CN107400079A - A kind of Regioselective synthesis of 2,5 disubstituted pyrroles - Google Patents
A kind of Regioselective synthesis of 2,5 disubstituted pyrroles Download PDFInfo
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- CN107400079A CN107400079A CN201710689707.1A CN201710689707A CN107400079A CN 107400079 A CN107400079 A CN 107400079A CN 201710689707 A CN201710689707 A CN 201710689707A CN 107400079 A CN107400079 A CN 107400079A
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- compound
- pyrroles
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- organic phase
- ether
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- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 40
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 38
- -1 2,5 disubstituted pyrroles Chemical class 0.000 title claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 143
- 150000003233 pyrroles Chemical class 0.000 claims abstract description 86
- 150000001875 compounds Chemical class 0.000 claims abstract description 78
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 9
- 125000002346 iodo group Chemical group I* 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 190
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 142
- 229910052757 nitrogen Inorganic materials 0.000 claims description 99
- 239000002904 solvent Substances 0.000 claims description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 87
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 87
- 239000012074 organic phase Substances 0.000 claims description 65
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 64
- 125000002252 acyl group Chemical group 0.000 claims description 55
- 239000000203 mixture Substances 0.000 claims description 55
- 239000007832 Na2SO4 Substances 0.000 claims description 53
- 238000001704 evaporation Methods 0.000 claims description 53
- 230000008020 evaporation Effects 0.000 claims description 53
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 53
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(I) nitrate Inorganic materials [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 52
- 238000005406 washing Methods 0.000 claims description 51
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 50
- 239000000243 solution Substances 0.000 claims description 43
- 238000003756 stirring Methods 0.000 claims description 42
- 238000000926 separation method Methods 0.000 claims description 38
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- 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 description 28
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 22
- 239000000758 substrate Substances 0.000 claims description 21
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 20
- 239000003513 alkali Substances 0.000 claims description 18
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 claims description 17
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 17
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 16
- KNPNGMXRGITFLE-UHFFFAOYSA-N methylperoxy(phenyl)borinic acid Chemical compound COOB(O)C1=CC=CC=C1 KNPNGMXRGITFLE-UHFFFAOYSA-N 0.000 claims description 15
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 15
- ZOQCZTRFTARYGJ-UHFFFAOYSA-N chlorooxy(phenyl)borinic acid Chemical compound ClOB(O)C1=CC=CC=C1 ZOQCZTRFTARYGJ-UHFFFAOYSA-N 0.000 claims description 14
- 239000011261 inert gas Substances 0.000 claims description 12
- 229940126214 compound 3 Drugs 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000006555 catalytic reaction Methods 0.000 claims description 9
- OPPWASLOVKWHCT-UHFFFAOYSA-N boric acid;phenol Chemical compound OB(O)O.OC1=CC=CC=C1 OPPWASLOVKWHCT-UHFFFAOYSA-N 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 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 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 8
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 claims description 7
- 239000004327 boric acid Substances 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 6
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 claims description 5
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 5
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 4
- 235000011009 potassium phosphates Nutrition 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 claims description 2
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 claims description 2
- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 claims description 2
- LDIOUQIXNSSOGU-UHFFFAOYSA-N 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5h-cyclopenta[d]pyrazolo[1,5-a]pyrimidine Chemical compound CC1=NN2C(NC(CC)CC)=C3CCCC3=NC2=C1C1=CC=C(OC)C=C1Cl LDIOUQIXNSSOGU-UHFFFAOYSA-N 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- HBEDNENASUYMPO-LJQANCHMSA-N n-hydroxy-4-[[(2r)-3-oxo-2-(thiophen-2-ylmethyl)-2,4-dihydroquinoxalin-1-yl]methyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1CN1C2=CC=CC=C2NC(=O)[C@H]1CC1=CC=CS1 HBEDNENASUYMPO-LJQANCHMSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- 229910020364 ClSO2 Inorganic materials 0.000 claims 1
- 206010011224 Cough Diseases 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims 1
- VZRJNLFAIIISJP-UHFFFAOYSA-N boric acid 1-phenylethanone Chemical compound B(O)(O)O.C(C)(=O)C1=CC=CC=C1 VZRJNLFAIIISJP-UHFFFAOYSA-N 0.000 claims 1
- 239000012259 ether extract Substances 0.000 claims 1
- ZOUWOGOTHLRRLS-UHFFFAOYSA-N palladium;phosphane Chemical compound P.[Pd] ZOUWOGOTHLRRLS-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 claims 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 abstract description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 abstract description 15
- 125000001424 substituent group Chemical group 0.000 abstract description 8
- 238000010189 synthetic method Methods 0.000 abstract description 7
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229920000642 polymer Polymers 0.000 abstract description 2
- 230000000977 initiatory effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000002070 nanowire Substances 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 89
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 84
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 50
- 239000007787 solid Substances 0.000 description 42
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 6
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 3
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 3
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 3
- 229940125907 SJ995973 Drugs 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
- 229940125872 compound 4d Drugs 0.000 description 3
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000006086 Paal-Knorr synthesis reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- XTBAUKUZANNIHE-UHFFFAOYSA-N 2,2-dimethylpropanoyl azide Chemical compound CC(C)(C)C(=O)N=[N+]=[N-] XTBAUKUZANNIHE-UHFFFAOYSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KWGASIUWELSTHP-UHFFFAOYSA-N boron;phenol Chemical compound [B].OC1=CC=CC=C1 KWGASIUWELSTHP-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000006049 ring expansion reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
Classifications
-
- 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
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of Regioselective synthesis of 2,5 disubstituted pyrroles, belong to the field of chemical synthesis.This method using substep iodo and coupling reaction, a series of 2,5 disubstituted pyrroles for being connected with different substituents is synthesized by the reaction of 6 steps, its yield is more than 60%, structure warp using simple pyrroles as initiation material1H NMR、13C NMR and HRMS are confirmed.It is of the invention compared with Paal Knorr synthetic methods traditional before, building block molecule need not be constructed in advance, it is raw material with cheap and easily-available pyrroles, simplify building-up process, can be the 2 of pyrroles, 5 neatly introduce different substituents, are laid the foundation for compounds such as synthetic drug, molecular wire and high molecular polymers.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to the regio-selective synthesis side of one kind 2,5- disubstituted pyrroles
Method.
Background technology
2,5- disubstituted pyrroles are a kind of important polysubstituted pyrrole compounds, have good bioactivity or photo electric
Can, it is prevalent in the natural products or unnatural products with bioactivity, is many medicines, porphyrin analog, high score
The essential building blocks of sub- polymer, alkaloid and amino acid.2,5- disubstituted pyrroles have good application prospect, and it is synthesized
Research causes people and more and more paid close attention to.
At present, the synthetic method of 2,5- disubstituted pyrroles is broadly divided into the cyclization and pyrrole ring of two classes, i.e. chain compound
Function dough.At present, the application of chain compound cyclization is more, such as traditional Paal-Knorr synthetic methods, while also have one
A little new synthetic methods, such as by the condensation reaction of 1,3- diines and primary amine, metal catalytic synthetic method, pivaloyl azide
Cyclisation and the cyclisation and aromatisation and ring expansion method of isomerization, α-nitro ketal with α-acylamino- sulfone synthesize 2,5- disubstituted pyrroles
Deng.But in the synthetic method of these pyrroles, the substituent on upper 2, the 5- positions of pyrroles introduces before pyrrole ring is formed, this
So that the introducing of substituent is restricted, while the cost of these synthetic routes is higher, and raw material is unstable or has hypertoxicity, production
Species are more complicated, and applicable is limited in scope.Therefore, exploring a method that can with flexible and changeable introduce substituent has ten
Divide important meaning.
The content of the invention
It is an object of the invention to design one to synthesize 2,5- disubstituted pyrroles with the method being coupled by substep iodo
Route.Using the pyrroles of cheap and simple as raw material, by using the palladium that the halogenating reaction in situ of trimethyl silicon substrate and research are more ripe
The coupling reaction of catalysis devises the synthetic route of 2, a 5- disubstituted pyrroles, and the method make it that the conversion of substituent is cleverer
Work is changeable, and reaction condition is gentleer, and product is more easily separated, has in the synthesis of many functional compounds and applies valency well
Value.
Technical scheme：
The Regioselective synthesis of one kind 2,5- disubstituted pyrroles, the reaction equation of synthesis 2,5- disubstituted pyrroles are：
The specific steps of synthesis 2,5- disubstituted pyrroles include：
The first step, synthesize compound 2
Under inert gas shielding, NaH organic solutions, pyrroles's organic solution are prepared；It is under ice bath stirring that pyrroles is organic
Solution is added dropwise in NaH organic solutions, reacts 1-3 hours, forms solution A, the mol ratio of NaH and pyrroles are wherein in solution A
1:1-3；N, N- dimethylsulphamoyl chlorides (ClSO are added dropwise into solution A2NMe2), at 0 DEG C to 2-5h is reacted at room temperature, obtain solution
B；Solution B is extracted with ether, collects organic phase, and uses water and saturated common salt water washing organic phase respectively, then with nothing
Water Na2SO4Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, obtains compound 2.
N in described solution B, N- dimethylsulphamoyl chloride (ClSO2NMe2) with the mol ratio of pyrroles it is 1-2:1.
Second step, synthesize compound 3
Under inert gas shielding, compound 2 is 1 in molar ratio with n-BuLi:2-4 is mixed, and is subzero 50- in temperature
1-3h is reacted at subzero 90 DEG C, hydrogen lithium exchange reactions is completed, obtains solution C；Solution C is mixed with trim,ethylchlorosilane, wherein,
Compound 2 and trim,ethylchlorosilane molar concentration rate in solution C are 1:2-5, it is raised to naturally after room temperature and continues to react 2-5 small
When, substitution reaction is completed, obtains mix products A；Appropriate water is added in mix products A, is extracted with ether, is collected organic
Phase, respectively with saturated sodium bicarbonate, water, saturated common salt water washing organic phase, then use anhydrous Na2SO4Dry, be evaporated under reduced pressure and remove
Post separation is crossed after solvent, obtains compound 3.
3rd step, synthesize compound 4
Under inert gas shielding, by compound 3 and N- N-iodosuccinimides (NIS) in AgNO3Catalysis is lower to occur iodine
Generation reaction, obtains mix products B, wherein, compound 3, NIS and AgNO3Mol ratio be 1:(1-2)：(0.1-0.3), room temperature
Under, after reacting 6-10 hours, saturated aqueous sodium thiosulfate is added, is extracted with ether, collected organic phase, use water respectively
With saturated common salt water washing organic phase, then anhydrous Na is used2SO4Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, obtains chemical combination
Thing 4.
4th step, synthesis compound 5a-5d
Under inert gas shielding, using compound 4, aryl boric acid as raw material, it is dissolved in reaction dissolvent, adds alkali and four
Triphenylphosphine palladium, in alkaline environment under the catalysis of tetra-triphenylphosphine palladium, Suzuki coupling reaction occurs, obtains mix products C, instead
It is 80-110 DEG C to answer temperature, and the reaction time is 3-5 hours；Water is added into mix products C, is extracted with ether, collection has
Machine phase, respectively with water and saturated common salt water washing organic phase, then use anhydrous Na2SO4Dry, post is crossed after solvent removed by evaporation at reduced pressure
Separation, respectively obtains compound 5a-5d.
Described compound 5a is 2- phenyl -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；5b is
2- (4- methoxyphenyls) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；5c is 2- (4- chlorphenyls) -5-
(trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；5d is 2- (4- acetylphenyls) -5- (trimethyl silicon substrate) -1-
(N, N- dimethyl methyl acyl group) pyrroles.
Described compound 4, aryl boric acid, alkali, the mol ratio of tetra-triphenylphosphine palladium are 1:(1-2)：(3-5): (0.05-
0.2).Described alkali is sodium carbonate.Described aryl boric acid be phenyl boric acid, to methoxyphenylboronic acid, to chlorophenylboronic acid or to second
Acyl group phenyl boric acid etc..Described reaction dissolvent is that toluene and methanol are 1 by volume:The mixed solution of (1-3)；Per 0.1mmol
The corresponding 3-7mL reaction dissolvents of compound 4.
5th step, compound 6a-6c is under inert gas shielding for synthesis, the compound 5a- obtained by the 4th step column chromatography
5c is raw material, and iodide reaction occurs in organic solvent under silver nitrate catalysis with N- N-iodosuccinimides (NIS), is mixed
Product D, reaction temperature are 20-45 DEG C, and the reaction time is 1-5 hours；It is water-soluble that saturated sodium thiosulfate is added into mix products D
Liquid, extracted with ether, organic phase is collected, respectively with water and saturated common salt water washing organic phase, then anhydrous Na2SO4Dry,
Post separation is crossed after solvent removed by evaporation at reduced pressure, respectively obtains compound 6a-6c.
Described compound 6a is the iodo- 5- phenyl -1- of 2- (N, N- dimethyl methyl acyl group) pyrroles, and 6b is the iodo- 5- (4- of 2-
Methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles, 6c is the iodo- 5- of 2- (4- chlorphenyls) -1- (N, N- dimethyl sulphonyl
Base) pyrroles.
Described compound 5a-5c：N- N-iodosuccinimides：The mol ratio of silver nitrate is 1:(1-2):(0.01-
0.5)。
Described reaction dissolvent is ethanol, acetonitrile, N,N-Dimethylformamide；Per 4 corresponding 3-7mL of 0.1mmol compounds
Reaction dissolvent.
6th step, synthesis compound 7a-7d
Under inert gas shielding, respectively with compound 6b and to methoxyphenylboronic acid, compound 6b and para hydroxybenzene boron
Acid, compound 6c and be raw material to methoxyphenylboronic acid, compound 6b and to chlorophenylboronic acid, add the raw material into organic solvent
In, and add Pd (PPh3)4And alkali, in Pd (PPh3)4Catalysis under, Suzuki coupling reaction occurs in alkaline environment, is mixed
Product E, reaction temperature are 80-110 DEG C, and the reaction time is 1-8 hours；Water is added into mix products E, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing organic phase, then anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure
Post separation is crossed afterwards, respectively obtains compound 7a-7d.
Described compound 7a is 2,5- bis- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles, compound
7b is 2- (4- hydroxy phenyls) -5- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles, and compound 7c is 2,5-
Two (4- chlorphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles, compound 7d are 2- (4- chlorphenyls) -5- (4- methoxybenzenes
Base) -1- (N, N- dimethyl methyl acyl group) pyrroles.
Described compound 6b, to methoxyphenylboronic acid or para hydroxybenzene boric acid, Pd (PPh3)4, alkali mol ratio be 1:
(1-3)：(0.05-0.1)：Compound 6c described in (3-6), to methoxyphenylboronic acid or to chlorophenylboronic acid, Pd (PPh3)4, alkali
Mol ratio is 1:(1-3)：(0.05-0.1)：(3-6).Described alkali is sodium carbonate, potassium carbonate or potassium phosphate.Described aryl boron
Acid for phenyl boric acid, to methoxyphenylboronic acid, to chlorophenylboronic acid or para hydroxybenzene boric acid.
Described reaction dissolvent is that toluene and methanol are 1 by volume:The mixed solution of (1-3)；Per 0.1mmol chemical combination
The corresponding 3-7mL reaction dissolvents of thing 4.
Beneficial effects of the present invention are：
(1) compared with Paal-Knorr synthetic methods traditional before, it is not necessary to construct building block molecule in advance, use is cheap and easily-available
Pyrroles be raw material, simplify building-up process.
(2) direct function dough is carried out to pyrrole ring, in pyrroles it is difficult to introduce 2 and 5 property selected introducings of substituent
Substituent.
(3) it is good for the universality of the substituent of introducing, the introducing for realizing various substituents of high yield.
Embodiment
Below in conjunction with technical scheme, embodiment of the invention is further illustrated.
Embodiment 1
The first step, the synthesis of compound 2
Under nitrogen protection, NaH (1.73g, 43.2mmol), DMF (50 mL) are added in bis- mouthfuls of flasks of 250mL；100mL
Pyrroles (2.42g, 36mmol) and DMF (20mL) are added in two mouthfuls of flasks, it is washed to be added dropwise to n-hexane under ice bath stirring
NaH DMF solution in, stir 1h；ClSO is added dropwise2NMe2(3.9mL, 36mmol), react 2h at 0 DEG C.Into two mouthfuls of bottles
Appropriate frozen water is added, is extracted with ether, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4It is dry
It is dry, post separation is crossed after solvent removed by evaporation at reduced pressure, solvent is n-hexane:Ether (10:1) white solid 4.39g, yield, are obtained
70.0%.mp:61-62℃；1H NMR(500MHz,CDCl3) δ 2.79 (s, 6H), 6.31 (t, 1H, J=2 Hz), 7.09 (t,
1H, J=2Hz)；13C NMR(125MHz,CDCl3)δ38.3,111.7,120.9.HRMS (ESI-TOF)for C6H10N2O2S[M
+H]+:calcd,175.0536.found 175.0536.
Second step, the synthesis of compound 3
Under nitrogen protection, THF (60mL), TMP (2,2,6,6- tetramethyl piperidine) are added in bis- mouthfuls of flasks of 250mL
(8.05mL, 47.4mmol), n-BuLi (18.5mL/2.5M, 46.8 mmol), less than -65 DEG C temperature are slowly added dropwise at -78 DEG C
The lower reaction 1h of degree, pyrroles 2 (3.14g, 18mmol) are dissolved in THF (20mL), are slowly dropped into syringe to two mouthfuls of flasks
In, 1.5h is stirred under the conditions of -78 DEG C, then by Me3SiCl (6mL, 46.8mmol) is dissolved in THF (20mL), with injection
Device is slowly dropped into reaction solution, and low temperature stirring 0.5h, when temperature is slowly warmed to room temperature, reaction 2h stops reaction.To reaction
Appropriate water is added in the mix products of gained, is extracted with ether, organic phase is collected, respectively with saturated sodium bicarbonate, water
With saturated common salt water washing, anhydrous Na2SO4Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, solvent is n-hexane:Ether
(20:1) white solid 5.62g, yield 98.0%, are obtained.mp:81-83℃；1H NMR (500MHz,CDCl3)δ0.30(s,
18H),2.62(s,6H),6.56(s,2H)；13C NMR(125MHz, CDCl3)δ0.6,37.7,125.2,142.8.HRMS
(ESI-TOF)for C12H26N2O2SSi2[M+H]+: calcd,319.1326.found 319.1326.
3rd step, the synthesis of compound 4
Under nitrogen protection, the addition compound 3 (160mg, 0.5mmol) in bis- mouthfuls of flasks of 100mL, NIS (138mg,
0.6mmol), AgNO3(15mg, 0.09mmol) and CH2Cl2(20mL), 8h is stirred at ambient temperature, stop reaction.To reaction
Appropriate sodium thiosulfate solution is added in the mix products of gained, is extracted with ether, organic phase is collected, uses water respectively
With saturated common salt water washing, anhydrous Na2SO4Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, solvent is n-hexane:Ether
(30:1) Bluish white solid 156mg, yield 84.0%, are obtained.mp:48-49℃；1H NMR(500MHz,CDCl3)δ0.30(s,
9H), 2.88 (s, 6H), 6.42 (d, 1H, J=3.5Hz), 6.60 (d, 1H, J=3.5Hz)；13C NMR(125 MHz,CDCl3)δ
0.6,37.9,125.2,126.3,144.5.HRMS(ESI-TOF)for C9H17IN2O2SSi [M+H]+:calcd,
372.9897.found 372.9893.
4th step, compound 5a-5d synthesis
Under nitrogen protection, compound 4a (37mg, 0.1mmol), phenyl boric acid are added in bis- mouthfuls of flasks of 50mL
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
Stirring reaction 4h under the conditions of DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- phenyl -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5a)
White solid 27mg, yield 84%；mp:74-75℃；1H NMR(500MHz,(CD3)2CO)δ0.33(s,9H),
2.29 (s, 6H), 6.26 (d, J=3.5Hz, 1H), 6.53 (d, J=3Hz, 1H), 7.43 (tdd, J=8.0Hz, J=5.0Hz,
J=3.0Hz, 3H), 7.49 (dt, J=5Hz, J=2Hz, 2H)；13C NMR (125MHz,(CD3)2CO)δ0.9,36.5,
115.9,122.9,123.0,128.4,129.0,131.2,133.4, 139.6,139.9.HRMS(ESI-TOF)for
C15H22N2O2SSi[M+H]+:calcd,323.1244.found 323.1240.
Under nitrogen protection, compound 4b (37mg, 0.1mmol), phenyl boric acid are added in bis- mouthfuls of flasks of 50mL
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
Stirring reaction 5h under the conditions of DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- methoxyphenyls) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5b)
White solid 27mg, yield 78%；mp:169-170℃；1H NMR(500MHz,CDCl3)δ0.34 (s,9H),
2.30 (s, 6H), 3.83 (s, 3H), 6.19 (d, J=3Hz, 1H), 6.47 (d, J=3Hz, 1H), 6.91 (d, J=9Hz, 1H),
7.41 (d, J=9Hz, 1H)；13C NMR(125MHz,CDCl3)δ0.7,36.5, 55.3,113.0,115.1,122.0,
124.9,131.9,138.4,139.8,159.6.HRMS(ESI-TOF)for C16H24N2O3SSi[M+H]+:calcd,
353.1350.found353.1351.
Under nitrogen protection, compound 4c (37mg, 0.1mmol), phenyl boric acid are added in bis- mouthfuls of flasks of 50mL
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
Stirring reaction 3h under the conditions of DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- chlorphenyls) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5c)
White solid 26mg, yield 73%；mp:169-170℃；1H NMR(500MHz,CDCl3)δ0.34(s,9H),
2.32 (s, 6H), 6.23 (d, J=3.5Hz, 1H), 6.49 (d, J=3.5Hz, 1H), 7.36 (d, J=8.5Hz, 1H), 7.43
(d, J=8.5Hz, 1H)；13C NMR(125MHz,(CD3)2CO)δ0.9, 36.7,116.5,123.1,128.5,132.1,
132.8,134.6,138.3,140.6.HRMS(ESI-TOF)for C15H21ClN2O2SSi[M+H]+:calcd,
357.0854.found357.0853.
Under nitrogen protection, compound 4d (37mg, 0.1mmol), phenyl boric acid are added in bis- mouthfuls of flasks of 50mL
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
Stirring reaction 4h under the conditions of DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- acetylphenyls) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5d)
White solid 27mg, yield 75%；mp:114-115℃；1H NMR(500MHz,CDCl3)δ0.36 (s,9H),
2.29 (s, 6H), 2.63 (s, 3H), 6.30 (d, J=3.5Hz, 1H), 6.51 (d, J=3.5Hz, 1H), 7.61 (d, J=
8.5Hz, 1H), 7.98 (d, J=8.5Hz, 1H)；13C NMR(125MHz,CDCl3)δ0.7, 26.7,36.7,116.2,
122.4,127.6,130.5,136.4,137.4,137.7,141.5,197.6.HRMS (ESI-TOF)for C17H24N2O3SSi
[M+H]+:calcd,365.1350.found365.1352.
5th step, compound 6a-6d synthesis
Under nitrogen protection, the addition compound 5a (0.16mmol) in bis- mouthfuls of flasks of 50mL, NIS (44mg,
0.20mmol), AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL), stirring reaction 1h under the conditions of 35 DEG C, stop reaction.To
React in the mix products of gained and add appropriate sodium thiosulfate solution, extracted with ether, collect organic phase, respectively
With water and saturated common salt water washing, anhydrous Na2SO4Dry, cross post separation after solvent removed by evaporation at reduced pressure, solvent be n-hexane/
Ether, obtain required compound.
The iodo- 5- phenyl -1- of 2- (N, N- dimethyl methyl acyl group) pyrroles (6a)
White solid 43mg, yield 71%；mp:86-87℃；1H NMR(500MHz,CDCl3)δ2.62(s, 6H),6.16
(d, J=3.5Hz, 1H), 6.65 (d, J=3.5Hz, 1H), 7.36 (dd, J=7Hz, J=1.5Hz, 3H), 7.40 (d, J=
2Hz,2H)；13C NMR(125MHz,CDCl3)δ37.9,116.9,125.9,127.5, 128.2,130.2,133.4,
141.6.HRMS(ESI-TOF)for C12H13IN2O2S[M+H]+:calcd, 376.9815.found376.9823.
Under nitrogen protection, the addition compound 5b (0.16mmol) in bis- mouthfuls of flasks of 50mL, NIS (44mg,
0.20mmol), AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL), stirring reaction 5h under the conditions of 35 DEG C, stop reaction.To
React in the mix products of gained and add appropriate sodium thiosulfate solution, extracted with ether, collect organic phase, respectively
With water and saturated common salt water washing, anhydrous Na2SO4Dry, cross post separation after solvent removed by evaporation at reduced pressure, solvent be n-hexane/
Ether, obtain required compound.
The iodo- 5- of 2- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (6b)
White solid 35mg, yield 86%；mp:199-200℃；1H NMR(500MHz,CDCl3)δ 2.62(s,6H),
3.83 (s, 3H), 6.12 (d, J=3.5Hz, 1H), 6.63 (d, J=3.5Hz, 1H), 6.89 (d, J=8.5Hz, 2H), 7.33
(d, J=8.5Hz, 2H)；13C NMR(125MHz,CDCl3)δ37.9,55.3, 112.9,116.6,125.9,131.6,
141.4,159.6.HRMS(ESI-TOF)for C13H15IN2O3S [M+H]+:calcd,406.9921.found406.9911.
Under nitrogen protection, the addition compound 5c (0.16mmol) in bis- mouthfuls of flasks of 50mL, NIS (44mg,
0.20mmol), AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL), stirring reaction 1h under the conditions of 35 DEG C, stop reaction.To
React in the mix products of gained and add appropriate sodium thiosulfate solution, extracted with ether, collect organic phase, respectively
With water and saturated common salt water washing, anhydrous Na2SO4Dry, cross post separation after solvent removed by evaporation at reduced pressure, solvent be n-hexane/
Ether, obtain required compound.
The iodo- 5- of 2- (4- chlorphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (6c)
White solid 42mg, yield 84%；mp:111-112℃；1H NMR(500MHz,CDCl3)δ2.67 (s,6H),
6.16 (d, J=3.5Hz, 1H), 6.65 (d, J=3.5Hz, 1H), 7.33 (s, 4H)；13C NMR (125MHz,CDCl3)δ
38.1,117.2,126.1,127.7,131.4,131.9,134.3,140.5.HRMS (ESI-TOF)for C12H12ClIN2O2S
[M+H]+:calcd,410.9425.found 410.9422.
6th step, compound 7a-7d synthesis
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to methoxyphenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
Stirring reaction 1h at 100 DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether,
Organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post separation crossed after solvent removed by evaporation at reduced pressure,
Solvent is n-hexane：Ether, obtain required compound.
2,5- bis- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (7a)
White solid, yield 83%；mp:192-193℃；1H NMR(500MHz,CDCl3)δ2.33(s, 6H),3.84
(s, 6H), 6.21 (s, 2H), 6.93 (d, J=9Hz, 4H), 7.48 (d, J=9Hz, 4H)；13C NMR(125MHz,CDCl3)δ
37.2,55.2,113.2,113.8,126.4,130.5,139.2,159.2. HRMS(ESI-TOF)for C20H22N2O4S[M+
H]+:calcd,387.1373.found387.1372.
Under nitrogen protection, compound 6b (0.15mmol), para hydroxybenzene boric acid are added in bis- mouthfuls of flasks of 50mL
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
Stirring reaction 8h at DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether, is received
Collect organic phase, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post separation, exhibition are crossed after solvent removed by evaporation at reduced pressure
It is n-hexane to open agent：Ether, obtain required compound.
2- (4- hydroxy phenyls) -5- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (7b)
White solid, yield 84%；mp:233-234℃；1H NMR(500MHz,CDCl3)δ2.33(s, 6H),3.84
(s, 3H), 6.21 (s, 2H), 6.85 (d, J=8.5Hz, 2H), 6.93 (d, J=8.5Hz, 2H), 7.43 (d, J=8.5Hz,
2H), 7.48 (d, J=8.5Hz, 2H)；13C NMR(125MHz,CDCl3)δ 37.2,55.3,113.2,113.8,114.7,
126.4,126.5,130.5,130.7,139.2,139.2,155.3,159.2. HRMS(ESI-TOF)for C19H20N2O4S[M
+H]+:calcd,373.1217.found373.1229.
Under nitrogen protection, compound 6c (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to chlorophenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
Stirring reaction 1h at 100 DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether,
Organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane：Ether, obtain required compound.
2,5- bis- (4- chlorphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (7c)
White solid, yield 81%；mp:126-127℃；1H NMR(500MHz,CDCl3)δ2.34(s, 6H),6.30
(s, 2H), 7.37 (d, J=8.5Hz, 4H), 7.49 (d, J=8.5Hz, 4H)；13C NMR(125 MHz,CDCl3)δ37.2,
114.9,128.0,130.4,131.9,133.8,139.1.HRMS(ESI-TOF)for C18H16Cl2N2O2S[M+H]+:calcd,
395.0382.found395.0382.
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to chlorophenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
Stirring reaction 1.5h at 100 DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane：Ether, obtain required compound.
2- (4- chlorphenyls) -5- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (7d)
White solid, yield 75%；mp:211-212℃；1H NMR(500MHz,CDCl3)δ2.33(s, 6H),3.85
(s, 3H), 6.24 (d, J=1.5Hz, 1H), 6.27 (d, J=1.5Hz, 1H), 6.94 (d, J=9Hz, 2H), 7.36 (d, J=
8.5Hz, 2H), 7.49 (dd, J=8.5Hz, J=5Hz, 4H)；13C NMR(125 MHz,CDCl3)δ37.2,55.3,113.3,
113.9,114.8,125.8,127.9,130.3,130.7,132.4, 133.4,138.5,139.9,159.4.HRMS(ESI-
TOF)for C19H19ClN2O3S[M+H]+:calcd, 391.0878.found391.0878.
Embodiment 2
The first step, the synthesis of compound 2
Under nitrogen protection, NaH (1.44g, 36mmol), DMF (50 mL) are added in bis- mouthfuls of flasks of 250mL；100mL bis-
Pyrroles (2.42g, 36mmol) and DMF (20mL) are added in mouth flask, it is washed to be added dropwise to n-hexane under ice bath stirring
In NaH DMF solution, 1h is stirred；ClSO is added dropwise2NMe2(3.9mL, 36mmol), react 2h at 0 DEG C.Add into two mouthfuls of bottles
Enter appropriate frozen water, extracted with ether, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4It is dry
It is dry, post separation is crossed after solvent removed by evaporation at reduced pressure, solvent is n-hexane:Ether (10:1) white solid 4.39g, yield, are obtained
80%.
Second step, the synthesis of compound 3
Under nitrogen protection, THF (60mL), TMP (2,2,6,6- tetramethyl piperidine) are added in bis- mouthfuls of flasks of 250mL
(8.05mL, 47.4mmol), n-BuLi (14.2mL/2.5M, 36mmol) is slowly added dropwise at -90 DEG C, at a temperature of -65 DEG C
1h is reacted, pyrroles 2 (3.14g, 18mmol) is dissolved in THF (20mL), is slowly dropped into syringe into two mouthfuls of flasks ,-
1.5h is stirred under the conditions of 90 DEG C, then by Me3SiCl (4.6mL, 36mmol) is dissolved in THF (20mL), slow with syringe
It is added dropwise in reaction solution, low temperature stirring 0.5h, when temperature is slowly warmed to room temperature, reaction 2h stops reaction.To reaction gained
Appropriate water is added in mix products, is extracted with ether, organic phase is collected, respectively with saturated sodium bicarbonate, water and saturation
Brine It, anhydrous Na2SO4Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, solvent is n-hexane:Ether (20:
1) white solid 5.62g, yield 99%, are obtained.
3rd step, the synthesis of compound 4
Under nitrogen protection, the addition compound 3 (160mg, 0.5mmol) in bis- mouthfuls of flasks of 100mL, NIS (115mg,
0.5mmol), AgNO3(8.33mg, 0.05mmol) and CH2Cl2(20mL), 6h is stirred at ambient temperature, stop reaction.To anti-
Appropriate sodium thiosulfate solution should be added in the mix products of gained, be extracted with ether, collect organic phase, use respectively
Water and saturated common salt water washing, anhydrous Na2SO4Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, solvent is n-hexane:Second
Ether (30:1) Bluish white solid 156mg, yield 93%, are obtained..
4th step, compound 5a-5d synthesis
Under nitrogen protection, compound 4a (37mg, 0.1mmol), phenyl boric acid are added in bis- mouthfuls of flasks of 50mL
(0.1mmol), 2M Na2CO3(0.3mL), Pd (PPh3)4(6mg, 0.005mmol) and toluene and methanol (1:1) (3mL), 80 DEG C
Under the conditions of stirring reaction 3h, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether,
Organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post separation crossed after solvent removed by evaporation at reduced pressure,
Solvent is n-hexane/ether, obtains required compound.5a-5d
2- phenyl -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5a), white solid 25mg, yield
79%；
Under nitrogen protection, compound 4b (37mg, 0.1mmol), phenyl boric acid are added in bis- mouthfuls of flasks of 50mL
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
Stirring reaction 5h under the conditions of DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- methoxyphenyls) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5b), white solid
25mg, yield 73%；
Under nitrogen protection, compound 4c (37mg, 0.1mmol), phenyl boric acid are added in bis- mouthfuls of flasks of 50mL
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
Stirring reaction 3h under the conditions of DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- chlorphenyls) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5c), white solid 24
Mg, yield 68%；
Under nitrogen protection, compound 4d (37mg, 0.1mmol), phenyl boric acid are added in bis- mouthfuls of flasks of 50mL
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
Stirring reaction 4h under the conditions of DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- acetylphenyls) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5d), white solid
25mg, yield 70%；
5th step, compound 6a-6c synthesis
Under nitrogen protection, the addition compound 5a (0.16mmol) in bis- mouthfuls of flasks of 50mL, NIS (35.2mg,
0.16mmol), AgNO3(2mg, 0.016mmol) and absolute ethyl alcohol (3mL), stirring reaction 1h under the conditions of 20 DEG C, stop reaction.
Appropriate saturated aqueous sodium thiosulfate is added into the mix products of reaction gained, is extracted with ether, is collected organic
Phase, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, solvent is
N-hexane/ether, obtain required compound 6a-6c.
The iodo- 5- phenyl -1- of 2- (N, N- dimethyl methyl acyl group) pyrroles (6a), white solid 42mg, yield 76%；
Under nitrogen protection, the addition compound 5b (0.16mmol) in bis- mouthfuls of flasks of 50mL, NIS (44mg,
0.20mmol), AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL), stirring reaction 5h under the conditions of 35 DEG C, stop reaction.To
React in the mix products of gained and add appropriate sodium thiosulfate solution, extracted with ether, collect organic phase, respectively
With water and saturated common salt water washing, anhydrous Na2SO4Dry, cross post separation after solvent removed by evaporation at reduced pressure, solvent be n-hexane/
Ether, obtain required compound.
The iodo- 5- of 2- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (6b), white solid 37mg, yield
91%；
Under nitrogen protection, the addition compound 5c (0.16mmol) in bis- mouthfuls of flasks of 50mL, NIS (44mg,
0.20mmol), AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL), stirring reaction 1h under the conditions of 35 DEG C, stop reaction.To
React in the mix products of gained and add appropriate sodium thiosulfate solution, extracted with ether, collect organic phase, respectively
With water and saturated common salt water washing, anhydrous Na2SO4Dry, cross post separation after solvent removed by evaporation at reduced pressure, solvent be n-hexane/
Ether, obtain required compound.
The iodo- 5- of 2- (4- chlorphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (6c), white solid 44mg, yield 89%；
6th step, compound 7a-7d synthesis
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to methoxyphenylboronic acid
(0.15mmo1), 2M Na2CO3(0.15mL), Pd (PPh3)4(9mg, 0.0075mmol) and toluene and methanol (1:1) (3mL),
Stirring reaction 1h at 80 DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether,
Organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post separation crossed after solvent removed by evaporation at reduced pressure,
Solvent is n-hexane：Ether, obtain required compound.7a-7d
2,5- bis- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (7a), white solid, yield 78%；
Under nitrogen protection, compound 6b (0.15mmol), para hydroxybenzene boric acid are added in bis- mouthfuls of flasks of 50mL
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
Stirring reaction 8h at 100 DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether,
Organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post separation crossed after solvent removed by evaporation at reduced pressure,
Solvent is n-hexane：Ether, obtain required compound.
2- (4- hydroxy phenyls) -5- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (7b), white are solid
Body, yield 79%；
Under nitrogen protection, compound 6c (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to chlorophenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
Stirring reaction 1h at 100 DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether,
Organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane：Ether, obtain required compound.
2,5- bis- (4- chlorphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (7c), white solid, yield 75%；
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to chlorophenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
Stirring reaction 1.5h at 100 DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post is crossed after solvent removed by evaporation at reduced pressure
Separation, solvent is n-hexane：Ether, obtain required compound.
2- (4- chlorphenyls) -5- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (7d), white solid,
Yield 70%；
Embodiment 3
The first step, the synthesis of compound 2
Under nitrogen protection, NaH (4.32g, 108mmol), DMF (50 mL) are added in bis- mouthfuls of flasks of 250mL；100mL bis-
Pyrroles (2.42g, 36mmol) and DMF (20mL) are added in mouth flask, it is washed to be added dropwise to n-hexane under ice bath stirring
In NaH DMF solution, 3h is stirred；ClSO is added dropwise2NMe2(7.8mL, 72mmol), reacts 5h at room temperature.Add into two mouthfuls of bottles
Enter appropriate frozen water, extracted with ether, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4It is dry
It is dry, post separation is crossed after solvent removed by evaporation at reduced pressure, solvent is n-hexane:Ether (10:1) white solid 4.39g, yield, are obtained
70%.
Second step, the synthesis of compound 3
Under nitrogen protection, THF (60mL), TMP (2,2,6,6- tetramethyl piperidine) are added in bis- mouthfuls of flasks of 250mL
(8.05mL, 47.4mmol), n-BuLi (28.5mL/2.5M, 72mmol) is slowly added dropwise at -78 DEG C, at a temperature of -50 DEG C
1h is reacted, pyrroles 2 (3.14g, 18mmol) is dissolved in THF (20mL), is slowly dropped into syringe into two mouthfuls of flasks ,-
1.5h is stirred under the conditions of 50 DEG C, then by Me3SiCl (11.5mL, 90mmol) is dissolved in THF (20mL), is delayed with syringe
Slowly it is added dropwise in reaction solution, low temperature stirring 0.5h, when temperature is slowly warmed to room temperature, reaction 5h stops reaction.To reaction gained
Mix products in add appropriate water, extracted with ether, collect organic phase, respectively with saturated sodium bicarbonate, water and full
And brine It, anhydrous Na2SO4Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, solvent is n-hexane:Ether
(20:1) white solid 5.62g, yield 94%, are obtained.
3rd step, the synthesis of compound 4
Under nitrogen protection, the addition compound 3 (160mg, 0.5mmol) in bis- mouthfuls of flasks of 100mL, NIS (230mg,
1mmol), AgNO3(25mg, 0.15mmol) and CH2Cl2(20mL), 10h is stirred at ambient temperature, stop reaction.To reaction
Appropriate sodium thiosulfate solution is added in the mix products of gained, is extracted with ether, organic phase is collected, uses water respectively
With saturated common salt water washing, anhydrous Na2SO4Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, solvent is n-hexane:Ether
(30:1) Bluish white solid 156mg, yield 83%, are obtained..
4th step, compound 5a-5d synthesis
Under nitrogen protection, compound 4a (37mg, 0.1mmol), phenyl boric acid are added in bis- mouthfuls of flasks of 50mL
(0.2mmol), 2M Na2CO3(0.5mL), Pd (PPh3)4(24mg, 0.02mmol) and toluene and methanol (1:3) (7mL), 100
Stirring reaction 5h under the conditions of DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.5a-5d
2- phenyl -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5a), white solid 25mg, yield
79%；
Under nitrogen protection, compound 4b (37mg, 0.1mmol), phenyl boric acid are added in bis- mouthfuls of flasks of 50mL
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
Stirring reaction 5h under the conditions of DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- methoxyphenyls) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5b), white solid
25mg, yield 73%；
Under nitrogen protection, compound 4c (37mg, 0.1mmol), phenyl boric acid are added in bis- mouthfuls of flasks of 50mL
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
Stirring reaction 3h under the conditions of DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- chlorphenyls) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5c), white solid 24
Mg, yield 68%；
Under nitrogen protection, compound 4d (37mg, 0.1mmol), phenyl boric acid are added in bis- mouthfuls of flasks of 50mL
(0.15mmol), 2M Na2CO3(0.2mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL), 100
Stirring reaction 4h under the conditions of DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane/ether, obtains required compound.
2- (4- acetylphenyls) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (5d), white solid
25mg, yield 70%；
5th step, compound 6a-6c synthesis
Under nitrogen protection, the addition compound 5a (0.16mmol) in bis- mouthfuls of flasks of 50mL, NIS (71mg,
0.32mmol), AgNO3(13.6mg, 0.08mmol) and anhydrous N,N-Dimethylformamide (11mL), stir under the conditions of 45 DEG C anti-
5h is answered, stops reaction.Appropriate sodium thiosulfate solution is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post is crossed after solvent removed by evaporation at reduced pressure
Separation, solvent is n-hexane/ether, obtains required compound 6a-6c.
The iodo- 5- phenyl -1- of 2- (N, N- dimethyl methyl acyl group) pyrroles (6a), white solid 42mg, yield 86%；
Under nitrogen protection, the addition compound 5b (0.16mmol) in bis- mouthfuls of flasks of 50mL, NIS (44mg,
0.20mmol), AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL), stirring reaction 5h under the conditions of 35 DEG C, stop reaction.To
React in the mix products of gained and add appropriate sodium thiosulfate solution, extracted with ether, collect organic phase, respectively
With water and saturated common salt water washing, anhydrous Na2SO4Dry, cross post separation after solvent removed by evaporation at reduced pressure, solvent be n-hexane/
Ether, obtain required compound.
The iodo- 5- of 2- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (6b), white solid 37mg, yield
91%；
Under nitrogen protection, compound 5c (0.16mmol), NIS (44mg, 0.20mmol) are added in bis- mouthfuls of flasks of 50mL,
AgNO3(8mg, 0.05mmol) and anhydrous acetonitrile (5mL), stirring reaction 1h under the conditions of 35 DEG C, stop reaction.To reaction gained
Appropriate sodium thiosulfate solution is added in mix products, is extracted with ether, organic phase is collected, respectively with water and saturation
Brine It, anhydrous Na2SO4Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, solvent is n-hexane/ether, is obtained
Required compound.
The iodo- 5- of 2- (4- chlorphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (6c), white solid 44mg, yield
89%；
6th step, compound 7a-7d synthesis
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to methoxyphenylboronic acid
(0.45mmo1), 2M Na2CO3(0.6mL), Pd (PPh3)4(18mg, 0.01mmol) and toluene and methanol (1:3) (11mL),
Stirring reaction 8h at 110 DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether,
Organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane：Ether, obtain required compound.7a-7d
2,5- bis- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (7a), white solid, yield 88%；
Under nitrogen protection, compound 6b (0.15mmol), para hydroxybenzene boric acid are added in bis- mouthfuls of flasks of 50mL
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
Stirring reaction 8h at 100 DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether,
Organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post separation crossed after solvent removed by evaporation at reduced pressure,
Solvent is n-hexane：Ether, obtain required compound.
2- (4- hydroxy phenyls) -5- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (7b), white are solid
Body, yield 89%；
Under nitrogen protection, compound 6c (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to chlorophenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
Stirring reaction 1h at 100 DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether,
Organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post point is crossed after solvent removed by evaporation at reduced pressure
From solvent is n-hexane：Ether, obtain required compound.
2,5- bis- (4- chlorphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (7c), white solid, yield 85%；
Under nitrogen protection, compound 6b (0.15mmol) is added in bis- mouthfuls of flasks of 50mL, to chlorophenylboronic acid
(0.225mmo1), 2M Na2CO3(0.3mL), Pd (PPh3)4(12mg, 0.01mmol) and toluene and methanol (1:1) (5mL),
Stirring reaction 1.5h at 100 DEG C, stop reaction.Appropriate water is added into the mix products of reaction gained, is extracted with ether
Take, organic phase is collected, respectively with water and saturated common salt water washing, anhydrous Na2SO4Dry, post is crossed after solvent removed by evaporation at reduced pressure
Separation, solvent is n-hexane：Ether, obtain required compound.
2- (4- chlorphenyls) -5- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles (7d), white solid,
Yield 80%.
Claims (10)
1. one kind 2, the Regioselective synthesis of 5- disubstituted pyrroles, it is characterised in that：
The reaction equation of the Regioselective synthesis of described 2,5- disubstituted pyrroles is：
The method of synthesis 2,5- disubstituted pyrroles comprises the following steps：
The first step, synthesize compound 2
Under inert gas shielding, NaH organic solutions, pyrroles's organic solution are prepared；By pyrroles's organic solution under ice bath stirring
It is added dropwise in NaH organic solutions, reacts 1-3 hours, form solution A, the mol ratio of NaH and pyrroles is 1 wherein in solution A:1-
3；N, N- dimethylsulphamoyl chlorides ClSO are added dropwise into solution A2NMe2, at 0 DEG C to 2-5h is reacted at room temperature, obtain solution B；Use second
Ether extracts to solution B, collects organic phase, and uses water and saturated common salt water washing organic phase respectively, then uses anhydrous Na2SO4
Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, obtains compound 2；
N in described solution B, N- dimethylsulphamoyl chloride ClSO2NMe2Mol ratio with pyrroles is 1-2:1；
Second step, synthesize compound 3
Under inert gas shielding, compound 2 is 1 in molar ratio with n-BuLi:2-4 is mixed, and is that subzero 50- is subzero in temperature
1-3h is reacted at 90 DEG C, hydrogen lithium exchange reactions is completed, obtains solution C；Solution C is mixed with trim,ethylchlorosilane, wherein, solution
Compound 2 and trim,ethylchlorosilane molar concentration rate in C are 1:2-5, continue to react 2-5 hours after being raised to room temperature naturally, it is complete
Into substitution reaction, mix products A is obtained；Appropriate water is added in mix products A, is extracted with ether, collects organic phase, point
Not Yong saturated sodium bicarbonate, water, saturated common salt water washing organic phase, then use anhydrous Na2SO4Dry, after solvent removed by evaporation at reduced pressure
Post separation is crossed, obtains compound 3；
3rd step, synthesize compound 4
Under inert gas shielding, by compound 3 and N- N-iodosuccinimides (NIS) in AgNO3The lower generation iodo of catalysis is anti-
Should, mix products B is obtained, wherein, compound 3, NIS and AgNO3Mol ratio be 1:1-2：0.1-0.3, at room temperature, react 6-
After 10 hours, saturated aqueous sodium thiosulfate is added, is extracted with ether, collect organic phase, eaten respectively with water and saturation
Salt water washing organic phase, then use anhydrous Na2SO4Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, obtains compound 4；
4th step, synthesis compound 5a-5d
Under inert gas shielding, using compound 4, aryl boric acid as raw material, it is dissolved in reaction dissolvent, adds alkali and four triphens
Base phosphine palladium, in alkaline environment under the catalysis of tetra-triphenylphosphine palladium, Suzuki coupling reaction occurs, obtain mix products C, reaction temperature
Spend for 80-110 DEG C, the reaction time is 3-5 hours；Water is added into mix products C, is extracted with ether, collects organic phase,
Water and saturated common salt water washing organic phase are used respectively, then use anhydrous Na2SO4Dry, post separation crossed after solvent removed by evaporation at reduced pressure,
Respectively obtain compound 5a-5d；
Described compound 5a is 2- phenyl -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；5b is 2- (4-
Methoxyphenyl) -5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；5c is 2- (4- chlorphenyls) -5- (front threes
Base silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；5d is 2- (4- acetylphenyls) -5- (trimethyl silicon substrate) -1- (N, N-
Dimethyl methyl acyl group) pyrroles；Described compound 4, aryl boric acid, alkali, the mol ratio of tetra-triphenylphosphine palladium are 1:1-2：3-5:
0.05-0.2；
5th step, synthesis compound 6a-6c
Under inert gas shielding, the compound 5a-5c obtained by the 4th step column chromatography is raw material, with N- N-iodosuccinimides
Under silver nitrate catalysis in organic solvent iodide reaction occurs for NIS, obtains mix products D, and reaction temperature is 20-45 DEG C, reaction
Time is 1-5 hours；Saturated aqueous sodium thiosulfate is added into mix products D, is extracted with ether, is collected organic
Phase, respectively with water and saturated common salt water washing organic phase, then anhydrous Na2SO4Dry, post separation crossed after solvent removed by evaporation at reduced pressure,
Respectively obtain compound 6a-6c；
Described compound 6a is the iodo- 5- phenyl -1- of 2- (N, N- dimethyl methyl acyl group) pyrroles, and 6b is 2- iodo- 5- (4- methoxyl groups
Phenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles, 6c is the iodo- 5- of 2- (4- chlorphenyls) -1- (N, N- dimethyl methyl acyl group) pyrrole
Cough up；Described compound 5a-5c：N- N-iodosuccinimides：The mol ratio of silver nitrate is 1:1-2:0.01-0.5；
6th step, synthesis compound 7a-7d
Under inert gas shielding, respectively with compound 6b and to methoxyphenylboronic acid, compound 6b and para hydroxybenzene boric acid, change
Compound 6c and be raw material to methoxyphenylboronic acid, compound 6b and to chlorophenylboronic acid, is added the raw material into organic solvent, and is added
Enter Pd (PPh3)4And alkali, in Pd (PPh3)4Catalysis under Suzuki coupling reaction occurs, obtain mix products E, reaction temperature is
80-110 DEG C, the reaction time is 1-8 hours；Water is added into mix products E, is extracted with ether, collects organic phase, respectively
With water and saturated common salt water washing organic phase, then anhydrous Na2SO4Dry, post separation is crossed after solvent removed by evaporation at reduced pressure, respectively
To compound 7a-7d；
Described compound 7a is 2,5- bis- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles, and compound 7b is
2- (4- hydroxy phenyls) -5- (4- methoxyphenyls) -1- (N, N- dimethyl methyl acyl group) pyrroles, compound 7c are the (4- of 2,5- bis-
Chlorphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles, compound 7d is 2- (4- chlorphenyls) -5- (4- methoxyphenyls) -1-
(N, N- dimethyl methyl acyl group) pyrroles；
Described compound 6b, to methoxyphenylboronic acid or para hydroxybenzene boric acid, Pd (PPh3)4, alkali mol ratio be 1:1-3：
0.05-0.1：Compound 6c described in 3-6, to methoxyphenylboronic acid or to chlorophenylboronic acid, Pd (PPh3)4, alkali mol ratio be 1:
1-3：0.05-0.1：3-6.
A kind of 2. Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 1, it is characterised in that：The
Aryl boric acid described in four steps for phenyl boric acid, to methoxyphenylboronic acid, to chlorophenylboronic acid or to acetylbenzene boric acid；6th step
Described in aryl boric acid for phenyl boric acid, to methoxyphenylboronic acid, to chlorophenylboronic acid or para hydroxybenzene boric acid.
3. a kind of Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 1 or 2, its feature exist
In：Reaction dissolvent described in 4th step is that toluene and methanol are 1 by volume:1-3 mixed solution, per 0.1mmol chemical combination
The corresponding 3-7mL reaction dissolvents of thing 4.
4. a kind of Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 1 or 2, its feature exist
In：Reaction dissolvent described in 5th step is ethanol, acetonitrile, N,N-Dimethylformamide；Per 4 corresponding 3- of 0.1mmol compounds
7mL reaction dissolvents.
A kind of 5. Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 3, it is characterised in that：The
Reaction dissolvent described in five steps is ethanol, acetonitrile, N,N-Dimethylformamide；Per 0.1mmol compounds 4, corresponding 3-7mL is anti-
Answer solvent.
6. the Regioselective synthesis of one kind 2,5- disubstituted pyrroles according to claim 1 or 2 or 5, its feature
It is：Reaction dissolvent described in 6th step is that toluene and methanol are 1 by volume:Mixed solution 1-3)；Per 0.1mmolization
The corresponding 3-7mL reaction dissolvents of compound 4.
A kind of 7. Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 3, it is characterised in that：The
Reaction dissolvent described in six steps is that toluene and methanol are 1 by volume:Mixed solution 1-3)；It is right per 0.1mmol compounds 4
Answer 3-7mL reaction dissolvents.
8. the Regioselective synthesis of one kind 2,5- disubstituted pyrroles according to claim 1 or 2 or 5 or 7, it is special
Sign is：Alkali in 4th step is sodium carbonate；Alkali in 6th step is sodium carbonate, potassium carbonate or potassium phosphate.
A kind of 9. Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 3, it is characterised in that：The
Alkali in four steps is sodium carbonate；Alkali in 6th step is sodium carbonate, potassium carbonate or potassium phosphate.
A kind of 10. Regioselective synthesis of 2,5- disubstituted pyrroles according to claim 6, it is characterised in that：
Alkali in 4th step is sodium carbonate；Alkali in 6th step is sodium carbonate, potassium carbonate or potassium phosphate.
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