CN108341778A - A kind of synthetic method of phenanthridines ketone compounds - Google Patents
A kind of synthetic method of phenanthridines ketone compounds Download PDFInfo
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- CN108341778A CN108341778A CN201710053228.0A CN201710053228A CN108341778A CN 108341778 A CN108341778 A CN 108341778A CN 201710053228 A CN201710053228 A CN 201710053228A CN 108341778 A CN108341778 A CN 108341778A
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- ketone compounds
- phenanthridines ketone
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- OBZPCIKTTLKEIT-UHFFFAOYSA-N COc(c(OC)c1)cc(-c(c2c3)cc4c3OCO4)c1N(c1c3ncccc3ccc1)C2=O Chemical compound COc(c(OC)c1)cc(-c(c2c3)cc4c3OCO4)c1N(c1c3ncccc3ccc1)C2=O OBZPCIKTTLKEIT-UHFFFAOYSA-N 0.000 description 1
- FFUDRXLGHIIDBB-UHFFFAOYSA-N COc(c(OC)c1)cc(-c2ccccc2N2c3c4ncccc4ccc3)c1C2=O Chemical compound COc(c(OC)c1)cc(-c2ccccc2N2c3c4ncccc4ccc3)c1C2=O FFUDRXLGHIIDBB-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
- C07D221/12—Phenanthridines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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Abstract
The present invention relates to a kind of synthetic methods of phenanthridines ketone compounds, this method is will be with the benzamide and aryne precursor of homing device, under the collective effect of catalyst, inorganic base, additive, solvent and oxygen, it carries out C-H bond and hydrogen bound to nitrogen activates cyclization, generate phenanthridines ketone compounds core skeleton, homing device is removed again, that is, synthesizes phenanthridines ketone compounds.Compared with prior art, the method of the present invention uses copper catalyst cheap and easy to get and environmental-friendly, reaction process avoids using rare metal, such as, the catalyst such as ruthenium, rhodium, palladium, substrate has diversity, reaction condition is milder, favorable repeatability, the phenanthridines ketone natural products such as Phenaglydon, Crinasiadine can be synthesized using the method for the present invention, synthesis for phenanthridines ketone compounds and the synthesis to amaryllidaceae alkaloid natural products provide new thinking, have good application prospect.
Description
Technical field
The invention belongs to organic chemical synthesis technical fields, are related to a kind of synthetic method of phenanthridines ketone compounds.
Background technology
Phenanthridone Alkaloid is widely present in nature, as a kind of high-activity natural product, many of which molecule
And its derivative in disease of cardiovascular system and anticancer, antibacterial and antiviral etc. shows good physiological activity.
Therefore, it is always in the hot spot of Synthetic Organic Chemistry to develop phenanthridone Alkaloid and its novel synthesis of derivative compound
Hold, and has a vast market foreground.
In prior synthesizing method, used starting material synthesis step is complicated, and synthetic route yield is relatively low, cost of material
Expensive and be not easy to obtain, synthetic product type is limited.For example, the Chinese invention patent application No. is 201210566411.8 discloses
A method of it is catalyzed by copper compound and prepares 6 (5H)-phenanthridines ketone derivatives, i.e., in air or closed environment, copper compound
It is catalyzed 2- phenylbenzamaide derivatives under ligands, N- arylation reactions 6 (5H)-phenanthridines ketone derivatives of generation occur.Shen
Number a kind of preparation method of phenanthridines ketone derivatives please be disclosed for 201310195297.7 Chinese invention patent, including：It will urge
Agent, oxidant and 2- amino aryl-linking compounds are added in organic solvent, in the carbon monoxide atmosphere of an atmospheric pressure
It is reaction a period of time, post-treated after the completion of reaction to obtain phenanthridines ketone derivatives；The catalyst is divalent palladium catalyst.Application
Number a kind of synthetic method of phenanthridines ketone compounds is disclosed for 201510269511.8 Chinese invention patent, takes adjacent halogen arylamine
It is added to organic solvent with aryl methanol (or arylamine and adjacent halogen aryl methanol), ruthenium catalyst, palladium salt, azacyclo- imidazole salts and alkali
In, in N2It is heated under gas shielded, reacting a step by hydrogen transfer reaction and carbon-hydrogen bond activation generates phenanthridines ketone compounds.This hair
The method of bright offer avoids using CO gas and noble metal catalyst, and reaction condition is mild, and substrate applicability is wide, economical
Property is more preferable.
Invention content
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of reaction condition is mild,
Operation is easy, and controllability is good, favorable repeatability, and used raw material is cheap and easily-available and substantially nontoxic, wide application range of substrates, economical
The synthetic method of the good phenanthridines ketone compounds of property.
The purpose of the present invention can be achieved through the following technical solutions：
A kind of synthetic method of phenanthridines ketone compounds, which is will be with the benzamide and benzene of homing device
Alkynes precursor carries out carbon-hydrogen link and nitrogen-hydrogen bond is lived under the collective effect of catalyst, inorganic base, additive, solvent and oxygen
Change cyclization, generate phenanthridines ketone compounds core skeleton, then remove homing device, that is, synthesizes phenanthridines ketone compounds；
The chemical structural formula of the benzamide with homing device is：
The chemical structural formula of the aryne precursor is：
The chemical structural formula of the phenanthridines ketone compounds core skeleton is：
The chemical structural formula of the phenanthridines ketone compounds is：
Wherein, R1Selected from H, alkyl, branched alkyl, naphthenic base, aromatic radical, the aromatic radical containing substituent group, heterocycle, containing taking
Heterocycle, halogenic substituent, nitro or the cyano of Dai Ji；
R2Selected from H, alkyl, branched alkyl, naphthenic base, aromatic radical, the aromatic radical containing substituent group, heterocycle, contain substituent group
Heterocycle or halogenic substituent；
R3Selected from 8- aminoquinolines base, the chloro- 8- aminoquinolines bases of 5- or 5- methoxyl group -8- aminoquinoline bases.
A kind of synthetic method of phenanthridines ketone compounds, specifically includes following steps：
Step (1)：By aryne precursor with the benzamide with homing device in catalyst, additive, organic solvent A
Under effect, a certain amount of inorganic base is added, carbon-hydrogen link and nitrogen-hydrogen bond are carried out in oxygen atmosphere and activates cyclization, by subtracting
Pressure distillation, column chromatography purification, are made phenanthridines ketone compounds core skeleton；
Step (2)：By phenanthridines ketone compounds core skeleton made from step (1) and Boron tribromide in tetrahydrofuran,
React at room temperature 12-20h, dissolved by solvent B, then with trifluoracetic acid iodobenzene react 2-3h in 0 DEG C, by extraction, vacuum distillation,
Column chromatography purifies, i.e. synthesis obtains the phenanthridines ketone compounds.
Catalyst described in step (1) includes one kind in copper acetate or five hydration copper acetates, and the additive includes
One kind in tetrabutylammonium bromide or tetrabutylammonium iodide, the inorganic base include one kind in cesium fluoride or potassium fluoride.
Organic solvent A described in step (1) includes one in N,N-dimethylformamide, acetonitrile, toluene or tetrahydrofuran
Kind is several, and the solvent B described in step (2) is mixed by acetonitrile, tetrahydrofuran and water.
The molar ratio of aryne precursor described in step (1) and the benzamide with homing device is 1:0.5-5.
Aryne precursor described in step (1) rubs with the benzamide with homing device as a preferred technical solution,
You are than being 1:1.8-2.5.
The molar ratio of catalyst described in step (1) and the benzamide with homing device is 0.5-2.5:1.
Mole of catalyst described in step (1) and the benzamide with homing device as a preferred technical solution,
Than for 1-2:1.
The molar ratio of additive described in step (1) and the benzamide with homing device is 0.2-1.5:1.
Mole of additive described in step (1) and the benzamide with homing device as a preferred technical solution,
Than for 0.5-1:1.
The molar ratio of inorganic base described in step (1) and the benzamide with homing device is 0.5-2:1.
Mole of inorganic base described in step (1) and the benzamide with homing device as a preferred technical solution,
Than for 1.2-1.5:1.
The temperature of cyclization described in step (1) is 40-120 DEG C, reaction time 4-24h.
The synthetic route of the above method is as follows：
The mentality of designing of the method for the present invention is using benzamide and aryne precursor cheap and easy to get as raw material, in homing device
Carbon-to-carbon/carbon-nitrogen bond is built by novel carbon-hydrogen/nitrogen-one step of hydrogen bond priming reaction under the action of copper catalyst, to high
Effect synthesis phenanthridines ketone compounds core skeleton, then reacted with Boron tribromide, convert 5 methoxyl groups of quinoline to hydroxyl, then
It is reacted again with trifluoracetic acid iodobenzene, converts quinoline to quinones, to remove homing device, synthesis obtains the phenanthridines ketone
Compound.Homing device R3In quinoline N can be complexed with metallic copper, while forming N with the N in amide, N- bidentates match
Body.
The benzamide with homing device synthesizes for laboratory in the present invention：By acyl chlorides or carboxylic acid with amine the system of reacting
.At 0 DEG C, triethylamine and chlorobenzoyl chloride are added into the dichloromethane solution of 8- aminoquinolines, 12h is stirred at room temperature；Or to benzene
The n,N-Dimethylformamide of thionyl chloride and catalytic amount is added in the dichloromethane solution of formic acid, flow back 5h at 55 DEG C, subtracts
Solvent is distilled off in pressure, after crude product is re-dissolved, 8- aminoquinolines and triethylamine is added at 0 DEG C, 12h is stirred at room temperature.
It is extracted with saturated sodium bicarbonate quenching, dichloromethane after the reaction was complete, after organic phase water and saturated salt solution washs respectively, is passed through
Dry, vacuum distillation, column chromatography purify up to the benzamide with homing device.
Compared with prior art, the invention has the characteristics that：
1) the method for the present invention uses copper catalyst cheap and easy to get and environmental-friendly, and reaction process, which avoids, uses rare gold
Belong to, such as ruthenium, rhodium, palladium catalyst；
2) the method for the present invention substrate has diversity, can synthesize the phenanthridines ketone compounds of a variety of different substituents；
3) the method for the present invention processing step is simple, and operation is easy, and reaction condition is milder, favorable repeatability；
4) it uses the method for the present invention that can synthesize the phenanthridines ketone natural products such as Phenaglydon, Crinasiadine, is
The synthesis of phenanthridines ketone compounds and new thinking is provided to the synthesis of amaryllidaceae alkaloid natural products, had good
Application prospect.
Specific implementation mode
The present invention is further elaborated below by embodiment, purpose, which is only that, is best understood from present disclosure.
Therefore, the protection domain of this patent is not limited to these examples.
In present embodiment, the hydrogen nuclear magnetic resonance spectrum of compound (1H NMR) it is surveyed by Bruker AVANCE III HD 400
It is fixed；Mass spectrum (ESI-MS) is measured by SolariX-70FT-MS；Agents useful for same is commercial reagent.
The synthetic method of the present invention can prepare phenanthridines ketone skeletal structure of compound (Q=8- amino quinolines as shown in formula
Quinoline)：
Embodiment 1：The preparation of compound intermediate (I-1)
By 0.2mmol 2- methyl-benzoyl -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol Cu (OAc)2、
0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL n,N-Dimethylformamide, 1mL MeCN are added in reaction bulb,
Oxygen blow is heated to 80 DEG C of reaction 12h after sealing, after being cooled to room temperature, clear crystal chemical combination is obtained after vacuum distillation, purification
Object (I-1), yield 37%.
Compound (I-1) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.80 (dd, J=4.2,1.7Hz, 1H), 8.33-8.26 (m, 3H),
8.04-8.00 (m, 1H), 7.77-7.73 (m, 2H), 7.66 (t, J=7.8Hz, 1H), 7.44-7.41 (m, 1H), 7.40 (d, J
=7.4Hz, 1H), 7.21 (td, J=7.2,1.4Hz, 1H), 7.14 (td, J=8.5,1.6Hz, 1H), 6.37 (dd, J=8.2,
1.0Hz,1H),2.91(s,3H)；13CNMR(CDCl3,100MHz,ppm)δ162.97,151.54,144.84,143.34,
139.77,136.80,136.49,136.15,132.03,131.89,130.85,130.02,129.33,129.05,127.04,
124.61,123.56,122.28,122.08,120.32,119.42,116.61,24.69；HRMS:calculated for
C23H17N2O[M+H+]:337.1335；found:337.1333.
Embodiment 2：The preparation of compound intermediate (I-2)
By 0.2mmol 3- methyl-benzoyl -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol Cu (OAc)2、
0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL n,N-Dimethylformamide, 1mL MeCN are added in reaction bulb,
Oxygen blow is heated to 80 DEG C of reaction 12h after sealing, after being cooled to room temperature, clear crystal chemical combination is obtained after vacuum distillation, purification
Object (I-2), yield 57%.
Compound (I-2) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.78 (dd, J=4.2,1.7Hz, 1H), 8.37 (s, 1H), 8.31-8.25
(m, 3H), 8.02 (dd, J=7.0,2.7Hz, 1H), 7.77-7.72 (m, 2H), 7.63 (dd, J=8.3,1.7Hz, 1H),
7.42-7.39 (m, 1H), 7.23 (td, J=8.4,2.3Hz, 1H), 7.15 (td, J=8.4,1.5Hz, 1H), 6.47 (dd, J=
8.3,1.0Hz,1H),2.52(s,3H)；13CNMR(CDCl3,100MHz,ppm)δ162.20,151.50,144.76,139.36,
138.22,136.43,134.21,132.11,130.72,129.94,129.47,129.00,128.66,126.90,126.02,
122.96,122.52,122.03,119.41,116.95,21.53；HRMS:calculated for C23H17N2O[M+H+]:
337.1335；found:337.1334.
Embodiment 3：The preparation of compound intermediate (I-3)
By 0.2mmol 4- methyl-benzoyl -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol Cu (OAc)2、
0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL n,N-Dimethylformamide, 1mL MeCN are added in reaction bulb,
Oxygen blow is heated to 80 DEG C of reaction 12h after sealing, after being cooled to room temperature, clear crystal chemical combination is obtained after vacuum distillation, purification
Object (I-3), yield 70%.
Compound (I-3) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.78 (dd, J=4.2,1.7,1H), 8.46 (d, J=8.1 Hz, 1H),
8.33 (dd, J=7.9,1.4Hz, 1H), 8.26 (dd, J=8.3,1.7Hz, 1H), 8.17 (s, 1H), 8.02 (dd, J=7.2,
2.5Hz,1H),7.78-7.72(m,2H),7.44-7.40(m,2H),7.25-7.21(m,1H),7.19-7.15(m,1H),
6.47 (dd, J=8.2,1.0Hz, 1H), 2.60 (s, 3H)；13CNMR(CDCl3,100MHz,ppm)δ162.18,151.54,
144.84,143.36,139.88,136.42,134.58,130.78,129.94,129.51,129.46,129.29,129.02,
126.91,123.95,123.15,122.45,122.07,122.03,119.27,117.03,22.39；HRMS:calculated
for C23H17N2O[M+H+]:337.1335；found:337.1334.
Embodiment 4：The preparation of compound intermediate (I-4)
By 0.2mmol 3- methoxy-benzoyl -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol Cu (OAc)2、
0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL n,N-Dimethylformamide, 1mL MeCN are added in reaction bulb,
Oxygen blow is heated to 80 DEG C of reaction 12h after sealing, after being cooled to room temperature, clear crystal chemical combination is obtained after vacuum distillation, purification
Object (I-4), yield 73%.
Compound (I-4) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.79 (dd, J=4.2,1.7Hz, 1H), 8.30-8.23 (m, 3H),
8.04-8.01(m,2H),7.78-7.72(m,2H),7.42-7.39(m,2H),7.25-7.20(m,1H),7.15-7.11(m,
1H), 6.48 (dd, J=8.3,1.0Hz, 1H), 3.93 (s, 3H)；13CNMR(CDCl3,100MHz,ppm)δ161.93,
159.70,151.55,144.75,138.69,136.42,130.61,129.91,129.50,128.16,128.09,127.42,
126.87,123.84,122.70,122.64,122.03,119.41,116.93,109.63,55.73；HRMS:calculated
for C23H17N2O2[M+H+]:353.1284；found:353.1282.
Embodiment 5：The preparation of compound intermediate (I-5)
By 0.2mmol 3- Trifluoromethyl-phenacyl -8- quinolinamines, 0.4mmol aryne precursors, 0.4mmol Cu
(OAc)2, 0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL N,N-dimethylformamides, 1mL MeCN be added it is anti-
It answers in bottle, oxygen blow, 80 DEG C of reaction 12h is heated to after sealing, after being cooled to room temperature, obtained after vacuum distillation, purification colourless
Crystalline compounds (I-5), yield 67%.
Compound (I-5) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.86 (s, 1H), 8.79 (dd, J=4.2,1.7Hz, 1H), 8.49 (d, J
=8.6Hz, 1H), 8.35 (dd, J=7.9,1.9Hz, 1H), 8.30 (dd, J=8.4,1.7Hz, 1H), 8.09-8.04 (m,
1H), 8.02 (dd, J=8.6,1.9Hz, 1H), 7.80-7.75 (m, 2H), 7.46-7.43 (m, 1H), 7.32-7.24 (m, 2H),
6.53 (dd, J=7.9,1.1Hz, 1H)；13CNMR(CDCl3,100MHz,ppm)δ161.25,151.64,144.49,140.28,
137.38,136.55,135.73,130.57,130.48,130.18,129.99,129.85,129.03,129.00,126.94,
126.22,125.36,123.77,123.01,122.99,122.65,122.22,118.19,117.30；HRMS:
calculated for C23H14F3N2O[M+H+]:391.1053；found:391.1049.
Embodiment 6：The preparation of compound intermediate (I-6)
By the bromo- benzoyl -8- quinolinamines of 0.2mmol 3-, 0.4mmol aryne precursors, 0.07mmol Cu (OAc)2、
0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL n,N-Dimethylformamide, 1mL MeCN are added in reaction bulb,
Oxygen blow is heated to 80 DEG C of reaction 12h after sealing, after being cooled to room temperature, clear crystal chemical combination is obtained after vacuum distillation, purification
Object (I-6), yield 85%.
Compound (I-6) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.79 (dd, J=4.2,1.7Hz, 1H), 8.70 (d, J=2.2Hz, 1H),
(8.30-8.28 m, 2H), 8.25 (d, J=8.8Hz, 1H), 8.08-8.03 (m, 1H), 7.92 (dd, J=8.7,2.2Hz, 1H),
7.77-7.76 (m, 2H), 7.46-7.43 (m, 1H), 7.29-7.19 (m, 2H), 6.49 (dd, J=8.1,1.0Hz, 1H)；13CNMR(CDCl3,100MHz,ppm)δ160.94,151.61,144.54,139.61,136.54,136.01,135.92,
133.44,131.93,130.64,129.99,129.75,129.63,127.63,126.95,123.95,123.18,122.89,
122.26,122.19,118.61,117.20；HRMS:calculated for C22H14BrN2O[M+H+]:401.0284；
found:401.0280.
Embodiment 7：The preparation of compound intermediate (I-7)
By 0.2mmol 4- tertiary butyls-benzoyl -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol Cu (OAc)2、
0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL n,N-Dimethylformamide, 1mL MeCN are added in reaction bulb,
Oxygen blow is heated to 80 DEG C of reaction 12h after sealing, after being cooled to room temperature, clear crystal chemical combination is obtained after vacuum distillation, purification
Object (I-7), yield 83%.
Compound (I-7) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.76 (dd, J=4.2,1.7Hz, 1H), 8.50 (d, J=8.4Hz, 1H),
8.38 (t, J=4.0,1.7Hz, 2H), 8.26 (dd, J=8.4,1.7Hz, 1H), 8.02 (dd, J=7.1,2.6Hz, 1H),
7.78-7.72 (m, 2H), 7.68 (dd, J=8.4,1.8Hz, 1H), 7.42-7.39 (m, 1H), 7.27-7.23 (m, 1H),
7.19-7.15 (m, 1H), 6.48 (dd, J=8.3,1.0Hz, 1H), 1.49 (s, 9H)；13CNMR(CDCl3,100MHz,ppm)δ
162.06,156.24,151.44,144.70,139.81,136.37,136.29,134.17,130.73,129.87,129.41,
129.02,128.91,126.84,126.00,123.83,122.99,122.38,121.98,119.52,118.13,117.00,
35.60,31.59；HRMS:calculated forC26H23N2O[M+H+]:379.1805；found:379.1803.
Embodiment 8：The preparation of compound intermediate (I-8)
By 0.2mmol 4- nitro-benzoyl -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol Cu (OAc)2、
0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL n,N-Dimethylformamide, 1mL MeCN are added in reaction bulb,
Oxygen blow is heated to 80 DEG C of reaction 12h after sealing, after being cooled to room temperature, clear crystal chemical combination is obtained after vacuum distillation, purification
Object (I-8), yield 40%.
Compound (I-8) is：
1HNMR(CDCl3,400MHz,ppm):δ 9.24 (d, J=2.1Hz, 1H), 8.79 (dd, J=4.2,1.6Hz, 1H),
8.74 (d, J=8.7Hz, 1H), 8.42-8.36 (m, 2H), 8.31 (dd, J=8.3,1.6Hz, 1H), 8.10-8.06 (m, 1H),
7.81-7.76 (m, 2H), 7.48-7.45 (m, 1H), 7.35 (td, J=7.3,1.2Hz, 1H), 7.29 (td, J=8.4,
1.6Hz, 1H), 6.54 (dd, J=8.2,1.0Hz, 1H)；13CNMR(CDCl3,100MHz,ppm)δ160.70,151.71,
150.84,144.36,140.20,136.61,135.81, 135.53,131.40,130.76,130.50,130.10,
130.00,126.97,123.68,123.37,122.32,121.78,118.09,117.94,117.43；HRMS:
calculated for C22H14N3O3[M+H+]:368.1030；found:368.1027.
Embodiment 9：The preparation of compound intermediate (I-9)
By the iodo- benzoyl -8- quinolinamines of 0.2mmol 4-, 0.4mmol aryne precursors, 0.07mmol Cu (OAc)2、
0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL n,N-Dimethylformamide, 1mL MeCN are added in reaction bulb,
Oxygen blow is heated to 80 DEG C of reaction 12h after sealing, after being cooled to room temperature, clear crystal chemical combination is obtained after vacuum distillation, purification
Object (I-9), yield 80%.
Compound (I-9) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.79 (dd, J=4.2,1.7Hz, 1H), 8.75 (d, J=1.5Hz, 1H),
8.29-8.24 (m, 3H), 8.07-8.02 (m, 1H), 7.92 (dd, J=8.4,1.6Hz, 1H), 7.76 (s, 1H), 7.75 (d, J
=1.5Hz, 1H), 7.45-7.42 (m, 1H), 7.28-7.19 (m, 2H), 6.48 (dd, J=8.1,1.1Hz, 1H)；13CNMR
(CDCl3,100MHz,ppm)δ161.81,151.62,144.58,139.97,137.09,136.51,136.13,135.96,
131.37,130.83,130.64,129.96,129.88,129.71,126.94,125.40,123.29,122.86,122.17,
117.88,117.19,101.07；HRMS:calculated for C22H14IN2O[M+H+]:449.0145；found:
449.0141.
Embodiment 10：The preparation of compound intermediate (I-10)
By 0.2mmol 3,4,5- trifluoro-benzene formyl -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol Cu
(OAc)2, 0.24mmol cesium fluorides, 0.2mmol tetrabutylammonium iodides, 1mL N,N-dimethylformamides, 1mL MeCN be added it is anti-
It answers in bottle, oxygen blow, 80 DEG C of reaction 12h is heated to after sealing, after being cooled to room temperature, obtained after vacuum distillation, purification colourless
Crystalline compounds (I-10), yield 45%.
Compound (I-10) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.78 (dd, J=4.2,1.7Hz, 1H), 8.70 (dt, J=8.2,
1.8Hz,1H),8.31-8.24(m,2H),8.09-8.04(m,1H),7.79-7.75(m,2H),7.47-7.44(m,1H),
7.32-7.23 (m, 2H), 6.53 (dd, J=8.2,1.2Hz, 1H)；13CNMR(CDCl3,100MHz,ppm)δ159.74,
151.70,144.34,139.34,136.57,135.67,130.49,130.01,129.93,127.37,127.14,126.95,
123.41,122.43,122.30,121.66,117.17,116.11,112.60,112.56,112.41,112.37；HRMS:
calculated for C22H12F3N2O[M+H+]:377.0896；found:377.0894.
Embodiment 11：The preparation of compound intermediate (I-11)
By 0.2mmol 3,4- dimethoxys-benzoyl -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol Cu
(OAc)2, 0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL N,N-dimethylformamides, 1mL MeCN be added it is anti-
It answers in bottle, oxygen blow, 80 DEG C of reaction 12h is heated to after sealing, after being cooled to room temperature, obtained after vacuum distillation, purification colourless
Crystalline compounds (I-11), yield 92%.
Compound (I-11) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.80 (dd, J=4.2,1.7Hz, 1H), 8.28 (dd, J=8.3,
1.7Hz, 1H), 8.21 (dd, J=8.1,1.1Hz, 1H), 8.06-8.01 (m, 1H), 7.98 (s, 1H), 7.78-7.73 (m,
2H), 7.71 (s, 1H), 7.44-7.41 (m, 1H), 7.26-7.22 (m, 1H), 7.16 (td, J=8.4,1.4Hz, 1H), 6.50
(dd, J=8.3,1.0Hz, 1H), 4.13 (s, 3H), 4.01 (s, 3H)；13C NMR(CDCl3,100MHz,ppm)δ161.71,
153.76,151.56,149.99,144.84,139.22,136.45,130.72,129.91,129.48,129.42,128.32,
126.88,122.64,122.43,122.02,120.13,119.19,117.05,109.49,56.34,56.25；HRMS:
calculated for C24H19N2O3[M+H+]:383.1390；found:383.1388.
Embodiment 12：The preparation of compound intermediate (I-12)
By 0.2mmol 2- naphthalene formyl -8- quinolinamines, 0.4mmol aryne precursors, 0.4mmol Cu (OAc)2、0.24mmol
Cesium fluoride, 0.2mmol tetrabutylammonium iodides, 1mL n,N-Dimethylformamide, 1mL MeCN are added in reaction bulb, and oxygen is blown
It sweeps, 80 DEG C of reaction 12h is heated to after sealing, after being cooled to room temperature, colorless crystalline compound (I- is obtained after vacuum distillation, purification
12), yield 73%.
Compound (I-12) is：
1HNMR(CDCl3,400MHz,ppm):δ 9.15 (s, 1H), 8.99 (d, J=6.4Hz, 2H), 8.79 (dd, J=
4.1,1.7Hz, 1H), 8.33 (dd, J=8.3,1.6Hz, 1H), 8.14-8.80 (m, 3H), 7.99 (d, J=8.07Hz, 1H),
7.88 (dd, J=7.2,1.5Hz, 1H), 7.83 (t, J=8.0Hz, 1H), 7.70-7.66 (m, 1H), 7.61-7.57 (m, 1H),
7.46-7.41(m,2H),7.40-7.36(m,2H),6.80(s,1H)；13CNMR(CDCl3,100MHz,ppm)δ162.42,
151.62,144.83,138.30,136.61,136.56,135.63,133.56,132.71,130.93,130.86,130.54,
130.11,129.64,129.52,128.64,128.30,128.10,127.21,127.08,126.90,126.84,125.05,
124.33,122.96,122.13,121.50,120.54,113.30；HRMS:calculated for C30H19N2O[M+H+]:
423.1492；found:423.1489.
Embodiment 13：The preparation of compound intermediate (I-13)
By 0.2mmol 3,4- methylene-dioxy benzoyl -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol Cu
(OAc)2, 0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL N,N-dimethylformamides, 1mL MeCN be added it is anti-
It answers in bottle, oxygen blow, 80 DEG C of reaction 12h is heated to after sealing, after being cooled to room temperature, obtained after vacuum distillation, purification colourless
Crystalline compounds (I-13), yield 95%.
Compound (I-13) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.82 (dd, J=4.2,1.7Hz, 1H), 8.28 (dd, J=8.3,
1.7Hz, 1H), 8.23 (s, 1H), 8.22 (d, J=9.3Hz, 1H), 8.03 (dd, J=7.8,1.9Hz, 1H), 7.80-7.74
(m, 2H), 7.45-7.42 (m, 1H), 7.08 (d, J=8.4Hz, 1H), 6.30 (dd, J=4.3,1.4Hz, 2H), 5.93 (s,
1H),3.97(s,3H),3.40(s,3H)；13CNMR(CDCl3,100MHz,ppm)δ161.59,151.66,150.99,
150.10,144.91,144.68,142.25,136.54,136.48,134.77,130.78,129.88,129.57,126.87,
125.03,122.10,120.38,119.87,110.09,109.72,108.53,102.13,100.12,56.47,55.68,
31.09；HRMS:calculated for C25H19N2O5[M+H+]:427.1288；found:427.1286.
Embodiment 14：The preparation of compound intermediate (I-14)
By 0.2mmol 3,4- dimethoxys-benzoyl -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol Cu
(OAc)2, 0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL N,N-dimethylformamides, 1mL MeCN be added it is anti-
It answers in bottle, oxygen blow, 80 DEG C of reaction 12h is heated to after sealing, after being cooled to room temperature, obtained after vacuum distillation, purification colourless
Crystalline compounds (I-14), yield 95%.
Compound (I-14) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.83 (dd, J=4.2,1.7Hz, 1H), 8.28 (dd, J=8.4,
1.7Hz, 1H), 8.03 (dd, J=7.9,1.8Hz, 1H), 7.96 (s, 1H), 7.80-7.73 (m, 2H), 7.56 (s, 1H), 7.51
(s,1H),7.45-7.41(m,1H),5.99(s,1H),4.13(s,3H),4.00(s,6H),3.42(s,3H)；13CNMR
(CDCl3,100MHz,ppm)δ161.65,153.75,151.66,150.18,149.26,145.45,144.74,136.60,
136.48,134.24,130.69,129.84,129.57,129.48,126.81,122.06,119.17,111.98,109.55,
105.33,102.53,100.60,56.84,56.36,56.21,55.78；HRMS:calculated for C26H23N2O5[M+H+]:443.1601；found:443.1599.
Embodiment 15：The preparation of compound intermediate (I-15)
By 0.2mmol 3,4- methylene-dioxy benzoyl -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol Cu
(OAc)2, 0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL N,N-dimethylformamides, 1mL MeCN be added it is anti-
It answers in bottle, oxygen blow, 80 DEG C of reaction 12h is heated to after sealing, after being cooled to room temperature, obtained after vacuum distillation, purification colourless
Crystalline compounds (I-15), yield 49%.
Compound (I-15) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.82 (dd, J=4.2,1.7Hz, 1H), 8.28 (dd, J=8.4,
1.7Hz, 1H), 8.05-8.01 (m, 1H), 7.88 (s, 1H), 7.77-7.73 (m, 2H), 7.53 (d, J=6.1Hz, 2H),
7.45-7.42 (m, 1H), 6.13 (s, 2H), 5.96 (s, 1H), 5.92 (dd, J=13.5,1.3Hz, 2H)；13CNMR(CDCl3,
100MHz,ppm)δ161.40,152.68,151.69,148.61,147.90,144.65,144.11,136.65,136.52,
135.22,131.81,130.67,130.00,129.63,126.96,122.13,121.86,120.61,113.25,107.29,
102.03,101.69,101.66,100.48,98.04；HRMS:calculated for C24H15N2O5[M+H+]:
411.0975；found:411.0973.
Embodiment 16：The preparation of compound intermediate (I-16)
By 0.2mmol 3,4- dimethoxys-benzoyl -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol Cu
(OAc)2, 0.24mmol cesium fluorides, 0.2mmol tetrabutylammonium iodides, 1mL N,N-dimethylformamides, 1mL MeCN be added it is anti-
It answers in bottle, oxygen blow, 80 DEG C of reaction 12h is heated to after sealing, after being cooled to room temperature, obtained after vacuum distillation, purification colourless
Crystalline compounds (I-16), yield 95%.
Compound (I-16) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.81 (dd, J=4.2,1.6Hz, 1H), 8.31 (dd, J=8.3,
1.6Hz,1H),8.10-8.05(m,1H),7.98-7.93(m,2H),7.79-7.75(m,2H),7.50-7.45(m,2H),
6.30 (dd, J=12.1,7.2Hz, 1H), 4.14 (s, 3H), 4.01 (s, 3H)；13C NMR(CDCl3,100MHz,ppm)δ
161.55,154.00,151.76,150.30,144.46,136.62,135.90,130.64,130.05,130.00,128.13,
126.96,124.61,122.28,119.90,110.84,110.66,109.58,106.09,105.86,103.03,56.46,
56.34；HRMS:calculated for C24H17F2N2O3[M+H+]:419.1202；found:419.1199.
Embodiment 17：The preparation of Phenaglydon
By 0.2mmol 4- methyl-benzoyls-(5- methoxyl groups) -8- quinolinamines, 0.4mmol aryne precursors, 0.07mmol
Cu(OAc)2, 0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL N,N-dimethylformamides, 1mL MeCN be added
In reaction bulb, oxygen blow is heated to 80 DEG C of reaction 12h after sealing, after being cooled to room temperature, nothing is obtained after vacuum distillation, purification
Color crystalline compounds (I), yield 91%.
0.15mmol compounds (I), 0.8mmol 1M Boron tribromides are dissolved in tetrahydrofuran in room temperature reaction 16h afterwards.Through
Acetonitrile/tetrahydrofuran/water=6:2:5 (volume ratios) make solvent, 2.3mmol trifluoracetic acids iodobenzene are added after 0 DEG C is reacted 2h, warp
Colorless crystalline compound (II), yield 62% are obtained after crossing extraction, vacuum distillation, purification.
Compound (I) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.77 (dd, J=4.2,1.8Hz, 1H), 8.66 (dd, J=8.5,
1.8Hz, 1H), 8.46 (d, J=8.1Hz, 1H), 8.32 (dd, J=7.9,1.6Hz, 1H), 8.16 (s, 1H), 7.65 (d, J=
8.2Hz, 1H), 7.42 (dd, J=8.1,1.0Hz, 1H), 7.40-7.37 (m, 1H), 7.22 (td, J=7.2,1.3Hz, 1H),
7.18 (td, J=8.3,1.7Hz, 1H), 7.03 (d, J=8.2Hz, 1H), 6.56 (dd, J=8.1,1.1Hz, 1H), 4.10 (s,
3H),2.60(s,3H)；13CNMR(CDCl3,100MHz,ppm)δ162.41,155.99,151.69,145.20,143.24,
140.17,134.54,131.33,130.61,129.43,129.32,128.65,123.99,123.08,122.35,122.19,
122.01,121.04,119.28,117.17,104.38,56.15,22.39；HRMS:calculated for C24H19N2O2[M
+H+]:367.1441；found:367.1440.
Compound (II) is：
Phenaglydon provides related data and bibliography here as known compound：1HNMR(CDCl3,
400MHz,ppm):δ 10.34 (s, 1H), 8.48 (d, J=8.0Hz, 1H), 8.22 (d, J=8.0Hz, 1H), 8.10 (s, 1H),
7.46 (dd, J=12.0,7.6Hz, 2H), 7.34-7.26 (m, 2H), 2.60 (s, 3H) .Ref：Rajeshkumar,V.,Lee,
T.-H.&Chuang,S.-C.Palladium-catalyzed oxidative insertion of carbon monoxide
to N-sulfonyl-2-aminobiaryls through C–H bond activation:access to bioactive
phenanthridinone derivatives in one pot.Org.Lett.15,1468-1471(2013).
Embodiment 18：The preparation of Crinasiadine
By 0.2mmol 3,4- methylene-dioxies-benzoyl-(5- methoxyl groups) -8- quinolinamines, 0.4mmol aryne precursors,
0.07mmol Cu(OAc)2, 0.24mmol cesium fluorides, 0.1mmol tetrabutylammonium iodides, 1mL N,N-dimethylformamides, 1mL
MeCN is added in reaction bulb, oxygen blow, and 80 DEG C of reaction 12h, after being cooled to room temperature, vacuum distillation, purification are heated to after sealing
After obtain colorless crystalline compound (I), yield 46%.
0.15mmol compounds (I), 0.8mmol 1M Boron tribromides are dissolved in tetrahydrofuran in room temperature reaction 16h afterwards.Through
Acetonitrile/tetrahydrofuran/water=6:2:5 (volume ratios) make solvent, 2.3mmol trifluoracetic acids iodobenzene are added after 0 DEG C is reacted 2h, warp
Colorless crystalline compound (II), yield 55% are obtained after crossing extraction, vacuum distillation, purification.
Compound (I) is：
1HNMR(CDCl3,400MHz,ppm):δ 8.78 (dd, J=4.2,1.7Hz, 1H), 8.67 (dd, J=8.5,
1.8Hz, 1H), 8.14 (dd, J=8.0,1.4,1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.65 (d, J=8.2,1H),
7.41-7.38 (m, 1H), 7.24-7.20 (m, 1H), 7.18-7.14 (m, 1H), 7.03 (d, J=8.2Hz, 1H), 6.56 (dd, J
=8.2,1.1Hz, 1H), 6.15 (s, 2H), 4.11 (s, 3H)；13CNMR(CDCl3,100MHz,ppm)δ161.70,156.03,
152.56,151.75,148.48,145.16,139.40,131.52,131.36,130.57,128.61,128.51,122.85,
122.40,122.20,121.90,121.09,119.24,117.15,107.47,104.37,102.08,100.85；HRMS:
calculated for C24H17N2O4[M+H+]:397.1183；found:397.1184.
Compound (II) is：
Crinasiadine provides related data and bibliography here as known compound：1HNMR(CDCl3,
400MHz,ppm):δ 9.14 (s, 1H), 8.01 (d, J=8.4Hz, 1H), 7.73 (d, J=8.4Hz, 1H), 7.15-7.36 (m,
3H), 7.06 (d, J=8.1Hz, 1H), 6.22 (s, 2 Η) .Ref：Rajeshkumar,V.,Lee,T.-H.&Chuang,S.-
C.Palladium-catalyzed oxidative insertion of carbon monoxide to N-sulfonyl-2-
aminobiaryls through C–H bond activation:access to bioactive phenanthridinone
derivatives in one pot.Org.Lett.15,1468-1471(2013).
The above description of the embodiments is intended to facilitate ordinary skill in the art to understand and use the invention.
Person skilled in the art obviously easily can make various modifications to these embodiments, and described herein general
Principle is applied in other embodiment without having to go through creative labor.Therefore, the present invention is not limited to the above embodiments, ability
Field technique personnel announcement according to the present invention, improvement and modification made without departing from the scope of the present invention all should be the present invention's
Within protection domain.
Claims (10)
1. a kind of synthetic method of phenanthridines ketone compounds, which is characterized in that the synthetic method is will be with the benzene of homing device
Formamide and aryne precursor carry out carbon-hydrogen link under the collective effect of catalyst, inorganic base, additive, solvent and oxygen
Cyclization is activated with nitrogen-hydrogen bond, phenanthridines ketone compounds core skeleton is generated, then remove homing device, that is, synthesizes phenanthridone
Class compound；
The chemical structural formula of the benzamide with homing device is：
The chemical structural formula of the aryne precursor is：
The chemical structural formula of the phenanthridines ketone compounds core skeleton is：
The chemical structural formula of the phenanthridines ketone compounds is：
Wherein, R1Selected from H, alkyl, branched alkyl, naphthenic base, aromatic radical, the aromatic radical containing substituent group, heterocycle, contain substituent group
Heterocycle, halogenic substituent, nitro or cyano；
R2Selected from H, alkyl, branched alkyl, naphthenic base, aromatic radical, the aromatic radical containing substituent group, heterocycle, containing the heterocycle of substituent group
Base or halogenic substituent；
R3Selected from 8- aminoquinolines base, the chloro- 8- aminoquinolines bases of 5- or 5- methoxyl group -8- aminoquinoline bases.
2. a kind of synthetic method of phenanthridines ketone compounds according to claim 1, which is characterized in that the synthetic method has
Body includes the following steps：
Step (1)：By aryne precursor and has the function of the benzamide of homing device in catalyst, additive, organic solvent A
Under, a certain amount of inorganic base is added, carbon-hydrogen link is carried out in oxygen atmosphere and nitrogen-hydrogen bond activates cyclization, is steamed by decompression
It evaporates, column chromatography purification, phenanthridines ketone compounds core skeleton is made；
Step (2)：By phenanthridines ketone compounds core skeleton made from step (1) and Boron tribromide in tetrahydrofuran, room temperature
12-20h is reacted, is dissolved by solvent B, then 2-3h is reacted in 0 DEG C with trifluoracetic acid iodobenzene, by extraction, vacuum distillation, column color
Spectrum purification, i.e. synthesis obtain the phenanthridines ketone compounds.
3. a kind of synthetic method of phenanthridines ketone compounds according to claim 2, which is characterized in that step (1) is described
Catalyst include copper acetate or five hydration copper acetates in one kind, the additive includes tetrabutylammonium bromide or the tetrabutyl
One kind in ammonium iodide, the inorganic base include one kind in cesium fluoride or potassium fluoride.
4. a kind of synthetic method of phenanthridines ketone compounds according to claim 2, which is characterized in that step (1) is described
Organic solvent A include one or more of n,N-Dimethylformamide, acetonitrile, toluene or tetrahydrofuran, step (2) is described
Solvent B mixed by acetonitrile, tetrahydrofuran and water.
5. a kind of synthetic method of phenanthridines ketone compounds according to claim 2, which is characterized in that step (1) is described
Aryne precursor with homing device benzamide molar ratio be 1:0.5-5.
6. a kind of synthetic method of phenanthridines ketone compounds according to claim 2, which is characterized in that step (1) is described
Catalyst with homing device benzamide molar ratio be 0.5-2.5:1.
7. a kind of synthetic method of phenanthridines ketone compounds according to claim 2, which is characterized in that step (1) is described
Additive with homing device benzamide molar ratio be 0.2-1.5:1.
8. a kind of synthetic method of phenanthridines ketone compounds according to claim 2, which is characterized in that step (1) is described
Inorganic base with homing device benzamide molar ratio be 0.5-2:1.
9. a kind of synthetic method of phenanthridines ketone compounds according to claim 2, which is characterized in that step (1) is described
Cyclization temperature be 40-120 DEG C, reaction time 4-24h.
10. a kind of synthetic method of phenanthridines ketone compounds according to claim 2, which is characterized in that the conjunction of this method
It is as follows at route：
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| CN108794572A (en) * | 2017-04-27 | 2018-11-13 | 上海交通大学 | A kind of natural products Lucentamycin A total synthesis methods |
| CN109705060A (en) * | 2019-01-16 | 2019-05-03 | 华东理工大学 | A kind of preparation method of N- (2- morpholinyl -5- trifluoromethyl) -2- (3- methylphenoxy) propionamide |
| CN110857286A (en) * | 2018-08-23 | 2020-03-03 | 上海交通大学 | Preparation method of micromolecule yNA with biological activity |
| CN111393322A (en) * | 2020-03-24 | 2020-07-10 | 石河子大学 | Cyclization synthesis method of naphthalocyanide and derivative thereof |
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| CN108794572A (en) * | 2017-04-27 | 2018-11-13 | 上海交通大学 | A kind of natural products Lucentamycin A total synthesis methods |
| CN108794572B (en) * | 2017-04-27 | 2021-10-15 | 上海交通大学 | Total synthesis method of natural product Lucentamycin A |
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| CN109705060A (en) * | 2019-01-16 | 2019-05-03 | 华东理工大学 | A kind of preparation method of N- (2- morpholinyl -5- trifluoromethyl) -2- (3- methylphenoxy) propionamide |
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