CN114890944A - Preparation method and application of quinoline compound - Google Patents
Preparation method and application of quinoline compound Download PDFInfo
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- CN114890944A CN114890944A CN202210664590.2A CN202210664590A CN114890944A CN 114890944 A CN114890944 A CN 114890944A CN 202210664590 A CN202210664590 A CN 202210664590A CN 114890944 A CN114890944 A CN 114890944A
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- quinoline
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- -1 quinoline compound Chemical class 0.000 title claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- 239000000654 additive Substances 0.000 claims abstract description 12
- 230000000996 additive effect Effects 0.000 claims abstract description 12
- 229940126062 Compound A Drugs 0.000 claims abstract description 10
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- 229910052751 metal Inorganic materials 0.000 claims abstract description 9
- 239000002184 metal Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 18
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 13
- 229940112669 cuprous oxide Drugs 0.000 claims description 13
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 13
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- 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 7
- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 6
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 5
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 5
- 229940045803 cuprous chloride Drugs 0.000 claims description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 229960003280 cupric chloride Drugs 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- PYQRMDHLMKGZJP-UHFFFAOYSA-M potassium;2-chloro-2,2-difluoroacetate Chemical compound [K+].[O-]C(=O)C(F)(F)Cl PYQRMDHLMKGZJP-UHFFFAOYSA-M 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 150000003248 quinolines Chemical class 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 description 1
- HKHXJNHHRULHOH-UHFFFAOYSA-N 2-(1-cyclopentylethenyl)aniline Chemical compound NC1=CC=CC=C1C(=C)C1CCCC1 HKHXJNHHRULHOH-UHFFFAOYSA-N 0.000 description 1
- BYTLHHFRLLQLDH-UHFFFAOYSA-N 2-(1-phenylethenyl)aniline Chemical compound NC1=CC=CC=C1C(=C)C1=CC=CC=C1 BYTLHHFRLLQLDH-UHFFFAOYSA-N 0.000 description 1
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 1
- ZAUZAFBZKHUIGP-UHFFFAOYSA-N 2-[1-(4-chlorophenyl)ethenyl]aniline Chemical compound ClC1=CC=C(C=C1)C(=C)C1=C(N)C=CC=C1 ZAUZAFBZKHUIGP-UHFFFAOYSA-N 0.000 description 1
- RSSAOYGNGJHIPY-UHFFFAOYSA-N 2-anilino-1,3-dioxane-4,6-dione Chemical compound O1C(=O)CC(=O)OC1NC1=CC=CC=C1 RSSAOYGNGJHIPY-UHFFFAOYSA-N 0.000 description 1
- OVCDSSHSILBFBN-UHFFFAOYSA-N Amodiaquine Chemical compound C1=C(O)C(CN(CC)CC)=CC(NC=2C3=CC=C(Cl)C=C3N=CC=2)=C1 OVCDSSHSILBFBN-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 238000005614 Skraup synthesis reaction Methods 0.000 description 1
- 229960001444 amodiaquine Drugs 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 239000011280 coal tar Substances 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229960004643 cupric oxide Drugs 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960001962 mefloquine Drugs 0.000 description 1
- JUBPYGCSSZMGRR-UHFFFAOYSA-N n-phenyl-2-prop-1-en-2-ylaniline Chemical compound CC(=C)C1=CC=CC=C1NC1=CC=CC=C1 JUBPYGCSSZMGRR-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- UCRHFBCYFMIWHC-UHFFFAOYSA-N piperaquine Chemical compound ClC1=CC=C2C(N3CCN(CC3)CCCN3CCN(CC3)C=3C4=CC=C(C=C4N=CC=3)Cl)=CC=NC2=C1 UCRHFBCYFMIWHC-UHFFFAOYSA-N 0.000 description 1
- 229950006717 piperaquine Drugs 0.000 description 1
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229960005179 primaquine Drugs 0.000 description 1
- INDBQLZJXZLFIT-UHFFFAOYSA-N primaquine Chemical compound N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 INDBQLZJXZLFIT-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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
-
- 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
- C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Quinoline Compounds (AREA)
Abstract
The invention provides a preparation method and application of a quinoline compound, wherein the preparation method comprises the following steps: and mixing the compound A with a difluorocarbene reagent, a metal additive, a base and a solvent for reaction to obtain the quinoline compound. The preparation method provided by the invention has the advantages of low cost, high yield, simple operation and convenient post-treatment.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method and application of a quinoline compound, in particular to a preparation method and application of a quinoline compound with high yield.
Background
Quinoline and its derivatives are important structural motifs in a series of compounds and have wide applications in organic synthesis, biology and materials. Quinoline is an aromatic compound that can be extracted from wash oil of coal tar and naphthalene oil. Quinolines are a special structural model and can be found in many drugs and natural products with biological activity, such as quinine, abachi, amodiaquine, primaquine, mefloquine, pitavastatin, piperaquine, and the like.
The traditional method for preparing quinoline comprises Skraup quinoline reaction, in 1981, Skraup generates quinoline by refluxing aniline and glycerol in strong acid and oxidant, the reaction can strongly release heat, the requirements of overhigh temperature and strong acid environment on the oxidant and medium are high, and the subsequent separation is complicated; gould et al in 1939 reported the use of aniline and diethyl malonate to form quinoline, a reaction that can be subdivided into the condensation of aniline and diethyl malonate to form anilinomethylene malonate, followed by cyclization to give 4-hydroxy-alkanoylquinoline, followed by hydrolysis to give the acid and finally decarboxylation to give 4-hydroxyquinoline. This reaction is a classical thermal cyclization reaction, and the reaction conditions require high temperatures and long heating times, and therefore, has a disadvantage of complicated post-treatment. While these methods have made some progress, they have some important disadvantages, most of which produce only one type of quinoline by either de novo construction or post functionalization of the existing quinoline backbone. There remains a great need to find a general method that allows the modular synthesis of a wide variety of functionalized quinolines from readily available starting materials.
CN102140078B discloses an improved Skraup method for preparing quinoline or quinoline derivatives, which specifically comprises: uniformly stirring glycerol, aminobenzene and nitrobenzene, adding concentrated sulfuric acid or/and fuming sulfuric acid, adding an organic solvent to obtain an organic phase, heating the organic phase to 70-150 ℃, adding an aqueous phase solvent to wash after the aminobenzene reaction is finished, collecting the aqueous phase, adjusting the pH to 6.5-10, and removing the aqueous phase solvent after solid is separated out, wherein the solid is quinoline or a quinoline derivative; compared with the existing preparation method, the addition of the organic phase promotes the forward reaction, effectively controls the reaction severity, reduces the usage amount of sulfuric acid by 30-60%, reduces the usage amount of raw materials and the discharge amount of waste water, reduces the reaction severity, reduces side reactions and makes the reaction appear milder.
The prior preparation method of quinoline also has the defects of complex post-treatment and severe reaction conditions. Therefore, how to provide a quinoline synthesis method with simple post-treatment, low cost and simple operation becomes a problem to be solved urgently.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a preparation method and application of a quinoline compound, and particularly provides a preparation method and application of a quinoline compound with high yield. The preparation method provided by the invention has the advantages of low cost, high yield, simple operation and convenient post-treatment.
In order to achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the present invention provides a method for preparing a quinoline compound, comprising the steps of:
mixing the compound A with a difluorocarbene reagent, a metal additive, alkali and a solvent for reaction to obtain the quinoline compound; the reaction route is as follows
Wherein R is 1 Is selected from any one of C1-C6 substituted or unsubstituted alkyl, C3-C7 substituted or unsubstituted cycloalkyl, C6-C12 substituted or unsubstituted aryl and C1-C6 substituted or unsubstituted heteroaryl.
The substituted substituent is selected from any one of halogen, C1-C6 alkoxy or C1-C6 alkyl.
According to the preparation method, the difluorocarbene reagent and the compound A are reacted under the conditions of the metal additive and the alkali, the required quinoline compound can be prepared through one-step reaction, the reaction steps are few, the reaction cost is low, the yield is high, the product can be obtained through post-treatment only by column chromatography, the treatment is convenient, and the operation is simple.
Preferably, the difluorocarbene reagent comprises sodium difluorochloroacetate and/or potassium difluorochloroacetate.
Preferably, the molar ratio of the compound a to the difluorocarbene reagent is 1 (1-2), such as 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8 or 1:2, but not limited to the above-listed values, and other values not listed within the above-mentioned range of values are also applicable.
Preferably, the base includes any one or a combination of at least two of triethylamine, sodium tert-butoxide, sodium hydrogen carbonate, potassium tert-butoxide, DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene) or DBN (1, 5-diazabicyclo [4.3.0] non-5-ene), for example, a combination of triethylamine and sodium tert-butoxide, a combination of sodium tert-butoxide and potassium carbonate or a combination of potassium tert-butoxide and DBU, and the like, but is not limited to the combinations enumerated above, and combinations not enumerated within the above-mentioned range are equally applicable, preferably triethylamine.
Preferably, the molar ratio of the compound A to the base is 1 (1-2), for example, 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8 or 1:2, but not limited to the above-listed values, and other values not listed within the above-mentioned range of values are also applicable.
Preferably, the metal additive is a copper additive, and the copper additive includes any one or a combination of at least two of cuprous chloride, cuprous iodide, cuprous oxide, and cupric chloride, for example, a combination of cuprous chloride and cuprous iodide, a combination of cuprous chloride and cuprous oxide, or a combination of cupric chloride and cuprous chloride, and the like, but is not limited to the above-listed combinations, and other combinations not listed within the above-mentioned combinations are also applicable, and cuprous oxide is preferable.
Preferably, the molar ratio of the compound A to the metal additive is 1 (0.2-1), for example 1:0.2, 1:0.4, 1:0.6, 1:0.8 or 1:1, but not limited to the above-mentioned values and other values not listed within the above-mentioned range of values are also applicable.
Preferably, the solvent comprises any one or a combination of at least two of DMF (N, N-dimethylformamide), DMA (N, N-dimethylaniline) or NMP (N-methylpyrrolidone), such as but not limited to DMF and DMA, DMF and NMP, or DMA and NMP, and the like, and combinations not listed within the above combinations are equally applicable, preferably DMF.
Preferably, the reaction temperature is 100-150 ℃ and the reaction time is 12-18h, wherein the temperature can be 100 ℃, 110 ℃, 120 ℃, 130 ℃, 140 ℃ or 150 ℃, and the reaction time can be 12h, 13h, 14h, 15h, 16h, 17h or 18h, but not limited to the above-mentioned values, and other values not listed in the above-mentioned value range are also applicable.
On the other hand, the invention also provides the application of the preparation method in the preparation of quinoline and derivatives thereof.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a preparation method of a quinoline compound, which is characterized in that a difluorocarbene reagent is adopted to react with a compound A under the conditions of a metal additive and alkali, so that the required quinoline compound can be prepared by one-step reaction, the reaction steps are few, the reaction cost is low, the yield is high, the product can be obtained by post-treatment only through column chromatography, the treatment is convenient, and the operation is simple; and by optimizing the raw materials, the yield of the reaction can be further improved.
Detailed Description
To further illustrate the technical means and effects of the present invention, the following further describes the technical solution of the present invention with reference to the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.
Example 1
The embodiment provides a preparation method of a quinoline compound 3a, which comprises the following specific steps:
o-isopropenylphenylaniline 1a (0.2mmol, 26mg), sodium difluorochloroacetate 2(0.2mmol, 30mg), and cuprous oxide (0.2mmol, 28mg) were placed in a 25mL reaction tube, evacuated, and charged with nitrogen (three times). Triethylamine (0.4mmol, 40mg) was then weighed and dissolved in 2mL of DMF solution, and the mixture was injected into the reaction tube via syringe. Stirred in an oil bath at 140 ℃ for 18 h. After completion of the reaction, it was cooled to 20 ℃ and 15mL of methylene chloride was added to the reaction system to dilute and filter it, and a small amount of silica gel was added for spin-dry column chromatography to obtain the product 3a as a yellow oil (yield 80%).
The reaction process of the above steps is shown as the following formula:
the nuclear magnetic data for product 3a is as follows:
1 H NMR(400MHz,CDCl 3 )δ8.78(d,J＝4.4Hz,1H),8.11(d,J＝8.4Hz,1H),8.00(dd,J＝8.4,0.9Hz,1H),7.71(ddd,J＝8.4,6.9,1.4Hz,1H),7.57(ddd,J＝8.2,6.9,1.2Hz,1H),7.23(dd,J＝4.3,0.6Hz,1H),2.71(d,J＝0.7Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ150.09(s),147.90(s),144.36(s),129.95(s),129.12(s),128.27(s),126.28(s),123.79(s),121.83(s),18.63(s)。
example 2
The embodiment provides a preparation method of a quinoline compound 3b, which comprises the following specific steps:
2- (1-Phenylvinyl) aniline 1b (0.2mmol, 40mg), sodium difluorochloroacetate 2(0.2mmol, 30mg), and cuprous oxide (0.2mmol, 28mg) were placed in a 25mL reaction tube, evacuated, and purged with nitrogen (three times). Triethylamine (0.2mmol, 20mg) was then weighed and dissolved in 2mL of DMF solution, and the mixture was injected into the reaction tube via syringe. Stirred in an oil bath at 140 ℃ for 18 h. After completion of the reaction, it was cooled to 20 ℃ and 15mL of methylene chloride was added to the reaction system to dilute and filter it, and a small amount of silica gel was added for spin-dry column chromatography to obtain the product 3b as a yellow oil (yield 61%).
The reaction process of the above steps is shown as the following formula:
the nuclear magnetic data for product 3b is as follows:
1 H NMR(400MHz,CDCl 3 )δ8.95(d,J＝4.4Hz,1H),8.19(d,J＝8.4Hz,1H),7.92(d,J＝8.4Hz,1H),7.73(ddd,J＝8.3,6.9,1.3Hz,1H),7.56–7.46(m,6H),7.34(d,J＝4.4Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ149.89(s),148.60(s),148.48(s),137.94(s),129.78(s),129.49(s),129.29(s),128.53(s),128.39(s),126.72(s),126.59(s),125.83(s),121.28(s)。
example 3
The embodiment provides a preparation method of a quinoline compound 3c, which comprises the following specific steps:
2- (1-Cyclopentylvinyl) aniline 1c (0.2mmol, 38mg), sodium difluorochloroacetate 2(0.2mmol, 30mg), and cuprous oxide (0.2mmol, 28mg) were placed in a 25mL reaction tube, evacuated, and purged with nitrogen (three times). Triethylamine (0.2mmol, 20mg) was then weighed and dissolved in 2mL of DMF solution, and the mixture was injected into the reaction tube via syringe. Stirred in an oil bath at 140 ℃ for 18 h. After completion of the reaction, it was cooled to 20 ℃ and 15mL of methylene chloride was added to the reaction system to dilute and filter it, and a small amount of silica gel was added for spin-dry column chromatography to obtain the product 3c as a yellow oil (yield 56%).
The reaction process of the above steps is shown as the following formula:
the nuclear magnetic data for product 3c is as follows:
1 H NMR(400MHz,CDCl 3 )δ8.83(d,J＝4.5Hz,1H),8.12(t,J＝7.7Hz,2H),7.69(ddd,J＝8.3,6.9,1.3Hz,1H),7.55(ddd,J＝8.3,6.9,1.2Hz,1H),7.30(d,J＝4.6Hz,1H),3.84–3.72(m,1H),2.22(m,2H),1.94–1.70(m,6H). 13 C NMR(101MHz,CDCl 3 )δ152.31(s),150.34(s),148.32(s),130.19(s),128.78(s),127.79(s),126.03(s),123.72(s),117.12(s),40.51(s),33.32(s),25.43(s)。
example 4
The embodiment provides a preparation method of a quinoline compound 3d, which comprises the following specific steps:
2- (3-phenylprop-1-en-2-yl) aniline 1d (0.2mmol, 42mg), sodium difluorochloroacetate 2(0.2mmol, 30mg), cuprous oxide (0.2mmol, 28mg) were placed in a 25mL reaction tube, evacuated, and charged with nitrogen (three times). Triethylamine (0.2mmol, 20mg) was then weighed and dissolved in 2mL of DMF solution, and the mixture was injected into the reaction tube via syringe. Stirred in an oil bath at 140 ℃ for 18 h. After completion of the reaction, it was cooled to 20 ℃ and 15mL of methylene chloride was added to the reaction system to dilute and filter it, and a small amount of silica gel was added for spin-dry column chromatography to obtain the product 3d as a yellow oil (yield 51%).
The reaction process of the above steps is shown as the following formula:
the nuclear magnetic data for product 3d are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.83(d,J＝4.4Hz,1H),8.14(dd,J＝8.4,0.5Hz,1H),8.04(dd,J＝8.4,0.8Hz,1H),7.70(ddd,J＝8.4,6.9,1.3Hz,1H),7.53(ddd,J＝8.3,6.9,1.2Hz,1H),7.31(m,2H),7.22(m,3H),7.14(d,J＝4.4Hz,1H),4.45(s,2H). 13 C NMR(101MHz,CDCl 3 )δ150.29(s),148.36(s),146.54(s),138.58(s),130.18(s),129.11(s),128.90(s),128.70(s),127.60(s),126.61(s),126.54(s),123.83(s),121.83(s),38.13(s)。
example 5
The embodiment provides a preparation method of a quinoline compound 3e, which comprises the following specific steps:
2- (1- (4-chlorophenyl) ethenyl) aniline, 1e (0.2mmol, 46mg), sodium difluorochloroacetate, 2(0.2mmol, 30mg), and cuprous oxide (0.2mmol, 28mg) were placed in a 25mL reaction tube, evacuated, and purged with nitrogen (three times). Triethylamine (0.2mmol, 20mg) was then weighed and dissolved in 2mL of DMF solution, and the mixture was injected into the reaction tube via syringe. Stirred in an oil bath at 140 ℃ for 18 h. After completion of the reaction, it was cooled to room temperature, and 15mL of methylene chloride was added to the reaction system to dilute it and filter it, and a small amount of silica gel was added thereto for spin-dry column chromatography to obtain the product 3e as a yellow solid (yield 44%). The reaction process of the above steps is shown as the following formula:
the nuclear magnetic data for product 3e is as follows:
1 H NMR(400MHz,CDCl 3 )δ8.95(d,J＝4.4Hz,1H),8.18(d,J＝8.4Hz,1H),7.86(d,J＝7.8Hz,1H),7.74(ddd,J＝8.3,6.9,1.3Hz,1H),7.55–7.49(m,3H),7.45(d,J＝8.5Hz,2H),7.31(d,J＝4.4Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ149.93(s),148.66(s),147.17(s),136.37(s),134.66(s),130.81(s),129.96(s),129.47(s),128.85(s),126.85(s),126.50(s),125.47(s),121.22(s)。
example 6
This example provides a method for preparing quinoline compound 3a, which is the same as in example 1 except that the cuprous oxide is replaced with equal amount of cupric oxide.
The final yield of compound 3a was 42%.
Example 7
This example provides a method for preparing quinoline compound 3a, which is the same as in example 1 except that cuprous oxide is replaced with equal amount of cuprous iodide in the specific steps.
The final yield of compound 3a was 56%.
Example 8
This example provides a method for preparing quinoline compounds 3a, which is the same as in example 1 except that the amount of DMA to replace DMF is the same.
The final yield of compound 3a was 25%.
Example 9
This example provides a method for preparing quinoline compound 3a, which is the same as in example 1 except that triethylamine is replaced with an equal amount of sodium bicarbonate.
Compound 3a was finally obtained in 35% yield.
Example 10
This example provides a method for preparing quinoline compound 3a, which is the same as in example 1 except that the amount of potassium tert-butoxide is replaced with the same amount of triethylamine in the specific step.
The final yield of compound 3a was 15%.
Example 11
This example provides a process for the preparation of quinoline compound 3a, which is the same as in example 1 except that the reaction temperature is 100 ℃.
The final yield of compound 3a was 13%.
Example 12
This example provides a preparation method of quinoline compound 3a, which is the same as example 1 except that the amount of triethylamine added in the specific step is 0.2 mmol.
The final yield of compound 3a was 77%.
Example 13
The embodiment provides a preparation method of a quinoline compound 3a, and the rest of the steps are the same as those of the embodiment 1 except that the addition amount of cuprous oxide is 0.04 mmol.
The final yield of compound 3a was 49%.
The data show that the preparation method of the quinoline compound has the characteristics of high yield, simple operation and low cost; it can also be seen from a comparison of example 1 and examples 6 to 10 that the present invention can further improve the reaction yield by selecting specific reaction raw materials.
The applicant states that the preparation method and application of the quinoline compound of the present invention are illustrated by the above examples, but the present invention is not limited to the above examples, i.e. it is not meant that the present invention must be implemented by the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
Claims (10)
1. A process for the preparation of a quinoline compound, comprising the steps of:
mixing the compound A with a difluorocarbene reagent, a metal additive, alkali and a solvent for reaction to obtain the quinoline compound; the reaction route is as follows
Wherein R is 1 Any one selected from C1-C6 substituted or unsubstituted alkyl, C3-C7 substituted or unsubstituted cycloalkyl, C6-C12 substituted or unsubstituted aryl and C1-C6 substituted or unsubstituted heteroaryl;
the substituted substituent is selected from any one of halogen, C1-C6 alkoxy or C1-C6 alkyl.
2. The method of claim 1, wherein the difluorocarbene reagent comprises sodium difluorochloroacetate and/or potassium difluorochloroacetate.
3. The preparation method of claim 1 or 2, wherein the molar ratio of the compound A to the difluorocarbene reagent is 1 (1-2).
4. The method according to any one of claims 1 to 3, wherein the base comprises any one or a combination of at least two of triethylamine, sodium tert-butoxide, sodium hydrogen carbonate, potassium tert-butoxide, DBU or DBN, preferably triethylamine.
5. The method according to any one of claims 1 to 4, wherein the molar ratio of the compound A to the base is 1 (1-2).
6. The method of any one of claims 1 to 5, wherein the metal additive is a copper additive comprising any one or a combination of at least two of cuprous chloride, cuprous iodide, cuprous oxide or cupric chloride, preferably cuprous oxide.
7. The method according to any one of claims 1 to 6, wherein the molar ratio of the compound A to the metal additive is 1 (0.2 to 1).
8. The method of any one of claims 1-7, wherein the solvent comprises any one or a combination of at least two of DMF, DMA, or NMP, preferably DMF.
9. The method according to any one of claims 1 to 8, wherein the reaction temperature is 100 ℃ and 150 ℃ and the reaction time is 12 to 18 hours.
10. Use of the preparation process according to any one of claims 1 to 9 in the preparation of quinoline and its derivatives.
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| BEN-JIE JIANG，等: "Synthesis of Quinolines and 2-Functionalized Quinolines by Difluorocarbene Incorporation", 《ADV. SYNTH. CATAL.》 * |
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