CN114394967B - 一种2-吡唑苯胺与1,3-二羰基化合物合成吡唑并喹啉衍生物的方法 - Google Patents
一种2-吡唑苯胺与1,3-二羰基化合物合成吡唑并喹啉衍生物的方法 Download PDFInfo
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- CN114394967B CN114394967B CN202210104371.9A CN202210104371A CN114394967B CN 114394967 B CN114394967 B CN 114394967B CN 202210104371 A CN202210104371 A CN 202210104371A CN 114394967 B CN114394967 B CN 114394967B
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- phenyl
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- UXYHZIYEDDINQH-UHFFFAOYSA-N C1=CNC2=C3C=NN=C3C=CC2=C1 Chemical class C1=CNC2=C3C=NN=C3C=CC2=C1 UXYHZIYEDDINQH-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title description 8
- 230000002194 synthesizing effect Effects 0.000 title description 6
- NRSKRRKWPPDKNI-UHFFFAOYSA-N 2-(1h-pyrazol-5-yl)aniline Chemical compound NC1=CC=CC=C1C1=CC=NN1 NRSKRRKWPPDKNI-UHFFFAOYSA-N 0.000 title description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 43
- 125000001424 substituent group Chemical group 0.000 claims abstract description 34
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 23
- -1 2-pyrazolyl aniline compound Chemical class 0.000 claims abstract description 19
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 5
- 238000001308 synthesis method Methods 0.000 claims abstract description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 22
- 239000000126 substance Substances 0.000 abstract description 5
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- 125000005702 oxyalkylene group Chemical group 0.000 abstract description 4
- 239000002184 metal Substances 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 65
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 41
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 23
- 239000003480 eluent Substances 0.000 description 21
- 239000003208 petroleum Substances 0.000 description 21
- 238000007867 post-reaction treatment Methods 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- 239000000203 mixture Substances 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 15
- GKKZMYDNDDMXSE-UHFFFAOYSA-N Ethyl 3-oxo-3-phenylpropanoate Chemical group CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 description 14
- ODLHPFCCSPUYTF-UHFFFAOYSA-N 2-(2,5-diphenylpyrazol-3-yl)aniline Chemical group NC1=CC=CC=C1C1=CC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 ODLHPFCCSPUYTF-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 125000003226 pyrazolyl group Chemical group 0.000 description 5
- ADEJACPCTOIQLO-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]quinoline Chemical class C1=NC2=CC=CC=C2C2=C1C=NN2 ADEJACPCTOIQLO-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 229910052736 halogen Chemical group 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical compound C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 description 1
- PRRBQHNMYJRHFW-UHFFFAOYSA-M 3-oxoheptanoate Chemical compound CCCCC(=O)CC([O-])=O PRRBQHNMYJRHFW-UHFFFAOYSA-M 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 101150046889 ADORA3 gene Proteins 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- JTYXHBIXMRVPGC-UHFFFAOYSA-N C1(=CC=CC=C1)N1N=C(C=C1C1=C(C=CC=C1)N)C1=CC=C(C=C1)C Chemical compound C1(=CC=CC=C1)N1N=C(C=C1C1=C(C=CC=C1)N)C1=CC=C(C=C1)C JTYXHBIXMRVPGC-UHFFFAOYSA-N 0.000 description 1
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 1
- RCHCZVUXDNMLQJ-UHFFFAOYSA-N ClC1=CC=C(C=C1)C=1C=C(N(N=1)C1=CC=CC=C1)C1=C(C=CC=C1)N Chemical compound ClC1=CC=C(C=C1)C=1C=C(N(N=1)C1=CC=CC=C1)C1=C(C=CC=C1)N RCHCZVUXDNMLQJ-UHFFFAOYSA-N 0.000 description 1
- DCANSQGSBJVUMP-UHFFFAOYSA-N ClC1=CC=C(C=C1)N1N=C(C=C1C1=C(C=CC=C1)N)C1=CC=CC=C1 Chemical compound ClC1=CC=C(C=C1)N1N=C(C=C1C1=C(C=CC=C1)N)C1=CC=CC=C1 DCANSQGSBJVUMP-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- MKMLGWNYPFURCF-UHFFFAOYSA-N NC(C=CC=C1)=C1C1=CC(C(C=C2)=CC=C2F)=NN1C1=CC=CC=C1 Chemical compound NC(C=CC=C1)=C1C1=CC(C(C=C2)=CC=C2F)=NN1C1=CC=CC=C1 MKMLGWNYPFURCF-UHFFFAOYSA-N 0.000 description 1
- ZMWIVTSYPMVRIE-UHFFFAOYSA-N NC1=C(C=CC=C1)C1=CC(=NN1C1=CC=CC=C1)C Chemical compound NC1=C(C=CC=C1)C1=CC(=NN1C1=CC=CC=C1)C ZMWIVTSYPMVRIE-UHFFFAOYSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 229940121359 adenosine receptor antagonist Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N carbostyril Natural products C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- DGCZHKABHPDNCC-UHFFFAOYSA-N ethyl 3-(4-chlorophenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=C(Cl)C=C1 DGCZHKABHPDNCC-UHFFFAOYSA-N 0.000 description 1
- SJUXLKYJKQBZLM-UHFFFAOYSA-N ethyl 3-(4-fluorophenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=C(F)C=C1 SJUXLKYJKQBZLM-UHFFFAOYSA-N 0.000 description 1
- KQWWVLVLVYYYDT-UHFFFAOYSA-N ethyl 3-oxohexanoate Chemical compound CCCC(=O)CC(=O)OCC KQWWVLVLVYYYDT-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- HFLMYYLFSNEOOT-UHFFFAOYSA-N methyl 4-chloro-3-oxobutanoate Chemical compound COC(=O)CC(=O)CCl HFLMYYLFSNEOOT-UHFFFAOYSA-N 0.000 description 1
- QGBPKJFJAVDUNC-UHFFFAOYSA-N methyl 4-methoxy-3-oxobutanoate Chemical compound COCC(=O)CC(=O)OC QGBPKJFJAVDUNC-UHFFFAOYSA-N 0.000 description 1
- HNNFDXWDCFCVDM-UHFFFAOYSA-N methyl 4-methyl-3-oxopentanoate Chemical compound COC(=O)CC(=O)C(C)C HNNFDXWDCFCVDM-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 150000003252 quinoxalines Chemical class 0.000 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
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- Organic Chemistry (AREA)
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Abstract
本发明属于有机合成技术领域,具体公开了多种具有式(Ⅰ)化学结构的吡唑并喹啉类衍生物,其中,取代基R1代表苯基、取代苯基、萘基或烷基,取代基R2代表苯基或取代苯基,取代基R3代表苯基、取代苯基、烷基或含氧亚烷基。本发明还给出了该类化合物的合成方法,在无金属催化条件下,利用2‑吡唑苯胺化合物与1,3‑二羰基化合物一步反应得到目标化合物,并且反应条件温和,反应收率较高。
Description
技术领域
本发明属于有机合成技术领域,涉及稠合杂环化合物的合成新工艺,具体涉及多种吡唑并喹啉衍生物及其制备方法。
背景技术
吡唑并喹啉化合物在医药领域占有重要地位,这类化合物在药物中有很多例子,包括A3腺苷受体拮抗剂,白介素,乙酰胆碱酯酶,NMDA受体和磷酸二酯酶抑制剂,抗癌、抗炎和抗溃疡剂等。专利CN200410004444.9进一步指出,吡唑[4,3-c]喹啉衍生物具有抗感染、扑热镇痛、治疗疱疹等药物疗效。因此,吡唑[4,3-c]喹啉衍生物在生物和医药领域,具有不容忽视的应用潜力。虽然吡唑并喹啉类化合物的合成已经投入了大量的工作,但是合成吡唑并喹啉骨架化合物最成功的方法,主要是在喹啉衍生物的结构修饰上。例如,4-羟基-3-酰基喹啉-2-酮或氯喹啉与肼结合得到目标吡唑[4,3-c]喹啉衍生物。为了满足生物化学和药物化学中不同结构特征的要求,开发一种通用的构建这些结构碎片的方法仍然是一个具有挑战性的任务。
专利CN200410004444.9记载吡唑[4,3-c]喹啉衍生物的合成方法分为两种:一种为先构筑喹啉环后构筑吡唑环并与喹啉环稠合,另一种为先构筑吡唑环后构筑喹啉环与吡唑环稠合。该专利合成了系列3-氨基-6/8取代-1H-吡唑[4,3-c]喹啉类化合物,其以6-/8-取代-4-氯喹啉酸为原料经过与3-芳基-4-氨基-5-巯基-1,2,4-三唑在三氯氧磷中合环和肼解开环两步反应得到目标化合物。Xie课题组描述了一种通过C-C键裂解1,3-二羰基化合物合成吡咯[1,2-a]喹草碱的方法(Xie C,Feng L,Li W,et al.Efficient synthesisofpyrrolo[1,2-a]quinoxalines catalyzed by a Bronsted acid through cleavageofC–C bonds[J].Organic&biomolecular chemistry,2016,14(36):8529-8535.)。在本专利发明人团队对亚胺阳离子引发的自由基环化反应的持续研究中,1,3-二羰基化合物已被证明是有效的C1合成子,能够通过C-C键裂解进行环化反应。经研究发现,2-吡唑苯胺衍生物和1,3-二羰基化合物反应,在酸催化下发生C-C键断裂进而生成亚胺阳离子,进而发生环化反应从而得到所需的吡唑并喹啉产物。
发明内容
鉴于吡唑并喹啉衍生物具有多样的生理活性,在生物和医药领域的应用前景广阔,本发明的目的在于提供高效、便捷合成吡唑并喹啉衍生物的思路和方法。
首先,本发明所述吡唑并喹啉类衍生物,或吡唑喹啉类衍生物表达相同的含义,是指具有式(Ⅰ)化学结构的化合物:
其中,取代基R1代表苯基、取代苯基、萘基或烷基,取代基R2代表苯基或取代苯基,取代基R3代表苯基、取代苯基、烷基或含氧亚烷基。
优选地,在所述的吡唑并喹啉类衍生物中,所述取代基R1代表的取代苯基为烷基取代的苯基,氰基取代的苯基,甲氧基取代的苯基或卤素取代的苯基;取代基R2代表的取代苯基为烷基取代的苯基,氰基取代的苯基或卤素取代的苯基;取代基R3代表的取代苯基为烷基取代的苯基,甲氧基取代的苯基或卤素取代的苯基。
进一步优选地,在所述的吡唑并喹啉类衍生物中,所述取代基R1选自苯基、甲基、对甲基苯基、邻甲基苯基、对甲氧基苯基、对氰基苯基、对氟苯基、对氯苯基、萘基中的一种。
进一步优选地,在所述的吡唑并喹啉类衍生物中,所述取代基R2选自苯基、对甲基苯基、对氰基苯基、对氯苯基中的一种。
进一步优选地,在所述的吡唑并喹啉类衍生物中,所述取代基R3选自苯基、对甲基苯基、对氯苯基、对氟苯基、对甲氧基苯基、正丙基、氯代甲基、甲氧基亚甲基、异丙基、乙基中的一种。
上述取代基R1、取代基R2、取代基R3可以组合成多种具有式(Ⅰ)化学结构的吡唑并喹啉类衍生物,在本发明的实施例中,基于本发明的合成策略,给出了多种化学结构明确的目标化合物。
还有,本发明还提供了所述吡唑并喹啉衍生物的合成方法。与现有技术不同的是,本发明在无金属催化条件下,利用2-吡唑苯胺化合物与1,3-二羰基化合物一步反应得到目标化合物,并且反应条件温和。具体地,本发明合成所述吡唑并喹啉类衍生物的方法,其合成路线如下:
其中,取代基R1代表苯基、取代苯基、萘基或烷基,取代基R2代表苯基或取代苯基,取代基R3代表苯基、取代苯基、烷基或含氧亚烷基,取代基R4代表烷基。
进一步优选地,取代基R4代表甲基或乙基。需要指出的是,基于本发明的合成思路,取代基R4还可代表除甲基或乙基外的烷基基团,或者是化学合成上可以接受的其他非烷基基团。
进一步优选地,本发明合成路线的反应温度设定为100℃。还需要指出的是,本发明所述合成路线的参数条件,比如试剂、溶剂、反应温度及反应时间等,可以根据所述吡唑并喹啉衍生物的化学结构、收率等做出适应性调整或优化。
作为本发明所述合成路线的优选实施方式之一,所述取代基R3代表苯基、取代基R4代表乙基,即:
不同吡唑取代基的邻苯胺类化合物与1,3-二羰基化合物反应。此实施方式的1,3-二羰基化合物优选为苯甲酰乙酸乙酯,反应试剂优选为对甲苯磺酸(TsOH)和六氟异丙醇(HFIP),反应温度优选为100℃。在反应温度100℃条件下反应过夜,经柱层析分离纯化得到目标化合物。
作为本发明所述合成路线的优选实施方式之一,所述取代基R1、R2均代表苯基。此实施方式的原料邻苯胺类化合物即为2-(1,3-二苯基-1H-吡唑-5-yl)苯胺。取代基R3代表苯基、取代苯基、烷基或含氧亚烷基,取代基R4代表烷基。
与现有技术相比,本发明所述吡唑并喹啉类衍生物及其制备方法,至少具有下述的优点或有益效果:
本发明以易获得的2-吡唑苯胺化合物为原料,与1,3-二羰基化合物一步反应得到目标化合物。本发明无金属催化,以对甲苯磺酸(TsOH)催化合成所述吡唑并喹啉类衍生物,合成路线新颖,反应收率较高,可以说是制备此类化合物的最优路线之一。本发明将为此类化合物的后续设计及其广泛药理活性的研究提供理论依据和技术支撑。
具体实施方式
在以下实施例中进一步描述本发明,而不以任何形式旨在限制如权利要求所表明的本发明的保护范围。
实施例1
本实施例提供部分所述吡唑并喹啉类衍生物的合成方法,以及部分目标化合物的结构鉴定数据。在本实施例中,1,3-二羰基化合物优选为苯甲酰乙酸乙酯,与不同吡唑取代基的2-吡唑苯胺类化合物反应合成部分目标化合物。
目标化合物1的合成
取20mL密封管,依次加入2-(1,3-二苯基-1H-吡唑-5-yl)苯胺(0.2mmol,62mg),对甲苯磺酸(0.2mmol,6mg),苯甲酰乙酸乙酯(0.2mmol,38mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到白色固体,收率82.0%。
1H NMR(400MHz,Chloroform-d):δ8.23(d,J=8.4Hz,1H),7.60(dt,J=28.3,5.8Hz,7H),7.38(d,J=7.6Hz,2H),7.27(t,J=7.7Hz,1H),7.09(ddt,J=32.6,12.7,7.4Hz,8H).
13C NMR(101MHz,Chloroform-d):δ156.48,148.64,145.92,141.53,140.80,138.85,132.52,130.41,129.86,129.80,129.68,129.55,129.15,128.62,127.85,127.79,127.65,127.43,126.03,121.60,115.40,114.15.
目标化合物2的合成
取20mL密封管,依次加入2-(3-甲基-1-苯基-1H-吡唑-5-yl)苯胺(0.2mmol,50mg),对甲苯磺酸(0.2mmol,34mg),苯甲酰乙酸乙酯(0.2mmol,38mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到白色固体,收率86.0%。
1H NMR(400MHz,Chloroform-d):δ8.19(d,J=8.3Hz,1H),7.68–7.61(m,2H),7.61–7.58(m,1H),7.55(s,5H),7.53–7.43(m,4H),7.29–7.21(m,1H),2.20(s,3H).
13C NMR(101MHz,Chloroform-d):δ156.75,145.78,144.84,140.97,140.75,139.58,130.30,129.73,129.49,129.05,128.96,128.26,127.14,125.81,121.59,115.94,115.54,14.78.
目标化合物3的合成
取20mL密封管,依次加入2-(1-苯基-3-(p-甲苯基)-1H-吡唑-5-yl)苯胺(0.2mmol,65mg),对甲苯磺酸(0.2mmol,34mg),苯甲酰乙酸乙酯(0.2mmol,38mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到白色固体,收率88.0%。
1H NMR(400MHz,Chloroform-d):δ8.20(d,J=8.3Hz,1H),7.60(dt,J=6.7,2.3Hz,2H),7.58–7.55(m,1H),7.55–7.48(m,4H),7.40–7.34(m,2H),7.26–7.20(m,1H),7.20–7.13(m,1H),7.06(t,J=7.6Hz,2H),7.01(d,J=7.9Hz,2H),6.80(d,J=7.8Hz,2H),2.18(s,3H).
13C NMR(101MHz,Chloroform-d):δ156.41,148.55,145.79,141.38,140.76,138.88,137.45,130.27,129.68,129.57,129.47,129.40,128.91,128.38,128.17,127.60,127.30,125.80,121.44,115.30,21.17.
目标化合物4的合成
取20mL密封管,依次加入2-(1-苯基-3-(o-甲苯基)-1H-吡唑-5-yl)苯胺(0.2mmol,65mg),对甲苯磺酸(0.2mmol,6mg),苯甲酰乙酸乙酯(0.2mmol,38mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率89.0%。
1H NMR(400MHz,Chloroform-d):δ8.24(d,J=8.3Hz,1H),7.65(ddd,J=7.0,5.7,2.0Hz,3H),7.62–7.55(m,4H),7.36–7.31(m,2H),7.29(dd,J=8.0,1.2Hz,1H),7.14–7.04(m,3H),6.97(dt,J=15.3,7.5Hz,3H),6.89(d,J=7.6Hz,1H),1.90(s,3H).
13C NMR(101MHz,Chloroform-d):δ156.62,148.03,145.95,140.99,140.83,137.96,137.20,132.62,130.65,130.43,129.75,129.64,129.60,129.27,129.12,128.46,128.41,127.30,127.28,126.00,125.23,121.67,115.50,115.42.
目标化合物5的合成
取20mL密封管,依次加入2-(3-(4-甲氧基苯基l)-1-苯基-1H-吡唑-5-yl)苯胺(0.2mmol,68mg),对甲苯磺酸(0.2mmol,34mg),苯甲酰乙酸乙酯(0.2mmol,38mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到白色固体,收率57.0%。
1H NMR(400MHz,Chloroform-d):δ8.25–8.20(m,1H),7.64(ddd,J=7.2,4.0,1.9Hz,3H),7.61–7.53(m,4H),7.44–7.37(m,2H),7.28(d,J=1.4Hz,1H),7.21(s,1H),7.13(d,J=7.5Hz,2H),7.11–7.05(m,2H),6.61–6.54(m,2H),3.70(s,3H).
13C NMR(101MHz,Chloroform-d):δ159.39,156.54,148.38,145.90,141.49,140.88,138.93,130.87,130.39,129.81,129.70,129.59,129.05,128.56,127.79,127.42,125.93,125.03,121.58,115.43,114.11,113.15,55.33.
目标化合物6的合成
取20mL密封管,依次加入4-(5-(2-氨基苯)-1-苯基-1H-吡唑-3-yl)苯甲腈(0.2mmol,67mg),对甲苯磺酸(0.2mmol,34mg),苯甲酰乙酸乙酯(0.2mmol,38mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率87.0%。
1H NMR(400MHz,Chloroform-d):δ8.25(d,J=8.3Hz,1H),7.71–7.59(m,6H),7.54(d,J=8.3Hz,1H),7.37(dd,J=7.7,1.5Hz,2H),7.33(d,J=8.0Hz,3H),7.30–7.23(m,3H),7.14(t,J=7.6Hz,2H).
13C NMR(101MHz,Chloroform-d):δ155.78,141.84,140.53,138.81,137.33,131.31,130.54,130.23,130.12,129.99,129.48,129.44,129.12,128.09,127.29,126.38,121.52,115.21,111.35.
目标化合物7的合成
取20mL密封管,依次加入2-(3-(4-氟苯基)-1-苯基-1H-吡唑-5-yl)苯胺(0.2mmol,66mg),对甲苯磺酸(0.2mmol,34mg),苯甲酰乙酸乙酯(0.2mmol,38mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率86.0%。
1H NMR(400MHz,Chloroform-d):δ8.22(d,J=8.3Hz,1H),7.67–7.59(m,3H),7.59–7.55(m,3H),7.53(d,J=8.2Hz,1H),7.39–7.34(m,2H),7.27(dd,J=8.3,7.1Hz,1H),7.24–7.19(m,1H),7.15–7.07(m,4H),6.72(t,J=8.7Hz,2H).
13C NMR(101MHz,Chloroform-d):δ156.28,147.58,145.95,141.56,140.74,138.80,131.43,131.35,130.45,129.88,129.86,129.54,129.22,128.77,127.88,127.38,126.10,121.58,115.37,114.74,114.53,114.14.
目标化合物8的合成
取20mL密封管,依次加入2-(3-(4-氯苯基)-1-苯基-1H-吡唑-5-yl)苯胺(0.2mmol,69mg),对甲苯磺酸(0.2mmol,34mg),苯甲酰乙酸乙酯(0.2mmol,38mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率80.0%。
1H NMR(400MHz,Chloroform-d):δ8.21(d,J=8.3Hz,1H),7.64–7.48(m,7H),7.40–7.32(m,2H),7.31–7.18(m,2H),7.11(t,J=7.6Hz,2H),7.05(d,J=8.5Hz,2H),6.98(d,J=8.5Hz,2H).
13C NMR(101MHz,Chloroform-d):δ156.07,147.24,145.83,141.51,140.60,138.72,133.87,130.99,130.80,130.35,129.78,129.42,129.14,128.74,127.83,127.68,127.25,126.03,121.44,115.21,113.98.
目标化合物9的合成
取20mL密封管,依次加入2-(3-(萘乙酰胺-2-yl)-1-苯基-1H-吡唑-5-yl)苯胺(0.2mmol,72mg),对甲苯磺酸(0.2mmol,34mg),苯甲酰乙酸乙酯(0.2mmol,38mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到白色固体,收率87.0%。
1H NMR(400MHz,Chloroform-d):δ8.25(d,J=8.6Hz,1H),7.77–7.70(m,2H),7.70–7.56(m,8H),7.36–7.25(m,3H),7.22–7.17(m,2H),7.13(d,J=7.6Hz,2H),6.83(t,J=7.4Hz,1H),6.67(t,J=7.6Hz,2H).
13C NMR(101MHz,Chloroform-d):δ147.02,146.04,141.14,140.85,138.12,133.25,130.50,129.80,129.72,129.21,128.87,128.77,128.71,128.19,127.84,127.36,126.88,126.14,126.07,125.58,124.72,121.71,115.54.
目标化合物10的合成
取20mL密封管,依次加入(3-苯基-1-(p-甲苯基)-1H-吡唑-5-yl)苯胺(0.2mmol,65mg),对甲苯磺酸(0.2mmol,34mg),苯甲酰乙酸乙酯(0.2mmol,38mg),HFIP(1mL)。100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率78.0%。
1H NMR(400MHz,Chloroform-d):δ8.22(d,J=8.3Hz,1H),7.64–7.53(m,2H),7.50(d,J=8.0Hz,2H),7.36(dd,J=9.7,7.7Hz,4H),7.27(t,J=7.7Hz,1H),7.18–7.11(m,4H),7.03(dt,J=21.3,7.5Hz,4H),2.45(s,3H).
13C NMR(101MHz,Chloroform-d):δ156.46,148.45,145.87,141.56,139.92,138.90,138.29,132.63,130.40,130.35,129.70,129.56,129.05,128.58,127.77,127.75,127.61,127.18,125.96,121.63,115.50,21.49.
目标化合物11的合成
取20mL密封管,依次加入2-(1-(4-氯苯基)-3-苯基-1H-吡唑-5-yl)苯胺(0.2mmol,69mg),对甲苯磺酸(0.2mmol,34mg),苯甲酰乙酸乙酯(0.2mmol,38mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率86.0%。
1H NMR(400MHz,Chloroform-d):δ8.24(d,J=8.3Hz,1H),7.68–7.61(m,1H),7.61–7.53(m,5H),7.40–7.29(m,3H),7.18–7.10(m,4H),7.05(dt,J=17.6,7.6Hz,4H).
13C NMR(101MHz,Chloroform-d):δ156.37,148.97,145.90,141.50,139.26,138.63,135.57,132.27,130.48,129.97,129.54,129.46,129.24,128.59,127.89,127.71,127.62,126.10,121.32,115.13.
目标化合物12的合成
取20mL密封管,依次加入4-(5-(2-氨基苯)-3-苯基-1H-吡唑-1-yl)苯甲腈(0.2mmol,67mg),对甲苯磺酸(0.2mmol,34mg),苯甲酰乙酸乙酯(0.2mmol,38mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率53.0%。
1H NMR(400MHz,Chloroform-d):δ8.27(d,J=8.3Hz,1H),7.86(q,J=8.6Hz,4H),7.68(ddd,J=8.5,6.8,1.3Hz,1H),7.66–7.60(m,1H),7.40–7.33(m,3H),7.18–7.02(m,8H).
13C NMR(101MHz,Chloroform-d):δ156.45,150.02,146.13,144.37,141.47,138.44,133.68,132.01,130.80,129.64,129.52,128.79,128.20,127.81,127.77,127.68,126.32,121.31,117.95,114.98,114.93,113.18.
实施例2
本实施例提供部分所述吡唑并喹啉类衍生物的合成方法,以及部分目标化合物的结构鉴定数据。在本实施例中,2-吡唑苯胺类化合物优选为2-(1,3-二苯基-1H-吡唑-5-yl)苯胺,与不同1,3-二羰基化合物反应合成部分目标化合物。
目标化合物13的合成
取20mL密封管,依次加入2-(1,3-二苯基-1H-吡唑-5-yl)苯胺(0.2mmol,62mg),对甲苯磺酸(0.2mmol,34mg),4-氟苯甲酰乙酸乙酯(0.2mmol,42mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率79.0%。
1H NMR(400MHz,Chloroform-d):δ8.22(d,J=8.3Hz,1H),7.69–7.62(m,3H),7.62–7.53(m,4H),7.41–7.35(m,2H),7.30(dd,J=8.5,6.9Hz,1H),7.16(dd,J=6.8,1.9Hz,3H),7.12–7.05(m,2H),6.78(t,J=8.7Hz,2H).
13C NMR(101MHz,Chloroform-d):δ155.24,140.76,132.47,131.47,131.39,130.35,129.85,129.82,129.74,129.21,128.08,127.76,127.39,126.12,121.59,115.40,114.80,114.58.
目标化合物14的合成
取20mL密封管,依次加入2-(1,3-二苯基-1H-吡唑-5-yl)苯胺(0.2mmol,62mg),对甲苯磺酸(0.2mmol,34mg),3-氧代-3-(对甲苯基)丙酸乙酯(0.2mmol,41mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率79.0%。
1H NMR(400MHz,Chloroform-d):δ8.22(d,J=8.3Hz,1H),7.62(ddd,J=8.5,6.2,2.1Hz,3H),7.58–7.50(m,4H),7.30–7.21(m,3H),7.17–7.11(m,3H),7.02(t,J=7.5Hz,2H),6.87(d,J=7.8Hz,2H).
13C NMR(101MHz,Chloroform-d):δ156.55,148.79,145.75,141.56,140.84,138.62,132.63,130.18,129.83,129.77,129.75,129.52,129.14,128.39,127.76,127.58,127.42,125.91,121.58,115.34,21.33.
目标化合物15的合成
取20mL密封管,依次加入2-(1,3-二苯基-1H-吡唑-5-yl)苯胺(0.2mmol,62mg),对甲苯磺酸(0.2mmol,34mg),3-(4-氯苯基)-3-氧丙酸乙酯(0.2mmol,45mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率81.0%。
1H NMR(400MHz,Chloroform-d):δ8.21(dd,J=8.4,1.2Hz,1H),7.63(td,J=7.0,6.3,3.0Hz,3H),7.61–7.52(m,4H),7.35–7.26(m,3H),7.19–7.14(m,3H),7.11–7.02(m,4H).
13C NMR(101MHz,Chloroform-d):δ155.05,148.41,145.86,141.56,140.74,137.29,134.79,132.40,130.90,130.39,129.86,129.84,129.74,129.24,128.15,127.88,127.79,127.38,126.23,121.60,115.44,77.25.
目标化合物16的合成
取20mL密封管,依次加入2-(1,3-二苯基-1H-吡唑-5-yl)苯胺(0.2mmol,62mg),对甲苯磺酸(0.2mmol,34mg),(4-甲氧基苯甲酰基)乙酸乙酯(0.2mmol,44mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率75.0%。
1H NMR(400MHz,Chloroform-d):δ8.21(d,J=8.3Hz,1H),7.70–7.49(m,7H),7.38–7.31(m,2H),7.31–7.23(m,1H),7.19–7.13(m,3H),7.08(t,J=7.5Hz,2H),6.66–6.53(m,2H),3.70(s,3H).
13C NMR(101MHz,Chloroform-d):δ160.17,156.06,148.66,146.01,141.58,140.87,132.74,131.51,131.01,130.27,129.81,129.79,129.73,129.06,127.82,127.68,127.42,125.73,121.55,115.29,113.23,55.43.
目标化合物17的合成
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取20mL密封管,依次加入2-(1,3-二苯基-1H-吡唑-5-yl)苯胺(0.2mmol,62mg),对甲苯磺酸(0.2mmol,34mg),丁酰乙酸乙酯(0.2mmol,32mg)或正丁酰乙酸甲酯(0.2mmol,29mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到白色固体,收率分别为79.0%和76%。
1H NMR(400MHz,Chloroform-d):δ8.09(d,J=8.3Hz,1H),7.64–7.58(m,5H),7.57–7.52(m,3H),7.50(dd,J=8.3,1.4Hz,1H),7.44(dd,J=5.1,2.0Hz,3H),7.23(s,1H),2.94–2.84(m,2H),1.59–1.51(m,2H),0.65(t,J=7.3Hz,3H).
13C NMR(101MHz,Chloroform-d):δ159.26,148.44,145.88,140.78,133.58,130.04,129.72,129.62,129.54,128.90,128.86,128.26,127.28,125.37,121.67,115.59,115.43,38.53,23.18,13.97.
目标化合物18的合成
取20mL密封管,依次加入2-(1,3-二苯基-1H-吡唑-5-yl)苯胺(0.2mmol,62mg),对甲苯磺酸(0.2mmol,34mg),4-氯乙酰乙酸甲酯(0.2mmol,30mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率27%。
1H NMR(400MHz,Chloroform-d):δ8.20–8.13(m,1H),7.70(dd,J=6.6,3.0Hz,2H),7.66–7.54(m,6H),7.54–7.44(m,4H),7.31(ddd,J=8.3,7.2,1.2Hz,1H),4.74(s,2H).
13C NMR(101MHz,Chloroform-d):δ152.13,147.82,145.63,141.22,140.51,132.88,130.25,129.86,129.83,129.27,129.25,128.54,127.28,126.80,121.68,116.00,114.59,44.74.
目标化合物19的合成
取20mL密封管,依次加入2-(1,3-二苯基-1H-吡唑-5-yl)苯胺(0.2mmol,62mg),对甲苯磺酸(0.2mmol,34mg),4-甲氧基乙酰乙酸甲酯(0.2mmol,29mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到白色固体,收率74%。
1H NMR(400MHz,Chloroform-d):δ8.20(d,J=8.3Hz,1H),7.68(dd,J=7.5,2.0Hz,2H),7.66–7.53(m,6H),7.53–7.40(m,4H),7.34–7.24(m,1H),4.59(s,2H),3.14(s,3H).
13C NMR(101MHz,Chloroform-d):δ153.34,148.20,145.50,140.65,133.50,130.31,129.78,129.74,129.01,128.87,128.29,127.30,126.34,121.61,115.99,115.19,73.84,58.71.
目标化合物20的合成
取20mL密封管,依次加入2-(1,3-二苯基-1H-吡唑-5-yl)苯胺(0.2mmol,62mg),对甲苯磺酸(0.2mmol,34mg),异丁酰乙酸甲酯(0.2mmol,29mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到黄色固体,收率65%。
1H NMR(400MHz,Chloroform-d):δ8.10(d,J=8.4Hz,1H),7.66–7.50(m,8H),7.48–7.41(m,4H),7.23(s,1H),3.45–3.35(m,1H),1.19(d,J=3.9Hz,9H).
目标化合物21的合成
取20mL密封管,依次加入2-(1,3-二苯基-1H-吡唑-5-yl)苯胺(0.2mmol,62mg),对甲苯磺酸(0.2mmol,34mg),丙酰乙酸乙酯(0.2mmol,29mg),HFIP(1mL),100℃反应过夜。反应后处理:浓缩,进行硅胶柱层析(洗脱液为石油醚:乙酸乙酯=2:1)得到白色固体,收率57%。
1H NMR(400MHz,Chloroform-d):δ8.09(d,J=8.3Hz,1H),7.73–7.52(m,8H),7.52–7.40(m,4H),7.23(t,J=7.7Hz,1H),2.94(q,J=7.5Hz,2H),1.11(t,J=7.5Hz,3H).
13C NMR(101MHz,Chloroform-d):δ160.13,148.39,145.96,140.79,140.64,133.64,130.01,129.73,129.63,129.58,128.88,128.86,128.28,127.29,125.38,121.66,115.43,29.73,13.17.
上面结合实施例对本发明做了进一步的叙述,但本发明并不限于上述实施方式,在本领域的普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下做出各种变化。
Claims (5)
1.一种吡唑并喹啉类衍生物的合成方法,其采用的合成路线如下:
所述取代基R1选自苯基、甲基、对甲基苯基、邻甲基苯基、对甲氧基苯基、对氰基苯基、对氟苯基、对氯苯基、萘基中的一种;
所述取代基R2选自苯基、对甲基苯基、对氰基苯基、对氯苯基中的一种;
所述取代基R3选自苯基、对甲基苯基、对氯苯基、对氟苯基、对甲氧基苯基、正丙基、氯代甲基、甲氧基亚甲基、异丙基、乙基中的一种;
所述取代基R4代表烷基。
2.根据权利要求1所述的合成方法,其特征在于,所述取代基R4代表甲基或乙基。
3.根据权利要求1所述的合成方法,其特征在于,所述取代基R3代表苯基、取代基R4代表乙基。
4.根据权利要求1所述的合成方法,其特征在于,所述取代基R1、R2均代表苯基。
5.根据权利要求1所述的合成方法,其特征在于,反应温度设定为100℃。
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