CN103130811B - Synthesis method of 5,6-2H-pyrrolo[1,5-c] quinazoline compounds - Google Patents
Synthesis method of 5,6-2H-pyrrolo[1,5-c] quinazoline compounds Download PDFInfo
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- CN103130811B CN103130811B CN201310076089.5A CN201310076089A CN103130811B CN 103130811 B CN103130811 B CN 103130811B CN 201310076089 A CN201310076089 A CN 201310076089A CN 103130811 B CN103130811 B CN 103130811B
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Abstract
The invention discloses a synthesis method of 5,6-2H-pyrrolo[1,5-c] quinazoline compounds. The technical scheme has the key points as follows: the synthesis method of the 5,6-2H-pyrrolo[1,5-c] quinazoline compounds is used for synthesizing various types of 5,6-2H-pyrrolo[1,5-c] quinazoline compounds at one step on the basis of simply and easily prepared 5-(2-bromoaryl)-1H-pyrazol through cascade reaction among 5-(2-bromoaryl)-1H-pyrazol, ammonia water and multiple components of a ketone compound. The synthesis method disclosed by the invention has the advantages of simply and easily prepared initial raw materials, wide substrate application range, easily separated and purified products and the like.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of 5,6-dihydro-pyrazolo [1,5-
c] synthetic method of quinazoline compounds.
Background technology
Nitrogen fused heterocycle skeleton is extensively present in alkaloid, causes the extensive concern of chemist and medicine scholar in recent years.Wherein, 5,6-dihydro-pyrazolo [1,5-
c] quinazoline compounds has wide spectrum physiology biological activity, has important development and application values in biological and medicine and other fields.5,6-dihydro-pyrazolo [1, the 5-reported in pertinent literature
c] synthetic method of quinazoline compounds mainly obtained by the condensation reaction of 5-(2-aminocarbonyl phenyl)-pyrazoles and aldehyde compound or ketone compounds etc.These traditional synthetic methods often need could successfully carry out under strong acid or highly basic promote, which greatly limits the range of application of such synthetic method, the more important thing is the more difficult preparation in enormous quantities of raw material 5-(2-aminocarbonyl phenyl)-pyrazoles of reacting and using, therefore, be limited by very large in actual production.In view of 5,6-dihydro-pyrazolo [1,5-
c] importance of quinazoline compounds, develop synthetic method that is simple and direct, this compounds efficiently extremely urgent.
Summary of the invention
The technical problem that the present invention solves there is provided a kind of 5,6-dihydro-pyrazolo [1,5-
c] synthetic method of quinazoline compounds, this synthetic method has starting raw material and is simple and easy to the advantages such as preparation, wide application range of substrates and the easily separated purifying of product.
Technical scheme of the present invention is: a kind of 5,6-dihydro-pyrazolo [1,5-
c] synthetic method of quinazoline compounds, it is characterized in that main with 5-(2-bromine aryl)-1
h-pyrazoles, ammoniacal liquor and ketone compounds are raw material, take transition metal salt as catalyzer, and the reaction equation in this synthetic method is:
Wherein R
1for alkyl or phenyl, R
2for hydrogen, chlorine or methoxyl group, R
3and R
4for alkyl or cycloalkyl.
5,6-dihydro-pyrazolo [1,5-of the present invention
c] concrete steps of synthetic method of quinazoline compounds are: by 5-(2-bromine aryl)-1
h-pyrazoles, ammoniacal liquor and ketone compounds are dissolved in organic solvent, then add transition-metal catalyst, heat i.e. obtained 5,6-dihydro-pyrazolo [1,5-in the presence of the air
c] quinazoline compounds.
5-of the present invention (2-bromine aryl)-1
hthe ratio of the amount of substance that feeds intake of-pyrazoles, ammoniacal liquor and ketone compounds is n(5-(2-bromine aryl)-1
h-pyrazoles): n(NH
3h
2o): n(ketone compounds)=1:7:2-4.
Organic solvent of the present invention is DMF or dimethyl sulfoxide (DMSO).
Transition-metal catalyst of the present invention is cuprous iodide or cuprous chloride.
Heating temperature of the present invention is 80
oc-100
oC.
Instant invention overcomes the shortcomings such as the more difficult preparation of starting raw material in such compou nd synthesis method current, severe reaction conditions, troublesome poeration and productive rate are low, is a kind of synthesis 5,6-dihydro-pyrazolos [1,5-
c] novel method of quinazoline compounds, this synthetic method has starting raw material and is simple and easy to the advantages such as preparation, wide application range of substrates and the easily separated purifying of product.
Embodiment
Following examples contribute to understanding the present invention, but are not limited to content of the present invention.
Embodiment 1
Add in the reaction tubes of 25 mL
1a(0.4 mmol, 95 mg),
2a(1.6 mmol, 93 mg), cuprous iodide (0.04 mmol, 7.6 mg) and DMF (2 mL), then add strong aqua (NH
3h
2o:2.8 mmol, 0.4 mL).Be heated to 100 under air
oc, stirred after 4 hours, and add 5 mL saturated ammonium chloride solution cancellation reactions, be extracted with ethyl acetate (10 mL × 2), organic phase washed with water and saturated aqueous common salt wash successively afterwards, anhydrous sodium sulfate drying.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=5/1) and obtain white solid product 2,5,5-trimethylammonium-5,6-dihydro-pyrazolo [1,5-
c] quinazoline
3a(46 mg, 54%).The characterization data of this compound is as follows:
1h NMR (CDCl
3, 400 MHz) and δ 1.72 (s, 6H), 2.34 (s, 3H), 4.20 (brs, 1H), 6.28 (s, 1H), 6.71 (d,
j=8.0 Hz, 1H), 6.85 (t,
j=7.6 Hz, 1H), 7.11-7.15 (m, 1H), 7.39-7.41 (m, 1H);
13c NMR (CDCl
3, 100 MHz) and δ 13.8,28.0,71.9,99.5,114.8,115.3,119.7,123.9,129.1,137.3,139.2,148.6. HRMS (ESI) calcd for C
13h
16n
3[M+H]
+: 214.1339, found:214.1319.
Embodiment 2
By the method described in embodiment 1, add in the reaction tubes of 25 mL
1a(0.4 mmol, 95 mg),
2b(0.8 mmol, 78 mg), cuprous chloride (0.04 mmol, 4.0 mg) and DMF (2 mL), then add strong aqua (NH
3h
2o:2.8 mmol, 0.4 mL).Be heated to 100 under air
oc, stirs after 4 hours, obtains white solid product 2'-methyl-6'
h-spiral shell [cyclohexane-1,5'-pyrazolo [1,5-
c] quinazoline]
3b(70 mg, 69%) (petrol ether/ethyl acetate=8/1).The characterization data of this compound is as follows:
1h NMR (CDCl
3, 400 MHz) and δ 1.27-1.37 (m, 2H), 1.43-1.53 (m, 2H), 1.70-1.81 (m, 2H), 2.00-2.03 (m, 2H), 2.19 (dt,
j=4.0,13,2 Hz, 2H), 2.34 (s, 3H), 4.60 (brs, 1H), 6.28 (s, 1H), 6.76 (d,
j=8.0 Hz, 1H), 6.85 (t,
j=7.2 Hz, 1H), 7.10-7.14 (m, 1H), 7.39 (d,
j=7.6 Hz, 1H);
13c NMR (CDCl
3, 100 MHz) and δ 13.9,22.3,24.6,34.6,72.9,99.5,115.4,115.8,119.7,123.8,129.0,137.4,138.7,148.4. HRMS (ESI) calcd for C
16h
20n
3[M+H]
+: 254.1652, found:254.1636.
Embodiment 3
By the method described in embodiment 1, add in the reaction tubes of 25 mL
1b(0.4 mmol, 120 mg),
2a(1.6 mmol, 93 mg), cuprous iodide (0.04 mmol, 7.6 mg) and dimethyl sulfoxide (DMSO) (2 mL), then add strong aqua (NH
3h
2o:2.8 mmol, 0.4 mL).Be heated to 80 under air
oc, stirred after 12 hours, obtained white solid product 2-phenyl-5,5-dimethyl-5,6-dihydro-pyrazolo [1,5-
c] quinazoline
3c(61 mg, 55%) (petrol ether/ethyl acetate=8/1).The characterization data of this compound is as follows:
1h NMR (CDCl
3, 400 MHz) and δ 1.80 (s, 6H), 4.13 (brs, 1H), 6.75 (d,
j=8.0 Hz, 1H), 6.80 (s, 1H), 6.91 (t,
j=8.0 Hz, 1H), 7.17 (t,
j=8.0 Hz, 1H), 7.31 (t,
j=7.2 Hz, 1H), 7.42 (t,
j=7.6 Hz, 2H), 7.51 (d,
j=7.2 Hz, 1H), 7.88 (d,
j=7.2 Hz, 2H);
13c NMR (CDCl
3, 100 MHz) and δ 28.0,72.3,96.9,114.8,115.5,119.9,124.0,125.8,127.6,128.6,129.2,133.7,137.6,139.2,151.3. HRMS (ESI) calcd for C
18h
18n
3[M+H]
+: 276.1495, found:276.1506.
Embodiment 4
By the method described in embodiment 1, add in the reaction tubes of 25 mL
1c(0.4 mmol, 108 mg),
2c(0.8 mmol, 68 mg), cuprous iodide (0.04 mmol, 7.6 mg) and DMF (2 mL), then add strong aqua (NH
3h
2o:2.8 mmol, 0.4 mL).Be heated to 100 under air
oc, stirs after 4 hours, obtains white solid product 2'-methyl-6'
hthe chloro-spiral shell of-9'-[pentamethylene-1,5'-pyrazolo [1,5-
c] quinazoline]
3d(59 mg, 54%) (petrol ether/ethyl acetate=8/1).The characterization data of this compound is as follows:
1h NMR (CDCl
3, 400 MHz) and δ 1.75-1.78 (m, 2H), 1.88-1.95 (m, 4H), 2.31 (s, 3H), 2.41-2.46 (m, 2H), 4.34 (brs, 1H), 6.27 (s, 1H), 6.65 (d
j=8.0 Hz, 1H), 7.05 (dd,
j=2.4,8.8 Hz, 1H), 7.35 (d,
j=2.8 Hz, 1H);
13c NMR (CDCl
3, 100 MHz) and δ 13.8,23.7,38.1,82.0,100.3,117.0,123.5,124.7,128.5,136.9,138.0,148.7. HRMS (ESI) calcd for C
15h
17clN
3[M+H]
+: 274.1106, found:274.1126.
Embodiment 5
By the method described in embodiment 1, add in the reaction tubes of 25 mL
1d(0.4 mmol, 107 mg),
2b(0.8 mmol, 78 mg), cuprous iodide (0.04 mmol, 7.6 mg) and DMF (2 mL), then add strong aqua (NH
3h
2o:2.8 mmol, 0.4 mL).Be heated to 100 under air
oc, stirs after 5 hours, obtains white solid product 2'-methyl-6'
h-9'-methoxyl group-spiral shell [cyclohexane-1,5'-pyrazolo [1,5-
c] quinazoline]
3e(68 mg, 60%) (petrol ether/ethyl acetate=8/1).The characterization data of this compound is as follows:
1h NMR (CDCl
3, 400 MHz) and δ 1.28-1.35 (m, 2H), 1.47-1.57 (m, 2H), 1.70-1.77 (m, 2H), 1.95-1.98 (m, 2H), 2.10-2.17 (m, 2H), 2.33 (s, 3H), 3.79 (s, 3H), 4.17 (brs, 1H), 6.27 (s, 1H), 6.73-6.79 (m, 2H), 6.95 (d
j=2.4 Hz, 1H);
13c NMR (CDCl
3, 100 MHz) and δ 13.8,22.3,24.8,34.3,55.7,73.0,99.8,108.5,115.2,117.7,118.6,132.1,137.2,148.2,154.1. HRMS (ESI) calcd for C
17h
22n
3o [M+H]
+: 284.1757, found:284.1744.
Claims (2)
1. dihydro-pyrazolo [1 a, 5-
c] synthetic method of quinazoline compounds, it is characterized in that main with 5-(2-bromine aryl)-1
h-pyrazoles, ammoniacal liquor and ketone compounds are raw material, and with transition metal salt cuprous iodide or cuprous chloride for catalyzer, the reaction equation in this synthetic method is:
Wherein R
1for alkyl or phenyl, R
2for hydrogen, chlorine or methoxyl group, R
3and R
4for alkyl or cycloalkyl, concrete steps are first by 5-(2-bromine aryl)-1
h-pyrazoles, ammoniacal liquor and ketone compounds are dissolved in organic solvent N, in dinethylformamide or dimethyl sulfoxide (DMSO), then add transition-metal catalyst cuprous iodide or cuprous chloride, be heated to 80-100 DEG C namely obtained 5 in the presence of the air, 6-dihydro-pyrazolo [1,5-
c] quinazoline compounds.
2. 5,6-dihydro-pyrazolo [1,5-according to claim 1
c] synthetic method of quinazoline compounds, it is characterized in that: described 5-(2-bromine aryl)-1
hthe ratio of the amount of substance that feeds intake of-pyrazoles, ammoniacal liquor and ketone compounds is n(5-(2-bromine aryl)-1
h-pyrazoles): n(NH
3h
2o): n(ketone compounds)=1:7:2-4.
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