CN117229206A - Preparation method for synthesizing polysubstituted 2-quinolinone compound by base catalysis - Google Patents
Preparation method for synthesizing polysubstituted 2-quinolinone compound by base catalysis Download PDFInfo
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- -1 polysubstituted 2-quinolinone compound Chemical class 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 230000002194 synthesizing effect Effects 0.000 title claims description 8
- 238000005815 base catalysis Methods 0.000 title claims description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 110
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000003513 alkali Substances 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 67
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 50
- 238000003756 stirring Methods 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 26
- 238000001816 cooling Methods 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 238000010791 quenching Methods 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 abstract description 24
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical class NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 abstract description 8
- 238000001308 synthesis method Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 229930014626 natural product Natural products 0.000 abstract 1
- 239000000047 product Substances 0.000 description 43
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 35
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 238000000926 separation method Methods 0.000 description 23
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- 230000000171 quenching effect Effects 0.000 description 18
- 238000007689 inspection Methods 0.000 description 17
- 239000012043 crude product Substances 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 15
- 239000007788 liquid Substances 0.000 description 15
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 15
- HGINADPHJQTSKN-UHFFFAOYSA-M 3-ethoxy-3-oxopropanoate Chemical compound CCOC(=O)CC([O-])=O HGINADPHJQTSKN-UHFFFAOYSA-M 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 14
- 230000003321 amplification Effects 0.000 description 13
- 238000003199 nucleic acid amplification method Methods 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 238000000605 extraction Methods 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 9
- 238000005580 one pot reaction Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000000758 substrate Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- ZUWXHHBROGLWNH-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-phenylmethanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 ZUWXHHBROGLWNH-UHFFFAOYSA-N 0.000 description 3
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 3
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 3
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000007112 amidation reaction Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- LXJVUGANBDAASB-UHFFFAOYSA-N (2-amino-5-bromophenyl)-phenylmethanone Chemical compound NC1=CC=C(Br)C=C1C(=O)C1=CC=CC=C1 LXJVUGANBDAASB-UHFFFAOYSA-N 0.000 description 2
- KWZYIAJRFJVQDO-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-(2-chlorophenyl)methanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1Cl KWZYIAJRFJVQDO-UHFFFAOYSA-N 0.000 description 2
- GTGMXPIQRQSORU-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-(2-fluorophenyl)methanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1F GTGMXPIQRQSORU-UHFFFAOYSA-N 0.000 description 2
- APHLSUBLNQBFTM-UHFFFAOYSA-N (2-aminophenyl)-(4-chlorophenyl)methanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=C(Cl)C=C1 APHLSUBLNQBFTM-UHFFFAOYSA-N 0.000 description 2
- FFFXIQFESQNINT-UHFFFAOYSA-N (2-aminophenyl)-(4-fluorophenyl)methanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=C(F)C=C1 FFFXIQFESQNINT-UHFFFAOYSA-N 0.000 description 2
- IIEJGTQVBJHMDL-UHFFFAOYSA-N 2-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-5-[2-oxo-2-[3-(sulfamoylamino)pyrrolidin-1-yl]ethyl]-1,3,4-oxadiazole Chemical compound C1CN(CC1NS(=O)(=O)N)C(=O)CC2=NN=C(O2)C3=CN=C(N=C3)NC4CC5=CC=CC=C5C4 IIEJGTQVBJHMDL-UHFFFAOYSA-N 0.000 description 2
- AQACHPDXIQVYSO-UHFFFAOYSA-N 2-amino-4,6-dibromobenzaldehyde Chemical compound NC1=C(C=O)C(=CC(=C1)Br)Br AQACHPDXIQVYSO-UHFFFAOYSA-N 0.000 description 2
- PBVZQAXFSQKDKK-UHFFFAOYSA-N 3-Methoxy-3-oxopropanoic acid Chemical compound COC(=O)CC(O)=O PBVZQAXFSQKDKK-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WPNMLCMTDCANOZ-UHFFFAOYSA-N [5-chloro-2-(methylamino)phenyl]-phenylmethanone Chemical compound CNC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 WPNMLCMTDCANOZ-UHFFFAOYSA-N 0.000 description 2
- 238000005882 aldol condensation reaction Methods 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 1
- ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 238000003309 Hoesch reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
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- 238000007086 side reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a high-efficiency preparation method for preparing polysubstituted 2-quinolinone by using 2-aminobenzophenone compounds and monoethyl malonate acyl chloride through the action of alkali. The preparation and synthesis method is simple and effective in operation, mild in reaction condition, high in yield and easy to amplify production, does not need inert gas protection, can well solve the technical problem that the existing polysubstituted 2-quinolinone compound has a complicated preparation route, and can provide an efficient synthesis method for preparing natural products or medicines containing a 2-quinolinone skeleton.
Description
Technical Field
The invention belongs to the field of medicinal chemistry and active heterocyclic compounds, and particularly relates to a preparation method for synthesizing a polysubstituted 2-quinolinone compound by an imidazole-promoted one-pot method.
Background
2-quinolinone is an important class of nitrogen-containing heterocyclic compounds, and is widely used for synthesis of drug molecules and various functional materials due to its unique parent skeleton structure. The nitrogenous heterocyclic compounds generally have good pharmaceutical activity, such as anticancer, antibacterial, antimalarial and Alzheimer disease treatment, schizophrenia treatment and the like. In addition, 2-quinolinone compounds are also important organic synthesis intermediates for the synthesis of fused heterocyclic compounds.
At present, the synthesis method of the 2-quinolinone compound is mainly reported to be a method such as a serial cyclization reaction (scheme 1 a) of aniline and alkyne, an intramolecular Houben-Hoesch reaction (scheme 1 b), pd catalyzed carbonyl insertion (scheme 1 c), stepwise amidation condensation, a strong base promoted intramolecular addition cyclization reaction (scheme 1 d) and the like. Although the method enriches the synthetic approaches of the 2-quinolinone compound, the method still has the defects of harsh reaction conditions, expensive catalyst or substrate, complicated steps and the like. Therefore, the development of a method for preparing the 2-quinolinone compound has the advantages of simple operation, mild condition, high yield and good substrate universality.
Aiming at the problems, the invention aims to design the efficiency and the method for constructing the diversity of the 2-quinolinone skeleton structure by starting from 2-aminobenzophenone and reacting with monoethyl malonate acyl chloride under the promotion of alkali without inert gas protection and directly synthesizing the 2-quinolinone compound by a one-pot method (the prior synthetic methods 1a-1d and the conception route 1e are shown in the following figures).
The condensation, addition and cyclization of the alkali-promoted 2-aminobenzophenone and the monoethyl malonate acyl chloride under mild conditions are the high-efficiency synthesis method which is feasible in theory, has obvious step economy and is in accordance with the green chemistry concept. The invention uses proper amount of alkali finally through optimized screening, has the functions of alkali and intramolecular aldol condensation catalyst, can promote amidation reaction and intramolecular addition cyclization reaction under mild conditions, and finally realizes the technical route of preparing polysubstituted 2-quinolinone compounds by an imidazole-promoted high-efficiency 'one-pot method'.
Disclosure of Invention
Aiming at the defects and drawbacks existing in the prior art, the invention discovers that under the mild condition, some alkali can promote the condensation, addition and cyclization 'one-pot method' reaction of 2-aminobenzophenone and monoethyl malonate acyl chloride under the mild condition, and can smoothly prepare the polysubstituted 2-quinolinone compound, thereby providing an efficient synthesis method of the polysubstituted 2-quinolinone compound promoted by the alkali, further developing a more efficient and convenient synthesis technical route, and the method has the characteristics of good substrate adaptability, low price and easy availability of used alkali, simple operation, mild reaction condition, easy scale-up production and the like.
The technical scheme provided by the invention is as follows:
a preparation method for synthesizing polysubstituted 2-quinolinone compounds by base catalysis is characterized by comprising the following steps: the method comprises the following steps:
1) The 2-aminobenzophenone compound and alkali are mixed according to the mol ratio of 1:1.5, adding the mixture into a corresponding solvent methylene dichloride to enable the solute concentration of the 2-aminobenzophenone compound to reach 0.5mol/L;
2) Slowly dropwise adding monoethyl malonate acyl chloride into the solution under the condition of stirring and cooling at low temperature, wherein the dosage of the monoethyl malonate acyl chloride is 110% of the molar dosage of the 2-aminobenzophenone compound according to the acyl chloride equivalent which can be provided by the monoethyl malonate acyl chloride;
3) After the dripping of the monoethyl malonate acyl chloride is finished, heating the reaction system to 20-60 ℃, stirring and reacting for 2-24 hours, and adding water to quench and react;
4) Extracting with ethyl acetate, separating, drying, filtering, concentrating, and purifying to obtain product;
the reaction formula for preparing the polysubstituted 2-quinolinone compounds is as follows:
wherein R is 1 -R 3 The number of substituents may be 0 to 4.
Preferably, said R 1 -R 3 The substituent may be selected from F, br, cl, I, CN, CO 2 Et、CO 2 Me、Ac、ArCO、CF 3 、NO 2 C1-8 alkyl, C1-8 alkoxy, et, n-Pr, i-Pr, bu, CH 2 One or several of = CH, OMe, OEt, OPr, ph, ar; further, the R 1 -R 3 The substituents may be selected from F, br, cl, I, CN, CO 2 Et、CO 2 Me、Ac、ArCO、CF 3 、NO 2 One or more of them; further, the R 1 -R 3 The substituents may be selected from Me, et, n-Pr, i-Pr, bu, CH 2 One or several of = CH, OMe, OEt, OPr, ph, ar.
Preferably, the base in step 1) is selected from KOH, naOH, K 2 CO 3 ，Na 2 CO 3 ，Cs 2 CO 3 DBU, triethylamine, imidazole, N-methylimidazole, further, the base may be preferably imidazole.
Preferably, the stirring speed of the step 2) is 200-500r/min, and further, the stirring speed of the step 2) is 300r/min.
Preferably, the cryogenically cooled conditions in step 2) may be selected from ice baths.
Preferably, the heating temperature in the step 3) is 40-60 ℃, and further, the heating temperature in the step 3) can be selected to be 50 ℃ or 60 ℃.
The preparation method for synthesizing the polysubstituted 2-quinolinone compound by the 'one-pot method' base catalysis has the following beneficial effects:
1. the 'one-pot method' is used for efficiently constructing the polysubstituted 2-quinolinone parent skeleton, greatly simplifying the operation, shortening the synthetic technical route, overcoming the defects of noble metal catalysis, harsh reaction conditions, complicated multi-step synthesis and the like.
2. The equivalent imidazole is used as a base catalyst, and the raw materials are cheap and easy to obtain. Imidazole not only can be used as a catalyst for catalyzing aldol condensation in molecules, but also can be used as an amidation acid-binding agent, and finally, the purpose of synthesizing the 2-quinolinone compound by a one-pot method is achieved conveniently.
3. The method has the characteristics of good substrate applicability, mild reaction conditions, no need of inert gas protection, simple synthesis steps, less side reaction, good product yield, short time consumption, simple and convenient operation, easy amplification, good safety and reliability and the like.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of product 3a of example 1 1 H-NMR(400MHz ind 6 -DMSO)
FIG. 2 is a nuclear magnetic carbon spectrum of the product 3a of example 1 13 C-NMR(400MHz in d 6 -DMSO)
FIG. 3 is a nuclear magnetic resonance spectrum of the product 3b of example 2 1 H-NMR(400MHz in d 6 -DMSO)
FIG. 4 is a nuclear magnetic carbon spectrum of the product 3b of example 2 13 C-NMR(400MHz in d 6 -DMSO)
FIG. 5 is a nuclear magnetic resonance spectrum of product 3c of example 3 1 H-NMR(400MHz in d 6 -DMSO)
FIG. 6 is a nuclear magnetic resonance spectrum of the product 3c of example 3 13 C-NMR(400MHz in d 6 -DMSO)
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of the product 3d of example 4 1 H-NMR(400MHz in d 6 -DMSO)
FIG. 8 is a nuclear magnetic resonance spectrum of the product 3d of example 4 13 C-NMR(400MHz in d 6 -DMSO)
FIG. 9 is a nuclear magnetic resonance hydrogen spectrum of the product 3e of example 5 1 H-NMR(400MHz in d 6 -DMSO)
FIG. 10 is a nuclear magnetic resonance spectrum of product 3e of example 5 13 C-NMR(400MHz in d 6 -DMSO)
FIG. 11 is a nuclear magnetic resonance spectrum of the product 3f of example 6 1 H-NMR(400MHz in d 6 -DMSO)
FIG. 12 is a nuclear magnetic resonance spectrum of the product 3f of example 6 13 C-NMR(400MHz in d 6 -DMSO)
FIG. 13 is a nuclear magnetic resonance spectrum of 3g of the product of example 1 1 H-NMR(400MHz ind 6 -DMSO)
FIG. 14 is a nuclear magnetic resonance spectrum of 3g of the product of example 1 13 C-NMR(400MHz in d 6 -DMSO)
FIG. 15 is a nuclear magnetic resonance hydrogen spectrum of the product of example 2, 3h 1 H-NMR(400MHz in d 6 -DMSO)
FIG. 16 is a nuclear magnetic resonance spectrum of the product of example 2 at 3h 13 C-NMR(400MHz in d 6 -DMSO)
FIG. 17 is a nuclear magnetic resonance spectrum of product 3i of example 3 1 H-NMR(400MHz in d 6 -DMSO)
FIG. 18 is a nuclear magnetic resonance spectrum of product 3i of example 3 13 C-NMR(400MHz in d 6 -DMSO)
FIG. 19 is a nuclear magnetic resonance hydrogen spectrum of the product 3j of example 4 1 H-NMR(400MHz in d 6 -DMSO)
FIG. 20 is a nuclear magnetic resonance spectrum of product 3j of example 4 13 C-NMR(400MHz in d 6 -DMSO)
FIG. 21 is a nuclear magnetic resonance hydrogen spectrum of the product 3k of example 5 1 H-NMR(400MHz in d 6 -DMSO)
FIG. 22 is a nuclear magnetic carbon spectrum of the product 3k of example 5 13 C-NMR(400MHz in d 6 -DMSO)
FIG. 23 is a nuclear magnetic resonance spectrum of the product 3l of example 6 1 H-NMR(400MHz in d 6 -DMSO)
FIG. 24 is a nuclear magnetic resonance spectrum of 3l of the product of example 6 13 C-NMR(400MHz in d 6 -DMSO)
Detailed Description
The reaction parameter conditions of examples 1-12 and the amplification reactions 1-1 to 1-9 are selected according to the invention by setting different alkali types, solvent conditions, heating temperatures and reaction substrate concentrations on the basis of the reactant raw materials of example 1, and searching and comparing the obtained materials with the reference table 1. The separation yields of examples 1-12 and the amplification reaction are all higher than 70%, which shows that the condensation, addition and cyclization 'one-pot method' reaction of the imidazole-promoted 2-aminobenzophenone and the malonic acid monoethyl ester acyl chloride obtained by the invention under mild conditions is very efficient, and the synthesis method for preparing the polysubstituted 2-quinolinone compound has very good conversion application value.
Example 1
The specific preparation method of the compound 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 a) comprises the following steps:
2-aminobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and monoethyl malonate acyl chloride (1.1 eq.) was slowly added dropwise to the reaction system under stirring and cooling at low temperature. After the acid chloride is added dropwise, heating the mixture under the air without inert gas protection and keeping the temperature of 50 ℃ for reacting for 12 hours, adding 10mL of water for quenching the reaction after TLC inspection until the reaction is complete, extracting the mixture with ethyl acetate (10 mL of 3), separating the liquid, drying, filtering and concentrating the liquid to obtain a crude product, separating and purifying the crude product by column chromatography to obtain a pure product 3a, and separating the pure productMHz,DMSO-d 6 ) Delta 165.1,158.6,148.5,138.7,134.1,131.6,129.0,128.6,128.5,127.1,126.7,122.5,118.3,115.8,60.6,13.6ppm as shown in FIG. 2; HRMS (ESI) m/z calcd for C 18 H 15 NO 3 Na[M+Na] + :316.0950,Found:316.0942.
Example 1-1 (amplification reaction)
The compound 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 a) is amplified by the following preparation method:
2-aminobenzophenone (10 mmol) and imidazole (15 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, after TLC inspection is carried out until the reaction is complete, 100mL of water is added for quenching reaction, extraction is carried out by ethyl acetate (100 mL of 3), drying, filtration and concentration are carried out after liquid separation, and the crude product is obtained and purified by column chromatography to obtain pure product 3a (2.78 g, separation yield 95%).
Example 2
The specific preparation method of the compound 6-chloro-4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 b) is as follows:
2-amino-5-chlorobenzophenone (1.0 mmol) and imidazole(1.5 mmol) was added to the corresponding solvent dichloromethane (2.0 mol/L), and after cooling under stirring at low temperature, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the method does not need to be inertThe structural characterization data are as follows: 1 H NMR(400MHz,DMSO-d 6 ) δ12.44 (s, 1H), 7.63 (dd, j=8.8, 2.4hz, 1H), 7.54 (dd, j=5.0, 1.7hz, 3H), 7.42 (d, j=8.8 hz, 1H), 7.34 (dd, j=6.6, 3.0hz, 2H), 7.00 (d, j=2.3 hz, 1H), 3.95 (q, j=7.1 hz, 2H), 0.84 (t, j=7.1 hz, 3H) ppm as shown in fig. 3; 13 C NMR(100MHz,DMSO-d 6 ) Delta 164.7,158.4,147.4,137.5,133.4,131.5,129.3,128.7,128.6,127.7,126.4,125.8,119.6,117.9,60.8,13.5ppm as shown in FIG. 4; HRMS (ESI) m/z calcd for C 18 H 14 ClNO 3 Na[M+Na] + :350.0560,Found:350.0561.
Example 2-1 (amplification reaction)
The compound 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 b) is amplified by the following preparation method:
2-amino-5-chlorobenzophenone (10 mmol) and imidazole (15 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature with stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, after TLC inspection is carried out until the reaction is complete, 100mL of water is added for quenching reaction, extraction is carried out by ethyl acetate (100 mL of 3), drying, filtration and concentration are carried out after liquid separation, and the crude product is obtained and purified by column chromatography to obtain pure product 3b (2.95 g, isolated yield 90%).
Example 3
The specific preparation method of the compound 6-chloro-4- (2' -fluorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 c) is as follows:
2-amino-5-chloro-2' -fluorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acyl chloride (1.1 eq.) was slowly added dropwise to the reaction system. To be acyl chloride dropAfter the addition, the reaction is carried out for 12 hours under the condition of heating and keeping the temperature of 50 ℃ under the air without the protection of inert gas, after TLC inspection till the reaction is complete, 10mL of water is added for quenching reaction, ethyl acetate is used for extraction (10 mL of 3), the crude product is obtained after liquid separation, drying, filtration and concentration, and the pure product 3c is obtained after separation and purification by column chromatographyFig. 5 shows; 13 c NMR (101 mhz, dmso-d 6) δ 164.7,159.1 (d, j=247.5 Hz), 158.6,142.7,137.8,132.6 (d, j=8.0 Hz), 132.4,131.2 (d, j=2.0 Hz), 129.4,127.2,125.6,125.5 (d, j=3.0 Hz), 121.3 (d, j=17.2 Hz), 119.6,118.5,116.4 (d, j=20.2 Hz), 61.4,14.0ppm, as shown in fig. 6; HRMS (ESI) m/z calcd for C 18 H 13 ClFNO 3 Na[M+Na] + :368.0466,Found:368.0461。
Example 3-1 (amplification reaction)
The compound 6-chloro-4- (2' -fluorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 c) is amplified by the following preparation method: 2-amino-5-chloro-2' -fluorobenzophenone (10 mmol) and imidazole (15 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature with stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, after TLC inspection is carried out until the reaction is complete, 100mL of water is added for quenching reaction, extraction is carried out by ethyl acetate (100 mL of 3), drying, filtration and concentration are carried out after liquid separation, and the crude product is obtained and purified by column chromatography to obtain pure product 3c (2.87 g, isolated yield is 83%).
Example 4
The specific preparation method of the compound 4- (4' -fluorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 d) is as follows:
2-amino-4' -fluorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature with stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the air heating and the temperature of 50 ℃ without the protection of inert gas, and the TLC check is carried out until the reaction is completeThe reaction was quenched with 10mL of waterNMR (101 mhz, dmso-d 6) δ 165.5, δ 162.9 (d, j= 246.0 Hz), 159.0,148.1,139.2,132.2,131.5 (d, j=8.4 Hz), 130.9 (d, j=3.1 Hz), 127.5,127.5,123.1,118.8,116.2 (d, j=14.9 Hz), 116.0,61.2,14.1ppm, as shown in fig. 8; HRMS (ESI) m/z calcd for C 18 H 14 FNO 3 Na[M+Na]+:334.0855,Found:334.0852.
Example 4-1 (amplification reaction)
The compound 4- (4' -fluorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 d) is amplified by the following preparation method: 2-amino-4' -fluorobenzophenone (10 mmol) and imidazole (15 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature with stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, after TLC inspection is carried out until the reaction is complete, 100mL of water is added for quenching reaction, extraction is carried out by ethyl acetate (100 mL of 3), drying, filtration and concentration are carried out after liquid separation, and the crude product is obtained and purified by column chromatography to obtain a pure product 3d (2.80 g, separation yield 90%).
Example 5
The specific preparation method of the compound 6-bromo-4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 e) is as follows:
2-amino-5-bromobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling under stirring at low temperature, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the protection of inert gas without heating in the air and keeping the temperature of 50 ℃, after TLC inspection is carried out until the reaction is complete, 10mL of water is added for quenching the reaction, and then the reaction is carried out by(d, j=1.4 hz, 1H), 7.54 (d, j=2.2 hz, 2H), 7.38-7.33 (m, 3H), 7.14 (d, j=2.2 hz, 1H), 3.95 (q, j=7.1 hz, 2H), 0.85 (t, j=7.1 hz, 3H) ppm, as shown in fig. 9; 13 C NMR(100MHz,DMSO-d 6 ) Delta 164.7,158.3,147.3,137.8,134.2,133.4,129.3,128.8,128.7,128.6,127.7,120.1,118.1,114.2,60.8,13.5ppm as shown in FIG. 10; HRMS (ESI) m/z calcd for C 18 H 14 BrNO 3 Na[M+Na] + :394.0055,Found:394.0047.
Example 5-1 (amplification reaction)
The amplifying reaction of the 6-bromo-4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 e) is specifically prepared by the following steps: 2-amino-5-bromobenzophenone (10 mmol) and imidazole (15 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, after TLC inspection is carried out until the reaction is complete, 100mL of water is added for quenching reaction, extraction is carried out by ethyl acetate (100 mL of 3), drying, filtration and concentration are carried out after liquid separation, and the crude product is obtained and purified by column chromatography to obtain pure product 3e (2.83 g, isolated yield 76%).
Example 6
The specific preparation method of the compound 5, 7-dibromo-2-quinolinone-3-carboxylic acid ethyl ester (3 f) is as follows:
2-amino-4, 6-dibromobenzaldehyde (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvent dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acyl chloride (1.1 eq) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the condition of heating in the air and keeping the temperature of 50 ℃ without the protection of inert gas, after TLC inspection is carried out until the reaction is complete, 10mL of water is added for quenching reaction,1H) 8.15 (s, 1H), 8.14 (s, 1H), 4.29 (q, j=7.1 hz, 2H), 1.30 (t, j=7.1 hz, 3H) ppm, as shown in fig. 11; 13 C NMR(100MHz,DMSO-d 6 ) Delta 163.3,157.9,142.0,137.0,131.0,128.1,124.9,120.2,116.2,113.5,60.8,13.7ppm, as shown in FIG. 12; HRMS (ESI) m/z calcd for C 12 H 9 Br 2 NO 3 Na[M+Na] + :395.8847,Found:395.8841.
Example 6-1 (amplification reaction)
The compound 5, 7-dibromo-2-quinolinone-3-carboxylic acid ethyl ester (3 f) is amplified and prepared by the following specific method: 2-amino-4, 6-dibromobenzaldehyde (10 mmol) and imidazole (15 mmol) were added to the corresponding solvent dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acid chloride (1.1 eq) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, after TLC inspection is carried out until the reaction is complete, 100mL of water is added for quenching reaction, extraction is carried out by ethyl acetate (100 mL of 3), drying, filtration and concentration are carried out after liquid separation, and the crude product is obtained and purified by column chromatography to obtain the pure product 3f (3.30 g, isolated yield 88%).
Example 7
The specific preparation method of the compound 4- (4' -chlorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 g) is as follows:
2-amino-4' -chlorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the protection of inert gas without the protection of inert gas and at 50 ℃, after TLC inspection is carried out until the reaction is complete, 10mL of water is added for quenching the reaction, and then the reaction is quenched by using ethyl acetateDMSO-d 6 ) Delta 163.3,157.9,142.0,137.0,131.0,128.1,124.9,120.2,116.2,113.5,60.8,13.7ppm, as shown in FIG. 12; HRMS (ESI) m/z calcd for C 12 H 9 Br 2 NO 3 Na[M+Na] + :395.8847,Found:395.8841. 1 H NMR(400MHz,DMSO-d 6 ) δ12.33 (s, 1H), 7.63-7.56 (m, 3H), 7.41 (d, j=8.2 hz, 1H), 7.38-7.34 (m, 2H), 7.18-7.13 (m, 1H), 7.10 (dd, j=8.2, 1.4hz, 1H), 3.98 (q, j=7.1 hz, 2H), 0.90 (t, j=7.1 hz, 3H) ppm as shown in fig. 13; 13 C NMR(101MHz,DMSO-d 6 ) Delta 165.0,158.4,147.4,138.7,133.9,132.9,131.8,130.6,128.7,127.037,126.8,122.7,118.1,115.9,60.819,13.6ppm, as shown in FIG. 14; HRMS (ESI) m/z calcd for C 18 H 14 ClNO 3 Na[M+Na] + :350.0560,Found:350.0561.
Example 7-1 (amplification reaction)
The compound 4- (4' -chlorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 g) was amplified as follows: 2-amino-4' -chlorobenzophenone (10 mmol) and imidazole (15 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature with stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, after TLC inspection is carried out until the reaction is complete, 100mL of water is added for quenching reaction, extraction is carried out by ethyl acetate (100 mL of 3), drying, filtration and concentration are carried out after liquid separation, and the crude product is obtained and purified by column chromatography to obtain 3g (2.30 g, separation yield 70%) of pure product.
Example 8
The specific preparation method of the compound 6-chloro- (2' -chlorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 h) is as follows:
2-amino-5, 2' -dichlorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents methylene chloride (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the protection of inert gas without heating in air and keeping the temperature of 50 ℃, after the TLC check is carried out until the reaction is complete, 10mL of water is added for quenching the reaction, the reaction is extracted by ethyl acetate (10 mL of 3), the solution is separated, dried, filtered and concentrated, the crude product is obtained, and the pure product is obtained after the separation and purification of column chromatography for 3 hours, the separation yield is 71 percent, the white solid is obtained, and the temperature is mp 218-219 ℃. The structural formula and the structural characterization data are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ
131.8,131.3,130.1,128.6,128.1,127.2,125.6,119.4,118.5,61.3,14.0ppm, as shown in fig. 16; HRMS (ESI) m/z calcd for C 18 H 13 Cl 2 NO 3 Na[M+Na] + :384.0170,Found:384.0164.
Example 8-1 (amplification reaction)
The compound 6-chloro- (2' -chlorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 h) is amplified by the following preparation method: 2-amino-5, 2' -dichlorobenzophenone (10 mmol) and imidazole (15 mmol) were added to the corresponding solvents methylene chloride (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, after TLC inspection is carried out until the reaction is complete, 100mL of water is added for quenching reaction, extraction is carried out by ethyl acetate (100 mL of 3), drying, filtration and concentration are carried out after liquid separation, and the crude product is obtained and purified by column chromatography to obtain a pure product for 3h (2.72 g, separation yield is 75%).
Example 9
The specific preparation method of the N-methyl-6-chloro-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 i) is as follows:
n-methyl-2-amino-5-chlorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acyl chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, heating under the air without inert gas protection and keeping the temperature of 50 ℃ for reacting for 12 hours, adding 10mL of water for quenching reaction after TLC inspection until the reaction is complete, extracting with ethyl acetate (10 mL of 3), drying, filtering and concentrating after liquid separation to obtain a crude product, separating and purifying by column chromatography to obtain a pure product 3i,chlorine-d) delta 165.4,158.8,147.0,138.5,133.8,131.7,129.3,128.9,128.7,128.2,127.9,127.8,121.6,116.0,61.6,30.0,13.8ppm, as shown in FIG. 18; HRMS (ESI) m/z calcd for C 19 H 16 ClNO 3 Na[M+Na] + :364.0716,Found:364.0711.
Example 9-1 (amplification reaction)
The amplification reaction of N-methyl-6-chloro-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 i) is specifically prepared by the following steps: n-methyl-2-amino-5-chlorobenzophenone (10 mmol) and imidazole (15 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature with stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, after TLC inspection is carried out until the reaction is complete, 100mL of water is added for quenching reaction, extraction is carried out by ethyl acetate (100 mL of 3), drying, filtration and concentration are carried out after liquid separation, and the crude product is obtained and purified by column chromatography to obtain pure product 3i (3.04 g, isolated yield is 89%).
Example 10
The specific preparation method of the compound 4-phenyl-2-quinolinone-3-carboxylic acid methyl ester (3 j) comprises the following steps:
2-aminobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monomethyl malonate acid chloride (1.1 equivalent) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the protection of inert gas without heating in the air and keeping the temperature of 50 ℃, after TLC inspection is carried out until the reaction is complete, 10mL of water is added for quenching reaction, ethyl acetate is used for extraction (10 mL of 3), the crude product is obtained after liquid separation, drying, filtration and concentration, and the pure product 3j is obtained after separation and purification by column chromatography, wherein the separation yield is thatNMR(101MHz,DMSO-d 6 ) Delta 165.9,158.6,148.7,138.76,134.1,131.7,129.1,128.6,128.5,127.2,126.6,122.6,118.3,115.9,52.0ppm as shown in figure 20; HRMS (ESI) m/z calcd for C 16 H 20 NO 3 S[M+H] + :162.1163,Found:162.1164.
Example 11
The specific preparation method of the compound 6-chloro-4-phenyl-2-quinolinone-3-carboxylic acid methyl ester (3 k) is as follows: 2-amino-5-chlorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monomethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the protection of inert gas without being protected by inert gas and maintained at 50 ℃, after TLC inspection is carried out until the reaction is complete, 10mL of water is added for quenching the reaction, and acetic acid is used for1H) 3.48 (s, 3H) ppm as shown in FIG. 21; 13 C NMR(101MHz,DMSO-d 6 ) Delta 165.4,158.4,147.5,137.8,134.3,133.4,129.4,128.9,128.8,128.5,127.6,120.1,118.2,114.2,52.1ppm as shown in FIG. 22; HRMS (ESI) m/z calcd for C 17 H 12 NO 3 NaBr[M+Na] + :379.9904,Found:379.9898.
Example 12
The specific preparation method of the compound 6-bromo-4-phenyl-2-quinolinone-3-carboxylic acid methyl ester (3 l) is as follows:taking (10 ml. Times.3), drying, filtering and concentrating after separating liquid, obtaining a crude product, and separating and purifying by column chromatography to obtain 3l of pure product, wherein the separation yield is 99%, white solid, mp 233-234 ℃. The structural formula and the structural characterization data are as follows: 1 H NMR(400MHz,DMSO-d 6 ) δ12.48 (s, 1H), 7.66 (dd, j=8.8, 2.4hz, 1H), 7.55 (d, j=1.7 hz, 1H), 7.54 (d, j=2.0 hz, 2H), 7.43 (d, j=8.8 hz, 1H), 7.37-7.33 (m, 2H), 7.01 (d, j=2.3 hz, 1H), 3.48 (s, 3H) ppm, as shown in fig. 23; 13 C NMR(101MHz,DMSO-d 6 ) Delta 165.5,158.4,147.5,137.5,133.4,131.7,129.4,128.8,128.5,127.6,126.4,125.9,119.6,118.0,52.1ppm as shown in FIG. 24; HRMS (ESI) m/z calcd for C 17 H 12 NO 3 NaCl[M+Na] + :336.0402,Found:336.0403.
Optimized screening test for reaction conditions
Using example 1 as the test base, the test parameters were adjusted according to the test parameters shown in Table 1 below to investigate the different base conditions, solvent conditions, heating temperature conditions and reaction concentration conditions, and the yield-level comparison data was isolated, and the test results were as follows:
TABLE 1 comparison of isolated yields of 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 a) under different experimental parameters
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From the comparison result of the test, the solvent is dichloromethane, the alkali is imidazole, the temperature is 50 ℃, and the reaction concentration is 2.0mol/L, so that the product yield of the reaction is optimal under the reaction condition. From this experimental data, it was demonstrated that the inventive intent of the present invention could be achieved without selecting conventional base types, conventional solvents, or setting conventional temperature conditions in the synthetic process of the present invention.
It should be understood that while the present description has been described in terms of embodiments, such description is for clarity only, and that the description as a whole should be construed by those skilled in the art to form other embodiments that will be apparent to those skilled in the art, and should also fall within the scope of the invention.
Claims (10)
1. A preparation method for synthesizing polysubstituted 2-quinolinone compounds by base catalysis is characterized by comprising the following steps: the method comprises the following steps:
1) The 2-aminobenzophenone compound and alkali are mixed according to the mol ratio of 1:1.5, adding the mixture into a corresponding solvent methylene dichloride to enable the solute concentration of the 2-aminobenzophenone compound to reach 0.5mol/L;
2) Slowly dropwise adding monoethyl malonate acyl chloride into the solution in the step 1) under the condition of stirring and cooling at low temperature, wherein the dosage of the monoethyl malonate acyl chloride is 110% of the molar dosage of the 2-aminobenzophenone compound according to the acyl chloride equivalent which can be provided by the monoethyl malonate acyl chloride;
3) After the dripping of the monoethyl malonate acyl chloride is finished, heating the reaction system to 20-60 ℃, stirring and reacting for 2-24 hours, and adding water to quench and react;
4) Extracting with ethyl acetate, separating, drying, filtering, concentrating, and purifying to obtain product;
the reaction formula for preparing the polysubstituted 2-quinolinone compounds is as follows:
wherein the number of R1-R3 substituents may be 0-4.
2. The method of manufacturing according to claim 1, characterized in that: the R1-R3 substituent may be selected from F, br, cl, I, CN, CO 2 Et、CO 2 Me、Ac、ArCO、CF 3 、NO 2 C1-8 alkyl, C1-8 alkoxy, et, n-Pr, i-Pr, bu, bn, CH 2 One or several of = CH, OMe, OEt, OPr.
3. The preparation method according to claim 2, characterized in that: the R1-R3 substituents may be selected from F, br, cl, I, CN, CO 2 Et、CO 2 Me、Ac、ArCO、CF 3 、NO 2 One or more of them.
4. A method of preparation according to claims 1-3, characterized in that: the alkali in the step 1) can be selected from KOH, naOH and K 2 CO 3 ，Na 2 CO 3 ，Cs 2 CO 3 DBU, triethylamine, imidazole and N-methylimidazole.
5. The method of manufacturing according to claim 4, wherein: the base in step 1) may preferably be imidazole.
6. The method of preparation according to claims 1-5, characterized in that: the stirring speed of the step 2) is 200-500r/min.
7. The method of manufacturing according to claim 6, wherein: the stirring speed of the step 2) is 300r/min.
8. The preparation method according to claims 1-7, characterized in that: the cryogenically cooled conditions in step 2) may be selected from ice baths.
9. The preparation method according to claims 1-8, characterized in that: the heating temperature in said step 3) may preferably be 40-60 ℃.
10. The method of manufacturing according to claim 9, wherein: the heating temperature in step 3) may be selected to be 50℃or 60 ℃.
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