CN106892866A - A kind of quinolone of 1,2 2 substitution 4 and its synthetic method - Google Patents
A kind of quinolone of 1,2 2 substitution 4 and its synthetic method Download PDFInfo
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- CN106892866A CN106892866A CN201710047517.XA CN201710047517A CN106892866A CN 106892866 A CN106892866 A CN 106892866A CN 201710047517 A CN201710047517 A CN 201710047517A CN 106892866 A CN106892866 A CN 106892866A
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- substitution
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- quinolones
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- reaction
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Links
- 238000006467 substitution reaction Methods 0.000 title claims abstract description 84
- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- 238000000605 extraction Methods 0.000 claims abstract description 26
- GTDQGKWDWVUKTI-UHFFFAOYSA-N o-aminoacetophenone Chemical class CC(=O)C1=CC=CC=C1N GTDQGKWDWVUKTI-UHFFFAOYSA-N 0.000 claims abstract description 25
- 150000001263 acyl chlorides Chemical class 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 238000003756 stirring Methods 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 239000002585 base Substances 0.000 claims description 25
- 239000012074 organic phase Substances 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 17
- -1 bromo compound Chemical class 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 claims description 7
- MVIVDSWUOGNODP-UHFFFAOYSA-N 2-iodobenzoyl chloride Chemical class ClC(=O)C1=CC=CC=C1I MVIVDSWUOGNODP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 6
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 3
- 125000006303 iodophenyl group Chemical group 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000004799 bromophenyl group Chemical group 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 9
- 229910000510 noble metal Inorganic materials 0.000 abstract description 6
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 abstract description 3
- 230000003247 decreasing effect Effects 0.000 abstract description 2
- 239000002360 explosive Substances 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 238000004821 distillation Methods 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 229910006124 SOCl2 Inorganic materials 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 5
- 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 150000007660 quinolones Chemical class 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- CJNZAXGUTKBIHP-UHFFFAOYSA-N 2-iodobenzoic acid Chemical class OC(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 description 3
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical class IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 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 description 2
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 2
- 238000003512 Claisen condensation reaction Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 235000005513 chalcones Nutrition 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Chemical group 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001789 chalcones Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052755 nonmetal Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 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
- C07D215/16—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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to a kind of quinolone of 1,2 two substitution 4 and its synthetic method, first replace acyl chlorides to be dissolved in solvent, add N substitution o-aminoacetophenones, stir, obtain reaction system；The mol ratio of wherein substitution acyl chlorides and N substitution o-aminoacetophenones is 1：(1~1.1), then to alkali is added in reaction system, extraction, back extraction are passed through in 25~60 DEG C of reactions, after reaction completely, is dried and solvent is evaporated off, obtain the quinolone of 1,2 two substitution 4.The present invention uses substitution acyl chlorides and N substitution o-aminoacetophenone reactions, and raw material is easy to get, prepares simply, and atom utilization is high, and yield is high；Reaction condition is gentle, it is not necessary to which high-temperature heating flows back, and in 25~60 DEG C of reactions, has saved the preparation cost of course of reaction；Avoid using the raw material such as inflammable and explosive phenylacetylene and n BuLi；Noble metal catalyst is not needed, cost is reduced, while decreasing the pollution to environment.
Description
【Technical field】
The present invention relates to synthesize field, and in particular to the substitution -4- quinolones of 1,2- of one kind bis- and its synthetic method.
【Background technology】
Quinolone compounds are the important nitrogen heterocyclics of a class, and nitrogen-atoms will in the quinolone compounds of nitrogen atom
The favourable interaction of attachment group and bioactive sites is promoted, since its discovery, it has turned into the various senses of application for the treatment of
First big antibacterials of dye.The has a broad antifungal spectrum that has due to it, it is employed to study in biology always the advantages of antibacterial activity is strong
The aspects such as medicine.Certainly in material science, carbostyril compound also plays very important effect, such as luminescent material, glimmering
Luminescent material etc..The synthesis of the wherein substitution -4- quinolones of 1,2- bis- and related derivative compounds causes many scholars and expert's
Extensive concern, and there are many pertinent literatures to report its synthetic method.2009, Robeeta Bernini et al. made
Substitution -4- the quinolones of the 1,2- bis- (1209- of Synthesis 2009, No, 7, pp have been obtained with copper catalyst cyclization
1219), 2010, Xu Bin et al. used palladium catalyst series connection ammoxidation to the substitution -4- quinolones of 1,2- bis-
(Organic Letter, Vol.12, No.2,2010), 2012, Zhu Yongming et al. chalcones were substrate by being coupled addition
Reaction has obtained substitution -4- quinolones (Eur.J.Org.Chem.2012,3001-3008) of 1,2- bis-.
Document above report synthesis 1, in the substitution -4- quinolone schemes of 2- bis-, first synthetic schemes complex steps and
Need PdCl2(PPh)3/ CuI is that catalyst synthesizes substrate acetylenic ketone；Although simplifying reactions steps in second synthetic schemes,
It is to be disadvantageous in that to have used n-BuLi to synthesize substrate acetylenic ketone under conditions of -78 DEG C, severe reaction conditions have safety hidden
Suffer from and increased the cost of substrate preparation；The chalcone that easy preparation is employed in 3rd synthetic schemes is substrate, but also
It is to need the Pd (OAc) under the conditions of high temperature reflux2Noble metal carrys out catalytic reaction process.To sum up, exist in current synthetic method
Complex steps, condition are harsh and need the weak points such as noble metal catalyst.
【The content of the invention】
It is an object of the invention to overcome problems of the prior art, there is provided the substitution -4- quinolones of 1,2- of one kind bis-
And its synthetic method, reaction condition is gentle, without noble metal catalyst.
In order to achieve the above object, the present invention is adopted the following technical scheme that：
Comprise the following steps：
(1) substitution acyl chlorides is dissolved in solvent, adds N- substitution o-aminoacetophenones, is stirred, and obtains reactant
System；The mol ratio of wherein substitution acyl chlorides and N- substitution o-aminoacetophenones is 1：(1~1.1),
(2) to alkali is added in reaction system, extraction, back extraction are passed through in 25~60 DEG C of reactions, after reaction completely, is dried and is steamed
Except solvent, the substitution -4- quinolones of 1,2- bis- are obtained.
Further, the structural formula of the substitution -4- quinolones of 1,2- bis- for obtaining is as follows：
R therein1Ethyl, cyclopropyl, phenyl, p-methylphenyl, right is with the substitution base in step (1) substitution acyl chlorides
Methoxyphenyl, thienyl, O-Nitrophenylfluorone, m-nitro base or halogenophenyl；R2Replace adjacent aminobenzene second with step (1) N-
Substitution base in ketone is pi-allyl, propargyl or phenyl.
Further, halogenophenyl includes rubigan, o-fluorophenyl, a fluorophenyl, p-fluorophenyl, adjacent iodophenyl or bromine
Phenyl.
Further, the preparation process of the 2- iodobenzoyl chlorides in step (1) is specifically included：Substitution acid is added to first
Excessive SOCl2Middle backflow 1~3 hour, then remove remaining SOC12, obtain replacing acyl chlorides.
Further, the solvent in step (1) is tetrahydrofuran；Substitution the ratio between acyl chlorides and solvent are in step (1)
5mmol：(10~30) mL.
Further, the preparation process of the N- substitution o-aminoacetophenones in step (1) is specifically included：First in ice-water bath and
Under stirring condition, o-aminoacetophenone, K are sequentially added in DMF2CO3And bromo compound, 50~80 DEG C react 22~
26h, wherein o-aminoacetophenone, K2CO3It is 1 with the mol ratio of bromo compound:1：(1.1~1.5)；After reaction terminates, successively
Solvent is extracted, is washed, is stripped and removed, N- substitution o-aminoacetophenones are obtained.
Further, stirring 10~30 minutes in step (1).
Further, BuOK highly basic more than substitution acyl chlorides mole twice is added in step (2).
Further, reaction 4~8 hours in step (2)；CH is used after reaction terminates in step (2)2C12Extraction three times,
And back extraction organic phase is washed with saturation NaCl, merge organic phase, anhydrous MgSO4Dry organic phase.
Substitution -4- quinolones its structural formula of 1,2- of the present invention bis- is as follows：
R therein1For ethyl, cyclopropyl, phenyl, p-methylphenyl, p-methoxyphenyl, thienyl, O-Nitrophenylfluorone,
M-nitro base or halogenophenyl；R2It is pi-allyl, propargyl or phenyl.
Compared with prior art, the present invention has following beneficial technique effect：
In the synthetic method of the substitution -4- quinolones of 1,2- of the present invention bis-, using substitution acyl chlorides and the adjacent aminobenzene second of N- substitutions
In reactive ketone, first N- substitution o-aminoacetophenone molecule, a pair of lone pair electrons on nitrogen-atoms enter to substitution chloride compounds
Row nucleophilic substitution, obtains tetrahedron intermediate state, then takes off an one's share of expenses for a joint undertaking hydrogen chloride and obtains amide compound.Then obtain
Amide compound α-H in the presence of highly basic leave away to form carbanion, so attack acid amides carbonyl, take off a molecule
Water, realizes Claisen condensation reaction；The present invention has further the advantage that：1) raw material is easy to get, and prepares simply, and atom utilization is high,
Yield is up to 92%；2) reaction condition is gentle, it is not necessary to which high-temperature heating flows back, and in 25~60 DEG C of reactions, has saved course of reaction
Preparation cost；3) avoid and use the raw materials such as inflammable and explosive phenylacetylene and n-BuLi；4) noble metal catalyst is not needed, is dropped
Low cost, while decreasing the pollution to environment.
Further, substitution acyl chlorides, easily storage and effectively reduces cost are prepared by replacing acid in the present invention.
【Specific embodiment】
The present invention has carried out a series of substrate expansion experiments, substitution acyl chlorides and N- substitutions to the compound of different substituents
O-aminoacetophenone, its reaction equation is as follows：
Wherein, R1Can be ethyl, cyclopropyl, phenyl, p-methylphenyl, p-methoxyphenyl, thienyl, ortho-nitrophenyl
Base, m-nitro base or halogenophenyl, wherein halogenophenyl include rubigan, o-fluorophenyl, a fluorophenyl, p-fluorophenyl,
Adjacent iodophenyl or bromophenyl etc.；R2Can be pi-allyl, propargyl or phenyl etc..
Step of the invention includes：
(1) weigh substitution acid 24mmol to be put into the round-bottomed flask of 100ml, add 10~40mL SOCl2After be heated to reflux
1~3 hour, subsequent air-distillation removed remaining SOC12, can be as far as possible cleared by it using the method for pump vacuum extraction, obtain
To yellow oily liquid, that is, replace acyl chlorides；The same R of substitution base in substitution acid1。
(2) under ice-water bath, stirring adds the DMF of 25mL, adds o-aminoacetophenone 30mmol, and K is added afterwards2CO3
33~45mmol of 30mmol and bromo compound, reaction carries out 22~26h at 50~80 DEG C.It is after reaction time terminates, this is anti-
Answer system to be poured into water, use CH2Cl2Extraction, washes organic phase (20mL × 3) with water, is stripped afterwards, is depressurized with round-bottomed flask afterwards
Revolving organic phase, removal solvent therein, the mixture for obtaining silica gel post separation, eluant, eluent volume ratio is 1 during separation:10
Ethyl acetate and petroleum ether mixture；Obtain N- substitution o-aminoacetophenones；The same R of substitution base wherein in bromo compound2。
(3) the substitution acyl chlorides that will be prepared weighs 5mmol and is dissolved in 10~30mL in advance by the tetrahydrofuran of Non-aqueous processing
(THF) in, then to N- substitution 5~5.5mmol of o-aminoacetophenone are slowly added into system, stir 10~30 minutes, use thin layer
Chromatogram TLC monitors extent of reaction, and question response completely, adds more than BuOK highly basic 10mmol, preferably in continuing to reaction system
10~20mmol；Temperature control is reacted 4~8 hours at 25~60 DEG C, is then put plate and is confirmed that reaction is complete, obtains final product.
Reaction uses CH after terminating2C12Extraction three times, and back extraction organic phase is washed with saturation NaCl, merge organic phase, anhydrous MgSO4It is dry
Dry organic phase solution, removes solvent and obtains faint yellow solid Carbostyril derivative using rotating pressure-decreasing distillation afterwards.
In the present invention, in the substitution o-aminoacetophenone molecules of N- first, a pair of lone pair electrons on nitrogen-atoms are to substitution acyl
Chlorine compound carries out nucleophilic substitution, obtains tetrahedron intermediate state, then takes off an one's share of expenses for a joint undertaking hydrogen chloride and obtains amide compound.
Then the amide compound that the obtains α-H in the presence of highly basic leave away to form carbanion, so attack acid amides carbonyl, take off
The water of one molecule, realizes Claisen condensation reaction；The structural formula of wherein amide compound is as follows：
Embodiment 1
Product：
(1) 2- iodo-benzoic acids 24mmol is dissolved in 12mL SOCl2In be heated to reflux 2 hours, subsequent air-distillation removes surplus
Remaining SOC12, can be as far as possible cleared by it using the method for pump vacuum extraction, obtain yellow oily liquid, i.e. 2- iodobenzenes formyl
Chlorine.
(2) under ice-water bath, stirring adds the DMF of 25mL, is adding o-aminoacetophenone 30mmol, adds afterwards
The K of 30mmol2CO3With the allyl bromide, bromoallylene of 33mmol, react carries out 24h at 60 DEG C.After reaction time terminates, the reaction system
It is poured into water, uses CH2Cl2Extraction, washes organic phase (20mL × 3) with water, is stripped afterwards, has with round-bottomed flask vacuum rotary steam afterwards
Machine phase, the mixture for obtaining is separated with silica gel column chromatography, obtains target product.
(3) the 2- iodobenzoyl chlorides that will be prepared weigh 5mmol be dissolved in 20mL in advance by the THF of Non-aqueous processing in, then
To adjacent allyl amino acetophenone 5mmol is slowly added into system, stir 10 minutes at room temperature, monitored with thin-layer chromatography TLC anti-
Answer progress, question response completely, adds the BuOK highly basic of 20mmol in continuing to reaction system, react 6 hours at 40 DEG C, then
Point plate confirms that reaction is complete, obtains final product.Reaction uses CH after terminating2C12Extraction three times, and washed instead with saturation NaCl
Extraction organic phase, merges organic phase, anhydrous MgSO4Organic phase solution is dried, removing solvent using rotating pressure-decreasing distillation afterwards obtains
Faint yellow solid Carbostyril derivative, yield is 84%.
The synthesis equation of the substitution -4- quinolones of 1,2- bis- in the present embodiment：
325mg (84%)；1H NMR(CDCl3,400MHz,δppm):δ 8.52-8.50 (q, J=2.6Hz, 1H) 7.95-
7.93 (d, J=8Hz, 1H) 7.66-7.63 (m, 1H) 7.51-7.48 (d, J=12Hz, 1H) 7.46-7.38 (m, 2H) 7.33-
7.31 (t, J=4Hz, 1H) 7.19-7.15 (m, 1H) 6.16 (s, 1H) 5.78-5.73 (t, J=10Hz, 1H) 5.18-5.15
(d, J=12Hz, 1H) 4.90-4.86 (d, J=16Hz, 1H) 4.71-4.70 (t, J=2Hz, 1H) 4.37-4.32 (q, J=
6.6Hz,1H).13C NMR(CDCl3,400MHz,δppm):δ177.70,155.03,140.57,140.36,139.31,
132.31,131.52,130.97,129.70,128.31,127.20,126.85,123.78,118.06,116.90,112.74,
98.01,50.18.
Embodiment 2
By R in experiment1Substitution base has changed phenyl into, and remaining step obtains yellow solid as embodiment 1, and yield is
75%.Product structure formula is：
1H NMR(CDCl3,400MHz,δppm):δ 8.50-8.48 (q, J=2.6Hz, 1H), 7.65-7.61 (m, 1H),
7.49-7.42 (m, 4H), 7.41-7.36 (m, 3H), 6.26 (s, 1H), 5.91-8.82 (m, 1H), 5.28-5.25 (d, J=
6Hz, 1H), 5.00-4.95 (d, J=10Hz), 4.61-4.60 (t, J=2Hz, 2H)13C NMR(CDCl3,400MHz,δ
ppm):δ177.49,154.76,140.97,135.70,132.30,132.18,129.63,128.10,127.01,126.72,
123.62,117.85,117.00,112.92,50.75.
Embodiment 3
Product：
By R in experiment1Substitution base has changed ethyl into, and remaining step obtains yellow solid as embodiment 1, and yield is
72%.
1H NMR(CDCl3,400MHz,δppm):δ 8.44-8.41 (q, J=4Hz, 1H) 7.59-7.58 (t, J=2Hz,
1H), 7.39-7.37 (d, J=8Hz, 1H), 7.34-7.30 (t, J=8Hz, 1H), 6.27 (s, 1H), 6.03-5.96 (q, J=
9.3Hz, 1H) 5.26-5.24 (d, J=8Hz, 1H), 4.94-4.89 (q, J=6Hz, 1H), 4.78-4.77 (q, J=1.3Hz,
2H), 2.72-2.66 (q, J=8Hz, 2H), 1.34-1.30 (t, J=5.3Hz, 3H)13C NMR(CDCl3,400MHz,δ
ppm):δ178.01,155.81,141.22,132.00,131.34,126.58,123.23,117.46,116.02,109.87,
47.98,26.45,12.89.
Embodiment 4
By R in experiment1Substitution base has changed cyclopropyl into, and remaining step obtains yellow solid as embodiment 1, and yield is
76%.
1H NMR(CDCl3,400MHz,δppm):δ8.32-8.30(m,1H),7.52-7.49(m,1H),7.33-7.31
(q, J=2.6Hz, 1H), 7.24-7.20 (m, 1Hz), 6.08 (s, 1H), 5.97-5.96 (t, J=2Hz, 1H), 5.19-5.16
(t, J=6Hz, 1H), 4.99 (s, 2H), 4.89-4.85 (t, 5.2Hz, 1H), 1.80-1.77 (m, 1H), 1.01-0.99 (m,
1H), 0.81-0.80 (d, J=2Hz, 1H)13C NMR(CDCl3,400MHz,δppm):δ178.20,155.18,141.30,
132.02,131.61,126.30,126.27,123.14,117.13,116.13,108.62,48.52,14.25,7.44.
Embodiment 5
By R in experiment1Substitution base has changed p-methylphenyl into, and remaining step obtains yellow solid as embodiment 1, produces
Rate is 80%.
1H NMR(CDCl3,400MHz,δppm):δ 8.41-8.39 (d, J=8Hz, 1H) 7.56-7.52 (m, 1H) 7.42-
7.39 (d, J=12Hz, 1H) 7.29-7.25 (q, J=5.3Hz, 1H) 7.22-7.16 (q, J=8Hz, 4H) 6.18 (s, 1H)
5.83-5.76 (m, 1H) 5.19-5.16 (d, J=12Hz, 1H) 4.91-4.86 (d, J=20Hz, 1H) 4.55 (s, 2H) 2.33
(s,3H).13C NMR(CDCl3,400MHz,δppm):δ177.13,154.71,140.67,139.42,132.50,132.15,
131.82,128.94,127.65,126.62,126.22,123.20,117.39,116.85,112.53,50.43,21.04.
Embodiment 6
By R in experiment1Substitution base has changed p-methoxyphenyl into, and remaining step obtains yellow solid as embodiment 1,
Yield is 77%.
1H NMR(CDCl3,400MHz,δppm):δ 8.49-8.47 (d, J=8Hz, 1H), 7.65-7.61 (m, 1H),
7.48-7.46 (d, J=4Hz, 1H), 7.39-7.33 (q, J=6Hz, 3H), 6.97-6.95 (d, J=4Hz, 2H), 6.26 (s,
1H), 5.92-2.85 (m, 1H) 5.29-5.26 (d, J=6Hz, 1H), 5.01-4.97 (d, J=8Hz, 1H), 4.64-4.63 (t,
J=2Hz, 2H), 3.86 (s.3H)13C NMR(CDCl3,400MHz,δppm):δ177.55,160.54,154.77,141.06,
132.52,132.10,129.54,128.02,126.97,126.69,123.54,117.77,117.05,113.95,113.10,
55.38,50.79.
Embodiment 7
By R in experiment1Substitution base has changed rubigan into, and remaining step obtains yellow solid, yield as embodiment 1
It is 92%.
1H NMR(CDCl3,400MHz,δppm):δ 8.46-8.44 (d, J=8Hz, 1H) 7.64-7.61 (t, J=6Hz,
1H) 7.46-7.41 (t, J=10Hz, 3H) 7.38-7.34 (t, J=8Hz, 3H) 6.20 (s, 1H) 5.87-5.83 (q, J=8Hz,
1H) 5.29-5.26 (d, J=12Hz, 1H) 4.98-4.94 (d, J=16Hz, 1H) 4.58 (s, 3H)13C NMR(CDCl3,
400MHz,δppm):δ177.37,153.49,140.95,135.92,134.03,132.35,132.15,129.51,128.92,
126.94,126.70,123.77,117.97,116.98,112.96,50.78.
Embodiment 8
By R in experiment1Fluorophenyl between replacing base to change into, remaining step obtains yellow solid, yield as embodiment 1
It is 88%.
1H NMR(CDCl3,400MHz,δppm):δ 8.488-8.481 (d, J=2.8Hz, 1H) 7.65-7.63 (m, 1H)
7.51-7.49 (d, J=8Hz, 2H) 7.37-7.33 (q, J=5.3Hz, 2H) 7.257.17 (m, 2H) .6.27-6.23 (m, 1H)
5.80-5.76 (m, 1H) 5.19-5.17 (d, J=8Hz, 1H) 4.95-4.89 (t, J=12Hz, 1H) 4.72-4.68 (d, J=
16Hz, 1H) 4.54-4.49 (d, J=20Hz, 1H)13C NMR(CDCl3,400MHz,δppm):δ177.49,160.07,
157.60,148.64,140.91,132.28,131.58,130.56,127.07,126.78,124.60,123.73,117.97,
116.86,116.19,115.98,113.55,50.52.
Embodiment 9
By R in experiment1Substitution base has changed thienyl into, and remaining step obtains yellow solid as embodiment 1, and yield is
83%.
1H NMR(CDCl3,400MHz,δppm):δ 8.30-8.28 (d, J=8Hz, 1H), 7.90-7.88 (d, J=8Hz,
1H), 7.51-7.49 (d, J=8Hz, 1H), 7.40-7.37 (t, J=6Hz, 1H), 7.34-7.30 (t, J=8Hz, 1H),
7.14-7.13 (d, J=4Hz, 1H), 7.01-7.00 (d, J=4Hz, 1H), 6.29 (s, 1H), 6.05-5.99 (q, J=8Hz,
1H), (s, the 2H) of 5.38-5.35 (d, J=12Hz, 1H), 5.09-5.05 (d, J=16Hz, 1H), 4.7813C NMR(CDCl3,
400MHz,δppm):δ177.34,147.80,139.47,132.62,132.53,129.10,128.29,127.36,126.80,
126.02,125.51,123.52,117.88,114.31,111.21,51.24.
Embodiment 10
By R in experiment1Substitution base has changed m-nitro base into, and remaining step obtains yellow solid as embodiment 1, produces
Rate is 82%.
1H NMR(CDCl3,400MHz,δppm):δ 8.35-8.33 (d, J=8Hz, 1H) 8.30-8.27 (t, J=6Hz,
2H) 7.77-7.76 (t, J=2Hz, 1H) 7.68-7.59 (m, 2H) 7.46-7.44 (d, J=8Hz, 1H) 7.35-7.31 (m, 1H)
6.14 (s, 1H) 5.89-5.82 (m, 1H) 5.30-5.27 (d, J=12Hz, 1H) 4.97-4.92 (d, J=20Hz, 1H) 4.56-
4.55 (t, J=2Hz, 2H)13C NMR(CDCl3,400MHz,δppm):δ177.17,151.95,147.90,140.91,
136.90,134.16,132.65,131.83,130.01,126.85,126.57,124.57,124.01,123.18,118.25,
117.02,113.04,50.97.
Embodiment 11
By R in experiment2Substitution base has changed propargyl into, and remaining step obtains yellow solid as embodiment 2, and yield is
76%.
Embodiment 12
(1) 2- iodo-benzoic acids 24mmol is dissolved in 10mL SOCl2In be heated to reflux 3 hours, subsequent air-distillation removes surplus
Remaining SOC12, can be as far as possible cleared by it using the method for pump vacuum extraction, obtain yellow oily liquid, i.e. 2- iodobenzenes formyl
Chlorine.
(2) under ice-water bath, stirring adds the DMF of 25mL, is adding o-aminoacetophenone 30mmol, adds afterwards
The K of 30mmol2CO3With the allyl bromide, bromoallylene of 36mmol, react carries out 22h at 50 DEG C.After reaction time terminates, the reaction system
It is poured into water, uses CH2Cl2Extraction, washes organic phase (20mL × 3) with water, is stripped afterwards, has with round-bottomed flask vacuum rotary steam afterwards
Machine phase, the mixture for obtaining is separated with silica gel column chromatography, obtains target product.
(3) the 2- iodobenzoyl chlorides that will be prepared weigh 5mmol be dissolved in 10mL in advance by the THF of Non-aqueous processing in, then
To adjacent allyl amino acetophenone 5.2mmol is slowly added into system, stir 20 minutes at room temperature, monitored with thin-layer chromatography TLC
Extent of reaction, question response completely, continue to reaction system in add 10mmol BuOK highly basic, 25 DEG C react 8 hours, so
Point plate confirms that reaction is complete afterwards, obtains final product.Reaction uses CH after terminating2C12Extraction three times, and washed with saturation NaCl
Back extraction organic phase, merges organic phase, anhydrous MgSO4Organic phase solution is dried, removing solvent using rotating pressure-decreasing distillation afterwards obtains
To faint yellow solid Carbostyril derivative.
Embodiment 13
(1) 2- iodo-benzoic acids 24mmol is dissolved in 40mL SOCl2In be heated to reflux 1 hour, subsequent air-distillation removes surplus
Remaining SOC12, can be as far as possible cleared by it using the method for pump vacuum extraction, obtain yellow oily liquid, i.e. 2- iodobenzenes formyl
Chlorine.
(2) under ice-water bath, stirring adds the DMF of 25mL, is adding o-aminoacetophenone 30mmol, adds afterwards
The K of 30mmol2CO3With the allyl bromide, bromoallylene of 45mmol, react carries out 26h at 80 DEG C.After reaction time terminates, the reaction system
It is poured into water, uses CH2Cl2Extraction, washes organic phase (20mL × 3) with water, is stripped afterwards, has with round-bottomed flask vacuum rotary steam afterwards
Machine phase, the mixture for obtaining is separated with silica gel column chromatography, obtains target product.
(3) the 2- iodobenzoyl chlorides that will be prepared weigh 5mmol be dissolved in 30mL in advance by the THF of Non-aqueous processing in, then
To adjacent allyl amino acetophenone 5.5mmol is slowly added into system, stir 30 minutes at room temperature, monitored with thin-layer chromatography TLC
Extent of reaction, question response completely, continue to reaction system in add 15mmol BuOK highly basic, 60 DEG C react 4 hours, so
Point plate confirms that reaction is complete afterwards, obtains final product.Reaction uses CH after terminating2C12Extraction three times, and washed with saturation NaCl
Back extraction organic phase, merges organic phase, anhydrous MgSO4Organic phase solution is dried, removing solvent using rotating pressure-decreasing distillation afterwards obtains
To faint yellow solid Carbostyril derivative.
Comparative example 1
Solvents tetrahydrofurane in step (3) is substituted for EtOAc, CH3CN and DMF, measures the yield such as table 1 below of product
It is shown.As shown in Table 1, in addition to tetrahydrofuran, other solvents are not suitable for the application reaction system.
The yield of product under the different solvents of table 1
Comparative example 2
BuOK highly basic in step (3) is substituted for K2CO3, DBU and Cs2CO3, discovery cannot make product or yield
It is very low.
The present invention is using adjacent iodobenzoyl chloride and the adjacent allyl amino acetophenone synthesis substitution -4- quinolones of 1,2- bis-, solution
Substrate preparation process in the prior art of having determined is cumbersome and needs the problem of noble metal catalyst, is prepared with substrate simple, former
Material is easy to get, step is simple, reaction condition is gentle, non-metal catalyst, outstanding yield the advantages of.
Claims (10)
1. one kind 1, the synthetic method of the substitution -4- quinolones of 2- bis-, it is characterised in that：Comprise the following steps：
(1) substitution acyl chlorides is dissolved in solvent, adds N- substitution o-aminoacetophenones, is stirred, and obtains reaction system；Its
The mol ratio of middle substitution acyl chlorides and N- substitution o-aminoacetophenones is 1：(1~1.1),
(2) to alkali is added in reaction system, extraction, back extraction are passed through in 25~60 DEG C of reactions, after reaction completely, is dried and is evaporated off molten
Agent, obtains the substitution -4- quinolones of 1,2- bis-.
2. the synthetic method of the substitution -4- quinolones of a kind of 1,2- according to claim 1 bis-, it is characterised in that：Obtain
The structural formula of the substitution -4- quinolones of 1,2- bis- is as follows：
R therein1With step (1) substitution acyl chlorides in substitution base be ethyl, cyclopropyl, phenyl, p-methylphenyl, to methoxy
Base phenyl, thienyl, O-Nitrophenylfluorone, m-nitro base or halogenophenyl；R2In step (1) N- substitution o-aminoacetophenones
Substitution base be pi-allyl, propargyl or phenyl.
3. the synthetic method of the substitution -4- quinolones of a kind of 1,2- according to claim 2 bis-, it is characterised in that：Halogeno-benzene
Base includes rubigan, o-fluorophenyl, a fluorophenyl, p-fluorophenyl, adjacent iodophenyl or bromophenyl.
4. the synthetic method of the substitution -4- quinolones of a kind of 1,2- according to claim 1 bis-, it is characterised in that：Step (1)
In the preparation process of 2- iodobenzoyl chlorides specifically include：Substitution acid is added to excessive SOCl first2Middle backflow 1~3 is small
When, then remove remaining SOC12, obtain replacing acyl chlorides.
5. the synthetic method of the substitution -4- quinolones of a kind of 1,2- according to claim 1 bis-, it is characterised in that：Step (1)
In solvent be tetrahydrofuran；Substitution the ratio between acyl chlorides and solvent are 5mmol in step (1)：(10~30) mL.
6. the synthetic method of the substitution -4- quinolones of a kind of 1,2- according to claim 1 bis-, it is characterised in that：Step (1)
In N- substitution o-aminoacetophenone preparation process specifically include：First under ice-water bath and stirring condition, add successively in DMF
Enter o-aminoacetophenone, K2CO3And bromo compound, react 22~26h, wherein o-aminoacetophenone, K at 50~80 DEG C2CO3
It is 1 with the mol ratio of bromo compound:1：(1.1~1.5)；After reaction terminates, extracted successively, washed, be stripped and removed
Solvent, obtains N- substitution o-aminoacetophenones.
7. the synthetic method of the substitution -4- quinolones of a kind of 1,2- according to claim 1 bis-, it is characterised in that：Step (1)
Middle stirring 10~30 minutes.
8. the synthetic method of the substitution -4- quinolones of a kind of 1,2- according to claim 1 bis-, it is characterised in that：Step (2)
The middle BuOK highly basic for adding more than substitution acyl chlorides mole twice.
9. the synthetic method of the substitution -4- quinolones of a kind of 1,2- according to claim 1 bis-, it is characterised in that：Step (2)
Middle reaction 4~8 hours；CH is used after reaction terminates in step (2)2C12Extraction three times, and it is organic that back extraction is washed with saturation NaCl
Phase, merges organic phase, anhydrous MgSO4Dry organic phase.
10. one kind 1, the substitution -4- quinolones of 2- bis-, it is characterised in that：Its structural formula is as follows：
R therein1It is ethyl, cyclopropyl, phenyl, p-methylphenyl, p-methoxyphenyl, thienyl, O-Nitrophenylfluorone, a nitre
Base phenyl or halogenophenyl；R2It is pi-allyl, propargyl or phenyl.
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| CN110194738B (en) * | 2019-06-03 | 2022-04-05 | 华侨大学 | Preparation method of 1,2, 3-trisubstituted 4-quinolone derivative |
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