CN107652229B - Method for synthesizing quinoline derivative by oxidizing and cyclizing acetophenone and aniline compounds - Google Patents
Method for synthesizing quinoline derivative by oxidizing and cyclizing acetophenone and aniline compounds Download PDFInfo
- Publication number
- CN107652229B CN107652229B CN201711088856.9A CN201711088856A CN107652229B CN 107652229 B CN107652229 B CN 107652229B CN 201711088856 A CN201711088856 A CN 201711088856A CN 107652229 B CN107652229 B CN 107652229B
- Authority
- CN
- China
- Prior art keywords
- acetophenone
- quinoline derivative
- synthesizing
- aniline
- quinoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 title claims abstract description 83
- 238000000034 method Methods 0.000 title claims abstract description 26
- 150000001448 anilines Chemical class 0.000 title claims abstract description 20
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 18
- 230000001590 oxidative effect Effects 0.000 title claims abstract description 10
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title claims abstract 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 37
- 150000001879 copper Chemical class 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000001301 oxygen Substances 0.000 claims abstract description 11
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 11
- 238000005580 one pot reaction Methods 0.000 claims abstract description 5
- -1 aniline compound Chemical class 0.000 claims description 33
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 30
- 238000007243 oxidative cyclization reaction Methods 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 7
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 abstract description 18
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 37
- 150000003248 quinolines Chemical class 0.000 description 37
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 9
- 238000006555 catalytic reaction Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000007800 oxidant agent Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 3
- DOLQYFPDPKPQSS-UHFFFAOYSA-N 3,4-dimethylaniline Chemical compound CC1=CC=C(N)C=C1C DOLQYFPDPKPQSS-UHFFFAOYSA-N 0.000 description 2
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 2
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000011831 acidic ionic liquid Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 150000002505 iron Chemical class 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229910052761 rare earth metal Inorganic materials 0.000 description 2
- 150000002910 rare earth metals Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 1
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical compound NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 1
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229930192334 Auxin Natural products 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- 229910002567 K2S2O8 Inorganic materials 0.000 description 1
- 241000784732 Lycaena phlaeas Species 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 238000005614 Skraup synthesis reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005256 alkoxyacyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 239000002363 auxin Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000011280 coal tar Substances 0.000 description 1
- 150000001868 cobalt Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- WSZKUEZEYFNPID-UHFFFAOYSA-N hydrogen sulfate;quinolin-1-ium Chemical compound OS(O)(=O)=O.N1=CC=CC2=CC=CC=C21 WSZKUEZEYFNPID-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 150000002561 ketenes Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002815 nickel Chemical class 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 1
- LRTFPLFDLJYEKT-UHFFFAOYSA-N para-isopropylaniline Chemical compound CC(C)C1=CC=C(N)C=C1 LRTFPLFDLJYEKT-UHFFFAOYSA-N 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940127224 quinoline drug Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Quinoline Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a method for synthesizing a quinoline derivative by oxidizing and cyclizing acetophenone and aniline compounds, which comprises the following steps of carrying out one-pot reaction on the acetophenone, the aniline compounds and dimethyl sulfoxide in the presence of a copper salt catalyst in an oxygen-containing atmosphere to obtain the quinoline derivative; the method enriches the variety of quinoline derivatives, provides more intermediates for drug synthesis, has wide raw material source, simple steps, mild reaction conditions and high yield, and is beneficial to industrial production.
Description
Technical Field
The invention relates to a method for synthesizing a quinoline derivative, in particular to a method for generating the quinoline derivative by performing air oxidation one-step reaction on acetophenone, aniline compounds and dimethyl sulfoxide under the catalysis of copper salt, and belongs to the field of synthesis of drug intermediates.
Background
As an important N-heterocyclic fine chemical raw material, the quinoline compound has wide application in the aspects of medicines, pesticides, spices, foods, dyes, synthetic feed additives, auxin and the like. The quinoline compound is widely existed in nature, but the separation and purification from nature not only has various operation steps, complicated separation devices, large energy consumption, higher process cost and serious environmental pollution, such as: quinoline was first extracted from wash oil of coal tar or naphthalene oil. Washing the naphthalene oil fraction and the wash oil fraction with dilute sulfuric acid to obtain quinoline sulfate base solution, steaming to remove impurities such as neutral oil, and decomposing with alkali or ammonia. The separated crude quinoline and the homologue thereof are rectified by a high-yield distillation tower after being dehydrated, and the distillation section with the boiling range of 237.5-239.5 ℃ is cut to obtain the crude quinoline containing 83% of quinoline and 15% of isoquinoline.
At present, the synthesis method of quinoline compounds becomes a hotspot of research of researchers, the most representative method for industrially synthesizing quinoline in early stage is a Skraup synthesis method, aromatic amine, concentrated sulfuric acid and glycerol are heated together with a mild oxidant, the glycerol is dehydrated into acrolein under the action of the concentrated sulfuric acid at high temperature, then condensed with aniline into dihydroquinoline, and finally oxidized to obtain quinoline, the reaction has the defects that the reaction is carried out in a concentrated sulfuric acid environment and under the high temperature condition, the reaction condition is harsh, and the yield is not high.
For example, Chinese patent Nos. CN 102134219A and CN 102070521A both disclose a method for preparing quinoline derivatives, specifically disclose that substituted aniline reacts with α unsaturated aldehyde, ketone or ester compounds in the presence of rare earth catalysts to obtain the target product (reaction formula 1 below), or aniline derivatives react with α, β -unsaturated aldehyde and ketone in acidic ionic liquid under the catalysis of iodine or iodide to obtain quinoline derivatives (reaction formula 2 below), which has the disadvantages of expensive ketene compounds and expensive rare earth metals in acidic ionic liquid, and high production cost, for example, Chinese patent No. CN103554020A discloses a method for synthesizing quinoline derivatives, specifically, imine and alkyne are used as substrates in organic solvents to react under iron catalysis to obtain quinoline compounds (reaction formula 3 below), which has the disadvantages of poor stability, and requires a sealed reaction of imine substrates under the conditions, and a method for preparing quinoline derivatives under the conditions of corrosion of triflic acid, which is not favorable for preparing quinoline derivatives under the conditions of trifluoro methanesulfonic acid, and requires the industrial corrosion of a novel method for preparing quinoline derivatives under the conditions of trifluoro methanesulfonic acid, and the disadvantages of the prior art (CN 106380463).
Reaction formula 1:
reaction formula 2:
reaction formula 3:
reaction formula 4:
disclosure of Invention
Aiming at the defects of the existing method for synthesizing the quinoline derivative, the invention aims to provide a method for generating the quinoline derivative by oxidizing acetophenone, aniline compounds and dimethyl sulfoxide in one step through oxygen under the catalysis of copper salt.
In order to realize the technical purpose, the invention provides a method for synthesizing a quinoline derivative by oxidizing and cyclizing acetophenone and aniline compounds, wherein the acetophenone, the aniline compounds shown in the formula 1 and dimethyl sulfoxide are subjected to one-pot reaction in the presence of a copper salt catalyst in an oxygen-containing atmosphere to obtain a quinoline derivative shown in the formula 2;
wherein,
R1and R2Independently selected from hydrogen, alkyl, alkoxy, alkylthio, alkoxyacyl, halogenCyano, aryl or arylheterocyclyl.
In a preferred embodiment, the aniline compound is aniline, 4-isopropylaniline, 3-methylaniline, 3, 4-dimethylaniline, 2-phenylaniline, 4-chloroaniline, 3-chloroaniline or 3-bromoaniline.
In a preferable scheme, the concentration of the acetophenone in the dimethyl sulfoxide is 0.05-0.5 mol/L; more preferably 0.1 to 0.3 mol/L; most preferably 0.15 to 0.25 mol/L.
In a preferable scheme, the molar weight of the copper salt catalyst is 5-30% of that of the arylethanone compound; more preferably 8 to 20%.
In a more preferable scheme, the copper salt comprises at least one of copper sulfate, copper halide and copper acetate; preferred copper halides include copper chloride and/or copper bromide; most preferred is copper chloride.
In a preferable scheme, the molar weight of the aniline compound is 2-5 times of that of acetophenone; more preferably 2.5 to 3.5 times.
In a preferred embodiment, the reaction conditions are as follows: the reaction temperature is 90-140 ℃, and the reaction time is 18-30 h. More preferably, the reaction conditions are as follows: the reaction temperature is 100-130 ℃, and the reaction time is 20-28 h; the most preferable reaction time is 22-26 h at 115-125 ℃.
Preferably, the oxygen-containing atmosphere is air, oxygen, or other oxygen-containing atmosphere.
In the technical scheme of the invention, the copper salt is used as a catalyst, and the oxygen-containing gas is used as an oxidant. The pyridine ring contained in the quinoline derivative is formed by cyclizing one molecule of aniline compound, one molecule of acetophenone and one molecule of dimethyl sulfoxide, wherein a series of complex chemical reactions such as oxidative dehydrogenation, condensation cyclization and the like are carried out on one molecule of acetyl of the acetophenone compound, one molecule of amino of the aniline compound and one molecule of methyl of the dimethyl sulfoxide under the catalysis of a copper salt catalyst, so that the quinoline derivative is obtained.
Compared with the prior art, the technical scheme of the invention has the beneficial technical effects that:
1) according to the technical scheme, the acetophenone, the aniline compound and the dimethyl sulfoxide are subjected to oxidative cyclization to obtain the quinoline compound for the first time, and a brand new thought is provided for synthesizing the pharmaceutical intermediate of the quinoline compound.
2) The technical scheme of the invention adopts the conventional acetophenone, aniline compounds and dimethyl sulfoxide as raw materials, and the raw materials have wide sources and have the advantage of low cost compared with keto-alkene compounds.
3) The technical scheme of the invention has simple steps and mild reaction conditions, can realize the synthesis of the quinoline compound by a one-pot method, has high reaction yield and is beneficial to large-scale production.
4) The quinoline compound synthesized by the technical scheme of the invention contains aryl and other groups which are easy to modify again, and has obvious advantages when being used as a quinoline drug synthesis intermediate.
5) The catalyst of the invention is common copper salt, and has wide source and low cost.
Drawings
FIG. 1 is a 1H NMR spectrum of the quinoline derivative in example 1;
FIG. 2 is a 13C NMR spectrum of the quinoline derivative in example 1;
FIG. 3 is a 1H NMR spectrum of the quinoline derivative in example 3;
FIG. 4 is a 13C NMR spectrum of the quinoline derivative in example 3;
FIG. 5 is a 1H NMR spectrum of the quinoline derivative in example 4;
FIG. 6 is a 13C NMR spectrum of the quinoline derivative in example 4;
FIG. 7 is a 1H NMR spectrum of the quinoline derivative in example 6;
FIG. 8 is a 13C NMR spectrum of the quinoline derivative in example 6.
Detailed Description
The following examples are intended to further illustrate the present disclosure, but not to limit the scope of the claims.
The substrate starting materials, solvents and the like mentioned in the following examples were all commercial products (analytical reagents) on the market and were not further purified.
The product is separated by chromatography, column silica gel (300-400 mesh).
1H NMR (400MHz), 13C NMR (100MHz), in CDCl3As solvent, TMS was used as internal standard.
Multiplicity is defined as follows: s (singlet); d (doublet); t (triplet); q (quartet) and m (multiplet). Coupling constant J (Hertz).
Condition optimization experiment: the optimal reaction conditions were found by the following control experimental groups: the reaction is exemplified by using acetophenone, aniline and dimethyl sulfoxide as reaction raw materials, and using excessive dimethyl sulfoxide as a reaction solvent, and the specific reaction is as follows:
the catalyst, acetophenone and aniline were dissolved in DMSO in a 25mL Schlenk tube and stirred in the presence of an oxidant at a temperature for 24 hours. After the reaction is finished, cooling the obtained solution to room temperature; the solution was diluted with ethyl acetate (10mL), washed with water (5mL), extracted with ethyl acetate (3X 5mL), and extracted with anhydrous Na2SO4Dried and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel to give the desired product.
Reaction conditions of a control experiment group 1-12 are acetophenone (0.5mmol), DMSO (2.5mL), aniline (1.5mmol), catalyst (10 mol%), oxygen (1 atm)/oxidant (1.0mmol), the reaction temperature is 120 ℃, and the reaction time is 24 h.
The reaction temperature of the control experiment group 13 was 100 deg.C, and other conditions were the same as those of the experiment group 1.
The reaction temperature of the control experiment group 14 was 130 deg.C, and other conditions were the same as those of the experiment group 1.
CuCl of control experiment group 152·2H2O (5 mol%), other conditions were the same as in Experimental group 1.
CuCl for control experiment group 162·2H2O (20 mol%), other conditions were the same as in Experimental group 1.
As can be seen from comparison experiment groups 1-8 in the table, the reaction can be smoothly carried out under the catalysis of copper salt and iron salt, and the catalytic reaction effect is lower than that of corresponding copper salt, iron salt and the like although cobalt salt and nickel salt have certain catalytic activity. Experiments show that the catalytic effect of copper salt is the best in all the catalysts, and the yield of the quinoline derivative is higher correspondingly.
As can be seen from comparison of experimental groups 1 and 9-12 in the table, except that oxygen can enable the reaction to be carried out smoothly, higher yield is obtained, other conventional oxidants such as hydrogen peroxide and K2S2O8And peroxide TBHP and the like are difficult to synthesize quinoline derivatives, and only low yield or target products cannot be obtained.
As can be seen from the comparison of experimental groups 1 and 13-14 in the table, the yield is correspondingly reduced when the reaction temperature is too high or too low, and the optimal reaction effect can be achieved at about 120 ℃.
In summary, the optimal reaction conditions can be obtained by comparing the experimental groups 1-16: acetophenone (0.5mmol), aniline (1.5mmol), DMSO (2.5mL), CuCl2·2H2O (10 mol%), oxygen (1atm), reaction temperature 120 ℃ and reaction time 24 h.
The following examples 1 to 9 and comparative examples 1 and 2 were reacted under the optimized reaction conditions as described above:
example 1
AnilineA compound of the following class:
acetophenone:
quinoline derivatives:
yield: 78 percent.
1H NMR(400MHz,CDCl3)δ8.23(d,J＝8.6Hz,1H),8.17(d,J＝8.5Hz,1H),8.13(d,J＝8.1Hz,2H),7.85(d,J＝3.6Hz,1H),7.83(d,J＝3.0Hz,1H),7.74(t,J＝7.7Hz,1H),7.57-7.48(m,3H).13C NMR(100MHz,CDCl3)δ156.0,148.2,138.0,137.1,135.6,129.9,129.7,129.0,128.9,127.5,127.2,126.6,118.6.
Example 2
Aniline compound:
acetophenone:
quinoline derivatives:
yield: 66 percent.
1H NMR(400MHz,CDCl3)δ8.19-8.04(m,4H),7.81(d,J＝8.6Hz,1H),7.56-7.49(m,4H),7.44(t,J＝7.2Hz,1H),2.53(s,3H).13C NMR(100MHz,CDCl3)δ156.5,146.8,139.8,136.2,136.2,132.0,129.4,129.2,128.8,127.5,127.2,126.4,119.0,21.6.
Example 3
Aniline compound:
acetophenone:
quinoline derivatives:
yield: 68 percent.
1H NMR(400MHz,CDCl3)δ8.20-8.07(m,4H),7.83(d,J＝8.5Hz,1H),7.65-7.58(m,2H),7.51(t,J＝7.5Hz,2H),7.44(t,J＝7.1Hz,1H),1.36(d,J＝6.9Hz,6H).13C NMR(100MHz,CDCl3)δ156.7,147.0,139.9,136.5,129.6,129.5,129.1,128.8,127.5,127.2,123.6,122.8,119.0,34.1,23.9.
Example 4
Aniline compound:
acetophenone:
quinoline derivatives:
yield: 51 percent.
1H NMR(400MHz,CDCl3)δ8.27(d,J＝7.6Hz,2H),8.20(d,J＝8.5Hz,1H),7.91(d,J＝8.5Hz,1H),7.67(d,J＝8.1Hz,1H),7.60-7.51(m,3H),7.49–7.40(m,2H),2.92(s,3H).13CNMR(100MHz,CDCl3)δ155.6,147.0,139.7,137.6,137.2,129.9,129.3,128.8,127.6,127.1,126.1,125.4,118.3,17.9.
Example 5
Aniline compound:
acetophenone:
quinoline derivatives:
yield: and 63 percent.
1H NMR(400MHz,CDCl3)δ8.31(d,J＝8.7Hz,1H),8.15(d,J＝7.6Hz,2H),7.88-7.76(m,2H),7.51(t,J＝7.4Hz,2H),7.45(t,J＝7.1Hz,1H),7.19(s,1H),2.65(s,3H),2.52(s,3H).13C NMR(100MHz,CDCl3)δ156.8,148.8,139.7,139.6,134.0,133.1,129.2,128.9,128.8,127.5,126.9,124.6,117.8,21.9,18.5.
Example 6
Aniline compound:
acetophenone:
quinoline derivatives:
yield: and 47 percent.
1H NMR(400MHz,CDCl3)δ8.25(d,J＝8.6Hz,1H),8.16(d,J＝7.8Hz,2H),7.95(d,J＝8.6Hz,1H),7.86(d,J＝7.8Hz,2H),7.83-7.76(m,2H),7.60-7.40(m,7H).13C NMR(100MHz,CDCl3)δ156.0,145.6,140.8,139.5,139.4,137.1,131.2,130.4,129.3,128.8,127.7,127.4,127.2,126.2,118.1.
Example 7
Aniline compound:
acetophenone:
quinoline derivatives:
yield: 71 percent.
1H NMR(400MHz,CDCl3)δ8.14(d,J＝7.6Hz,2H),8.10(d,J＝8.8Hz,2H),7.87(d,J＝8.7Hz,1H),7.78(s,1H),7.64(d,J＝8.9Hz,1H),7.49(dt,J＝14.0,7.6Hz,3H).13C NMR(100MHz,CDCl3)δ157.6,146.6,139.2,135.9,132.0,131.3,130.6,129.6,128.9,127.7,127.6,126.2,119.8.
Example 8
Aniline compound:
acetophenone:
quinoline derivatives:
yield: 75 percent.
1H NMR(400MHz,CDCl3)δ8.20-8.11(m,4H),7.85(d,J＝8.6Hz,1H),7.73(d,J＝8.6Hz,1H),7.54-7.45(m,4H).13C NMR(100MHz,CDCl3)δ158.2,148.6,139.1,136.6,135.5,131.0,129.7,128.9,128.7,127.6,127.3,125.5,119.1.
Example 9
Aniline compound:
acetophenone:
quinoline derivativesBiology:
yield: and 69 percent.
1H NMR(400MHz,CDCl3)δ8.37(s,1H),8.16(t,J＝8.5Hz,3H),7.88(d,J＝8.5Hz,1H),7.68(d,J＝8.6Hz,1H),7.60(d,J＝8.6Hz,1H),7.55-7.48(m,3H).13C NMR(100MHz,CDCl3)δ158.2,148.9,139.1,136.7,132.0,129.8,129.7,128.9,128.7,127.6,125.8,123.8,119.3.
Comparative example 1
Aniline compound:
acetophenone:
quinoline derivatives:
yield: none.
Comparative example 2
Amine compounds:
acetophenone:
quinoline derivatives:
yield: none.
Claims (9)
1. A method for synthesizing a quinoline derivative by oxidizing and cyclizing acetophenone and aniline compounds is characterized by comprising the following steps: in an oxygen-containing atmosphere, performing one-pot reaction on acetophenone, an aniline compound and dimethyl sulfoxide in the presence of a copper salt catalyst to obtain a quinoline derivative;
the aniline compound is
The quinoline derivative is
2. The method for synthesizing the quinoline derivative by the oxidative cyclization of the acetophenone and aniline compounds according to claim 1, characterized in that: the concentration of the acetophenone in the dimethyl sulfoxide is 0.05-0.5 mol/L.
3. The method for synthesizing the quinoline derivative by the oxidative cyclization of the acetophenone and aniline compounds according to claim 2, characterized in that: the concentration of the acetophenone in the dimethyl sulfoxide is 0.1-0.3 mol/L.
4. The method for synthesizing the quinoline derivative by the oxidative cyclization of the acetophenone and aniline compounds according to claim 1, characterized in that: the molar weight of the copper salt catalyst is 5-30% of that of the aryl ethanone compound.
5. The method for synthesizing the quinoline derivative by the oxidative cyclization of the acetophenone and aniline compounds according to claim 4, characterized in that: the copper salt comprises at least one of copper sulfate, copper halide and copper acetate.
6. The method for synthesizing the quinoline derivative by the oxidative cyclization of the acetophenone and aniline compounds according to claim 5, characterized in that: the copper halide comprises copper chloride and/or copper bromide.
7. The method for synthesizing the quinoline derivative by the oxidative cyclization of the acetophenone and aniline compounds according to claim 1, characterized in that: the molar weight of the aniline compound is 2-5 times of that of the acetophenone.
8. The method for synthesizing the quinoline derivative by the oxidative cyclization of the acetophenone and aniline compounds according to claim 1,3, 5 or 6, characterized in that: the reaction conditions are as follows: the reaction temperature is 90-140 ℃, and the reaction time is 18-30 h.
9. The method for synthesizing the quinoline derivative by the oxidative cyclization of the acetophenone and aniline compounds according to claim 8, characterized in that: the reaction conditions are as follows: the reaction temperature is 115-125 ℃, and the reaction time is 22-26 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711088856.9A CN107652229B (en) | 2017-11-08 | 2017-11-08 | Method for synthesizing quinoline derivative by oxidizing and cyclizing acetophenone and aniline compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711088856.9A CN107652229B (en) | 2017-11-08 | 2017-11-08 | Method for synthesizing quinoline derivative by oxidizing and cyclizing acetophenone and aniline compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107652229A CN107652229A (en) | 2018-02-02 |
| CN107652229B true CN107652229B (en) | 2020-03-31 |
Family
ID=61120802
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711088856.9A Active CN107652229B (en) | 2017-11-08 | 2017-11-08 | Method for synthesizing quinoline derivative by oxidizing and cyclizing acetophenone and aniline compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107652229B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175328B (en) * | 2015-10-26 | 2017-12-19 | 南阳师范学院 | It is a kind of using aromatic amine, aromatic aldehyde, ketone synthesis of quinoline derivatives method |
| CN106380463B (en) * | 2016-08-30 | 2020-12-15 | 南阳师范学院 | Method for synthesizing quinoline derivative |
-
2017
- 2017-11-08 CN CN201711088856.9A patent/CN107652229B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN107652229A (en) | 2018-02-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105801575A (en) | Synthetic method of imidazo[1,2-a]pyridine | |
| CN112142694A (en) | Polysubstituted tetrahydrofuran and tetrahydropyrane diene compound and preparation method thereof | |
| CN106380446B (en) | Synthesis method of quinoline-2 formate derivative | |
| CN112442008B (en) | Method for preparing 1, 4-dithiine and thiophene compounds by regulating elemental sulfur and active internal alkyne at temperature and conversion reaction of compound | |
| CN107892668B (en) | A kind of synthetic method of quinoline | |
| CN107793354B (en) | A kind of method of intermolecular cyclization synthesis of quinoline derivatives | |
| CN107814751B (en) | Method for preparing nitrile by catalytic oxidation of amine | |
| CN107652229B (en) | Method for synthesizing quinoline derivative by oxidizing and cyclizing acetophenone and aniline compounds | |
| CN109574818B (en) | Polysubstituted indanone derivative and preparation method thereof | |
| CN107628996B (en) | Synthesis method of polysubstituted quinoline | |
| CN111777564A (en) | Method for synthesizing quinazolinone compound through photocatalytic alcohol oxidation in aqueous phase | |
| CN108912076B (en) | Synthesis method of benzoxepin compound | |
| CN113698358B (en) | Method for synthesizing quinazolinone compound by visible light induction | |
| CN106366035B (en) | Synthesis method of quinoline derivative | |
| CN111848464B (en) | Method for preparing 2- (methylsulfinyl) benzoic acid | |
| CN113754544A (en) | Preparation method of polysubstituted (E) -trifluoromethyl olefin | |
| CN108997117B (en) | Novel method for preparing 4-acetoxyl-2-methyl-2-butenal | |
| CN113511986A (en) | Preparation method of aryl acetonitrile derivative | |
| CN111170837A (en) | Synthetic method of methyl ketone compound | |
| CN115304477B (en) | Preparation method of aromatic carboxylic ester | |
| CN110272344B (en) | Camphorylimidazole type ionic liquid and preparation method and application thereof | |
| CN113264820B (en) | Method for preparing ketone compound from olefin | |
| CN111205255B (en) | CMe-containing material 2 CF 3 Synthesis method of flavonoid compound of group | |
| CN110156716B (en) | Synthetic method of benzothiazole ester derivative | |
| CN115974825B (en) | Method for preparing 3-substituted chromanone by metal-free catalytic hydrogenation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240827 Address after: No. 87, Suzhong Avenue, Shangku Comprehensive Industrial Park, Korla City, Bazhou, Xinjiang Uygur Autonomous Region, 841000 Patentee after: Xinjiang Puhesu New Environmental Protection Materials Co.,Ltd. Country or region after: China Address before: 41007 No.1 Chuangye Road, shijihu Road, Yuanjiang City, Yiyang City, Hunan Province Patentee before: YUANJIANG HUALONG CATALYST TECHNOLOGY Co.,Ltd. Country or region before: China |