CN110183341A - 1,2-二羰基类化合物及其合成方法 - Google Patents
1,2-二羰基类化合物及其合成方法 Download PDFInfo
- Publication number
- CN110183341A CN110183341A CN201910230599.0A CN201910230599A CN110183341A CN 110183341 A CN110183341 A CN 110183341A CN 201910230599 A CN201910230599 A CN 201910230599A CN 110183341 A CN110183341 A CN 110183341A
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- China
- Prior art keywords
- substituted phenyl
- dicarbonyl
- compound
- reaction
- thioester
- Prior art date
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- -1 1,2- dicarbapentaborane class compound Chemical class 0.000 title claims abstract description 124
- 238000010189 synthetic method Methods 0.000 title claims abstract description 5
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 131
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 118
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 71
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 54
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 33
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 20
- IMEVSAIFJKKDAP-UHFFFAOYSA-N 4-methoxy-2-(4-methoxypyridin-2-yl)pyridine Chemical compound COC1=CC=NC(C=2N=CC=C(OC)C=2)=C1 IMEVSAIFJKKDAP-UHFFFAOYSA-N 0.000 claims description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 18
- QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 claims description 18
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical group 0.000 claims description 16
- 125000001041 indolyl group Chemical group 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 12
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- 239000000654 additive Substances 0.000 claims description 11
- 230000000996 additive effect Effects 0.000 claims description 11
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 11
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 11
- 239000011736 potassium bicarbonate Substances 0.000 claims description 11
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 10
- 125000001624 naphthyl group Chemical group 0.000 claims description 10
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 9
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 6
- 229950009195 phenylpropanol Drugs 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001308 synthesis method Methods 0.000 claims description 5
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 claims description 4
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims description 3
- 229960001701 chloroform Drugs 0.000 claims description 3
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- QSOKECQNOMLOPU-UHFFFAOYSA-N CC.CPC Chemical compound CC.CPC QSOKECQNOMLOPU-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical compound Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 claims description 2
- OZMJLTLNHVBQMB-UHFFFAOYSA-N dimethylphosphane propane Chemical compound CCC.CPC OZMJLTLNHVBQMB-UHFFFAOYSA-N 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims 2
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 claims 1
- CSIFGMFVGDBOQC-UHFFFAOYSA-N 3-iminobutanenitrile Chemical compound CC(=N)CC#N CSIFGMFVGDBOQC-UHFFFAOYSA-N 0.000 claims 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims 1
- QYJPSWYYEKYVEJ-FDGPNNRMSA-L copper;(z)-4-oxopent-2-en-2-olate Chemical compound [Cu+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O QYJPSWYYEKYVEJ-FDGPNNRMSA-L 0.000 claims 1
- 229960003280 cupric chloride Drugs 0.000 claims 1
- 229960004643 cupric oxide Drugs 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 239000004156 Azodicarbonamide Substances 0.000 abstract 1
- HMCAIOZZHFFUPV-UHFFFAOYSA-N BBBCC Chemical compound BBBCC HMCAIOZZHFFUPV-UHFFFAOYSA-N 0.000 abstract 1
- 235000019399 azodicarbonamide Nutrition 0.000 abstract 1
- 239000004327 boric acid Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 168
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 45
- 238000005160 1H NMR spectroscopy Methods 0.000 description 43
- 238000004440 column chromatography Methods 0.000 description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 239000003960 organic solvent Substances 0.000 description 39
- 239000000741 silica gel Substances 0.000 description 39
- 229910002027 silica gel Inorganic materials 0.000 description 39
- 238000000746 purification Methods 0.000 description 35
- 238000000926 separation method Methods 0.000 description 32
- 239000007832 Na2SO4 Substances 0.000 description 30
- 239000007787 solid Substances 0.000 description 27
- 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 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
- 238000001514 detection method Methods 0.000 description 19
- 238000007865 diluting Methods 0.000 description 19
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 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 15
- 229960004192 diphenoxylate Drugs 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 15
- 238000010791 quenching Methods 0.000 description 15
- 230000000171 quenching effect Effects 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000000605 extraction Methods 0.000 description 12
- 238000002156 mixing Methods 0.000 description 11
- 239000000126 substance Substances 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 8
- 125000004989 dicarbonyl group Chemical group 0.000 description 8
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 8
- 238000002390 rotary evaporation Methods 0.000 description 5
- VOXXGUAZBWSUSS-UHFFFAOYSA-N 2,4,6-triphenyl-1,3,5,2,4,6-trioxatriborinane Chemical compound O1B(C=2C=CC=CC=2)OB(C=2C=CC=CC=2)OB1C1=CC=CC=C1 VOXXGUAZBWSUSS-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Chemical group CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 150000007970 thio esters Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methyl-N-phenylamine Natural products CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 2
- 239000005751 Copper oxide Substances 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
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- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
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- 229940126650 Compound 3f Drugs 0.000 description 1
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- XJTWGMHOQKGBDO-GOSISDBHSA-N N-[(3-Fluorophenyl)methyl]-1-[(1r)-1-Naphthalen-1-Ylethyl]piperidine-4-Carboxamide Chemical compound C1CN([C@H](C)C=2C3=CC=CC=C3C=CC=2)CCC1C(=O)NCC1=CC=CC(F)=C1 XJTWGMHOQKGBDO-GOSISDBHSA-N 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- KSCRVOKQPYZBHZ-IXPOFIJOSA-N benzyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@H]1C(NCC1)=O)C(=O)C=1SC2=CC=CC=C2N=1)C(C)C)C(=O)OCC1=CC=CC=C1 KSCRVOKQPYZBHZ-IXPOFIJOSA-N 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
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
- 229960004979 fampridine Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- XNFNGGQRDXFYMM-PPHPATTJSA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate;hydrochloride Chemical compound Cl.C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 XNFNGGQRDXFYMM-PPHPATTJSA-N 0.000 description 1
- VXYFARNRGZWHTJ-FVGYRXGTSA-N methyl (2s)-2-amino-3-(4-hydroxyphenyl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VXYFARNRGZWHTJ-FVGYRXGTSA-N 0.000 description 1
- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 description 1
- KUGLDBMQKZTXPW-JEDNCBNOSA-N methyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)C(C)C KUGLDBMQKZTXPW-JEDNCBNOSA-N 0.000 description 1
- DODCBMODXGJOKD-RGMNGODLSA-N methyl (2s)-2-amino-4-methylpentanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC(C)C DODCBMODXGJOKD-RGMNGODLSA-N 0.000 description 1
- MEVUPUNLVKELNV-JEDNCBNOSA-N methyl (2s)-2-amino-4-methylsulfanylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CCSC MEVUPUNLVKELNV-JEDNCBNOSA-N 0.000 description 1
- HQEIPVHJHZTMDP-JEDNCBNOSA-N methyl (2s)-pyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@@H]1CCCN1 HQEIPVHJHZTMDP-JEDNCBNOSA-N 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 229960003732 tyramine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Abstract
本发明公开了一种1,2‑二羰基类化合物(1,2‑二羰基酰胺或α‑二酮类化合物)的合成方法,以1,2‑二羰基硫酯类化合物作为1,2‑二羰基试剂,在适当条件下,与胺类化合物或者硼酸酐类化合物反应,分别可以合成一系列1,2‑二羰基类化合物。本发明利用稳定的1,2‑二羰基硫酯类化合物作为二羰基化试剂,在温和条件下,一步构建得到1,2‑二羰基类化合物,避免了传统使用不稳定的α‑羰基酰氯合成1‑2二羰基化合物的弊端。
Description
技术领域
本发明属于有机化合物合成及应用技术领域,涉及1,2-二羰基类化合物及其合成方法。
背景技术
1,2-二羰基类化合物是一类非常重要的化合物,尤其是在天然产物、药物分子中被广泛应用。发展一类稳定、具有广泛用途的1,2-二羰基试剂显得尤为重要。
合成1,2-二羰基类化合物的方法主要是通过α-羰基酰氯转化而来。然而,α-羰基酰氯的制备方法不仅使用污染刺激性的试剂,而且它自身存在不稳定、副反应较多等居多缺点。因此,发展一种化学稳定,而且具有广谱用途的1,2-二羰基试剂具有重要意义。
发明内容
为了克服现有技术的上述缺陷,本发明创新性地提出了一种1,2-二羰基硫酯类化合物在温和条件下,直接高效的构建1,2-二羰基类化合物(1,2-二羰基酰胺或α-二酮类化合物)的方法。本发明的合成方法简单,原料廉价易得,底物普适性广,产率(33%-96%)较好。
本发明提出了一种1,2-二羰基类化合物(1,2-二羰基酰胺类化合物)的合成方法,在溶剂中,以1,2-二羰基硫酯化合物与胺类化合物为反应原料,在添加剂的作用下,反应得到如式(1)所示的1,2-二羰基酰胺类化合物,所述反应过程如下反应式(A)所示:
其中,
Ar为苯基、C1-C10烷基取代的苯基、C1-C10烷氧基取代的苯基、卤素取代的苯基、甲砜基取代的苯基、氰基取代的苯基、甲酯基取代的苯基、羟基取代的苯基、呋喃基、苯并呋喃基、吲哚基。
R,R1,R2分别独立地选自氢、D-苯丙醇、苯基、苄基、呋喃环、苯并呋喃环、吲哚环、C1-C18烷基、C1-C10烷基取代的苯基、C1-C10烷氧基取代的苯基、卤素取代的苯基、烯丙基及其衍生物、炔丙基、α-甲基苯乙基。
优选地,
Ar为苯基、C1-C5烷基取代的苯基、C1-C5烷氧基取代的苯基、卤素取代的苯基、甲砜基取代的苯基、氰基取代的苯基、甲酯基取代的苯基、羟基取代的苯基、呋喃基、苯并呋喃基、吲哚基。
R,R1,R2分别独立地选自氢、D-苯丙醇、苯基、苄基、呋喃环、苯并呋喃环、吲哚环、十八烷基、甲基、乙基、正丁烷基、环己烷基、叔丁基、甲基取代的苯基、甲氧基取代的苯基、氯取代的苯基、烯丙基、二甲基烯丙基、炔丙基、α-甲基苯乙基。
本发明中,所述反应的温度为20-120℃;优选地,为45℃。
本发明中,所述反应的时间为1-15小时;优选地,为12小时。
本发明中,所述溶剂选自乙腈、二氧六环、甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、四氢呋喃、1,4-二氧六环、环戊基甲醚、乙醚、叔丁基甲醚、乙酸乙酯、苯、苯甲腈、四氯化碳、二硫化碳、二氯甲烷、三氯甲烷等中的一种或多种;优选地,为四氢呋喃。
本发明中,所述添加剂选自4-二甲胺基吡啶、吡啶、三乙胺、硫酸钠、噻吩-2-甲酸亚铜、硫酸铜、碘化亚铜、溴化亚铜、氯化亚铜、三氟甲磺酸亚铜、三氟甲磺酸铜、氯化铜、溴化铜、乙酰丙酮铜、氧化铜等中的一种或多种;优选地,为4-二甲胺基吡啶或噻吩-2-甲酸亚铜。
本发明中,所述添加剂与所述1,2-二羰基硫酯的摩尔比为1∶(1-10);优选地,为1∶5。
本发明中,所述反应优选在氮气保护下进行。
本发明还提出了一种1,2-二羰基类化合物(α-二酮类化合物)的合成方法,在溶剂中,以1,2-二羰基硫酯化合物与硼酸酐类化合物为反应原料,在在催化剂、配体、碱、添加剂的作用下,反应得到如式(2)所示的α-二酮类化合物类化合物,所述反应过程如下反应式(B)所示:
其中,
Ar、Ar1分别独立地选自苯基、C1-C10烷基取代的苯基、C1-C10烷氧基取代的苯基、卤素取代的苯基、甲硫基取代的苯基、3,4-二亚甲氧基取代的苯基、甲砜基取代的苯基、氰基取代的苯基、甲酯基取代的苯基、羟基取代的苯基、萘基、呋喃基、苯并呋喃基、吲哚基、萘基。
R为苄基、C1-C10烷基取代的苄基、硝基取代的苄基、酯基取代的苄基、卤素取代的苄基、C1-C10烷基、烯丙基及其衍生物、炔丙基、α-甲基苯乙基。
优选地,
Ar、Ar1分别独立地选自苯基、甲氧基取代的苯基、甲硫基取代的苯基、3,4-二亚甲氧基取代的苯基、甲基取代的苯基、萘基、呋喃基、苯并呋喃基、甲酸乙酯基取代的苯基。
R为苄基、4-甲基苄基、4-硝基苄基、4-甲酯基苄基、4-氟苄基、乙基、正丁基、烯丙基及其衍生物、炔丙基、α-甲基苯乙基。
本发明中,所述溶剂选自乙腈、二氧六环、甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、四氢呋喃、1,4-二氧六环、环戊基甲醚、乙醚、叔丁基甲醚、乙酸乙酯、苯、苯甲腈、四氯化碳、二硫化碳、二氯甲烷、三氯甲烷等中的一种或多种;优选地,为四氢呋喃。
本发明中,所述添加剂选自4-二甲胺基吡啶、吡啶、三乙胺、硫酸钠、噻吩-2-甲酸亚铜、硫酸铜、碘化亚铜、溴化亚铜、氯化亚铜、三氟甲磺酸亚铜、三氟甲磺酸铜、氯化铜、溴化铜、乙酰丙酮铜、氧化铜等中的一种或多种;优选地,为4-二甲胺基吡啶或噻吩-2-甲酸亚铜。
本发明中,所述配体选自4,4′-二甲氧基-2,2′-联吡啶、联吡啶、4,4′-二甲基-2,2′-联吡啶、1,10-菲罗啉、三苯基膦、三叔丁基膦、三环己基膦、1,2-双(二甲基膦)乙烷、1,2-双(二甲基膦)丙烷等中的一种或多种;优选地,为4,4′-二甲氧基-2,2′-联吡啶。
本发明中,所述催化剂选自醋酸钯、氯化钯、四三苯基膦钯、乙酰丙酮钯、双(二亚苄基丙酮)钯、三(二亚苄基丙酮)二钯、四三苯基膦二氯化钯、烯丙基氯化钯、二乙腈氯化钯、钯碳等中的一种或多种;优选地,为三(二亚苄基丙酮)二钯。
本发明中,所述碱选自碳酸钾、碳酸钠、碳酸锂、碳酸氢钾、碳酸氢钠、碳酸氢锂、磷酸钾、磷酸氢钾、氢氧化钾、氢氧化钠、三乙胺、二异丙基乙基胺、甲酸钠、甲酸钾、醋酸钠、醋酸钾、氢氧化锂、醋酸锂、1,8-二氮杂二环十一碳-7-烯(DBU)、4-二甲氨基吡啶(DMAP)等中的一种或多种;优选地,为碳酸钾。
本发明中,所述1,2-二羰基硫酯与所述催化剂的摩尔比为(1-20)∶1;优选地,为20∶1。
本发明中,所述1,2-二羰基硫酯与所述配体的摩尔比为(1-20)∶1;优选地,为10∶1。
本发明中,所述1,2-二羰基硫酯与所述碱的摩尔比为1∶(1-5);优选地,为1∶1.5。
本发明中,所述所述添加剂与所述1,2-二羰基硫酯的摩尔比为1∶(1-10);优选地,为1∶5。
本发明中,所述反应的温度为20-120℃;优选地,为45℃。
本发明中,所述反应的时间为1-15小时;优选地,为12小时。
本发明中,所述反应优选在氮气保护下进行。
本发明还提出了如式(2)所示的1,2-二羰基酰胺类化合物,其结构如下式所示:
其中,
Ar为苯基、C1-C10烷基取代的苯基、C1-C10烷氧基取代的苯基、卤素取代的苯基、甲砜基取代的苯基、氰基取代的苯基、甲酯基取代的苯基、羟基取代的苯基、呋喃基、苯并呋喃基、吲哚基。
R1,R2分别独立地选自氢、D-苯丙醇、苯基、苄基、呋喃环、苯并呋喃环、吲哚环、C1-C18烷基、C1-C10烷基取代的苯基、C1-C10烷氧基取代的苯基、卤素取代的苯基、烯丙基及其衍生物、炔丙基、α-甲基苯乙基。
优选地,
Ar为苯基、C1-C5烷基取代的苯基、C1-C5烷氧基取代的苯基、卤素取代的苯基、甲砜基取代的苯基、氰基取代的苯基、甲酯基取代的苯基、羟基取代的苯基、呋喃基、苯并呋喃基、吲哚基。
R1,R2分别独立地选自氢、D-苯丙醇、苯基、苄基、呋喃环、苯并呋喃环、吲哚环、十八烷基、甲基、乙基、正丁烷基、环己烷基、叔丁基、甲基取代的苯基、甲氧基取代的苯基、氯取代的苯基、烯丙基、二甲基烯丙基、炔丙基、α-甲基苯乙基。
本发明还提出了如式(3)所示的α-二酮类化合物,其结构如下式所示:
其中,
Ar、Ar1分别独立地选自苯基、C1-C10烷基取代的苯基、C1-C10烷氧基取代的苯基、卤素取代的苯基、甲硫基取代的苯基、3,4-二亚甲氧基取代的苯基、甲砜基取代的苯基、氰基取代的苯基、甲酯基取代的苯基、羟基取代的苯基、萘基、呋喃基、苯并呋喃基、吲哚基、萘基。
优选地,
Ar、Ar1分别独立地选自苯基、甲氧基取代的苯基、甲硫基取代的苯基、3,4-二亚甲氧基取代的苯基、甲基取代的苯基、萘基、呋喃基、苯并呋喃基、甲酸乙酯基取代的苯基。
本发明的有益效果在于:本发明创新性地提出了一种1,2-二羰基硫酯类化合物在温和条件下,一步方便高效构建1,2-二羰基类化合物的方法。避免了传统使用不稳定的α-羰基酰氯合成1-2二羰基化合物的弊端。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁鉴定。
在实施例1~25,反应温度为25℃;在实施例26~40中,反应温度为45℃。
实施例1
化合物2a的合成:
将双羰基硫酯1a(0.2mmol),THF(2mL)加入到放置有磁子的反应管中,橡胶塞密闭,室温下向其中通入氨气鼓泡15分钟继续反应3小时后,再向其中鼓泡一次,点板检测待反应完全后用乙酸乙酯稀释,旋转蒸发仪去除有机溶剂后用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2a,产率79%,淡黄色固体。1H NMR(400MHz,CDCl3)δ8.43-8.15(m,2H),7.79-7.58(m,1H),7.47(t,J=7.7Hz,2H),7.08(s,1H),6.48(s,1H).13C NMR(100MHz,CDCl3)δ187.5,164.2,134.5,132.9,131.0,128.5.MS(EI)m/z 149(M+).
实施例2
化合物2b的合成:
将双羰基硫酯1a(0.2mmol),D-苯丙氨醇(0.2mmol)与THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待反应完全后用二氯甲烷稀释,旋转蒸发仪去除有机溶剂后用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2b,产率85%,白色固体。1H NMR(400MHz,CDCl3)δ8.18(d,J=7.4Hz,2H),7.60(t,J=7.4Hz,1H),7.48-7.35(m,3H),7.34-7.21(m,5H),4.37-4.25(m,1H),3.72(ddd,J=16.1,11.2,4.3Hz,2H),3.03-2.89(m,2H),2.65(s,1H).13C NMR(100MHz,CDCl3)δ187.9,162.1,137.2,134.4,133.1,131.1,129.2,128.7,128.4,126.7,63.5,52.8,37.0.MS(EI)m/z 283(M+).
实施例3
化合物2c的合成:
将双羰基硫酯1a(0.2mmol),十八胺(0.2mmol,1.0equiv)与THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待反应完全后用二氯甲烷稀释,旋转蒸发仪去除有机溶剂后用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2c,产率65%,白色固体。1H NMR(400MHz,CDCl3)δ8.37-8.29(m,2H),7.61(t,J=7.4Hz,1H),7.46(t,J=7.8Hz,2H),7.12(s,1H),3.37(dd,J=13.6,6.9Hz,2H),1.65-1.53(m,2H),1.36-1.17(m,30H),0.87(t,J=6.8Hz,3H).13C NMR(100MHz,CDCl3)δ187.9,161.7,134.3,133.4,131.2,128.4,39.4,31.9,29.7,29.6(3),29.6(0),29.5(4),29.5,29.3(3),29.3,29.2,26.9,22.7,14.1.HRMS(EI)Calcd for C26H43NO2401.3294,Found 401.3296.
实施例4
化合物2d的合成:
将双羰基硫酯1a(0.2mmol),2-丁胺(0.2mmol,1.0equiv)与THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待反应完全后用二氯甲烷稀释,旋转蒸发仪去除有机溶剂后用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2d,产率74%,无色油状物。1H NMR(400MHz,CDCl3)δ8.35-8.29(m,2H),7.63-7.57(m,1H),7.46(t,J=7.6Hz,2H),6.91(s,1H),4.04-3.93(m,1H),1.57(p,J=7.3Hz,2H),1.24-1.19(m,3H),0.95(t,J=7.4Hz,3H).13CNMR(100MHz,CDCl3)δ188.1,161.2,134.2,133.4,131.1,128.4,46.9,29.4,20.1,10.3.MS(EI)m/z 205(M+).
实施例5
化合物2e的合成:
将双羰基硫酯1a(0.2mmol),环己胺(0.2mmol,1.0equiv)与THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待反应完全后用二氯甲烷稀释,旋转蒸发仪去除有机溶剂后用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2e,产率80%,淡黄色固体。1H NMR(400MHz,CDCl3)δ8.32(d,J=7.3Hz,2H),7.59(d,J=7.4Hz,1H),7.46(t,J=7.8Hz,2H),6.98(s,1H),3.90-3.78(m,1H),2.03-1.92(m,2H),1.80-1.71(m,2H),1.68-1.58(m,1H),1.47-1.33(m,2H),1.32-1.18(m,3H).13C NMR(100MHz,CDCl3)δ188.1,160.8,134.2,133.4,131.1,128.4,48.4,32.6,25.4,24.7.MS(EI)m/z 231(M+).
实施例6
化合物2f的合成:
将双羰基硫酯1a(0.2mmol),叔丁胺(0.2mmol,1.0equiv),DMAP(0.06mmol,30mol%)与THF(2mL)加入到放置有磁子的反应管中,室温下反应34小时,点板检测待反应完全后用二氯甲烷稀释,旋转蒸发仪去除有机溶剂后用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2f,产率57%,淡黄色固体。1H NMR(400MHz,CDCl3)δ8.29(d,J=7.7Hz,2H),7.60(t,J=7.4Hz,1H),7.46(t,J=7.7Hz,2H),6.93(s,1H),1.45(s,9H).13CNMR(100MHz,CDCl3)δ188.6,161.1,134.1,133.4,131.2,128.3,51.6,28.4.MS(EI)m/z 205(M+).
实施例7
化合物2g的合成:
将双羰基硫酯1a(0.2mmol),苄胺(0.2mmol,1.0equiv)与THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待反应完全后用二氯甲烷稀释,旋转蒸发仪去除有机溶剂后用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2g,产率89%,白色固体。1H NMR(400MHz,CDCl3)δ8.39-8.32(m,2H),7.66-7.59(m,1H),7.51-7.41(m,3H),7.39-7.28(m,5H),4.57(d,J=6.1Hz,2H).13C NMR(100MHz,CDCl3)δ187.5,161.6,137.1,134.4,133.3,131.2,128.8,128.5,127.8(4),127.8,43.4.MS(EI)m/z 239(M+).
实施例8
化合物2h的合成:
将双羰基硫酯1a(0.2mmol),六氢吡啶(0.2mmol,1.0equiv)与THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待反应完全后用二氯甲烷稀释,旋转蒸发仪去除有机溶剂后用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2h,产率91%,无色油状物。1H NMR(400MHz,CDCl3)δ7.97-7.88(m,2H),7.66-7.57(m,1H),7.49(t,J=7.7Hz,2H),3.68(s,2H),3.31-3.22(m,2H),1.72-1.61(m,4H),1.52(s,2H).13C NMR(100MHz,CDCl3)δ191.9,165.4,134.6,133.2,129.5,128.9,46.9,42.0,26.1,25.3,24.3.MS(EI)m/z 217(M+).
实施例9
化合物2i的合成:
将双羰基硫酯1a(0.2mmol),吗啡啉(0.2mmol,1.0equiv)与THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待反应完全后用二氯甲烷稀释,旋转蒸发仪去除有机溶剂后用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2i,产率84%,淡黄色油状物。1H NMR(400MHz,CDCl3)δ7.98-7.91(m,2H),7.64(t,J=7.4Hz,1H),7.51(t,J=7.7Hz,2H),3.78(s,4H),3.66-3.61(m,2H),3.40-3.34(m,2H).13C NMR(100MHz,CDCl3)δ191.1,165.4,134.9,133.0,129.6,129.0,66.7,66.6,46.2,41.6.MS(EI)m/z 219(M+).
实施例10
化合物2j的合成:
将双羰基硫酯1a(0.2mmol),二丁胺(0.2mmol,1.0equiv)与THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待反应完全后用二氯甲烷稀释,旋转蒸发仪去除有机溶剂后用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2j,产率86%,黄色油状物。1H NMR(400MHz,CDCl3)δ7.94-7.88(m,2H),7.61(t,J=7.4Hz,1H),7.48(t,J=7.8Hz,2H),3.52-3.44(m,2H),3.16-3.09(m,2H),1.65(tt,J=7.8,6.6Hz,2H),1.52(tt,J=7.8,6.7Hz,2H),1.45-1.35(m,2H),1.22-1.11(m,2H),0.97(t,J=7.4Hz,3H),0.79(t,J=7.4Hz,3H).13C NMR(100MHz,CDCl3)δ191.5,167.0,134.4,133.3,129.5,128.8,47.4,44.0,30.6,29.4,20.2,19.7,13.8,13.5.MS(EI)m/z 261(M+).
实施例11
化合物2k的合成:
将双羰基硫酯1a(0.2mmol),对甲苯胺(0.2mmol,1.0equiv),DMAP(0.06mmol,30mol%)与THF(2mL)加入到放置有磁子的反应管中,室温下搅拌34小时,点板检测反应1a转化完全后,用二氯甲烷稀释,旋蒸除去有机溶剂后,用硅胶柱进行柱层析纯化分离得到目标产物2k,产率80%,黄色固体。1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.44-8.38(m,2H),7.68-7.62(m,1H),7.59(d,J=8.4Hz,2H),7.53-7.46(m,2H),7.19(d,J=8.2Hz,2H),2.35(s,3H).13C NMR(100MHz,CDCl3)δ187.5,158.8,135.0,134.5,134.1,133.1,131.4,129.6,128.5,119.9,20.9.MS(EI)m/z 239(M+).
实施例12
化合物2l的合成:
将双羰基硫酯1a(0.2mmol),2-甲苯胺(0.2mmol,1.0equiv),DMAP(0.06mmol,30mol%)溶于1mL甲苯,加热至80℃下反应48小时,点板检测反应1a转化完全后,用二氯甲烷稀释,旋蒸除去有机溶剂后,用硅胶柱进行柱层析纯化分离得到目标产物2l,产率90%,淡黄色固体。1H NMR(400MHz,CDCl3)δ8.93(s,1H),8.49-8.40(m,2H),8.11(d,J=8.0Hz,1H),7.70-7.63(m,1H),7.52(t,J=7.8Hz,2H),7.32-7.22(m,2H),7.14(td,J=7.5,0.8Hz,1H),2.38(s,3H).13C NMR(100MHz,CDCl3)δ187.5,158.9,134.6(2),134.6(0),133.1,131.5,130.7,128.7,128.6,126.9,125.7,121.7,17.6.MS(EI)m/z239(M+).
实施例13
化合物2m的合成:
将双羰基硫酯1a(0.2mmol),对甲氧基苯胺(0.2mmol,1.0equiv)与THF(2mL)加入到放置有磁子的反应管中,室温下搅拌34小时,点板检测反应1a转化完全后,用二氯甲烷稀释,旋蒸除去有机溶剂后,用硅胶柱进行柱层析纯化分离得到目标产物2m,产率96%,黄色固体。1H NMR(400MHz,CDCl3)δ8.91(s,1H),8.45-8.36(m,2H),7.71-7.58(m,3H),7.54-7.46(m 2H),6.97-6.88(m,2H),3.82(s,3H).13C NMR(100MHz,CDCl3)δ187.6,158.6,157.0,134.5,133.1,131.4,129.7,128.5,121.4,114.3),55.4.MS(EI)m/z 255(M+).
实施例14
化合物2n的合成:
将双羰基硫酯1a(0.2mmol),对氯苯胺(0.2mmol,1.0equiv),DMAP(0.06mmol,30mol%),K2CO3(0.1mmol,1.0equiv)溶于1mL甲苯,加热至80℃下反应48小时,点板检测反应1a转化完全后,用二氯甲烷稀释,旋蒸除去有机溶剂后,用硅胶柱进行柱层析纯化分离得到目标产物2n,产率83%,淡黄色固体。1H NMR(400MHz,CDCl3)δ8.99(s,1H),8.44-8.37(m,2H),7.71-7.63(m,3H),7.52(t,J=7.8Hz,2H),7.39-7.33(m,2H).13C NMR(100MHz,CDCl3)δ187.0,158.7,135.2,134.8,132.9,131.5,130.4,129.3128.6,121.1.MS(EI)m/z 259(M+).
实施例15
化合物2o的合成:
将双羰基硫酯1b(0.2mmol),N-甲基苯胺(0.2mmol,1.0equiv),DMAP(0.06mmol,30mol%)溶于1mL甲苯,加热至80℃下反应48小时,点板检测反应1b转化完全后,用二氯甲烷稀释,旋蒸除去有机溶剂后,用硅胶柱进行柱层析纯化分离得到目标产物2o,产率33%,黄色油状物。1H NMR(400MHz,CDCl3)δ7.89-7.83(m,2H),7.57(t,J=7.4Hz,1H),7.44(t,J=7.8Hz,2H),7.22(t,J=7.7Hz,3H),7.16-7.11(m,2H),3.49(s,3H).13C NMR(100MHz,CDCl3)δ190.8,167.1,141.20,134.2,133.6,129.5,129.4,128.7,128.1,126.8,36.2.MS(EI)m/z239(M+).
实施例16
化合物2p的合成:
将双羰基硫酯1a(0.2mmol),甘氨酸甲酯盐酸盐(0.2mmol,1.0equiv),碳酸氢钾(0.2mmol,1.0equiv),THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待双羰基硫酯全部转化完全后,DCM稀释,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2p,产率77%,黄色油状物。1H NMR(400MHz,CDCl3)δ7.89-7.83(m,2H),7.57(t,J=7.4Hz,1H),7.44(t,J=7.8Hz,2H),7.22(t,J=7.7Hz,3H),7.16-7.11(m,2H),3.49(s,3H).13C NMR(100MHz,CDCl3)δ8.32-8.26(m,2H),7.68-7.57(m,2H),7.49-7.43(m,2H),4.16(d,J=5.7Hz,2H),3.77(s,3H).13C NMR(100MHz,CDCl3)δ186.8,169.4,161.9,134.5,133.0,131.1,128.5,52.5,41.0.MS(EI)m/z221(M+).
实施例17
化合物2q的合成:
将双羰基硫酯1a(0.2mmol),L-亮氨酸甲酯盐酸盐(0.2mmol,1.0equiv),碳酸氢钾(0.2mmol,1.0equiv),THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待双羰基硫酯全部转化完全后,DCM稀释,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2q,产率83%,黄色油状物。1H NMR(400MHz,CDCl3)δ8.35-8.25(m,2H),7.60(t,J=7.4Hz,1H),7.51-7.41(m,3H),4.70(td,J=8.8,5.0Hz,1H),3.75(s,3H),1.78-1.62(m,3H),0.96(t,J=5.4Hz,6H).13C NMR(100MHz,CDCl3)δ187.0,172.4,161.4,134.4,133.1(3),131.1(1),128.4,52.4,50.7,41.3,24.8,22.7,21.8.MS(EI)m/z 277(M+).
实施例18
化合物2r的合成:
将双羰基硫酯1a(0.2mmol),L-异亮氨酸甲酯盐酸盐(0.2mmol,1.0equiv),碳酸氢钾(0.2mmol,1.0equiv),THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待双羰基硫酯全部转化完全后,DCM稀释,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2r,产率75%,白色固体。1H NMR(400MHz,CDCl3)δ8.31(dt,J=8.5,1.5Hz,2H),7.64-7.58(m,1H),7.54(d,J=8.5Hz,1H),7.49-7.43(m,1H),4.64(dd,J=8.9,5.0Hz,1H),3.76(s,3H),2.06-1.94(m,1H),1.53-1.47(m,1H),1.28-1.22(m,1H),0.99-0.91(m,6H).13C NMR(100MHz,CDCl3)δ187.0,171.4,161.4,134.4,133.2,131.1,128.5,56.5,52.2,37.9,25.1,15.5,11.5.MS(EI)m/z 277(M+).
实施例19
化合物2s的合成:
将双羰基硫酯1a(0.2mmol),L-缬氨酸甲酯盐酸盐(0.2mmol,1.0equiv),碳酸氢钾(0.2mmol,1.0equiv),THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待双羰基硫酯全部转化完全后,DCM稀释,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2s,产率77%,白色固体。1H NMR(400MHz,CDCl3)δ8.34-8.28(m,2H),7.64-7.58(m,1H),7.52(d,J=8.4Hz,1H),7.49-7.43(m,2H),4.60(dd,J=9.1,5.0Hz,1H),3.77(s,3H),2.33-2.23(m,1H),0.99(dd,J=11.9,6.9Hz,6H).13C NMR(100MHz,CDCl3)δ187.0,171.4,161.5,134.4,133.2,131.1,128.5,57.3,52.3,31.4,19.0,17.7.MS(EI)m/z 263(M+).
实施例20
化合物2t的合成:
将双羰基硫酯1a(0.2mmol),L-蛋氨酸甲酯盐酸盐(0.2mmol,1.0equiv),碳酸氢钾(0.2mmol,1.0equiv),THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待双羰基硫酯全部转化完全后,DCM稀释,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2t,产率74%,黄色油状物。1H NMR(400MHz,CDCl3)δ8.30(d,J=7.5Hz,2H),7.71(d,J=7.9Hz,1H),7.61(t,J=7.4Hz,1H),7.46(t,J=7.8Hz,2H),4.80(td,J=7.8,5.2Hz,1H),3.78(s,3H),2.56(t,J=7.4Hz,2H),2.25(dtd,J=12.8,7.5,5.2Hz,1H),2.15-2.04(m,4H).13C NMR(100MHz,CDCl3)δ186.8,171.4,161.5,134.5,133.0,131.1,128.5,52.6,51.5,31.4,29.9,15.4.HRMS(EI)Calcd for C14H17NO4S295.0878,Found 295.0876.
实施例21
化合物2u的合成:
将双羰基硫酯1a(0.2mmol),L-丝氨酸甲酯盐酸盐(0.2mmol,1.0equiv),碳酸氢钾(0.2mmol,1.0equiv),THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待双羰基硫酯全部转化完全后,DCM稀释,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2u,产率78%,白色固体。1H NMR(400MHz,CDCl3)δ8.27(dd,J=8.3,1.2Hz,2H),7.93(d,J=7.6Hz,1H),7.65-7.58(m,1H),7.46(t,J=7.8Hz,2H),4.78-4.71(m,1H),4.10(dd,J=11.4,3.8Hz,1H),3.99(dd,J=11.4,3.5Hz,1H),3.80(s,3H),2.69(s,1H).13C NMR(100MHz,CDCl3)δ187.2,170.1,162.1,134.6,133.0,131.1,128.5,62.7,54.6,52.9.HRMS(EI)Calcd for C12H13NO5251.0794,Found 251.0791.
实施例22
化合物2v的合成:
将双羰基硫酯1a(0.2mmol),L-酪氨酸甲酯盐酸盐(0.2mmol,1.0equiv),碳酸氢钾(0.2mmol,1.0equiv),THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待双羰基硫酯全部转化完全后,DCM稀释,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2v,产率89%,黄色油状物。1H NMR(400MHz,CDCl3)δ8.17(d,J=8.2Hz,2H),7.59(t,J=7.4Hz,1H),7.53(d,J=8.0Hz,1H),7.43(t,J=7.7Hz,2H),6.98(d,J=8.4Hz,2H),6.71(d,J=8.4Hz,2H),6.56(s,1H),4.94-4.86(m,1H),3.74(s,3H),3.10(ddd,J=20.8,14.1,6.1Hz,2H).13C NMR(100MHz,CDCl3)δ187.1,171.3,161.7,155.3,134.6,132.8,131.0,130.3,128.5,126.7,115.7,53.4,52.6,37.1.HRMS(EI)Calcd for C18H17NO5327.1107,Found 327.1110.
实施例23
化合物2w的合成:
将双羰基硫酯1a(0.2mmol),L-色氨酸甲酯盐酸盐(0.2mmol,1.0equiv),碳酸氢钾(0.2mmol,1.0equiv),THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待双羰基硫酯全部转化完全后,DCM稀释,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2w,产率79%,黄色油状物。1H NMR(400MHz,CDCl3)δ8.30(s,1H),8.27-8.20(m,2H),7.64-7.53(m,3H),7.44(dd,J=10.8,4.9Hz,2H),7.32(d,J=8.1Hz,1H),7.21-7.15(m,1H),7.14-7.08(m,1H),7.02(d,J=2.4Hz,1H),5.01(dt,J=8.2,5.7Hz,1H),3.71(s,3H),3.42(d,J=5.7Hz,2H).13C NMR(100MHz,CDCl3)δ187.1,171.5,161.5,136.1,134.4,133.0,131.0,128.4,127.2,123.0,122.2,119.6,118.4,111.3,109.3,52.8,52.5,27.6.HRMS(EI)Calcd for C20H18N2O4350.1267,Found 350.1271.
实施例24
化合物2x的合成:
将双羰基硫酯1a(0.2mmol),L-脯氨酸甲酯盐酸盐(0.2mmol,1.0equiv),碳酸氢钾(0.2mmol,1.0equiv),THF(2mL)加入到放置有磁子的反应管中,室温下过夜反应,点板检测待双羰基硫酯全部转化完全后,DCM稀释,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标双羰基酰胺化合物2x,产率70%,无色油状物。1H NMR(400MHz,CDCl3)δ8.09-8.05(m,2H),7.66-7.61(m,1H),7.51(dd,J=10.7,4.7Hz,2H),4.66(dd,J=8.8,3.9Hz,1H),3.81(s,3H),3.63-3.49(m,2H),2.37-2.15(m,2H),2.00-1.94(m,2H).13CNMR(100MHz,CDCl3)δ190.2,171.9,164.4,134.2,133.2,130.4,128.5,58.2,52.3,46.5,31.0,24.6.Rotamer B1H NMR(400MHz,CDCl3)δ8.04-8.00(m,2H),7.60-7.57(m,1H),7.46(dd,J=10.7,4.8Hz,2H),4.73(dd,J=8.4,3.6Hz,1H),3.85-3.68(m,2H),3.46(s,3H),2.12-2.01(m,4H).13C NMR(100MHz,CDCl3)δ190.2,171.9,164.4,134.2,133.2,130.4,128.5,59.3,52.3,46.5,31.0,22.4.MS(EI)m/z 261(M+).
实施例25
化合物2y的合成:
室温下,将N-Fmoc保护的三甘肽乙酯(87.9mg,0.2mmol,lequiv)与DBU(0.21mmol,1.05equiv)在DCM(2mL)中搅拌反应30分钟,脱除芴甲氧羰基保护,随后加入乙酸(0.21mmol,1.05equiv),搅拌30分钟后加入苯甲酰甲酸苄硫醇酯1a(0.2mmol),继续反应10小时,点板检测,待1a转化完全后,柱层析分离目标产物2y。两步产率69%,白色固体。1HNMR(400MHz,CDCl3)δ8.25(dd,J=8.3,1.2Hz,2H),8.02(t,J=5.3Hz,1H),7.64-7.58(m,1H),7.45(dd,J=10.8,4.9Hz,2H),7.26(s,1H),7.02(s,1H),4.18-4.10(m,4H),4.06-3.97(m,4H),1.24(t,J=7.1Hz,3H).13C NMR(100MHz,CDCl3)δ187.1,169.8,169.0,168.8,162.8,134.5,133.1,131.1,128.5,61.6,42.9,42.8,41.3,14.1.HRMS(ESI)Calcd forC16H19N3NaO6[M+Na]+372.1166,Found 372.1162.
实施例26
化合物3a的合成:
将苯甲酰甲酸乙硫酯(0.1mmol),对甲氧基苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3a,产率86%,黄色油状物。1H NMR(400MHz,CDCl3)δ8.01-7.91(m,4H),7.68-7.61(m,1H),7.53-7.47(m,2H),7.01-6.94(m,2H),3.89(s,3H).13C NMR(100MHz,CDCl3)δ194.8,193.2,165.0,134.7,133.1132.4,129.9,128.9,126.1,114.3,55.6.MS(EI)m/z 240(M+).
实施例27
化合物3b的合成:
将苯甲酰甲酸乙硫酯(0.1mmol),间甲氧基苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3b,产率78%,黄色固体。1H NMR(400MHz,CDCl3)δ7.99-7.94(m,2H),7.69-7.63(m,1H),7.56-7.45(m,4H),7.40(t,J=7.9Hz,1H),7.23-7.18(m,1H),3.87(s,3H).13C NMR(100MHz,CDCl3)δ194.50,194.48,160.0,134.9,134.2,132.9,130.0,129.9,129.0,123.2,121.9,112.7,55.5.MS(EI)m/z 240(M+).
实施例28
化合物3c的合成:
将苯甲酰甲酸乙硫酯(0.1mmol),对甲硫基苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3c,产率73%,黄色固体。1H NMR(400MHz,CDCl3)δ8.00-7.93(m,2H),7.87(d,J=8.6Hz,2H),7.65(t,J=7.4Hz,1H),7.51(t,J=7.8Hz,2H),7.29(d,J=8.6Hz,2H),2.52(s,3H).13C NMR(101 MHz,CDCl3)δ194.5,193.5,148.9,134.8,133.0,130.1,129.9,129.2,129.0,125.0,14.6.MS(EI)m/z 256(M+).
实施例29
化合物3d的合成:
将苯甲酰甲酸乙硫酯(0.1mmol),3,4-二亚甲氧基苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3d,产率80%,淡黄色固体。1H NMR(400MHz,CDCl3)δ7.96(d,J=7.3Hz,2H),7.65(t,J=7.4Hz,1H),7.55-7.46(m,4H),6.87(d,J=8.6Hz,1H),6.09(s,2H).13C NMR(100MHz,CDCl3)δ194.6,192.8,153.5,148.6,134.8,133.1,129.9,129.0,127.9,127.8,108.4,108.3,102.2.MS(EI)m/z254(M+).
实施例30
化合物3e的合成:
将苯甲酰甲酸乙硫酯(0.1mmol),邻甲基苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3e,产率56%,黄色油状物。1H NMR(400MHz,CDCl3)δ8.00-7.95(m,2H),7.69-7.62(m,2H),7.55-7.47(m,3H),7.35(d,J=7.7Hz,1H),7.30-7.24(m,1H),2.71(s,3H).13C NMR(100MHz,CDCl3)δ196.8,194.8,141.4,134.7,133.8,133.1,132.6,131.7,129.9,129.0,126.0,21.9.MS(EI)m/z 224(M+).
实施例31
化合物3f的合成:
将苯甲酰甲酸乙硫酯(0.1mmol),苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3f,产率73%,黄色固体。1H NMR(400MHz,CDCl3)δ8.00-7.95(m,2H),7.69-7.62(m,2H),7.55-7.47(m,3H),7.35(d,J=7.7Hz,1H),7.30-7.24(m,1H),2.71(s,3H).13C NMR(100MHz,CDCl3)δ8.02-7.93(m,4H),7.70-7.62(m,2H),7.56-7.48(m,4H).13C NMR(100MHz,CDCl3)δ194.6,134.9,132.9,129.9,129.0.MS(EI)m/z 210(M+).
实施例32
化合物3g的合成:
将苯甲酰甲酸乙硫酯(0.1mmol),1-萘苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3g,产率55%,黄色固体。1H NMR(400MHz,CDCl3)δ9.32(d,J=8.6Hz,1H),8.13(d,J=8.2Hz,1H),8.06-8.01(m,2H),7.97-7.90(m,2H),7.79-7.73(m,1H),7.69-7.61(m,2H),7.56-7.47(m,3H).13C NMR(100MHz,CDCl3)δ197.1,194.6,136.0,135.1,134.7,134.0,133.3,130.9,130.0,129.5,129.0,128.8,128.5,127.1,125.9,124.4.MS(EI)m/z 260(M+).
实施例33
化合物3h的合成:
将苯甲酰甲酸乙硫酯(0.1mmol),2-萘苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3h,产率60%,黄色固体。1H NMR(400MHz,CDCl3)δ8.41(s,1H),8.11(dd,J=8.6,1.6Hz,1H),8.04(dd,J=8.3,1.2Hz,2H),7.97(d,J=8.6Hz,1H),7.91(t,J=7.4Hz,2H),7.71-7.62(m,2H),7.59-7.50(m,3H).13CNMR(100MHz,CDCl3)δ194.6,136.3,134.9,133.6,133.0,132.3,130.2,123.0,129.9,129.5,129.2,129.0,127.9,127.2,123.6.MS(EI)m/z 260(M+).
实施例34
化合物3i的合成:
将对甲氧基苯甲酰甲酸乙硫酯(0.1mmol),对甲氧基苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3i,产率66%,黄色固体。1H NMR(400MHz,CDCl3)δ7.97-7.92(m,4H),6.99-6.94(m,4H),3.88(s,6H).13C NMR(100MHz,CDCl3)δ193.5,164.8,132.4,126.3,114.3,55.6.MS(EI)m/z 270(M+).
实施例35
化合物3j的合成:
将邻甲基苯甲酰甲酸乙硫酯(0.1mmol),对甲氧基苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3j,产率79%,淡黄色固体。1H NMR(400MHz,CDCl3)δ7.98-7.91(m,2H),7.64(d,J=7.8Hz,1H),7.51-7.45(m,1H),7.33(d,J=7.6Hz,1H),7.29-7.22(m,1H),7.01-6.95(m,2H),3.89(s,3H),2.70(s,3H).13C NMR(100MHz,CDCl3)δ197.1,193.5,164.8,141.3,133.6,133.0,132.5,132.4,132.0,126.1,125.9,114.3,55.6,21.9.MS(EI)m/z 254(M+).
实施例36
化合物3k的合成:
将间甲基苯甲酰甲酸乙硫酯(0.1mmol),对甲氧基苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3k,产率76%,淡黄色油状物。1H NMR(400MHz,CDCl3)δ7.98-7.91(m,2H),7.76(d,J=7.5Hz,2H),7.46(d,J=7.4Hz,1H),7.38(t,J=7.8Hz,1H),7.00-6.94(m,2H),3.88(s,3H),2.40(s,3H).13C NMR(100MHz,CDCl3)δ197.1,193.5,164.8,141.3,133.6,133.0,132.5,132.4,132.0,126.1,125.9,114.3,55.6,21.9.MS(EI)m/z 254(M+).
实施例37
化合物3l的合成:
将对甲基苯甲酰甲酸乙硫酯(0.1mmol),对甲氧基苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3l,产率82%,淡黄色固体。1H NMR(400MHz,CDCl3)δ7.97-7.91(m,2H),7.86(d,J=8.2Hz,2H),7.30(d,J=8.0Hz,2H),7.00-6.94(m,2H),3.88(s,3H),2.43(s,3H).13C NMR(100MHz,CDCl3)δ194.6,193.4,164.9,146.0,132.4,130.7,130.0,129.7,126.1,114.3,55.6,21.9.MS(EI)m/z254(M+).
实施例38
化合物3m的合成:
将2-呋喃基甲酰甲酸乙硫酯(0.1mmol),对甲氧基苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3m,产率82%,淡黄色固体。1H NMR(400MHz,CDCl3)δ8.05-7.97(m,2H),7.77-7.72(m,1H),7.37(d,J=3.6Hz,1H),7.01-6.93(m,2H),6.61(dd,J=3.6,1.7Hz,1H),3.89(s,3H).13C NMR(100MHz,CDCl3)δ190.1,180.8,165.0,150.0,149.0,132.7,125.5,123.2,114.2,112.9,55.6.MS(EI)m/z230(M+).
实施例39
化合物3n的合成:
将2-苯并呋喃基甲酰甲酸乙硫酯(0.1mmol),对甲氧基苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3n,产率50%,黄色固体。1H NMR(400MHz,CDCl3)δ8.10-8.03(m,2H),7.73(d,J=7.9Hz,1H),7.69(d,J=0.7Hz,1H),7.63(d,J=8.5Hz,1H),7.57-7.50(m,1H),7.37-7.31(m,1H),7.02-6.96(m,2H),3.90(s,3H).13CNMR(100MHz,CDCl3)δ189.8,183.0,165.1,156.5,149.8,132.8,129.6,126.8,125.5,124.3,123.9,119.4,114.3,112.7,55.7.MS(EI)m/z 280(M+).
实施例40
化合物3o的合成:
将苯甲酰甲酸乙硫酯(0.1mmol),4-甲酸乙酯苯硼酸酐(0.1mmol,1.0equiv),Pd2dba3(0.0025mmol,2.5mol%),4,4′-二甲氧基-2,2′-联吡啶(0.01mmol,10mol%),噻吩-2-甲酸亚铜(0.1mmol,1.0equiv),K2CO3(0.15mmol,1.5equiv)和无水Na2SO4(0.15mmol,1.5equiv)加入到放置有磁子的反应管中,抽空换氮三次后加DMF(1mL),反应体系加热至45℃反应过夜,点板检测,苯甲酰甲酸乙硫酯全部转化完全后,将反应体系冷却至室温,加水淬灭用乙酸乙酯进行萃取,无水Na2SO4干燥,旋转蒸发仪去除有机溶剂后,用硅胶柱进行柱层析分离纯化后得到目标联苯甲酰化合物3o,产率44%,黄色油状物。1H NMR(400MHz,CDCl3)δ8.17(d,J=8.5Hz,2H),8.04(d,J=8.5Hz,2H),7.98(dd,J=8.2,1.0Hz,2H),7.68(t,J=7.4Hz,1H),7.53(t,J=7.8Hz,2H),4.41(q,J=7.1Hz,2H),1.41(t,J=7.1Hz,3H).13C NMR(100MHz,CDCl3)δ193.8,193.7,165.4,135.9,135.7,135.1,132.7,130.04,129.95,129.7,129.1,61.7,14.2.MS(EI)m/z 282(M+).
实施例41
Indibulin的合成:
硫酯化合物(0.05mmol),4-氨基吡啶(7mg,0.075mmol,1.5equiv),Pd(OAc)2(0.6mg,0.0025mmol,5mol%),IPr·HCl(2.1mg,0.005mmol,10mol%)及K2CO3(10.4mg,0.075mmol,1.5equiv)于反应管中,抽空换氮三次后,加入甲苯(0.3mL),在110℃下过夜反应,冷却至室温后,丙酮稀释,过滤后柱层析,分离得到目标化合物Indibulin,淡黄色固体12.1mg,产率62%。1H NMR(400MHz,d6-DMSO)δ11.10(s,1H),9.00(s,1H),8.52(d,J=4.6Hz,2H),8.30(dd,J=6.2,2.1Hz,1H),7.87(d,J=4.6Hz,2H),7.60(dd,J=6.3,2.3Hz,1H),7.41(d,J=8.5Hz,2H),7.37-7.26(m,4H),5.62(s,2H).13C NMR(100MHz,d6-DMSO)δ180.7,163.0,150.4,144.9,141.4,136.3,135.6,132.5,129.3,128.8,126.9,124.0,123.4,121.6,114.3,111.7,111.2,49.2.MS(EI)m/z 389(M+).
实施例42
Polyandrocarpamide C的合成:
将二羰基硫酯化合物(0.1mmol)与酪胺(0.1mmol)溶于THF(1mL),过夜反应,点板检测,硫酯化合物全部转化后,柱层析分离得到当量的淡黄色固体,在0℃下,向该化合物(0.09mmol)的三氟乙酸(1.8mL)溶液中滴加苯甲醚(180μL),80℃下反应19小时,完全转化后经后处理柱层析,得到Polyandrocarpamide C,白色固体。1H NMR(400MHz,d6-acetone)δ11.25(s,1H),9.04(d,J=3.2Hz,1H),8.38-8.31(m,1H),8.14(s,1H),8.05(s,1H),7.59-7.53(m,1H),7.30-7.23(m,2H),7.12(d,J=8.4Hz,2H),6.81-6.75(m,2H),3.59-3.52(m,2H),2.83(t,J=7.2Hz,2H).13C NMR(100MHz,d6-acetone)δ182.3,163.6,156.8,139.5,137.3,130.9,130.6,127.8,124.4,123.4,122.8,116.2,113.8,113.1,41.6,35.4.HRMS(EI)Calcd for C18H16N2O3308.1161,Found 308.1164.
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
Claims (11)
1.一种1,2-二羰基类化合物的合成方法,其特征在于,在溶剂中,以1,2-二羰基硫酯类化合物与胺类化合物为反应原料,在添加剂的作用下,反应得到如式(1)所示的1,2-二羰基类化合物,所述反应过程如下反应式(A)所示:
其中,
Ar为苯基、C1-C10烷基取代的苯基、C1-C10烷氧基取代的苯基、卤素取代的苯基、甲砜基取代的苯基、氰基取代的苯基、甲酯基取代的苯基、羟基取代的苯基、呋喃基、苯并呋喃基、吲哚基;
R,R1,R2分别独立地选自氢、D-苯丙醇、苯基、苄基、呋喃环、苯并呋喃环、吲哚环、C1-C18烷基、C1-C10烷基取代的苯基、C1-C10烷氧基取代的苯基、卤素取代的苯基、烯丙基及其衍生物、炔丙基、α-甲基苯乙基。
2.一种1,2-二羰基类化合物的合成方法,其特征在于,在溶剂中,以1,2-二羰基硫酯类化合物与硼酸酐类化合物为反应原料,在催化剂、配体、碱、添加剂的作用下,反应得到如式(3)所示的1,2-二羰基类化合物,所述反应过程如下反应式(B)所示:
其中,
Ar、Ar1分别独立地选自苯基、C1-C10烷基取代的苯基、C1-C10烷氧基取代的苯基、卤素取代的苯基、甲硫基取代的苯基、3,4-二亚甲氧基取代的苯基、甲砜基取代的苯基、氰基取代的苯基、甲酯基取代的苯基、羟基取代的苯基、萘基、呋喃基、苯并呋喃基、吲哚基、萘基;
R为苄基、C1-C10烷基取代的苄基、硝基取代的苄基、酯基取代的苄基、卤素取代的苄基、C1-C10烷基、烯丙基及其衍生物、炔丙基、α-甲基苯乙基。
3.如权利要求1所述的合成方法,其特征在于,所述反应的温度为20-120℃;和/或,所述反应的时间为1-15小时;和/或,所述添加剂与所述1,2-二羰基硫酯的摩尔比为1∶(1-10)。
4.如权利要求1和2所述的合成方法,其特征在于,所述添加剂为4-二甲胺基吡啶、吡啶、三乙胺、硫酸钠、噻吩-2-甲酸亚铜、硫酸铜、碘化亚铜、溴化亚铜、氯化亚铜、三氟甲磺酸亚铜、三氟甲磺酸铜、氯化铜、溴化铜、乙酰丙酮铜、氧化铜中的一种或多种。
5.如权利要求1和2所述的合成方法,其特征在于,所述溶剂选自乙腈、二氧六环、甲苯、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、四氢呋喃、1,4-二氧六环、环戊基甲醚、乙醚、叔丁基甲醚、乙酸乙酯、苯、苯甲腈、四氯化碳、二硫化碳、二氯甲烷、三氯甲烷中的一种或多种。
6.如权利要求2所述的合成方法,其特征在于,所述催化剂选自醋酸钯、氯化钯、四三苯基膦钯、乙酰丙酮钯、双(二亚苄基丙酮)钯、三(二亚苄基丙酮)二钯、四三苯基膦二氯化钯、烯丙基氯化钯、二乙腈氯化钯、钯碳中的一种或多种;和/或,所述配体选自4,4′-二甲氧基-2,2′-联吡啶、联吡啶、4,4′-二甲基-2,2′-联吡啶、1,10-菲罗啉、三苯基膦、三叔丁基膦、三环己基膦、1,2-双(二甲基膦)乙烷、1,2-双(二甲基膦)丙烷中的一种或多种。
7.如权利要求2所述的合成方法,其特征在于,所述碱选自碳酸钾、碳酸钠、碳酸锂、碳酸氢钾、碳酸氢钠、碳酸氢锂、磷酸钾、磷酸氢钾、氢氧化钾、氢氧化钠、三乙胺、二异丙基乙基胺、甲酸钠、甲酸钾、醋酸钠、醋酸钾、氢氧化锂、醋酸锂、1,8-二氮杂二环十一碳-7-烯DBU、4-二甲氨基吡啶DMAP中的一种或多种。
8.如权利要求2所述的合成方法,其特征在于,所述添加剂与1,2-二羰基硫酯的摩尔比为1∶(1-10);所述1,2-二羰基硫酯与催化剂的摩尔比为(1-20)∶1;所述1,2-二羰基硫酯与配体的摩尔比为(1-20)∶1;所述1,2-二羰基硫酯与碱的摩尔比为1∶(1-5)。
9.如权利要求2所述的合成方法,其特征在于,所述反应的温度为20-120℃;
和/或,所述反应的时间为1-15小时。
10.1,2-二羰基类化合物,其特征在于,其结构如式(2)所示,
其中,Ar为苯基、C1-C10烷基取代的苯基、C1-C10烷氧基取代的苯基、卤素取代的苯基、甲砜基取代的苯基、氰基取代的苯基、甲酯基取代的苯基、羟基取代的苯基、呋喃基、苯并呋喃基、吲哚基;
R1,R2分别独立地选自氢、D-苯丙醇、苯基、苄基、呋喃环、苯并呋喃环、吲哚环、C1-C18烷基、C1-C10烷基取代的苯基、C1-C10烷氧基取代的苯基、卤素取代的苯基、烯丙基及其衍生物、炔丙基、α-甲基苯乙基。
11.1,2-二羰基类化合物,其特征在于,其结构如式(3)所示:
其中,
Ar、Ar1分别独立地选自苯基、C1-C10烷基取代的苯基、C1-C10烷氧基取代的苯基、卤素取代的苯基、甲硫基取代的苯基、3,4-二亚甲氧基取代的苯基、甲砜基取代的苯基、氰基取代的苯基、甲酯基取代的苯基、羟基取代的苯基、萘基、呋喃基、苯并呋喃基、吲哚基、萘基。
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CN114437061A (zh) * | 2020-10-30 | 2022-05-06 | 陕西莱特光电材料股份有限公司 | 双酮类化合物的制备方法和咪唑类衍生物的制备方法 |
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