CN108822145A - A kind of sulfamide compound and its preparation method and application - Google Patents
A kind of sulfamide compound and its preparation method and application Download PDFInfo
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- CN108822145A CN108822145A CN201810596499.5A CN201810596499A CN108822145A CN 108822145 A CN108822145 A CN 108822145A CN 201810596499 A CN201810596499 A CN 201810596499A CN 108822145 A CN108822145 A CN 108822145A
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- aliphatic hydrocarbon
- aryl
- hydrocarbon group
- compound
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- -1 sulfamide compound Chemical class 0.000 title claims abstract description 125
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 52
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 46
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 14
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 239000007800 oxidant agent Substances 0.000 claims description 9
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 8
- HSYLTRBDKXZSGS-UHFFFAOYSA-N silver;bis(trifluoromethylsulfonyl)azanide Chemical compound [Ag+].FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F HSYLTRBDKXZSGS-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical group [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZECJHXWYQJXFQQ-UHFFFAOYSA-L CC1=C(C)C(C)([Ir](Cl)Cl)C(C)=C1C Chemical class CC1=C(C)C(C)([Ir](Cl)Cl)C(C)=C1C ZECJHXWYQJXFQQ-UHFFFAOYSA-L 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 150000003303 ruthenium Chemical class 0.000 claims description 6
- 229910052710 silicon Inorganic materials 0.000 claims description 6
- 239000010703 silicon Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical group ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 claims description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000005499 phosphonyl group Chemical group 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229940071536 silver acetate Drugs 0.000 claims description 2
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 2
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 2
- 229910001923 silver oxide Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- QVLTVILSYOWFRM-UHFFFAOYSA-L CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C Chemical class CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C QVLTVILSYOWFRM-UHFFFAOYSA-L 0.000 claims 1
- 150000003456 sulfonamides Chemical class 0.000 abstract description 27
- 239000000758 substrate Substances 0.000 abstract description 7
- 238000005905 alkynylation reaction Methods 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 2
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 50
- KZGWPHUWNWRTEP-UHFFFAOYSA-N ethynyl-tri(propan-2-yl)silane Chemical group CC(C)[Si](C#C)(C(C)C)C(C)C KZGWPHUWNWRTEP-UHFFFAOYSA-N 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- 238000001228 spectrum Methods 0.000 description 16
- 150000002431 hydrogen Chemical class 0.000 description 12
- 238000005259 measurement Methods 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 8
- 125000005968 oxazolinyl group Chemical group 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 125000001624 naphthyl group Chemical group 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000539 dimer Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 125000006693 (C2-C9) heterocyclyl group Chemical group 0.000 description 4
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 3
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 3
- 238000013375 chromatographic separation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical group NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 2
- 238000010499 C–H functionalization reaction Methods 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 208000032023 Signs and Symptoms Diseases 0.000 description 2
- 150000001263 acyl chlorides Chemical group 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000007337 electrophilic addition reaction Methods 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000002636 imidazolinyl group Chemical group 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 125000002097 pentamethylcyclopentadienyl group Chemical group 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000001422 pyrrolinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical class O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 241000583905 Taraka hamada Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001336 alkenes Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
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- 229940047495 celebrex Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012650 click reaction Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005597 hydrazone group Chemical group 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-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](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Chemical group CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 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 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- ABBQGOCHXSPKHJ-WUKNDPDISA-N prontosil Chemical compound NC1=CC(N)=CC=C1\N=N\C1=CC=C(S(N)(=O)=O)C=C1 ABBQGOCHXSPKHJ-WUKNDPDISA-N 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- CMPVUVUNJQERIT-UHFFFAOYSA-N tertiary sulfonamide Natural products CC(C)CC1=NC=CS1 CMPVUVUNJQERIT-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to technical field of organic synthesis more particularly to a kind of sulfamide compound and its preparation method and application, wherein the invention discloses a kind of preparation methods of sulfonamide compounds, include the following steps：In the presence of atent solvent, under the action of catalyst, formula (II) compound is reacted with formula (III) compound, obtain formula (I) compound, formula (I) compound is completely new sulfamide compound, it can apply in biomedicine field, the substrate of such compound is simple and easy to get, the alkynylation reaction of the direct C-H bond of level-one or second level sulfonamide without additional guiding base, step is few, it is easy to operate, with good Atom economy and industrial application value, the synthesis step for solving existing sulfamide compound is complicated, the technical issues of being unfavorable for industrial application.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a sulfonamide compound and a preparation method and application thereof.
Background
Sulfonamide compounds are widely used in medicine, agricultural chemicals, dyes, etc. because of their important biological activities. Bayer corporation developed the first sulfonamide drug, bagadon (prontosil), in 1932, and acquired the nobel prize in 1939 for medicine. Bailangduo is the first drug found to be effective against bacteria in organisms so far, and plays a milestone role in the development of sulfonamide drugs. Many sulfonamide drugs have been used in clinical applications, and thus, interest in sulfonamide research has been stimulated. The pharmacological activity of the sulfonamide derivatives mainly comprises: antineoplastic, antiviral, antibacterial, antifungal, antituberculosis and antiparasitic [ wang xiaoling, wang xiaolong, gunny, zhou he, chinese new magazine, 2010,19,2050 ]. Over the last several decades, sulfonamides have been developed in the fields of anti-inflammatory, anti-viral, anti-tumor, etc. [ a.
However, the synthesis of sulfonamides is very challenging, on the one hand, sulfur atoms are often strongly coordinating functional groups for transition metals and tend to poison transition metal catalysts [ i.p. beletskaya, v.p. ananikov, chem.rev.,2011,111,1596 ]; on the other hand, to achieve reactivity of the C-H bond functionality of aryl sulfonamides, the chemistry is often mounted on sulfonamides using additional directing groups to achieve a balance of reactivity and regioselectivity. However, the transformation requires additional introduction and removal of the guide group, and the reaction steps are increased, so that the reaction of the sulfonamide compounds is complicated, and the application of the reaction in practical production is not facilitated.
Therefore, the research and development of a simple, high-efficiency and industrially-valuable sulfonamide compound and a preparation method thereof are technical problems which need to be solved at present.
Disclosure of Invention
The invention provides a sulfonamide compound as well as a preparation method and application thereof, and solves the technical problem that the existing sulfonamide compound is complex in synthesis steps and unfavorable for application in actual production.
The invention provides a sulfonamide compound which has a structure shown in a formula (I);
wherein,is C6-C10 aryl, S, O-containing C2-C9 heterocycle or C2-C9 heteroaryl, R1、R2Each represents a N, O, S-containing heterocycle of C4-C7, an N-containing heterocycle of C4, O, S,
or
R1、R2Each independently selected from hydrogen, C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, substituted amino, alkoxy, aryl, benzyl or-NHCOR8；
R3、R4、R5、R6Each independently selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C1-C40 alkoxy group, C1-C40 alkylthio group, methylenedioxy group, halogenated C1-C40 saturated aliphatic hydrocarbon group, halogenated C1-C40 unsaturated aliphatic hydrocarbon group, halogenated C1-C40 alkoxy group, halogen, nitro group, cyano group, formyl chloride group, CO2R8、-OC(O)R9、-P(O)(R10)(R11)、-P(O)(OR10)(OR11)、-NR12R13、-C(O)NR14R15C6-C14 aryloxy, C6-C14 aryl, -C1-C10 alkoxy, C2-C9 heteroaryl, C2-C9 heterocyclic group,
or
R3、R4、R5、R6Wherein two adjacent groups and the carbon atom connected with the two adjacent groups form C3-C6 naphthenic base or C2-C9 heterocyclic group;
R7selected from C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, methoxyl group, acetoxyl group, silicon base or benzene ring;
R8、R9、R10、R11、R12、R13、R14each independently selected from hydrogen, C1-C40 saturated aliphatic alkyl, C1-C40 unsaturated aliphatic alkyl, C6-C14 aryl, C2-C9 heteroaryl or C2-C9 heterocyclic radical;
R15selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C6-C14 aryl group, C6-C14 aryl sulfonyl group, C1-C10 alkyl sulfonyl group, C1-C10 acyl group, C2-C9 heteroaryl group or C2-C9 heterocyclic group.
Preferably, R5Selected from C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, phenyl, naphthyl or C2-C9 heterocyclic group, R6Is selected from saturated aliphatic hydrocarbon, unsaturated aliphatic hydrocarbon of C1-C40, phenyl, naphthyl or heterocyclic radical of C2-C9.
More preferably, R5Is a C1-C10 saturated or unsaturated alkyl radical, R6Is C1-C10 saturated or unsaturated alkyl.
Most preferably, R5Selected from methyl or benzyl, R6Is a tert-butyl group.
Preferably, R7When the substituent is a silicon group or a benzene ring, when the substituent is a benzene ring, the benzene ring may contain a substituent, wherein the substituent may be halogen, nitro, cyano orA carboxamide group.
The silicon base comprises trimethyl silicon base, triisopropyl silicon base or tert-butyl dimethyl silicon base.
Preferably, the C6-C14 aryl group includes at least one first substituent;
the first substituent is selected from hydrogen, halogen, C1-C40 alkyl, C1-C10 acyl, C1-C40 alkoxy, trifluoromethyl, C6-C14 aryl, C2-C9 heteroaryl, substituted amino, ester, cyano or phosphonyl.
More preferably, the substituents are selected from methyl, methoxy, trifluoromethyl, C6-C14 aryl, C2-C9 heteroaryl, -NR15R16、-CO2R9Cyano, halogen, -P (O) (R)11)(R12) OR-P (O) (OR)11)(OR12)。
Preferably, when the C6-C14 aryl group contains no substituent, the C6-C14 aryl group is selected from phenyl or naphthyl.
More preferably, when the C6-C14 aryl group contains a substituent, the C6-C14 aryl group is selected from the group consisting of phenyl, o-tolyl, o-methoxyphenyl, o-trifluoromethylphenyl, o-arylphenyl, o-heteroarylphenyl, o-substituted aminophenyl, o-esterphenyl, o-cyanophenyl, o-halophenyl, m-tolyl, m-methoxyphenyl, m-substituted aminophenyl, m-trifluoromethylphenyl, m-halophenyl, m-arylphenyl, m-heteroarylphenyl, m-esterphenyl, m-cyanophenyl, p-tolyl, p-methoxyphenyl, p-substituted aminophenyl, p-trifluoromethylphenyl, p-halophenyl, p-esterphenyl, p-cyanophenyl, p-arylphenyl and p-heteroarylphenyl, 2, 3-bismethoxyphenyl, 1-naphthyl, 2-naphthyl and phosphonophenyl groups.
Preferably, said aryl, said C2-C9 heteroaryl, and said C2-C9 heterocyclyl all contain at least one second substituent;
the second substituent is selected from halogen, C1-C40 alkyl, C1-C10 acyl and C1-C40 alkoxy.
Preferably, the heteroaryl group of C2-C9 is selected from furyl, benzofuryl, thienyl, benzothienyl, indolyl, isoindolyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyranyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl, or carbazolyl.
More preferably, the heteroaryl group from C2 to C9 is selected from 2-furyl, 3-furyl, 2-benzofuryl, 3-benzofuryl, 2-thienyl, 3-thienyl, 2-benzothienyl, 3-benzothienyl, 2-indolyl, 3-indolyl, 2-pyrrolyl, 3-pyrrolyl, 5-thiazolyl, 4-pyrazolyl, 3-pyridyl, 4-pyridyl, 6-quinolyl, 5-isoquinolyl, 2-pyridyl, 2-quinolyl, 2-pyrazinyl, 2-pyrimidinyl or 1-pyrazolyl, 2-thiazolyl.
Preferably, the C2-C9 heterocyclic group is selected from tetrahydroquinolyl, N-acyl tetrahydroquinolyl, oxazolinyl, substituted oxazolinyl, tetrahydroindolyl, N-acyl tetrahydroindolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydrofuryl, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl or imidazolinyl.
More preferably, the C2-C9 heterocyclyl is selected from 6-tetrahydroquinolinyl, N-acyltetrahydroquinolinyl, 5-tetrahydroindolyl, N-acyltetrahydroindolyl, oxazolinyl, substituted oxazolinyl, tetrahydroquinolinyl, tetrahydroindolyl, or 2-oxazolinyl.
The invention also provides a preparation method of the sulfonamide compound, which comprises the following steps:
reacting a compound of a formula (II) with a compound of a formula (III) in the presence of an inert solvent under the action of a catalyst to obtain a compound of a formula (I);
wherein X is selected from hydrogen, bromine or iodine, and when X is hydrogen, oxidant is added in the reaction，
Represents C6-C10 aryl, C4-C8S, O-containing heterocycle or heteroaryl;
R1、R2each represents a C4-C7N heterocycle, a C4-O, S N heterocycle,
or
R1、R2Each independently selected from hydrogen, C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, substituted amino, alkoxy, aryl, benzyl or-NHCOR8；
R3、R4、R5、R6Each independently selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C1-C40 alkoxy group, C1-C40 alkylthio group, methylenedioxy group, halogenated C1-C40 saturated aliphatic hydrocarbon group, halogenated C1-C40 unsaturated aliphatic hydrocarbon group, halogenated C1-C40 alkoxy group, halogen, nitro group, cyano group, formyl chloride group, CO2R8、-OC(O)R9、-P(O)(R10)(R11)、-P(O)(OR10)(OR11)、-NR12R13、-C(O)NR14R15C6-C14 aryloxy, C6-C14 aryl, -C1-C10 alkoxy, C2-C9 heteroaryl, C2-C9 heterocyclic group,
or
R3、R4、R5、R6Wherein two adjacent groups and the carbon atom connected with the two adjacent groups form C3-C6 naphthenic base or C2-C9 heterocyclic group;
R7selected from C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, methoxyl group, acetoxyl group, silicon base or benzene ring;
R8、R9、R10、R11、R12、R13、R14each independently selected from hydrogen, C1-C40 saturated aliphatic alkyl, C1-C40 unsaturated aliphatic alkyl, C6-C14 aryl, C2-C9 heteroaryl or C2-C9 heterocyclic radical;
R15selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C6-C14 aryl group, C6-C14 aryl sulfonyl group, C1-C10 alkyl sulfonyl group, C1-C10 acyl group, C2-C9 heteroaryl group or C2-C9 heterocyclic group.
Wherein the compound shown in the formula (II) is an aryl sulfonamide compound, and the compound shown in the formula (III) is a terminal alkyne compound.
Preferably, X is selected from hydrogen or bromine.
Preferably, R5Selected from C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, phenyl, naphthyl or C2-C9 heterocyclic group, R6Selected from C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, phenyl, naphthyl or C2-C9 heterocyclic group.
More preferably, R5Is a C1-C10 saturated or unsaturated alkyl radical, R6Is C1-C10 saturated or unsaturated alkyl;
most preferably, R5Selected from methyl or benzyl, R6Is tert-butyl;
preferably, R7When the compound is a silicon group or a benzene ring, the benzene ring can contain a substituent, wherein the substituent can be halogen, nitro, cyano or formamide. The silicon base comprises trimethyl silicon base, triisopropyl silicon base or tert-butyl dimethyl silicon base.
Preferably, the C6-C14 aryl group includes at least one first substituent;
the first substituent is selected from hydrogen, halogen, C1-C40 alkyl, C1-C10 acyl, C1-C40 alkoxy, trifluoromethyl, C6-C14 aryl, C2-C9 heteroaryl, substituted amino, ester, cyano or phosphonyl.
More preferably, the first substituent is selected from methyl, methoxy, trifluoromethyl, C6-C14 aryl, C2-C9 heteroaryl, -NR15R16、-CO2R9Cyano, halogen, -P (O) (R)11)(R12) OR-P (O) (OR)11)(OR12)。
Preferably, when the C6-C14 aryl group does not contain a first substituent, the C6-C14 aryl group is selected from phenyl or naphthyl.
More preferably, when C6-C14 contains a first substituent, the C6-C14 aryl group is selected from the group consisting of phenyl, o-tolyl, o-methoxyphenyl, o-trifluoromethylphenyl, o-arylphenyl, o-heteroarylphenyl, o-substituted aminophenyl, o-esterphenyl, o-cyanophenyl, o-halophenyl, m-tolyl, m-methoxyphenyl, m-substituted aminophenyl, m-trifluoromethylphenyl, m-halophenyl, m-arylphenyl, m-heteroarylphenyl, m-esterphenyl, m-cyanophenyl, p-tolyl, p-methoxyphenyl, p-substituted aminophenyl, p-trifluoromethylphenyl, p-halophenyl, p-esterphenyl, p-cyanophenyl, p-arylphenyl and p-heteroarylphenyl, 2, 3-bismethoxyphenyl, 1-naphthyl, 2-naphthyl and phosphonophenyl groups.
Preferably, said aryl, said C2-C9 heteroaryl, and said C2-C9 heterocyclyl all contain at least one second substituent;
the second substituent is selected from halogen, C1-C40 alkyl, C1-C10 acyl and C1-C40 alkoxy.
Preferably, the heteroaryl group of C2-C9 is selected from furyl, benzofuryl, thienyl, benzothienyl, indolyl, isoindolyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyranyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl, or carbazolyl.
More preferably, the heteroaryl group from C2 to C9 is selected from 2-furyl, 3-furyl, 2-benzofuryl, 3-benzofuryl, 2-thienyl, 3-thienyl, 2-benzothienyl, 3-benzothienyl, 2-indolyl, 3-indolyl, 2-pyrrolyl, 3-pyrrolyl, 5-thiazolyl, 4-pyrazolyl, 3-pyridyl, 4-pyridyl, 6-quinolyl, 5-isoquinolyl, 2-pyridyl, 2-quinolyl, 2-pyrazinyl, 2-pyrimidinyl or 1-pyrazolyl, 2-thiazolyl.
Preferably, the C2-C9 heterocyclic group is selected from tetrahydroquinolyl, N-acyl tetrahydroquinolyl, oxazolinyl, substituted oxazolinyl, tetrahydroindolyl, N-acyl tetrahydroindolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydrofuryl, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl or imidazolinyl.
More preferably, the C2-C9 heterocyclyl is selected from 6-tetrahydroquinolinyl, N-acyltetrahydroquinolinyl, 5-tetrahydroindolyl, N-acyltetrahydroindolyl, oxazolinyl, substituted oxazolinyl, tetrahydroquinolinyl, tetrahydroindolyl, or 2-oxazolinyl.
Preferably, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:10 to 10: 1.
More preferably, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:3 to 1:1, and still more preferably 1: 2-1: 1, most preferably 1: 2. 2: 3 and 1: 1.
preferably, the inert solvent is selected from toluene, ethylbenzene, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1, 2-dichloroethane, diethyl ether, ethylene glycol dimethyl ether, acetonitrile, ethyl acetate, dichloromethane or acetone;
more preferably, the inert solvent is 1, 2-dichloroethane.
Preferably, the catalyst is selected from the group consisting of iridium (pentamethylcyclopentadienyl) dichloride dimer, ruthenium (p-methylisophenyl) dichloride dimer, rhodium (pentamethylcyclopentadienyl) dichloride dimer, silver bis (trifluoromethanesulfonyl) imide or silver hexafluoroantimonate.
More preferably, the catalyst is selected from the group consisting of iridium dichloro (pentamethylcyclopentadienyl) dimer, ruthenium dichloro (p-methylisophenyl) dimer, silver bis (trifluoromethanesulfonyl) imide, and silver hexafluoroantimonate.
Preferably, the oxidizing agent is selected from silver acetate, silver oxide, silver carbonate, silver nitrate, copper acetate, copper sulfate, copper chloride or copper bromide.
Preferably, the amount of the catalyst is 0.1-20 mol% of the amount of the compound of formula (II).
More preferably, the catalyst is used in an amount of 0.2 to 20 mol%, more preferably 0.5 to 15 mol%, most preferably 2.5 mol% or 15 mol% of the compound of formula (II).
Preferably, the reaction temperature is 20-140 ℃;
the reaction time is 0.1-40 h.
More preferably, the reaction temperature is 80-120 ℃, and the reaction time is 12-24 h.
The invention also provides an application of the sulfonamide compound or the sulfonamide compound obtained by the preparation method of the sulfonamide compound in medicine synthesis.
Ordinary primary sulfonamide and secondary sulfonamide are relatively easily available raw materials, a method for quickly constructing complex sulfonamide derivatives is provided by directly introducing multifunctional and easily-converted functional groups on sulfonamide functional groups, and based on the potential biological activity of sulfonamide molecules, a later derivatization reaction can be directly carried out on drug molecules containing sulfonamides, so that a brand new thought is provided for the development of new sulfonamides, and a new method is provided for quickly constructing a drug molecule library [ P.R.Patel, C.Ramalingan, Y.T.park, bioorg.Med.Chem.2007, 17,6610 ].
The invention uses simple and easily obtained primary and secondary sulfamide as substrates, realizes the alkynylation reaction of the carbon-hydrogen bond of the common sulfamide through C-H activation, and aims to realize the high-efficiency conversion of the subsequent carbon-carbon triple bond, however, the reactions have chemical selectivity: i.e., competing reactions of the N-H bond of the primary and secondary sulfonamides with functionalization of the C-H bond of the aromatic ring, is somewhat challenging to achieve selective activation of the C-H bond in the presence of the N-H bond of the sulfonamide, given the bond energies of the N-H bond and the C-H bond of the aryl, and the better reactivity of the N-H bond of the sulfonamide found by Stahl et al [ t.hamada, x.ye, s.s.stahl, j.am.chem.soc.,2008,130,833 ].
Alkynyl is an important functional group in the fields of materials, medicaments and the like, and can be conveniently converted into other functional groups such as alkyl and olefin; the compound can be conveniently converted into a multi-functionalized compound through reactions such as electrophilic addition, nucleophilic addition and the like; meanwhile, alkyne can also be applied to organisms through Click reaction. It can be seen that it is very practical to introduce alkynyl fragments directly into the molecule. However, the existing synthetic methods are few, low in synthetic efficiency, not easy to obtain raw materials, easy to couple alkynyl per se and the like. It is to be noted that there is currently no report on a simple primary, secondary sulfonamide-directed alkynylation reaction. Therefore, it would be desirable to develop a C-H bond functionalization reaction facilitated by a common primary and secondary sulfonamide without additional directing groups.
It should be noted that the ortho-alkynylated sulfonamide products obtained by the preparation method of the present invention, especially the synthesis methods based on the primary and secondary sulfonamide products and their deficiencies, mainly focus on the coupling reaction of ortho-halogen substituted sulfonamides, while the substrates thereof are extremely difficult to obtain.
In conclusion, the invention has the following advantages:
1. the invention adopts primary and secondary sulfamide as substrates to prepare the sulfonamide compound, and the raw materials are simple and easy to obtain;
2. the method has the advantages that the direct carbon-hydrogen bond alkynylation reaction of common primary and secondary amides without additional guide group assistance is less in steps, simple and convenient to operate, economic and environment-friendly, and has industrial application value;
3. in the process of preparing the aryl sulfonamide compound, no pyridine or quinoline or other guide groups are required to be additionally arranged on the nitrogen atom of the sulfonamide, so that the guide groups are not required to be removed under severe conditions, only the hydrogen atoms or halogen atoms of two substrates are required to be removed, and the aryl sulfonamide compound has good atom economy;
4. the aromatic ring ortho alkynyl substituted sulfonamide derivative prepared by the invention can be used as a very multifunctional synthon to further synthesize more complex functional molecules, can be used for quickly modifying alkynyl with rich chemical activity (such as electrophilic addition, affinity addition and the like through region and stereoselectivity), and can directly realize the amine functionalization reaction in molecules in a catalytic mode to obtain a multi-substituted annular sulfonamide molecule which is widely applied in medicines, thereby providing a modular synthesis mode for the diversified synthesis of the medicine molecules;
5. the sulfonamide compound prepared by the invention is a brand-new sulfonamide compound, can be used as a simple organic raw material for synthesizing complex molecules, and is widely applied to the fields of medicines and materials;
6. the preparation method has good chemical selectivity, namely, the reaction only occurs on the carbon-hydrogen bond, but does not act on the nitrogen-hydrogen bond, namely, the nitrogen-hydrogen bond of the amide is kept unchanged in the reaction process;
7. the preparation method has very good regioselectivity, namely, the reaction only occurs at the ortho position of the benzene ring of the aryl sulfonamide, and any product substituted by alkynyl at the meta position or the para position of the benzene ring is not observed. This has not been possible with the conventional direct electrophilic substitution reactions.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without inventive exercise.
FIG. 1 shows the nuclear magnetic resonance of 2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3a) provided in the first embodiment of the present invention1H, spectrogram;
FIG. 2 shows the nuclear magnetic resonance of 2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3a) provided in the first embodiment of the present invention13C, spectrum;
FIG. 3 Nuclear magnetic resonance 4-methyl-2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3b) provided in example two of the present invention1H, spectrogram;
FIG. 4 Nuclear magnetic resonance 4-methyl-2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3b) provided in example two of the present invention13C, spectrum;
FIG. 5 Nuclear Magnetic Resonance (NMR) of 4- ((2Z,3E) 1-methyl-3-phenyl-2-propenylhydrazone) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3c) provided in example III of the present invention1H, spectrogram;
FIG. 6 NMR of 4- ((2Z,3E) 1-methyl-3-phenyl-2-propenylhydrazone) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3c) provided in example III of the present invention13C, spectrum;
FIG. 7 NMR of 4- (5-tolyl-3-trifluoromethylmonohydropyrazolyl) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d) provided in example IV of the present invention1H, spectrogram;
FIG. 8 NMR of 4- (5-tolyl-3-trifluoromethylmonohydropyrazolyl) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d) provided in example IV of the present invention13C, spectrum;
FIG. 9 NMR of 4-N, N-dipropylsulfonamido-3, 5-di- (triisopropylsilyl) ethynyl benzoyl chloride (3e) provided in EXAMPLE five of this invention1H, spectrogram;
FIG. 10 is a fifth embodiment of the present inventionNuclear magnetic resonance of supplied 4-N, N-dipropylsulfonamido-3, 5-di- (triisopropylsilyl) ethynyl benzoyl chloride (3e)13And C, spectrum.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Other embodiments, which can be derived by one of ordinary skill in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The sulfonamide compound, the preparation method thereof and the raw materials and reagents used in the application can be purchased from the market.
The sulfonamide compound provided by the present invention, the preparation method and the application thereof are further described below.
EXAMPLE one 2- ((Triisopropylsilyl) acetylene) benzenesulfonamide (3a)
To a 15mL Schlenk reaction tube, an arylsulfonamide compound 1a (14.4mg,0.10mmol), an alkynylating agent 2(28 μ L,0.20mmol, when X ═ Br or I, no additional oxidant is needed; when X ═ H, AgOAc (2 equiv.);, dichloro (pentamethylcyclopentadienyl) iridium dimer (2.3mg,0.0025mmol) or dichloro (p-methylisophenyl) ruthenium dimer (1.5mg,0.0025mmol), bis (trifluoromethanesulfonyl) imide silver (4.2mg,0.015mmol) or hexafluoroantimonate silver (5.2mg,0.015mmol), cesium acetate (30mg,0.36mmol), 1, 2-dichloroethane (DCE,1mL) were sequentially added under a nitrogen atmosphere, and reacted at 120 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 3:1, obtaining a product 2- ((triisopropylsilyl) acetylene) benzene sulfonamide (3 a): yellow liquid, yield 63% (21.2 mg).
The nuclear magnetic resonance hydrogen spectrum measurement result of the 2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3a) is as follows:1H NMR(400MHz,CDCl3)δ8.03-8.01(m,1H),7.67-7.65(m,1H),7.53-7.49(m,1H),7.44-7.43(m,1H),1.18-1.14(m,21H)。
the nuclear magnetic resonance carbon spectrum measurement result of the 2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3a) is as follows:13C NMR(100MHz,CDCl3)δ142.5,134.0,131.0,127.7,126.1,119.4,102.2,100.7,17.6,10.3。
example bis 4-methyl-2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3b)
To a 15mL Schlenk reaction tube, an arylsulfonamide compound 1b (17.1mg,0.10mmol), an alkynylating agent 2(20 μ L,0.15mmol, when X ═ Br or I, no additional oxidant is needed; when X ═ H, AgOAc (2 equiv.);, dichloro (pentamethylcyclopentadienyl) iridium dimer (2.3mg,0.0025mmol) or dichloro (p-methylisophenyl) ruthenium dimer (1.5mg,0.0025mmol), bis (trifluoromethanesulfonyl) imide silver (4.2mg,0.015mmol) or hexafluoroantimonate silver (5.2mg,0.015mmol), cesium acetate (30mg,0.36mmol), 1, 2-dichloroethane (DCE,1mL) were sequentially added under a nitrogen atmosphere, and reacted at 120 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 3:1 to obtain the product 2- (4-methyl-2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3b) as a yellow liquid with a yield of 38% (13.4 mg).
The nuclear magnetic resonance hydrogen spectrum measurement result of the 2- (4-methyl (triisopropylsilyl) acetylene) benzenesulfonamide (3b) is as follows:1H NMR(400MHz,CDCl3)δ7.90(d,J＝8.0Hz,1H),7.45(s,1H),7.24(d,J＝8.0Hz,1H),2.40(s,3H),1.18–1.14(m,21H)。
the nuclear magnetic resonance carbon spectrum measurement result of the 2- (4-methyl (triisopropylsilyl) acetylene) benzenesulfonamide (3b) is as follows:13C NMR(100MHz,CDCl3)δ141.8,139.9,134.4,128.3,126.2,119.3,102.3,100.0,20.1,17.62,10.32。
example tris 4- ((2Z,3E) 1-methyl-3-phenyl-2-propenylhydrazone) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3c)
To a 15mL Schlenk reaction tube, a sulfonamide compound 1c (31.5mg,0.10mmol), an alkynylating agent 2(20 μ L,0.15mmol, when X ═ Br or I, no additional oxidant is needed; when X ═ H, AgOAc (2 equiv.);), dichloro (pentamethylcyclopentadienyl) iridium dimer (2.3mg,0.0025mmol) or dichloro (p-methylisophenyl) ruthenium dimer (1.5mg,0.0025mmol), bis (trifluoromethanesulfonyl) imide silver (4.2mg,0.015mmol) or hexafluoroantimonate silver (5.2mg,0.015mmol), cesium acetate (30mg,0.36mmol), 1, 2-dichloroethane (DCE,1mL) were sequentially added under a nitrogen atmosphere, and reacted at 120 ℃ for 18 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. The crude product was chromatographed on a prepared silica gel plate using a developing solvent or eluent selected from petroleum ether and ethyl acetate at a volume ratio of 3:1 to give 4- ((2Z,3E) -1-methyl-3-phenyl-2-propenyl hydrazone) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3c) as a yellow liquid in 89% yield (44.1 mg).
4- ((2Z,3E) 1-methyl-3-phenyl-2-propenylhydrazone) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3c) nuclear magnetismThe resonance hydrogen spectrum measurement result is as follows:1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.65(d,J＝8.0Hz,1H),7.23-7.19(m,3H),7.12-7.07(m,3H),6.33(s,1H),5.96(d,J＝14.4Hz,2H),2.39(s,3H),0.97-0.96(m,21H)。
the result of nuclear magnetic resonance carbon spectrum measurement of 4- ((2Z,3E) 1-methyl-3-phenyl-2-propenyl hydrazone) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3c) is as follows:13C NMR(100MHz,CDCl3)δ150.5,145.3,144.4,142.7,131.5,129.4,129.1,128.6,128.4,128.0,126.5,123.5,106.8,100.5,99.7,18.4,13.3,11.1。
the conversion of the synthetic reaction in the embodiment can be well compatible with multifunctional hydrazone functional groups, hydrazone can be used as a precursor of metal carbene or a carbocation ion, and allyl hydrazone can be used as a precursor of a pyrazole derivative of an important structural framework of a pesticide molecule, so that the converted product has better application potential.
Example tetrakis 4- (5-tolyl-3-trifluoromethylpyrazolyl) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d)
To a 15mL Schlenk reaction tube, a sulfonamide compound 1d (38.1mg,0.10mmol), an alkynylating agent 2(20 μ L,0.15mmol, when X ═ Br or I, no additional oxidant is needed; when X ═ H, AgOAc (2 equiv.);), dichloro (pentamethylcyclopentadienyl) iridium dimer (2.3mg,0.0025mmol) or dichloro (p-methylisophenyl) ruthenium dimer (1.5mg,0.0025mmol), bis (trifluoromethanesulfonyl) imide silver (4.2mg,0.015mmol) or hexafluoroantimonate silver (5.0mg,0.015mmol), cesium acetate (30mg,0.36mmol), 1, 2-dichloroethane (DCE,1mL) were sequentially added under a nitrogen atmosphere, and reacted at 110 ℃ for 24 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 3:1, 4- (5-tolyl-3-trifluoromethylmonohydropyrazolyl) - -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d) is obtained in 63% yield (35.3mg) as a yellow solid.
The result of nuclear magnetic resonance hydrogen spectrum measurement of 4- (5-tolyl-3-trifluoromethyl monohydroxypyrazolyl) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d) is:1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.85-7.83(m,1H),7.37(d,J＝8.4Hz,1H),7.09(s,4H),6.74(s,1H),5.06(brs,1H),5.04(brs,1H),2.32(s,3H),0.97-0.96(m,21H)。
the result of nuclear magnetic resonance carbon spectrum measurement of 4- (5-tolyl-3-trifluoromethyl monohydroxypyrazolyl) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d) is:13C NMR(100MHz,CDCl3)δ145.5,143.1,142.0,138.4,130.8,128.5,128.3,127.1,125.5,124.3,123.3,103.3,99.8,98.6,20.2,17.4,10.0.
the result of nuclear magnetic resonance fluorine spectrum measurement of 4- (5-tolyl-3-trifluoromethyl monohydroxypyrazolyl) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d) is:19F NMR(300MHz,CDCl3)δ-62.4。
in the conversion of the synthetic reaction, the drug molecule celecoxib (celebrex) can be directly used as a substrate to participate in the ethynylation reaction of the direct carbon-hydrogen bond, and the celecoxib capsule can be used for relieving symptoms and signs of osteoarthritis, relieving symptoms and signs of adult rheumatoid arthritis, treating acute pain of adults and the like. Therefore, the molecule obtained by the conversion is expected to exhibit better pharmaceutical activity.
Example five 4-N, N-dipropylsulfonamido-3, 5-di- (triisopropylsilyl) ethynyl benzoyl chloride (3e)
To a 15mL Schlenk reaction tube, a sulfonamide compound 1e (30.3mg,0.10mmol), an alkynylating agent 2(40 μ L,0.25mmol, when X ═ Br or I, no additional oxidant is needed; when X ═ H, AgOAc (2 equiv.);), dichloro (pentamethylcyclopentadienyl) iridium dimer (2.3mg,0.0025mmol) or dichloro (p-methylisophenyl) ruthenium dimer (1.5mg,0.0025mmol), bis (trifluoromethanesulfonyl) imide silver (3.7mg,0.010mmol) or hexafluoroantimonate silver (5.2mg,0.015mmol), cesium acetate (30mg,0.36mmol), 1, 2-dichloroethane (DCE,1mL) were sequentially added under a nitrogen atmosphere, and reacted at 100 ℃ for 8 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. The crude product was chromatographed on a preparative silica gel pad using a 3:1 volume ratio of petroleum ether to ethyl acetate eluent to give 4-N, N-dipropylsulfonamido-3- (triisopropylsilyl) ethynyl benzoyl chloride (3e) as a yellow solid in 67% yield (44.4 mg).
The nuclear magnetic resonance hydrogen spectrum measurement result of the 4-N, N-dipropylsulfonamido-3, 5-di- (triisopropylsilyl) ethynyl benzoyl chloride (3e) is as follows:1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.94(s,1H),5.71(s,1H),3.20-3.17(m,4H),1.63-1.57(m,4H),1.19-1.17(m,21H),1.12-1.10(m,21H),0.91(t,J＝7.4Hz,6H)。
the result of nuclear magnetic resonance carbon spectrum measurement of 4-N, N-dipropylsulfonamido-3, 5-di- (triisopropylsilyl) ethynyl benzoyl chloride (3e) is as follows:13C NMR(100MHz,CDCl3)δ164.3,154.8,146.6,140.6,132.6,127.2,123.5,118.8,104.2,104.1,100.0,50.2,22.3,19.1,18.9,12.0,11.6,11.5。
the conversion of the synthetic reaction in the embodiment can be compatible with acyl chloride functional groups, acyl chloride as an active functional group can be directly converted into esters, ketones and amides, and the tertiary sulfonamide can also well participate in the conversion, so that the conversion has potential as an important synthetic block to quickly construct molecules with biological activity.
The above examples show that the substrate in the examples of the invention is simple and easy to obtain, the synthesis steps are few, and the amide compound can be simply and efficiently prepared, so that the method has industrial application value.
The above-mentioned embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the same; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. A sulfonamide compound is characterized by having a structure shown in a formula (I);
wherein,represents C6-C10 aryl, C4-C8S, O-containing heterocycle or heteroaryl;
R1、R2each represents a C4-C7N heterocycle, a C4-O, S N heterocycle,
or
R1、R2Each independently selected from hydrogen, C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, substituted amino, alkoxy, aryl, benzyl or-NHCOR8；
R3、R4、R5、R6Each independently selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C1-C40 alkoxy group, C1-C40 alkylthio group, methylenedioxy group, halogenated C1-C40 saturated aliphatic hydrocarbon group, halogenated C1-C40 unsaturated aliphatic hydrocarbon group, halogenated C1-C40 alkoxy group, halogen, nitro group, cyano group, formyl chloride group, CO2R8、-OC(O)R9、-P(O)(R10)(R11)、-P(O)(OR10)(OR11)、-NR12R13、-C(O)NR14R15C6-C14 aryloxy, C6-C14 aryl, C1-C10 alkoxy, C2-C9 heteroaryl, C2-C9 heterocyclic group,
or
R3、R4、R5、R6Wherein two adjacent groups and the carbon atom connected with the two adjacent groups form C3-C6 naphthenic base or C2-C9 heterocyclic group;
R7selected from C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, methoxyl group, acetoxyl group, silicon base or benzene ring;
R8、R9、R10、R11、R12、R13、R14each independently selected from hydrogen, C1-C40 saturated aliphatic alkyl, C1-C40 unsaturated aliphatic alkyl, C6-C14 aryl, C2-C9 heteroaryl or C2-C9 heterocyclic radical;
R15selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C6-C14 aryl group, C6-C14 aryl sulfonyl group, C1-C10 alkyl sulfonyl group, C1-C10 acyl group, C2-C9 heteroaryl group or C2-C9 heterocyclic group.
2. The sulfonamide compound according to claim 1, wherein the C6 to C14 aryl group includes at least one first substituent;
the first substituent is selected from hydrogen, halogen, C1-C40 alkyl, C1-C10 acyl, C1-C40 alkoxy, trifluoromethyl, C6-C14 aryl, C2-C9 heteroaryl, substituted amino, ester, cyano or phosphonyl.
3. The sulfonamide compound according to claim 1, wherein each of the aryl group, the C2-C9 heteroaryl group and the C2-C9 heterocyclic group has at least one second substituent;
the second substituent is selected from halogen, C1-C40 alkyl, C1-C10 acyl and C1-C40 alkoxy.
4. A preparation method of sulfonamide compounds is characterized by comprising the following steps:
reacting a compound of a formula (II) with a compound of a formula (III) in the presence of an inert solvent under the action of a catalyst to obtain a compound of a formula (I);
wherein X is selected from hydrogen, bromine or iodine, when X is hydrogen, an oxidant is required to be added in the reaction,represents C6-C10 aryl, C4-C8S, O-containing heterocycle or heteroaryl;
R1、R2each represents a C4-C7N heterocycle, a C4-O, S N heterocycle,
or
R1、R2Each independently selected from hydrogen, C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, substituted amino, alkoxy, aryl, benzyl or-NHCOR8；
R3、R4、R5、R6Each independently selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C1-C40 alkoxy group, C1-C40 alkylthio group, methylenedioxy group, halogenated C1-C40 saturated aliphatic hydrocarbon group, halogenated C1-C40 unsaturated aliphatic hydrocarbon group, halogenated C1-C40 alkoxy group, halogen, nitro group, cyano group, formyl chloride group, CO2R8、-OC(O)R9、-P(O)(R10)(R11)、-P(O)(OR10)(OR11)、-NR12R13、-C(O)NR14R15C6-C14 aryloxy, C6-C14 aryl, C1-C10 alkoxy, C2-C9 heteroaryl, C2-C9 heterocyclic group,
or
R3、R4、R5、R6Wherein two adjacent groups and the carbon atom connected with the two adjacent groups form C3-C6 naphthenic base or C2-C9 heterocyclic group;
R7selected from C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, methoxyl group, acetoxyl group, silicon base or benzene ring;
R8、R9、R10、R11、R12、R13、R14each independently selected from hydrogen, C1-C40 saturated aliphatic alkyl, C1-C40 unsaturated aliphatic alkyl, C6-C14 aryl, C2-C9 heteroaryl or C2-C9 heterocyclic radical;
R15selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C6-C14 aryl group, C6-C14 aryl sulfonyl group, C1-C10 alkyl sulfonyl group, C1-C10 acyl group, C2-C9 heteroaryl group or C2-C9 heterocyclic group.
5. The preparation method according to claim 4, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:10 to 10: 1.
6. The method according to claim 4, wherein the inert solvent is selected from the group consisting of toluene, ethylbenzene, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1, 2-dichloroethane, diethyl ether, ethylene glycol dimethyl ether, acetonitrile, ethyl acetate, dichloromethane, and acetone.
7. The process according to claim 4, wherein the catalyst is selected from the group consisting of dichloro (pentamethylcyclopentadienyl) iridium dimer, dichloro (p-methylisoprene) ruthenium dimer, dichloro (pentamethylcyclopentadienyl) rhodium dimer, silver bis (trifluoromethanesulfonyl) imide and silver hexafluoroantimonate;
the oxidant is selected from silver acetate, silver oxide, silver carbonate, silver nitrate, copper acetate, copper sulfate, copper chloride or copper bromide.
8. The method according to claim 7, wherein the catalyst is used in an amount of 0.1 to 20 mol% based on the compound of formula (II).
9. The preparation method according to claim 4, wherein the reaction temperature is 20-140 ℃;
the reaction time is 0.1-40 h.
10. Use of a sulfonamide compound according to any one of claims 1 to 3 or a sulfonamide compound obtained by the method for producing a sulfonamide compound according to any one of claims 4 to 9 in drug synthesis.
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| CN111170944A (en) * | 2020-02-19 | 2020-05-19 | 五邑大学 | 3-azabicyclo [6.2.0] compounds, and synthetic method and application thereof |
| CN111269182A (en) * | 2020-02-19 | 2020-06-12 | 五邑大学 | 3-azabicyclo [5.2.0] compounds, and synthetic method and application thereof |
| CN113292593A (en) * | 2021-06-24 | 2021-08-24 | 广东工业大学 | Alcohol derivative-oriented aromatic ring remote hydrocarbon activation method |
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