5.5Hz, 1H), 4.46 (d, J=14.7Hz, 1H), 4.29 (d, J=14.7Hz, 1H), 3.44 (td, J
=8.3,6.4Hz, 1H), 3.33 (td, J=8.8,5.3Hz, 1H), 2.37 (tdd, J=8.4,5.5,3.3Hz, 1H), 2.14-
1.92 (m, 2H), 1.77 (ddd, J=18.0,12.2,9.1Hz, 1H).13C NMR(126MHz,CDCl3)δ152.86,
144.28,133.13,128.25,125.69,122.16,120.08,119.73,118.09,112.23,103.30,75.02,
52.64,46.16,31.29,21.52。
Embodiment 11
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
Essentially identical, difference is the aromatic amine used for 4- nitroaniline, and the azacyclo- and quinazoline compounds being prepared are
4- (4- nitrobenzophenone) -1,2,3,3a, 4,5- hexahydropyrrolos simultaneously [1,2-a] quinazoline, yield 43%, yellow oily liquid.
Nuclear-magnetism characterize data are as follows:1HNMR(500MHz,CDCl3) δ 8.18-8.11 (m, 2H), 7.24 (t, J=7.5Hz,
1H), 7.10 (d, J=7.3Hz, 1H), 6.93-6.87 (m, 2H), 6.83 (t, J=7.3Hz, 1H), 6.71 (d, J=7.9Hz,
1H), 4.59-4.49 (m, 2H), 4.36 (d, J=14.3Hz, 1H), 3.51 (td, J=8.7,4.8Hz, 1H), 3.29 (td, J=
8.9,6.6Hz, 1H), 2.59-2.46 (m, 1H), 2.17-1.95 (m, 2H), 1.82 (ddt, J=12.3,10.0,8.2Hz,
1H)。13C NMR(126MHz,CDCl3)δ153.74,144.60,139.39,128.39,125.59,125.47,123.36,
118.98,116.16,112.57,74.53,50.45,45.61,31.16,21.10。
Embodiment 12
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
It is essentially identical, difference be the aromatic amine used for 3,4- dimethoxyaniline, the azacyclo- being prepared simultaneously quinazoline ditosylate salt
Conjunction object is 4- (3,4- Dimethoxyphenyl) -1,2,3,3a, and simultaneously [1,2-a] quinazoline, yield 41% are white for 4,5- hexahydropyrrolos
Color solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.13 (t, J=7.5Hz, 1H), 6.96 (d, J=
7.2Hz, 1H), 6.87-6.69 (m, 3H), 6.64 (t, J=7.3Hz, 1H), 6.52 (d, J=8.0Hz, 1H), 4.59 (dd, J=
7.9,5.1Hz, 1H), 4.37 (d, J=14.8Hz, 1H), 4.04 (d, J=14.8Hz, 1H), 3.85 (d, J=22.8Hz, 6H),
3.57-3.29 (m, 2H), 2.12-1.81 (m, 3H), 1.71 (dt, J=19.4,8.4Hz, 1H).13C NMR(126MHz,
CDCl3)δ148.93,146.70,143.22,127.83,126.05,120.59,116.67,116.02,111.20,111.05,
110.22,57.71,55.96,55.82,47.16,31.98,22.32。
Embodiment 13
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
Essentially identical, difference is the aromatic amine used for 3- chloroaniline, and simultaneously quinazoline compounds are 4- to the azacyclo- being prepared
(3- chlorphenyl) -1,2,3,3a, 4,5- hexahydropyrrolos simultaneously [1,2-a] quinazoline, yield 74%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.22 (dd, J=14.3,6.3Hz, 1H), 7.18-
7.11 (m, 2H), 7.09 (d, J=7.9Hz, 1H), 7.04 (d, J=8.0Hz, 1H), 6.96 (d, J=7.3Hz, 1H), 6.67
(t, J=7.4Hz, 1H), 6.54 (d, J=8.0Hz, 1H), 4.60 (dd, J=8.3,5.3Hz, 1H), 4.35 (d, J=
14.9Hz, 1H), 4.12 (d, J=14.9Hz, 1H), 3.52-3.30 (m, 2H), 2.11 (ddd, J=12.2,7.3,2.3Hz,
1H), 2.05-1.86 (m, 2H), 1.72 (tt, J=11.2,8.3Hz, 1H).13C NMR(126MHz,CDCl3)δ151.51,
143.36,134.33,129.87,127.92,125.89,124.73,124.49,123.05,120.50,116.44,111.48,
76.34,56.85,46.99,31.79,22.16。
Embodiment 14
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment 1
It is essentially identical, difference be the aromatic amine used for 4- 5-trifluoromethylaniline, the azacyclo- being prepared simultaneously quinazoline ditosylate salt chemical combination
Object is 4- (4- trifluoromethyl) -1,2,3,3a, and simultaneously [1,2-a] quinazoline, yield 76%, white are solid for 4,5- hexahydropyrrolos
Body.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.53 (d, J=8.5Hz, 2H), 7.16 (d, J=
8.4Hz, 3H), 6.99 (d, J=7.3Hz, 1H), 6.70 (t, J=7.4Hz, 1H), 6.57 (d, J=8.0Hz, 1H), 4.65
(dd, J=8.3,5.4Hz, 1H), 4.42 (d, J=15.0Hz, 1H), 4.21 (d, J=15.0Hz, 1H), 3.48-3.32 (m,
2H), 2.22 (tdd, J=7.7,5.5,2.7Hz, 1H), 2.08-1.87 (m, 2H), 1.74 (ddd, J=18.9,12.0,
8.6Hz,1H)。13C NMR(126MHz,CDCl3)δ153.01,143.78,128.07,126.14,126.05,125.86,
123.24,120.93,116.99,111.73,75.88,55.69,46.75,31.62,22.01。
Embodiment 15
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route are as follows:
Specifically includes the following steps:
1) take 10mL tool plug test tube, be added 0.4mmol 2- (1- nitrogen heterocyclic heptyl) benzaldehyde, 0.2mmol aniline,
The methanol aqueous solution of 15mg hog gastric mucosa protease and 2mL 50%；
2) reaction flask in step 1) is put into 55 DEG C of constant temperature oil baths, 36h is reacted under magnetic agitation and obtains crude product；
3) crude product obtained in step 2) is subjected to pillar layer separation, eluant, eluent uses methylene chloride and n-hexane, body
Product is than being 1:1, and azacyclo- and quinazoline compounds are prepared in dry 4h at 40 DEG C.
The azacyclo- and quinazoline compounds being prepared are 6- phenyl -5,6,6a, 7,8,9,10,11- octahydro azepine
Ring simultaneously [1,2-a] quinazoline, yield 84%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.24-7.20 (m, 2H), 7.09 (t, J=7.4Hz,
1H), 7.00 (d, J=7.3Hz, 1H), 6.95 (d, J=7.9Hz, 2H), 6.83 (t, J=7.3Hz, 1H), 6.64-6.55 (m,
2H), 4.88 (dd, J=9.9,4.2Hz, 1H), 4.58 (d, J=16.1Hz, 1H), 4.38 (d, J=16.1Hz, 1H), 3.88
(ddd, J=15.0,6.3,3.2Hz, 1H), 3.28-3.18 (m, 1H), 2.18-2.09 (m, 1H), 1.97-1.84 (m, 2H),
1.68-1.58 (m, 3H), 1.48 (ddd, J=17.2,9.6,4.0Hz, 1H), 1.35 (ddd, J=13.6,8.8,4.5Hz,
1H)。13C NMR(126MHz,CDCl3)δ149.75,142.61,129.26,129.17,127.75,126.53,117.82,
117.38,115.56,110.05,75.08,47.12,46.31,32.95,26.42,26.03,24.77.
Embodiment 16
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, difference be the aromatic amine used for 4- methylaniline, the azacyclo- being prepared simultaneously quinazoline compounds
For 6- (p-methylphenyl) -5,6,6a, simultaneously [1,2-a] quinazoline, yield 92%, white are solid for 7,8,9,10,11- octahydro azacyclo-s
Body.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.11-6.95 (m, 4H), 6.86 (d, J=8.5Hz,
2H), 6.64-6.53 (m, 2H), 4.80 (dd, J=10.1,4.0Hz, 1H), 4.56 (d, J=16.2Hz, 1H), 4.31 (d, J=
16.2Hz, 1H), 3.85 (ddd, J=15.0,6.3,3.3Hz, 1H), 3.27-3.13 (m, 1H), 2.24 (s, 3H), 2.13
(dtd, J=16.2,10.8,5.4Hz, 1H), 1.96-1.78 (m, 2H), 1.72-1.56 (m, 3H), 1.54-1.41 (m, 1H),
1.40-1.28(m,1H)。13C NMR(126MHz,CDCl3)δ147.70,142.67,129.71,129.53,127.73,
126.55,117.93,117.85,115.48,109.97,75.74,47.11,46.54,33.14,26.37,26.13,24.80,
20.56。
Embodiment 17
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, difference be the aromatic amine used for 3- methylaniline, the azacyclo- being prepared simultaneously quinazoline compounds
For -5,6,6a, 7,8,9,10,11- octahydro azacyclo- of 6- (tolyl), simultaneously [1,2-a] quinazoline, yield 89%, white are solid
Body.
Nuclear-magnetism characterize data are as follows:1HNMR(500MHz,CDCl3) δ 7.14-7.04 (m, 2H), 7.00 (d, J=7.2Hz,
1H), 6.75 (d, J=8.5Hz, 2H), 6.68-6.54 (m, 3H), 4.87 (dd, J=9.9,4.2Hz, 1H), 4.56 (d, J=
16.1Hz, 1H), 4.37 (d, J=16.1Hz, 1H), 3.88 (ddd, J=15.0,6.3,3.1Hz, 1H), 3.29-3.19 (m,
1H),2.30(s,3H),2.19-2.10(m,1H),1.94-1.81(m,2H),1.70-1.58(m,3H),1.53-1.44(m,
1H), 1.35 (ddd, J=18.6,9.2,4.2Hz, 1H).13C NMR(126MHz,CDCl3)δ149.68,142.60,138.81,
128.99,127.71,126.54,120.79,118.08,117.92,115.55,114.31,110.07,75.07,47.12,
46.27,32.73,26.43,26.03,24.76,21.90。
Embodiment 18
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, difference be the aromatic amine used for 4- aminoanisole, the azacyclo- being prepared simultaneously quinazoline ditosylate salt chemical combination
Object is 6- (4- methoxyphenyl) -5,6,6a, 7,8,9,10,11- octahydro azacyclo- simultaneously [1,2-a] quinazoline, yield 95%,
White solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.08 (t, J=7.4Hz, 1H), 6.94 (dd, J=
24.2,8.1Hz, 3H), 6.82-6.71 (m, 2H), 6.65-6.52 (m, 2H), 4.72-4.53 (m, 2H), 4.23 (d, J=
16.3Hz, 1H), 3.88-3.76 (m, 1H), 3.72 (s, 3H), 3.16 (ddd, J=15.4,10.2,5.6Hz, 1H), 2.16-
2.05 (m, 1H), 1.95 (d, J=6.1Hz, 1H), 1.86 (dtd, J=13.5,10.1,3.6Hz, 1H), 1.74-1.54 (m,
3H), 1.53-1.41 (m, 1H), 1.34 (dtd, J=14.1,9.8,4.4Hz, 1H).13C NMR(126MHz,CDCl3)δ
154.07,144.36,142.81,127.73,126.49,120.30,117.83,115.44,114.35,109.87,76.79,
55.51,47.25,47.02,33.87,26.35,26.21,24.79。
Embodiment 19
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, difference be the aromatic amine used for 4- 5-trifluoromethylaniline, the azacyclo- being prepared simultaneously quinazoline ditosylate salt
Conjunction object is that simultaneously [1,2-a] quinazoline, yield are 6- (4- trifluoromethyl) -5,6,6a, 7,8,9,10,11- octahydro azacyclo-
82%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.47 (d, J=8.7Hz, 2H), 7.11 (t, J=
7.8Hz, 1H), 7.03 (d, J=7.5Hz, 1H), 6.94 (d, J=8.7Hz, 2H), 6.69-6.60 (m, 2H), 4.96 (dd, J=
9.3,5.0Hz, 1H), 4.51 (dd, J=45.7,16.0Hz, 2H), 3.91 (ddd, J=15.1,6.6,3.0Hz, 1H), 3.31-
3.19 (m, 1H), 2.17 (ddt, J=20.3,10.4,6.2Hz, 1H), 1.91-1.83 (m, 2H), 1.71-1.62 (m, 3H),
1.54-1.47(m,1H),1.39-1.33(m,1H)。13C NMR(126MHz,CDCl3)δ151.50,142.35,128.03,
126.70,126.59,126.50,125.82,117.45,116.13,115.34,110.50,73.78,47.31,45.90,
32.35,26.59,25.82,24.67。
Embodiment 20
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, difference be the aromatic amine used for 4- aminobenzonitrile, the azacyclo- being prepared simultaneously quinazoline compounds
For -5,6,6a, 7,8,9,10,11- octahydro azacyclo- of 6- (4- cyano-phenyl), simultaneously [1,2-a] quinazoline, yield 83% are white
Solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.50 (d, J=8.9Hz, 2H), 7.13 (t, J=
7.5Hz, 1H), 7.03 (d, J=7.3Hz, 1H), 6.87 (d, J=8.9Hz, 2H), 6.73-6.61 (m, 2H), 5.07-4.93
(m, 1H), 4.57-4.42 (m, 2H), 3.92 (ddd, J=15.1,6.6,2.7Hz, 1H), 3.35-3.21 (m, 1H), 2.25-
2.12 (m, 1H), 1.86 (dd, J=12.7,6.9Hz, 2H), 1.76-1.56 (m, 3H), 1.56-1.45 (m, 1H), 1.45-
1.33(m,1H)。13C NMR(126MHz,CDCl3)δ151.29,142.23,133.64,128.17,126.58,120.14,
117.40,116.56,114.55,110.86,100.23,72.77,47.51,45.52,31.82,26.85,25.63,24.61。
Embodiment 21
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, and difference is the aromatic amine used for 4- chloroaniline, and the azacyclo- and quinazoline compounds being prepared are
Simultaneously [1,2-a] quinazoline, yield 85%, white are solid for -5,6,6a, 7,8,9,10,11- octahydro azacyclo- of 6- (4- chlorphenyl)
Body.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.22-7.14 (m, 2H), 7.09 (t, J=7.5Hz,
1H), 6.99 (d, J=7.3Hz, 1H), 6.90-6.83 (m, 2H), 6.66-6.56 (m, 2H), 4.79 (dd, J=10.0,
4.2Hz, 1H), 4.56 (d, J=16.2Hz, 1H), 4.31 (d, J=16.2Hz, 1H), 3.87 (ddd, J=15.0,6.3,
3.3Hz, 1H), 3.25-3.14 (m, 1H), 2.20-2.09 (m, 1H), 1.96-1.81 (m, 2H), 1.67 (dddd, J=27.8,
13.9,8.7,4.8Hz,3H),1.54-1.43(m,1H),1.40-1.30(m,1H)。13C NMR(126MHz,CDCl3)δ
148.45,142.48,129.04,127.91,126.54,124.81,118.77,117.41,115.78,110.16,75.25,
47.12,46.50,33.15,26.37,26.01,24.72。
Embodiment 22
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, and difference is the aromatic amine used for 2-aminotoluene, the azacyclo- being prepared and quinazoline compounds
For -5,6,6a, 7,8,9,10,11- octahydro azacyclo- of 6- (tolyl), simultaneously [1,2-a] quinazoline, yield 90%, white are solid
Body.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.08 (d, J=7.2Hz, 1H), 7.03 (t, J=
7.7Hz, 1H), 6.93 (dd, J=10.8,4.3Hz, 1H), 6.85 (dd, J=13.6,6.9Hz, 3H), 6.52 (t, J=
7.1Hz, 2H), 4.65 (d, J=16.9Hz, 1H), 4.16 (dd, J=10.1,4.3Hz, 1H), 3.88 (d, J=16.9Hz,
1H),3.09-2.86(m,1H),2.26(s,3H),2.11-1.85(m,3H),1.64-1.24(m,6H)。13C NMR(126MHz,
CDCl3)δ151.34,143.27,132.78,130.86,127.68,126.71,126.17,123.41,121.79,118.35,
115.25,109.57,76.95,47.77,46.93,35.43,26.49,26.17,24.87,18.47。
Embodiment 23
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, and difference is the aromatic amine used for 3- chloroaniline, and the azacyclo- and quinazoline compounds being prepared are
Simultaneously [1,2-a] quinazoline, yield 82%, white are solid for -5,6,6a, 7,8,9,10,11- octahydro azacyclo- of 6- (3- chlorphenyl)
Body.
Nuclear-magnetism characterize data are as follows:1HNMR(500MHz,CDCl3) δ 7.16-7.07 (m, 2H), 7.00 (d, J=7.4Hz,
1H), 6.89 (t, J=2.1Hz, 1H), 6.82-6.77 (m, 2H), 6.67-6.59 (m, 2H), 4.88-4.80 (m, 1H), 4.54
(d, J=16.0Hz, 1H), 4.37 (d, J=16.1Hz, 1H), 3.90 (ddd, J=15.1,6.5,3.0Hz, 1H), 3.25
(ddd, J=15.8,10.3,5.9Hz, 1H), 2.15 (ddt, J=12.2,10.5,6.1Hz, 1H), 1.91-1.82 (m, 2H),
1.71-1.60(m,3H),1.53-1.45(m,1H),1.40-1.31(m,1H)。13C NMR(126MHz,CDCl3)δ150.70,
142.45,134.97,130.22,128.00,126.64,119.50,117.51,116.78,115.97,114.94,110.38,
74.51,47.19,46.28,32.66,26.51,25.95,24.72。
Embodiment 24
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, difference be the aromatic amine used for 4- nitroaniline, the azacyclo- being prepared simultaneously quinazoline compounds
For -5,6,6a, 7,8,9,10,11- octahydro azacyclo- of 6- (4- nitrobenzophenone) simultaneously [1,2-a] quinazoline, yield 71%, yellow
Oily liquids.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 8.14 (d, J=9.3Hz, 2H), 7.16 (t, J=
7.6Hz, 1H), 7.06 (d, J=7.4Hz, 1H), 6.82 (d, J=9.3Hz, 2H), 6.78-6.64 (m, 2H), 5.09 (t, J=
7.3Hz, 1H), 4.54 (q, J=15.9Hz, 2H), 3.94 (ddd, J=15.3,6.5,2.4Hz, 1H), 3.38-3.23 (m,
1H), 2.25-2.13 (m, 1H), 1.87 (dd, J=12.9,6.9Hz, 2H), 1.78-1.66 (m, 2H), 1.66-1.48 (m,
2H),1.47-.35(m,1H)。13C NMR(126MHz,CDCl3)δ152.47,142.18,138.32,128.30,126.60,
126.14,117.47,116.93,112.62,111.16,72.44,47.71,45.58,31.44,27.13,25.49,24.60。
Embodiment 25
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, difference be the aromatic amine used for 3,4- dimethoxyaniline, the azacyclo- being prepared simultaneously quinazoline ditosylate salt
Compound is 6- (3,4- Dimethoxyphenyl) -5,6,6a, 7,8,9,10,11- octahydro azacyclo- simultaneously [1,2-a] quinazoline, is produced
Rate is 89%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.09 (t, J=7.5Hz, 1H), 6.98 (d, J=
7.3Hz, 1H), 6.72 (d, J=8.7Hz, 1H), 6.60 (dd, J=17.2,8.6Hz, 3H), 6.49 (dd, J=8.6,2.3Hz,
1H), 4.74-4.55 (m, 2H), 4.24 (d, J=16.0Hz, 1H), 3.83 (t, J=13.5Hz, 7H), 3.19 (ddd, J=
15.4,10.1,5.6Hz, 1H), 2.12 (qd, J=10.7,5.5Hz, 1H), 2.03-1.82 (m, 2H), 1.77-1.56 (m,
3H),1.54-1.44(m,1H),1.41-1.31(m,1H)。13C NMR(126MHz,CDCl3)δ149.27,144.88,
143.77,142.67,127.78,126.43,117.75,115.50,111.75,110.43,109.88,104.59,76.88,
56.16,55.85,47.49,46.99,33.89,26.31,26.20,24.76。
Embodiment 26
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, and difference is the aromatic amine used for 4- bromaniline, and the azacyclo- and quinazoline compounds being prepared are
Simultaneously [1,2-a] quinazoline, yield 88%, white are solid for -5,6,6a, 7,8,9,10,11- octahydro azacyclo- of 6- (4- bromophenyl)
Body.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.34-7.28 (m, 2H), 7.10 (t, J=7.4Hz,
1H), 6.99 (d, J=7.7Hz, 1H), 6.85-6.78 (m, 2H), 6.67-6.55 (m, 2H), 4.80 (dd, J=10.0,
4.2Hz, 1H), 4.55 (d, J=16.2Hz, 1H), 4.32 (d, J=16.2Hz, 1H), 3.87 (ddd, J=15.0,6.4,
3.2Hz, 1H), 3.22 (ddd, J=15.6,10.2,5.8Hz, 1H), 2.24-2.08 (m, 1H), 1.96-1.80 (m, 2H),
1.74-1.60(m,3H),1.54-1.44(m,1H),1.41-1.30(m,1H)。13C NMR(126MHz,CDCl3)δ148.86,
142.49,132.00,127.98,126.60,119.07,117.44,115.85,112.08,110.24,75.04,47.16,
46.41,33.08,26.42,26.04,24.75。
Embodiment 27
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, and difference is the aromatic amine used for 4- Iodoaniline, and the azacyclo- and quinazoline compounds being prepared are
Simultaneously [1,2-a] quinazoline, yield 93%, white are solid for -5,6,6a, 7,8,9,10,11- octahydro azacyclo- of 6- (4- iodophenyl)
Body.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.48 (d, J=8.6Hz, 2H), 7.09 (t, J=
7.7Hz, 1H), 6.99 (d, J=7.3Hz, 1H), 6.77-6.53 (m, 4H), 4.81 (dd, J=9.9,4.1Hz, 1H), 4.53
(d, J=16.1Hz, 1H), 4.32 (d, J=16.1Hz, 1H), 3.87 (ddd, J=14.8,6.2,3.0Hz, 1H), 3.34-
3.05 (m, 1H), 2.23-2.08 (m, 1H), 1.96-1.78 (m, 2H), 1.77-1.58 (m, 3H), 1.48 (ddd, J=18.4,
11.9,3.8Hz,1H),1.41-1.29(m,1H)。13CNMR(126MHz,CDCl3)δ149.35,142.41,137.88,
127.94,126.56,119.37,117.40,115.83,110.22,81.76,74.76,47.16,46.18,32.92,
26.40,25.97,24.71。
Embodiment 28
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
15 is essentially identical, and difference is the aromatic amine used for naphthalidine, and simultaneously quinazoline compounds are 6- to the azacyclo- being prepared
(1- naphthalene) -5,6,6a, 7,8,9,10,11- octahydro azacyclo- simultaneously [1,2-a] quinazoline, yield 78%, white solid.
Nuclear-magnetism characterize data are as follows:13C NMR(126MHz,CDCl3)δ149.11,142.97,134.81,129.56,
128.60,127.81,126.34,126.18,125.79,125.65,123.85,123.76,118.26,117.55,115.40,
109.71,77.90,60.58,48.70,46.90,26.42,26.15,24.86,17.88。
Embodiment 29
A kind of synthetic method of [1,2-a] quinazoline compounds, synthetic route are as follows:
Specifically includes the following steps:
1) take a 10mL tool plug test tube, be added 0.4mmol 2- (3,4- dihydro -2 (1H) isoquinolyl) benzaldehyde,
0.2mmol aniline, 25mg hog gastric mucosa protease and 2mL methanol aqueous solution；
2) reaction flask in step 1) is put into 60 DEG C of constant temperature oil baths, 48h is reacted under magnetic agitation and obtains crude product；
3) crude product obtained in step 2) is subjected to pillar layer separation, eluant, eluent uses methylene chloride and n-hexane, body
Product is than being 1:1, and azacyclo- and quinazoline compounds are prepared in dry 3h at 50 DEG C.
The azacyclo- and quinazoline compounds being prepared are 5- phenyl -4b, and 5,12,13 tetrahydro -6H- isoquinolin are simultaneously
[2,1-a] quinazoline, yield 88%, white solid, nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3)δ7.60(d,J
=7.4Hz, 1H), 7.32-7.11 (m, 6H), 7.09 (t, J=7.6Hz, 1H), 7.02 (d, J=7.2Hz, 1H), 6.95 (d, J
=8.2Hz, 1H), 6.88 (t, J=6.6Hz, 2H), 6.66 (t, J=7.3Hz, 1H), 6.03 (s, 1H), 4.40 (d, J=
16.6Hz, 1H), 4.32 (d, J=16.6Hz, 1H), 4.22 (dd, J=14.4,5.2Hz, 1H), 3.45 (td, J=14.2,
3.8Hz,1H),3.22-3.02(m,1H),2.62-2.42(m,1H)。13C NMR(126MHz,CDCl3)δ150.86,143.84,
137.40,136.66,129.32,129.03,127.70,127.59,126.96,126.43,125.99,122.15,120.81,
118.54,118.14,113.72,73.90,46.52,45.33,24.96。
Embodiment 30
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
29 is essentially identical, difference be the aromatic amine used for 4- methylaniline, the azacyclo- being prepared simultaneously quinazoline compounds
For 5- (4- aminomethyl phenyl) -4b, 5,12,13 tetrahydro -6H- isoquinolin simultaneously [2,1-a] quinazoline, yield 93%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.72 (d, J=7.3Hz, 1H), 7.34-7.23 (m,
2H), 7.20-7.06 (m, 6H), 7.02 (d, J=8.1Hz, 1H), 6.96 (d, J=7.0Hz, 1H), 6.73 (t, J=7.1Hz,
1H), 6.05 (s, 1H), 4.47 (d, J=16.7Hz, 1H), 4.31 (dd, J=26.7,11.2Hz, 2H), 3.51 (t, J=
11.9Hz, 1H), 3.19 (t, J=11.8Hz, 1H), 2.59 (d, J=16.3Hz, 1H), 2.32 (s, 3H).13C NMR
(126MHz,CDCl3)δ148.61,143.89,137.51,136.66,130.37,129.79,128.94,127.60,
127.51,126.92,126.37,126.03,122.20,118.99,118.03,113.62,74.45,46.69,45.27,
25.02,20.66。
Embodiment 31
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
29 is essentially identical, difference be the aromatic amine used for 3- methylaniline, the azacyclo- being prepared simultaneously quinazoline compounds
For 5- (3- aminomethyl phenyl) -4b, 5,12,13 tetrahydro -6H- isoquinolin simultaneously [2,1-a] quinazoline, yield 86%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.58 (d, J=7.4Hz, 1H), 7.23-7.05 (m,
4H), 7.02 (d, J=7.3Hz, 1H), 6.99-6.91 (m, 3H), 6.88 (d, J=7.3Hz, 1H), 6.77-6.58 (m, 2H),
6.04 (s, 1H), 4.39 (d, J=16.6Hz, 1H), 4.30 (d, J=16.7Hz, 1H), 4.23 (dd, J=14.5,5.3Hz,
1H), 3.54-3.38 (m, 1H), 3.20-3.03 (m, 1H), 2.51 (dd, J=16.6,3.4Hz, 1H), 2.29 (s, 3H).13C
NMR(126MHz,CDCl3)δ150.87,143.81,139.03,137.51,136.67,129.18,129.03,127.65,
127.57,126.94,126.41,125.97,122.23,121.63,119.13,118.14,115.27,113.74,73.86,
46.28,45.39,24.88,21.92。
Embodiment 32
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
29 is essentially identical, and difference is the aromatic amine used for 4- fluoroaniline, and the azacyclo- and quinazoline compounds being prepared are
5- (4- fluorophenyl) -4b, 5,12,13 tetrahydro -6H- isoquinolin simultaneously [2,1-a] quinazoline, yield 81%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.65 (d, J=7.6Hz, 1H), 7.27-7.14 (m,
2H), 7.14-7.05 (m, 3H), 7.03 (d, J=7.4Hz, 1H), 6.99-6.82 (m, 4H), 6.67 (t, J=7.3Hz, 1H),
5.87 (s, 1H), 4.40 (d, J=16.8Hz, 1H), 4.27-4.15 (m, 2H), 3.52-3.31 (m, 1H), 3.19-2.97 (m,
1H), 2.52 (dd, J=16.5,3.2Hz, 1H).13C NMR(126MHz,CDCl3)δ158.84,156.93,147.29,
143.94,137.11,136.63,128.97,127.79,126.99,126.41,126.08,121.88,121.18,121.12,
118.23,115.73,115.56,113.65,74.78,47.67,45.13,25.19。
Embodiment 33
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
29 is essentially identical, and difference is the aromatic amine used for 4- chloroaniline, and the azacyclo- and quinazoline compounds being prepared are
5- (4- chlorphenyl) -4b, 5,12,13 tetrahydro -6H- isoquinolin simultaneously [2,1-a] quinazoline, yield 67%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.56 (d, J=7.4Hz, 1H), 7.26-7.14 (m,
4H), 7.14-7.00 (m, 4H), 6.96 (d, J=8.3Hz, 1H), 6.88 (d, J=7.3Hz, 1H), 6.68 (t, J=7.3Hz,
1H), 5.96 (s, 1H), 4.40 (d, J=16.6Hz, 1H), 4.25 (dt, J=20.5,7.4Hz, 2H), 3.51-3.35 (m,
1H), 3.17-3.02 (m, 1H), 2.54 (dd, J=16.6,3.5Hz, 1H).13C NMR(126MHz,CDCl3)δ149.39,
143.70,136.87,136.57,129.12,129.04,127.84,127.68,126.97,126.42,125.88,125.71,
121.72,120.06,118.31,113.79,73.95,46.98,45.28,24.99。
Embodiment 34
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
29 is essentially identical, difference be the aromatic amine used for 4- 5-trifluoromethylaniline, the azacyclo- being prepared simultaneously quinazoline ditosylate salt
Conjunction object is 5- (4- trifluoromethyl) -4b, 5,12,13 tetrahydro -6H- isoquinolin simultaneously [2,1-a] quinazoline, yield 71%,
White solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3)δ7.54-7.39(m,3H),7.25-7.08(m,5H),
7.07-7.01 (m, 1H), 6.98 (d, J=8.2Hz, 1H), 6.90 (d, J=7.3Hz, 1H), 6.69 (t, J=7.3Hz, 1H),
6.12 (s, 1H), 4.50-4.33 (m, 2H), 4.26 (dd, J=14.5,5.3Hz, 1H), 3.50 (td, J=14.3,4.0Hz,
1H), 3.22-3.03 (m, 1H), 2.56 (dd, J=16.7,3.3Hz, 1H).13C NMR(126MHz,CDCl3)δ153.04,
143.46,136.52,136.48,129.21,127.99,127.83,127.00,126.66,126.63,126.50,125.65,
121.56,118.56,116.87,114.01,72.82,46.25,45.48,24.75。
Embodiment 35
The synthetic method of a kind of azacyclo- and quinazoline compounds, synthetic route is as above, preparation method and embodiment
29 is essentially identical, difference be the aromatic amine used for 4- aminobenzonitrile, the azacyclo- being prepared simultaneously quinazoline compounds
For 5- (4- aminophenyl) -4b, 5,12,13 tetrahydro -6H- isoquinolin simultaneously [2,1-a] quinazoline, yield 43%, white solid.
Nuclear-magnetism characterize data are as follows:1H NMR(500MHz,CDCl3) δ 7.52 (d, J=8.6Hz, 2H), 7.31 (d, J=
6.4Hz, 1H), 7.12 (ddd, J=36.9,18.5,9.3Hz, 6H), 7.01 (d, J=8.2Hz, 1H), 6.92 (d, J=
7.3Hz, 1H), 6.72 (t, J=7.3Hz, 1H), 6.17 (s, 1H), 4.52-4.36 (m, 2H), 4.29 (dd, J=14.4,
5.3Hz,1H),3.61-3.46(m,1H),3.23-3.07(m,1H),2.67-2.51(m,1H)。13C NMR(126MHz,
CDCl3)δ153.29,143.16,136.36,135.85,133.72,129.32,128.10,127.96,126.96,126.48,
125.42,121.20,119.90,118.77,116.32,114.15,101.74,71.96,45.92,45.57,24.55。
Substrate is larger to the yield impact of synthesis of azacyclic of the present invention and quinazoline compounds, and yield impact is shown in Table 1.
Influence of 1 substrate of table to the yield of synthesis of azacyclic of the present invention and quinazoline compounds
Comparative example
Reaction process is as follows:
It is reacted in the solvent of 2mL with the aniline of 2- (1- pyrrolidinyl) benzaldehyde of 0.2mmol and 0.22mmol, temperature
It is 50 DEG C, with 15mg hog gastric mucosa albumen enzymic catalytic reaction, yield is as shown in table 2 below under different condition, it can be seen that works as methanol
When being mixed with water with 1:1, yield is best.
Reaction yield contrast table under the conditions of 2 different solvents of table
It is discussed in detail although the contents of the present invention have passed through above preferred embodiment, but it should be appreciated that above-mentioned
Description is not considered as limitation of the present invention.After those skilled in the art have read above content, for of the invention
A variety of modifications and substitutions all will be apparent.Therefore, protection scope of the present invention should be limited to the appended claims.
Claims (10)
1. the synthetic method of a kind of azacyclo- and quinazoline compounds, which is characterized in that this method includes:
By the benzaldehyde with the structure as shown in formula A and have the aromatic amine as shown in formula B in methanol aqueous solution or methanol solution
In, and the molar ratio of the benzaldehyde and aromatic amine be more than or equal to 2:1, under the catalytic action of hog gastric mucosa protease,
Constant temperature stirs at 40~65 DEG C, and reaction obtains azacyclo- and quinazoline compounds with the structure as shown in formula C；
Wherein, R1And R2Connect and compose azacyclo-.
2. the synthetic method of azacyclo- according to claim 1 and quinazoline compounds, which is characterized in that the methanol
The volume ratio of methanol and water is 1:2~2:1 in aqueous solution.
3. the synthetic method of azacyclo- according to claim 1 and quinazoline compounds, which is characterized in that the stirring
Revolving speed is 150~250rpm.
4. the synthetic method of azacyclo- according to claim 1 and quinazoline compounds, which is characterized in that the reaction
Time is not less than 36h.
5. the synthetic method of azacyclo- according to claim 1 and quinazoline compounds, which is characterized in that the pig stomach
The quality molar ratio of mucosal protein enzyme and aromatic amine is 75mg:1mmol~150mg:1mmol；The methanol aqueous solution and fragrance
The Molar ratio of amine is 5mL:1mmol~10mL:1mmol.
6. the synthetic method of azacyclo- according to claim 1 and quinazoline compounds, which is characterized in that the reaction
After, using column chromatography separating purification.
7. the synthetic method of azacyclo- described according to claim 1~any one of 6 and quinazoline compounds, feature
It is, R1And R2Include :-CH2-(CH2)n-CH2, n=1~6；OrN=0~4, D are carbocyclic ring or heterocycle.
8. the synthetic method of azacyclo- according to claim 7 and quinazoline compounds, which is characterized in that D is fragrance
Ring.
9. the synthetic method of azacyclo- described according to claim 1~any one of 6 and quinazoline compounds, feature
It is, the aromatic amine has the structure as shown in formula E or F:
Wherein, R3And R4It is each independently H or electron donating group or electron-withdrawing substituent；G is carbocyclic ring or heterocycle.
10. the synthetic method of azacyclo- according to claim 9 and quinazoline compounds, which is characterized in that the confession
Any one of electron substituent group in methyl, ethyl, methoxyl group and ethyoxyl；The electron-withdrawing substituent be selected from halogen,
Any one in trifluoromethyl, nitro and cyano.
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| CN111620824A (en) * | 2020-06-24 | 2020-09-04 | 武汉理工大学 | Method for synthesizing quinazoline compound by taking aromatic aldehyde as substrate |
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| CN113373187A (en) * | 2021-05-26 | 2021-09-10 | 江苏阿尔法药业股份有限公司 | Nitrogen heterocyclic compound C27H30FNO6Enzyme-catalyzed synthesis method of |
| CN113373187B (en) * | 2021-05-26 | 2023-11-10 | 江苏阿尔法药业股份有限公司 | Nitrogen heterocyclic compound C 27 H 30 FNO 6 Is a method for enzymatic synthesis of (a) |
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