CN105801591B - 一种五环吡咯类生物碱及其制备方法 - Google Patents
一种五环吡咯类生物碱及其制备方法 Download PDFInfo
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- CN105801591B CN105801591B CN201610172663.0A CN201610172663A CN105801591B CN 105801591 B CN105801591 B CN 105801591B CN 201610172663 A CN201610172663 A CN 201610172663A CN 105801591 B CN105801591 B CN 105801591B
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- 238000002360 preparation method Methods 0.000 title abstract description 18
- 150000003233 pyrroles Chemical class 0.000 title abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 120
- -1 OR' Chemical group 0.000 claims abstract description 49
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims abstract description 5
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 233
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 96
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 80
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 66
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 66
- 239000002904 solvent Substances 0.000 claims description 60
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 36
- 239000003054 catalyst Substances 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 239000002808 molecular sieve Substances 0.000 claims description 28
- 239000003153 chemical reaction reagent Substances 0.000 claims description 25
- 239000002585 base Substances 0.000 claims description 22
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000008096 xylene Substances 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 17
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 16
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 14
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 238000006086 Paal-Knorr synthesis reaction Methods 0.000 claims description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 12
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 10
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 10
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002243 precursor Substances 0.000 claims description 10
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- 239000007818 Grignard reagent Substances 0.000 claims description 7
- 238000006845 Michael addition reaction Methods 0.000 claims description 7
- 150000004795 grignard reagents Chemical class 0.000 claims description 7
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 6
- USLRUYZDOLMIRJ-UHFFFAOYSA-N 5-Hexenal Chemical compound C=CCCCC=O USLRUYZDOLMIRJ-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000011985 first-generation catalyst Substances 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000011986 second-generation catalyst Substances 0.000 claims description 6
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 6
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 6
- MVLMPMUGCWJDLE-UHFFFAOYSA-M dibutylboron trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.CCCC[B+]CCCC MVLMPMUGCWJDLE-UHFFFAOYSA-M 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- WQADWIOXOXRPLN-UHFFFAOYSA-N 1,3-dithiane Chemical compound C1CSCSC1 WQADWIOXOXRPLN-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 4
- PBFHCNBIJXCPQZ-UHFFFAOYSA-N CCN1C(C)=C(CCO)SC1.Br Chemical compound CCN1C(C)=C(CCO)SC1.Br PBFHCNBIJXCPQZ-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000005865 alkene metathesis reaction Methods 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 4
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- ILWJAOPQHOZXAN-UHFFFAOYSA-N 1,3-dithianyl Chemical group [CH]1SCCCS1 ILWJAOPQHOZXAN-UHFFFAOYSA-N 0.000 claims description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical group N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 238000005882 aldol condensation reaction Methods 0.000 claims description 3
- 150000001336 alkenes Chemical class 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 238000000354 decomposition reaction Methods 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 claims description 3
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 claims description 3
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 claims description 3
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 claims description 2
- CQMJEZQEVXQEJB-UHFFFAOYSA-N 1-hydroxy-1,3-dioxobenziodoxole Chemical compound C1=CC=C2I(O)(=O)OC(=O)C2=C1 CQMJEZQEVXQEJB-UHFFFAOYSA-N 0.000 claims description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 2
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000005751 Copper oxide Substances 0.000 claims description 2
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 238000007296 Stetter synthesis reaction Methods 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- 229910021536 Zeolite Inorganic materials 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical group Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 claims description 2
- FCDPQMAOJARMTG-UHFFFAOYSA-M benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphanium Chemical compound C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 claims description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000431 copper oxide 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
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 2
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 2
- TWNOVENTEPVGEJ-UHFFFAOYSA-K europium(3+);trifluoromethanesulfonate Chemical compound [Eu+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F TWNOVENTEPVGEJ-UHFFFAOYSA-K 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000002608 ionic liquid Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 2
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 2
- 229910001923 silver oxide Inorganic materials 0.000 claims description 2
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 claims description 2
- JPJIEXKLJOWQQK-UHFFFAOYSA-K trifluoromethanesulfonate;yttrium(3+) Chemical compound [Y+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F JPJIEXKLJOWQQK-UHFFFAOYSA-K 0.000 claims description 2
- 239000011995 wilkinson's catalyst Substances 0.000 claims description 2
- UTODFRQBVUVYOB-UHFFFAOYSA-P wilkinson's catalyst Chemical compound [Cl-].C1=CC=CC=C1P(C=1C=CC=CC=1)(C=1C=CC=CC=1)[Rh+](P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UTODFRQBVUVYOB-UHFFFAOYSA-P 0.000 claims description 2
- 239000010457 zeolite Substances 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 229910000166 zirconium phosphate Inorganic materials 0.000 claims description 2
- LEHFSLREWWMLPU-UHFFFAOYSA-B zirconium(4+);tetraphosphate Chemical compound [Zr+4].[Zr+4].[Zr+4].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O LEHFSLREWWMLPU-UHFFFAOYSA-B 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 4
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种五环吡咯类生物碱及其制备方法。该五环吡咯类生物碱的通式如式I所示,R1和R3选自H、X、羟基、OR'、氨基、带R'基团单取代基的氨基、带R'基团双取代基的氨基、巯基、SR'、氰基、羧基、C1‑C12烷氧羰基、被R”基团取代的C1‑C12烷氧羰基、C1‑C12酰基等。R2和R4选自H、C1‑C12烷基、C1‑C12烷氧基甲基、C1‑C12烷氧基乙基、C3‑C12芳基、苄基、对甲氧基苄基、C1‑C12烷氧羰基、C1‑C12酰基、三甲基硅基、三乙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、三异丙基硅基、三苯基硅基和C1‑C12磺酰基。本发明步骤简捷,原料价格便宜,反应条件温和,产率较高,操作简单,便于放大,便于对产物进行衍生,具有较大工业生产的潜力。
Description
技术领域
本发明涉及一种五环吡咯类生物碱及其制备方法,属于化学合成领域。
背景技术
灵菌红素(Prodigiosins,简称PG)及其类似物是一类含甲氧基吡咯骨架结构的天然色素(如式a-f所示),是一些放线菌、沙雷菌及其他细菌的次级代谢产物,具有很强的抗肿瘤、抗细菌、抗真菌、抗疟疾和免疫抑制等多种生物活性,是一类潜在的抗癌物质。
具有式Ⅰ所示骨架的五环吡咯类生物碱,它们具有5个环系和5个手性中心,其结构特点在于左部大环吡咯和右部螺环结构,并不局限于含有甲氧基。对这类生物碱化合物的生物活性测试表明:该类化合物对于结肠癌细胞(HCT-116)显示出良好的生物活性,另外它们还对黑色素瘤和白血病癌细胞具有很好的选择抑制活性,所以对其研究改造有望用于开发新型的抗癌临床药物的先导化合物。
然而,现有的具有式Ⅰ所示骨架结构的化合物主要来自放线菌的代谢衍生物,然而采用此类方法进行提取这类化合物受到产率低、产物单一等特点的限制。利用化学合成的方式,不仅能够大量制备这类化合物,而且,可以制备该类化合物的衍生物,建立化合物库,便于开展相关生物学和药学等方面的研究。
发明内容
本发明的目的是提供一种五环吡咯类生物碱及其制备方法。
本发明提供的五环吡咯类生物碱的结构式如式I所示:
式I中,R1和R3选自下述基团中的任意一种:氢原子、卤素原子、羟基、OR'、氨基、带R'基团单取代基的氨基、带R'基团双取代基的氨基、巯基、SR'、氰基、羧基、C1-C12烷氧羰基、被R″基团取代的C1-C12烷氧羰基、C1-C12酰基、被R″基团取代的C1-C12酰基、C1-C12烷基、被R″基团取代的C1-C12烷基、C3-C12环烷基、C3-C12杂环基、C3-C12芳基、被R″基团取代的C3-C12芳基、C3-C12杂芳基、被R″基团取代的C3-C12杂芳基、C1-C12磺酰基、C2-C12烯基和C2-C12炔基;其中,R'基团选自下述任意一种基团:C1-C12烷氧羰基、C1-C12酰基、三氟甲基、C1-C12烷基、苄基、对甲氧基苄基、C3-C12芳基、C1-C12磺酰基、C1-C12烷氧基甲基和C1-C12烷氧基乙基;R″基团选自下述任意一种基团:卤素原子、羟基、C1-C12烷氧基、氨基、C1-C12烷基胺基、C1-C12双烷基胺基、C1-C12芳基胺基、C3-C12杂环基、C3-C12芳基、C3-C12杂芳基、巯基、C1-C12烷巯基和C1-C12烷基;
R2和R4选自下述基团中的任意一种:氢原子、C1-C12烷基、C1-C12烷氧基甲基、C1-C12烷氧基乙基、C3-C12芳基、苄基、对甲氧基苄基、C1-C12烷氧羰基、C1-C12酰基、三甲基硅基、三乙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、三异丙基硅基、三苯基硅基和C1-C12磺酰基。
本发明提供的一种制备式Ⅰ所示化合物的方法,包括如下步骤:
式II中,R2和R4的定义同式I;
将式II所示化合物先在Paal-Knorr反应条件下与氮源反应,然后置于Vilsmeier-Haack反应条件下与反应完毕得到式I所示化合物;所述Paal-Knorr反应的氮源为醋酸铵碳酸铵或R3-NH2;
中,R1为氢原子、卤素原子、羟基、OR'、氨基、带R'基团单取代基的氨基、带R'基团双取代基的氨基、巯基、SR'、氰基、羧基、C1-C12烷氧羰基、被R″基团取代的C1-C12烷氧羰基、C1-C12酰基、被R″基团取代的C1-C12酰基、C1-C12烷基、被R″基团取代的C1-C12烷基、C3-C12环烷基、C3-C12杂环基、C3-C12芳基、被R″基团取代的C3-C12芳基、C3-C12杂芳基、被R″基团取代的C3-C12杂芳基、C1-C12磺酰基、C2-C12烯基和C2-C12炔基;其中,R'基团选自下述任意一种基团:C1-C12烷氧羰基、C1-C12酰基、三氟甲基、C1-C12烷基、苄基、对甲氧基苄基、C3-C12芳基、C1-C12磺酰基、C1-C12烷氧基甲基和C1-C12烷氧基乙基;R″基团选自下述任意一种基团:卤素原子、羟基、C1-C12烷氧基、氨基、C1-C12烷基胺基、C1-C12双烷基胺基、C1-C12芳基胺基、C3-C12杂环基、C3-C12芳基、C3-C12杂芳基、巯基、C1-C12烷巯基和C1-C12烷基。
上述式Ⅰ所示化合物的制备方法中,所述Paal-Knorr反应可在催化剂的条件下进行;所述催化剂选自沸石、三氧化铝、对甲苯磺酸、樟脑磺酸、磷酸锆、四异丙氧基钛和微波中的至少一种,优选微波条件;所述Paal-Knorr反应中,所述式II所示化合物和所述氮源投料摩尔比可为(1.0):(1.0~100.0),具体可为1.0:25.0;所述Paal-Knorr反应在溶剂中进行;所述溶剂选自甲醇、乙醇、水、甲苯、N,N-二甲基甲酰胺和离子液体中的任一种;所述Paal-Knorr反应的温度可为-100℃~200℃,优选25~150℃,更优选140℃;时间可为1分钟~1000分钟,优选10~100分钟,更优选25分钟。
上述式Ⅰ所示化合物的制备方法中,所述Vilsmeier-Haack(维尔斯迈尔-哈克)反应在氮气条件下进行;所述Vilsmeier-Haack反应在试剂的条件下进行;所述试剂选自三氯氧磷、三溴氧磷、草酰氯和三氟甲磺酸酐中的任一种;所述Vilsmeier-Haack反应中,所述式II所示化合物、所述和所述试剂的投料摩尔比为(1.0):(1.0~1000):(1.0~10.0),具体可为1.0:540.0:2.0(注:吡咯为溶剂);所述Vilsmeier-Haack反应的温度可为-20℃~100℃,具体可为25℃;时间可为0.1小时~50小时,具体可为3小时。
式I所示化合物或其药学上可接受的盐、酯、溶剂合物在制备下述1)和/或2)中的应用,也在本发明的保护范围内:1)真核生物肿瘤细胞增殖抑制剂;2)预防和/或治疗肿瘤的药物。
上述的应用中,所述真核生物可为哺乳动物。所述肿瘤细胞可为癌细胞;所述癌细胞包括但不限于:肺癌细胞、结肠癌细胞、肝癌细胞、乳腺癌细胞、子宫颈癌细胞等。其中,所述肺癌细胞具体可为人肺癌细胞A549;所述结肠癌细胞具体可为人结肠癌细胞HCT116;所述肝癌细胞具体可为人肝癌细胞HepG2;所述乳腺癌细胞具体可为人乳腺癌细胞MCF-7;所述子宫颈癌细胞具体可为人子宫颈癌细胞Hela。
上述应用中,所述肿瘤可为癌;所述癌包括但并不限于:肺癌、结肠癌、肝癌、乳腺癌、宫颈癌等。
上述制备式I所示化合物的方法中,所用中间体化合物式II所示化合物,其结构通式如下:
式II中,R2和R4的定义同式I。
本发明提供的制备式II所示化合物的方法,包括如下步骤:
式III中,R2和R4的定义同式I;
将式III所示十三元大环骨架化合物在催化剂存在的条件下和氢气条件下进行选择性氢化反应,反应完毕得到所述式II所示化合物。
上述制备式II所示化合物的方法中,所述氢气的压力可为1.0~50bar,具体可为1.02bar;所述催化剂可为钯碳、威尔金森催化剂或氧化铂;所述选择性氢化反应步骤中,温度可为0℃~100℃,优选10~40℃,更优选25℃;时间可为0.01小时~24小时,优选5~15小时,更优选12小时;所述催化剂与所述式III所示化合物的投料摩尔比可为(0.01~1.0):1.0,具体可为0.2:1;所述选择性氢化反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、乙酸乙酯、四氢呋喃、二氯甲烷和二氧六环中的至少一种。
上述制备式II所示化合物的方法中,所用中间体化合物式III所示化合物,其结构通式如下:
式III中,R2和R4的定义同式I。
本发明提供的制备式III所示化合物的方法,包括如下步骤:
式IV中,R2和R4的定义同式I;
将式IV所示化合物在催化剂存在的条件下进行烯烃复分解反应,反应完毕得到所述式III所示化合物。
上述式III所示化合物的制备方法中,所述催化剂可为Grubbs一代催化剂、Grubbs二代催化剂、Grubbs-Hoveyda一代催化剂、Grubbs-Hoveyda二代催化剂、Schrock催化剂、Zhan-1B催化剂、Zhan-1C一代催化剂或Zhan二代催化剂;所述烯烃复分解反应步骤中,温度可为0℃~100℃,优选25~60℃,更优选45℃;时间可为0.01小时~48小时,优选12~40小时,更优选36小时;所述催化剂与所述式IV所示化合物的投料摩尔比可为(0.01~1.0):1.0,优选0.1:1;所述烯烃复分解反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、四氢呋喃和二氯甲烷中的至少一种。
上述制备式III所示化合物的方法中,所用中间体化合物式IV所示化合物,其结构通式如下:
式IV中,R2和R4的定义同式I。
本发明提供的制备式IV所示化合物的方法,包括如下步骤:
式V中,R2和R4的定义同式I,R5为C1-C12烷基;
将式V所示化合物在酸存在的条件下进行关螺环反应,反应完毕得到所述式IV所示化合物。
上述式IV所示化合物的制备方法中,所述酸选自对甲苯磺酸、对甲苯磺酸吡啶盐、樟脑磺酸、三氟化硼乙醚、三氟甲磺酸镱、三氟甲磺酸铕、三氟甲磺酸钇、氯化铁、氯化锌和氯化锡等路易斯酸中的任一种;所述反应步骤中,温度可为-20℃~100℃,优选0~30℃,更优选25℃;时间可为0.01小时~48小时,优选5~24小时,更优选15小时;所述酸与所述式V所示化合物的投料摩尔比可为(0.01~10):1.0,优选3.0:1;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、四氢呋喃和二氯甲烷中的至少一种。
上述制备式IV所示化合物的方法中,所用中间体化合物式V所示化合物,其结构通式如下:
式V中,R2和R4的定义同式I,R5为C1-C12烷基。
本发明提供的一种制备式V所示化合物的方法,包括如下步骤:
式VI中,R2、R4和R5的定义同式V;
将式VI所示化合物在催化剂存在的条件下与5-己烯醛进行Stetter反应,反应完毕得到所述式V所示化合物。
上述式V所示化合物的制备方法中,所述催化剂选自对氰化钾、氰化钠、3-乙基-5-(2-羟乙基)-4-甲基噻唑溴化物和3-苄基3-乙基-5-(2-羟乙基)-4-甲基噻唑氯化物等噻唑盐类化合物中的任一种,优选为3-乙基-5-(2-羟乙基)-4-甲基噻唑溴化物;所述反应步骤中,温度可为0℃~200℃,优选50~100℃,更优选78℃;时间可为0.01小时~48小时,优选5~24小时,更优选18小时;所述催化剂、所述5-己烯醛和所述式VI所示化合物的投料摩尔比可为(0.01~10):(1.0~10.0):1.0,优选1.3:4.0:1;所述反应在溶剂中进行;所述溶剂选自甲醇、乙醇、N,N-二甲基甲酰胺、四氢呋喃、二甲亚砜和1,4-二氧六环中的至少一种;所述反应在有机碱存在的条件下进行,所述有机碱为三乙胺、二异丙基乙胺、吡啶和2,6-二甲基吡啶中的任一种;所述有机碱和所述VI所示化合物的投料摩尔比可为(0.01~20):1.0,优选(1~10):1,具体可为6:1。
上述制备式V所示化合物的方法中,所用中间体化合物式VI所示化合物,其结构通式如下:
式VI中,R2、R4和R5的定义同式V。
上述式VI所示化合物的制备方法,为下述A)或B):
A)式VI所示化合物中,R4为氢原子;所述方法包括如下步骤:
A1)式VII所示化合物和格氏试剂进行迈克尔加成反应,可以得到式VIII所示化合物;
A2)将步骤A1)所得式VIII所示化合物在三氟甲磺酸二丁硼、二异丙基乙胺和丙烯醛存在的条件下进行羟醛缩合反应,得到式IX所示化合物;
A3)在有机碱存在下,将步骤A2)所得式IX所示化合物与保护基试剂反应,对式IX所示化合物中的羟基进行保护,得到式X所示化合物;所述保护基试剂为R6-Cl或R6-CF3SO3;
A4)将步骤A3)所得式X所示化合物在甲酰基前体和强碱存在的条件下进行反应,得到式XI所示化合物;所述甲酰基前体为R7-H;
A5)将步骤A4)所得式XI所示化合物在酸性条件下与醇进行关环反应,反应完毕得到式XII所示化合物;所述醇为R5-OH;
A6)将步骤A5)所得式XII所示化合物经过转化,可以得到式XIII所示化合物;
A7)将步骤A6)所得式XIII所示化合物在乙腈、强碱的存在条件下进行反应,反应完毕得到式XIV所示化合物;
A8)将步骤A7)所得式XV所示化合物在双氧水、碳酸钾、二甲亚砜存在下把氰基水解为酰胺,反应完毕得到式XVI所示化合物;
A9)将步骤A8)所得式XVI所示化合物在碱性条件下脱R6保护,反应完毕得到式XVII所示化合物;
A10)将步骤A9)所得式XVII所示化合物在氧化剂存在的条件下对烯丙醇羟基进行选择性氧化,反应完毕得到式VI所示化合物;
所述式VI至式XVII中,R2选自氢原子、C1-C12烷基、C1-C12烷氧基甲基、C1-C12烷氧基乙基、C3-C12芳基、苄基、对甲氧基苄基、C1-C12烷氧羰基、C1-C12酰基、三甲基硅基、三乙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、三异丙基硅基、三苯基硅基或C1-C12磺酰基;
R5为C1-C12烷基;
R6为叔丁基二甲基硅基、叔丁基二甲基硅基、三乙基硅基、叔丁基二苯基硅基或三异丙基硅基;
R7为2-噻唑基、1,3-二硫代坊基或1,3-二噻烷基;
B)式VI所示化合物中,R4为C1-C12烷基、C1-C12烷氧基甲基、C1-C12烷氧基乙基、C3-C12芳基、苄基、对甲氧基苄基、C1-C12烷氧羰基、C1-C12酰基、三甲基硅基、三乙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、三异丙基硅基、三苯基硅基或C1-C12磺酰基;所述方法包括如下步骤:
B1)式VII所示化合物和格氏试剂进行迈克尔加成反应,可以得到式VIII所示化合物;
B2)将步骤B1)所得式VIII所示化合物在三氟甲磺酸二丁硼、二异丙基乙胺和丙烯醛存在的条件下经行羟醛缩合反应,得到式IX所示化合物;
B3)在有机碱存在下,将步骤B2)所得式IX所示化合物与保护基试剂反应,对式IX所示化合物中的羟基进行保护,得到式X所示化合物;所述保护基试剂为R6-Cl或R6-CF3SO3;
B4)将步骤B3)所得式X所示化合物在甲酰基前体和强碱存在的条件下进行反应,得到式XI所示化合物;所述甲酰基前体为R7-H;
B5)将步骤B4)所得式XI所示化合物在酸性条件下与醇进行关环反应,反应完毕得到式XII所示化合物;所述醇为R5-OH;
B6)将步骤B5)所得式XII所示化合物经过转化,可以得到式XIII所示化合物;
B7)将步骤B6)所得式XIII所示化合物在乙腈、强碱的存在条件下进行反应,反应完毕得到式XIV所示化合物;
B8)将步骤B7)所得式XIV所示化合物中的羟基在保护基试剂和碱的存在下进行保护,反应完毕得到式XV所示化合物;
B9)将步骤B8)所得式XV所示化合物在双氧水、碳酸钾、二甲亚砜存在下把氰基水解为酰胺,反应完毕得到式XVI所示化合物;
B10)将步骤B9)所得式XVI所示化合物在碱性条件下脱R6保护,反应完毕得到式XVII所示化合物;
B11)将步骤B10)所得式XVII所示化合物在氧化剂存在的条件下进行氧化,反应完毕得到式VI所示化合物;
所述式VI至式XVII中,R2选自氢原子、C1-C12烷基、C1-C12烷氧基甲基、C1-C12烷氧基乙基、C3-C12芳基、苄基、对甲氧基苄基、C1-C12烷氧羰基、C1-C12酰基、三甲基硅基、三乙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、三异丙基硅基、三苯基硅基或C1-C12磺酰基;
R4选自C1-C12烷基、C1-C12烷氧基甲基、C1-C12烷氧基乙基、C3-C12芳基、苄基、对甲氧基苄基、C1-C12烷氧羰基、C1-C12酰基、三甲基硅基、三乙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、三异丙基硅基、三苯基硅基或C1-C12磺酰基;
R5为C1-C12烷基;
R6为叔丁基二甲基硅基、叔丁基二甲基硅基、三乙基硅基、叔丁基二苯基硅基或三异丙基硅基;
R7为2-噻唑基、1,3-二硫代坊基或1,3-二噻烷基。
上述式VI所示化合物的制备方法中:
步骤A1)和步骤B1)中,所述格氏试剂可为高烯丙基溴化镁;所述迈克尔加成反应在催化剂的条件下进行;所述催化剂可为碘化亚铜;所述格氏试剂、所述催化剂、所述式VII所示化合物的投料摩尔比可为(1~10):(0.01~10):1,优选2:0.5:1;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚和四氢呋喃中的至少一种,优选为四氢呋喃;所述迈克尔加成反应的温度可为-78~0℃,优选为-35℃;时间可为1~10小时,优选4小时;
所述步骤A2)和步骤B2)中,所述三氟甲磺酸二丁硼、二异丙基乙胺、式VIII所示化合物和丙烯醛的投料摩尔比可为(1.0~10.0):(1.25~12.5):1.0:(1.0~5.0),优选为2.0:2.5:1.0:2.5;所述步骤2)反应步骤中,温度可为-78℃~0℃,时间可为5~24小时;所述溶剂选自甲苯、二甲苯、四氢呋喃和二氯甲烷中的至少一种;
所述步骤A3)和步骤B3)中,所述保护基试剂可为叔丁基二甲基硅基氯、叔丁基二甲基硅基三氟甲磺酸酯、三乙基硅基氯、叔丁基二苯基硅基氯和三异丙基硅基氯中的任一种,优选为叔丁基二甲基硅基三氟甲磺酸酯;所述有机碱可为三乙胺、二异丙基乙胺、吡啶和2,6-二甲基吡啶中的一种,优选为2,6-二甲基吡啶;所述反应的温度可为0℃~25℃,时间可为0.1小时~50小时,优选0.3~1小时,更优选0.5小时;所述保护基试剂与式IX所示化合物的投料摩尔比可为(1~10):1.0,优选1.1:1;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、四氢呋喃和二氯甲烷中的至少一种,优选为二氯甲烷;
所述步骤A4)和步骤B4)中,所述甲酰基前体选自噻唑、1,3-二噻烷和1,3-二硫代坊中的任一种,优选为噻唑;所述强碱性化合物选自正丁基锂、叔丁基锂、二异丙氨基锂、六甲基二硅胺基锂、六甲基二硅胺基钠和六甲基二硅胺基钾中的至少一种,优选正丁基锂;所述甲酰基前体与式X所示化合物的投料摩尔比可为(1~10):1.0,优选1.2:1;所述步骤4)反应步骤中,温度可为-78℃~-35℃,时间可为3~10小时;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、四氢呋喃和二氯甲烷中的至少一种;
所述步骤A5)和步骤B5)中,所述酸选自对甲苯磺酸、对甲苯磺酸吡啶盐、樟脑磺酸、三氟化硼乙醚、三氯化铁中的至少一种,优选对甲苯磺酸;所述醇为C1-C12的烷基醇,比如甲醇,乙醇,丙醇,优选为甲醇;所述酸与式XI所示化合物的投料摩尔比为(0.01~10):1.0,优选0.15:1;所述步骤5)反应步骤中,温度为10℃~40℃,时间为2~10小时;所述反应在溶剂中进行,所述溶剂选自甲醇、乙醇、乙醚、四氢呋喃、二氯甲烷中的至少一种,优选为甲醇;
所述A6)和步骤B6)中,所述转化条件选自三氟甲磺酸甲酯、硼氢化钠、硝酸银体系或者三氟甲磺酸甲酯、硼氢化钠、氧化铜、氯化铜体系以及硝酸铈铵体系,优选为三氟甲磺酸甲酯、硼氢化钠、硝酸银体系;所述三氟甲磺酸甲酯、硼氢化钠、硝酸银与式XII所示化合物的投料摩尔比为(1~10):(1~10):(1~10):1.0,优选2:2:1.5:1;所述步骤6)反应步骤中,温度可为0℃~30℃,优选为25℃,反应时间可为1~2小时,优选1.5小时;
所述A7)和步骤B7)中,所述强碱性化合物选自正丁基锂、叔丁基锂、二异丙氨基锂、六甲基二硅胺基锂、六甲基二硅胺基钠和六甲基二硅胺基钾中的至少一种,优选六甲基二硅胺基锂;所述乙腈、强碱化合物与式XIII所示化合物的投料摩尔比为(1~10):(1~10):1.0,优选7:7:1;所述步骤7)反应步骤中,温度为-78℃,时间为2~5小时;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、四氢呋喃中的至少一种,优选为四氢呋喃;
所述步骤B8)中,所述保护基试剂选自C1-C12烷基卤化物、C1-C12烷氧基甲基卤化物、C1-C12烷氧基乙基卤化物、C3-C12芳基卤化物、苄基卤化物、对甲氧基苄基卤化物、三甲基硅基卤化物、三乙基硅基卤化物、叔丁基二甲基硅基卤化物、叔丁基二苯基硅基卤化物、三异丙基硅基卤化物、三苯基硅基卤化物和C1-C12磺酰基,具体可为碘甲烷、硫酸二甲酯、三甲基氧翁四氟硼酸盐和三氟甲磺酸甲酯、叔丁基二苯基氯硅烷、叔丁基二甲基氯硅烷中的一种,优选为碘甲烷;所述碱性化合物选自氢化钠、氧化银、2,6-二叔丁基-4-甲基吡啶、2,6-二叔丁基吡啶和碳酸铯中的至少一种;所述保护基试剂与式XIV所示化合物的投料摩尔比为(1~10):1.0,优选3:1;所述步骤8)反应步骤中,温度为0℃~25℃,时间为2~10小时;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、四氢呋喃和二氯甲烷中的至少一种,优选为四氢呋喃;
所述步骤A8)和B9)中,所述双氧水、碳酸钾与式XV所示化合物的投料摩尔比可为(1~50):(1~10):1.0,优选10:2:1;所述反应步骤中,温度可为20℃~40℃,时间可为10~18小时;所述反应在溶剂中进行;所述溶剂选自二甲基亚砜;
所述步骤A9)和B10)中,所述碱选自四丁基氟化铵、氟化钾、氟化氢吡啶、三氧化铝和氟化铯中的一种,优选为四丁基氟化铵;所述碱性化合物与式XVI所示化合物的投料摩尔比可为(1~10):1.0,优选2:1;温度可为0℃~100℃,优选为55℃;时间可为18~30小时;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、四氢呋喃和二氯甲烷中的至少一种;所述反应在分子筛的条件下进行,所述分子筛为分子筛、分子筛和分子筛中的任一种,所述分子筛的量为:每1mmol式XVI所示化合物加入分子筛50mg~200mg,具体可为每毫摩尔底物加入100mg分子筛。
所述步骤A10)中,所述氧化剂可为二氧化锰;步骤B11)中,所述氧化剂选自高锰酸钾、二氧化锰、二氯二氰对苯醌、邻碘酰苯甲酸、戴斯-马丁氧化剂、氧气、四氯对苯醌、四丙基高钌酸铵和氮甲基吗啉氧化物中的至少一种,优选为四丙基高钌酸铵和氮甲基吗啉氧化物;所述氧化反应步骤中,温度可为-100℃~50℃,优选-10~50℃,更优选0℃~25℃;时间可为0.01小时~50小时,优选1~10小时,更优选3小时;所述四丙基高钌酸铵和氮甲基吗啉氧化物与所述式XVII化合物的投料摩尔比可为(0.01~1.0):(1.0~10):1.0,优选0.1:1.6:1;所述反应在溶剂中进行;所述溶剂选自二氯甲烷、乙腈、四氢呋喃、乙醚中的至少一种,优选为二氯甲烷和乙腈;所述反应在分子筛的条件下进行,所述分子筛为分子筛、分子筛和分子筛中的任一种,所述分子筛的量为:每1mmol式XVII所示化合物加入分子筛50mg~2000mg,具体可为每毫摩尔底物加入1.0g分子筛。
本发明五环吡咯类生物碱具有优异的抗肿瘤活性。本发明提供的制备方法步骤简捷,原料价格便宜,反应条件温和,产率较高,操作简单,便于放大,便于对产物进行衍生,具有较大工业生产的潜力。
附图说明
图1为实施例中制备式6所示化合物的流程示意图。
图2为实施例中制备式1所示五环吡咯类生物碱的流程示意图。
图3为实施例中制备得到的式1所示五环吡咯类生物碱的单晶结构图。
图4为实施例中4种化合物处理后肿瘤细胞的IC50值的柱形图。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
下述实施例中所用的式6所示化合物按照包括如下步骤的方法制备,反应流程图如图1所示,具体步骤如下:
步骤(a):将4.8g碘化亚铜加入一个500mL三口瓶,抽真空通氮气3次,加入60mL四氢呋喃,冷却至-78℃,将201mL高烯丙基溴化镁(0.5M的四氢呋喃溶液)加入体系,然后拿到-35℃反应30分钟,将5.65g不饱和内酯(式7所示化合物)溶于30mL无水四氢呋喃,在-35℃条件下用注射泵滴加至反应体系(用时3小时),滴加完毕,在相同温度下继续反应1小时,然后缓慢加入饱和氯化铵溶液淬灭反应,乙酸乙酯(3x80mL)萃取,二次水和饱和食盐水洗涤有机相,有机相用MgSO4干燥,过滤,浓缩过快速色谱柱纯化得到6.0g式8所示化合物(71%)。黄色液体;[α]D 25=-46.5(c 1.03,CHCl3);IR(film):1740,1250,1092cm-1;1H NMR(400MHz,CDCl3)δ5.82-5.70(m,1H),5.07-4.94(m,2H),4.58-4.46(m,1H),2.57(dd,J=16.4,5.6Hz,1H),2.16(dd,J=16.4,9.6Hz,1H),2.12-2.00(m,3H),1.79-1.69(m,1H),1.68-1.58(m,1H),1.47(q,J=7.6Hz,2H),1.35(d,J=6.4Hz,3H);13C NMR(100MHz,CDCl3)δ172.6,137.7,115.5,73.8,35.7,35.2,35.0,31.0,28.3,21.5;HRMS calcd for C10H16O2Na[M+Na]:191.1043;found:191.1048.
步骤(b):一个500mL三口瓶,抽真空通氮气3次,将3.0g式8所示化合物溶于60mL二氯甲烷中,冷却至-78℃搅拌,将35.7ml三氟甲磺酸二丁硼(1.0M的二氯甲烷溶液)和7.4mL二异丙基乙胺加入反应体系,-78℃反应2小时,将3mL丙烯醛缓慢加入反应体系,-78℃反应1小时,然后拿到0℃反应2小时,向反应体系加入50mL磷酸缓冲液(pH=6.8),100mL甲醇,50mL双氧水,然后把反应体系拿到室温搅拌过夜,二氯甲烷(3x50mL)萃取,二次水和饱和食盐水洗涤有机相,有机相用Na2SO4干燥,过滤,浓缩过快速色谱柱纯化得到3.2g式9所示化合物(80%)。淡黄色液体;[α]D 25=-33.0(c 1.01,CHCl3);IR(film):3435,1718,1200,1097cm-1;1H NMR(400MHz,CDCl3)δ6.02(ddd,J=16.8,10.4,6.4Hz,1H),5.82-5.70(m,1H),5.28(dt,J=17.2,1.2Hz,1H),5.18(dt,J=10.4,1.2Hz,1H),5.06-4.92(m,2H),4.50-4.38(m,1H),4.32-4.22(m,1H),3.41(d,J=7.6Hz,1H),2.27(dd,J=7.6,4.4Hz,1H),2.20-1.96(m,3H),1.74-1.61(m,3H),1.48-1.37(m,1H),1.34(d,J=6.4Hz,3H);13C NMR(100MHz,CDCl3)δ174.5,139.0,137.6,116.6,115.6,73.1,72.4,50.2,34.8,33.9,31.04,31.00,21.2;HRMScalcd for C13H20O3Na[M+Na]:247.1305;found:247.1305.
步骤(c):将3.80g式9所示化合物溶于60mL二氯甲烷中,冷却至0℃,然后加入(3.0mL)2,6-二甲基吡啶,0℃反应5分钟,然后向体系加入4.3mL叔丁基二甲基三氟甲磺酸酯,然后把反应体系拿到室温反应30分钟,随后浓缩过快速色谱柱纯化得到5.50g式10所示化合物(95%)。淡黄色液体;[α]D 25=-38.4(c 1.22,CHCl3);IR(film):1725,1253,1096cm-1;1H NMR(400MHz,CDCl3)δ6.88(ddd,J=17.2,10.4,4.8Hz,1H),5.82-5.70(m,1H),5.31(d,J=16.8Hz,1H),5.16(d,J=10.4Hz,1H),5.00(d,J=17.2Hz,1H),4.96(d,J=10.4Hz,1H),4.89(t,J=4.4Hz,1H),4.54-4.42(m,1H),2.46(t,J=4.4Hz,1H),2.17-1.95(m,3H),1.80-1.69(m,1H),1.69-1.55(m,2H),1.49-1.36(m,1H),1.32(d,J=6.4Hz,3H),0.90(s,9H),0.07(s,3H),0.04(s,3H);13C NMR(100MHz,CDCl3)δ172.5,138.1,137.8,116.1,115.2,73.6,72.8,51.1,34.6,34.0,31.4,29.1,26.1,21.7,18.4,-4.6,-4.8;HRMS calcd forC19H34O3NaSi[M+Na]:361.2169;found:361.2166.
步骤(d):一个250mL三口瓶,抽真空通氮气3次,将1.66g噻唑溶于80mL乙醚中,冷却至-78℃搅拌,向体系中加入8.1ml正丁基锂(2.4M的正己烷溶液),于-78℃反应1小时,将5.5g式10所示化合物溶于20mL乙醚中,加入反应体系,然后-78℃到-35℃反应5小时,然后缓慢加入饱和氯化铵溶液淬灭反应,乙酸乙酯(3x50mL)萃取,二次水和饱和食盐水洗涤有机相,有机相用MgSO4干燥,过滤,浓缩过快速色谱柱纯化得到6.1g式11所示化合物(89%)。黄色液体;[α]D 25=+5.5(c 0.97,CHCl3);IR(film):3366,1681,1394,1252,1064cm-1;1HNMR(400MHz,CDCl3)δ7.98(d,J=2.8Hz,1H),7.65(d,J=3.2Hz,1H),5.84(ddd,J=17.6,10.0,8.4Hz,1H),5.72-5.60(m,1H),5.30(d,J=17.2Hz,1H),5.20(d,J=10.0Hz,1H),4.92(d,J=17.2Hz,1H),4.85(d,J=10.0Hz,1H),4.69(t,J=9.2Hz,1H),4.25-4.10(m,2H),3.68(br s,1H),2.17-2.04(m,1H),2.04-1.88(m,2H),1.74-1.63(m,1H),1.62-1.44(m,2H),1.42-1.30(m,1H),1.20(d,J=6.0Hz,3H),0.67(s,9H),0.00(s,3H),-0.02(s,3H);13CNMR(100MHz,CDCl3)δ194.1,168.7,144.5,140.1,138.5,126.5,117.5,115.0,73.7,65.0,53.7,40.8,34.7,31.8,29.7,25.8,23.2,18.1,-3.7,-5.1;HRMS calcd for C22H37O3NNaSSi[M+Na]:446.2156;found:446.2153.
步骤(e):将1.36g式11所示化合物溶解于30mL甲醇中,然后加入0.0829g对甲苯磺酸,反应体系于室温反应3小时,随后向体系加入5mL三乙胺淬灭反应,浓缩过快速色谱柱纯化得到1.27g式12所示化合物(91%)。白色固体;mp.55-56℃;[α]D 25=-78.2(c 1.00,CHCl3);IR(film):1252,1128,1040cm-1;1H NMR(400MHz,CDCl3)δ7.87(d,J=3.2Hz,1H),7.32(d,J=3.2Hz,1H),5.98(ddd,J=17.2,10.8,3.2Hz,1H),5.90-5.78(m,1H),5.11(dt,J=17.2,2.0,Hz,1H),5.04-4.86(m,3H),4.04-3.92(m,1H),3.70-3.62(m,1H),2.95(s,3H),2.33(d,J=3.6Hz,1H),2.20-2.00(m,3H),1.89-1.65(m,3H),1.30-1.24(m,1H),1.24(d,J=6.0Hz,1H),0.84(s,9H),-0.02(s,3H),-0.15(s,3H);13C NMR(100MHz,CDCl3)δ171.5,143.4,139.6,119.9,114.2,112.8,101.5,71.2,63.1,51.1,49.1,35.7,33.4,32.7,29.2,26.1,21.8,18.3,-4.8,-5.0;HRMS calcd for C23H39O3NNaSSi[M+Na]:460.2312;found:460.2307.
步骤(f):将2.50g式12所示化合物溶于60mL无水乙腈中,然后加入6.0g分子筛,于室温搅拌10分钟后向体系加入1.88g三氟甲磺酸甲酯,在室温搅拌15分钟,直接旋干,将所得混合物直接溶于60ml无水乙醇,并冷却到0℃,分批加入0.43g硼氢化钠,反应在0℃反应30分钟再在室温反应30分钟,随后用丙酮淬灭,过一段硅胶柱滤去分子筛,旋干,将粗产品溶于60mL乙腈,在剧烈搅拌下加入6mL水,然后加入1.46g硝酸银,反应于室温反应10分钟,向反应体系加入50mL磷酸缓冲液(pH=6.8)淬灭反应,二氯甲烷(3x80mL)萃取,二次水和饱和食盐水洗涤有机相,有机相用Na2SO4干燥,过滤,浓缩过快速色谱柱纯化得到1.57g式13所示化合物(72%)。黄色液体;[α]D 25=-14.2(c 1.20,CHCl3);IR(film):1745,1252,1036cm-1;1H NMR(400MHz,CDCl3)δ9.25(s,1H),5.86-5.69(m,2H),5.13(d,J=11.2Hz,1H),5.12(d,J=16.8Hz,1H),4.99(d,J=17.2Hz,1H),4.93(d,J=10.4Hz,1H),4.21(t,J=8.0Hz,1H),3.95-3.82(m,1H),3.13(s,3H),2.10-2.00(m,2H),1.92-1.75(m,3H),1.65-1.49(m,2H),1.35-1.27(m,1H),1.26(d,J=6.0Hz,3H),0.86(s,9H),0.03(s,3H),0.01(s,3H);13C NMR(100MHz,CDCl3)δ195.8,140.3,139.0,116.7,114.7,100.9,74.6,63.1,49.7,48.7,33.7,32.9,32.3,31.6,26.3,21.8,18.5,-3.4,-4.1;HRMS calcd for C21H38O4NaSi[M+Na]:405.2432;found:405.2427.
步骤(g):一个250mL三口瓶,抽真空通氮气3次,将2.2mL乙腈溶于40mL无水四氢呋喃中,冷却至-78℃搅拌,向体系中加入42.0mL双三甲基硅基胺基锂(1.0M的四氢呋喃溶液),于-78℃反应1小时,将2.3g式13所示化合物溶于10mL无水四氢呋喃中并加入反应体系,于-78℃反应5小时,然后缓慢加入饱和氯化铵溶液淬灭反应,乙酸乙酯(3x50mL)萃取,二次水和饱和食盐水洗涤有机相,有机相用MgSO4干燥,过滤,浓缩过快速色谱柱纯化得到6.1g式14所示化合物(89%)。黄色液体;[α]D 25=-23.1(c 1.11,CHCl3);IR(film):3425,2253,1254cm-1;1H NMR(400MHz,CDCl3)δ6.07(ddd,J=17.2,10.0,7.6Hz,1H),5.86-5.75(m,1H),5.16(d,J=16.8Hz,1H),5.10(d,J=10.4Hz,1H),5.01(dd,J=17.2,1.6Hz,1H),4.96(d,J=10.0Hz,1H),4.46(dd,J=7.2,4.8Hz,1H),4.35(br s,1H),3.99-3.87(m,2H),3.23(s,3H),2.89(dd,J=16.8,2.8Hz,1H),2.52(dd,J=17.2,9.2Hz,1H),2.19-2.07(m,1H),2.04-1.91(m,3H),1.72-1.60(m,1H),1.56-1.39(m,2H),1.35-1.27(m,1H),1.15(d,J=6.4Hz,3H),0.91(s,9H),0.12(s,3H),0.09(s,3H);13C NMR(100MHz,CDCl3)δ140.1,138.7,119.6,115.4,114.9,100.6,74.4,71.3,64.9,49.6,44.7,33.7,33.6,31.9,30.1,26.1,21.6,20.0,18.4,-3.5,-4.6;HRMS calcd for C23H41O4NNaSi[M+Na]:446.2697;found:446.2695.
步骤(h):将0.14g氢化钠(60%质量分数)加入一个100mL两口瓶,抽真空通氮气3次,向反应瓶加入50mL无水四氢呋喃,冷却至0℃,然后将1.02g式14所示化合物溶于10mL无水四氢呋喃并加入体系,反应于0℃反应30分钟,然后缓慢加入0.45mL碘甲烷,并将反应体系拿至室温反应4小时,然后缓慢加入饱和氯化铵溶液淬灭反应,乙酸乙酯(3x50mL)萃取,二次水和饱和食盐水洗涤有机相,有机相用MgSO4干燥,过滤,浓缩过快速色谱柱纯化得到0.73g式15所示化合物(70%)。无色液体;[α]D 25=-67.8(c 1.10,CHCl3);IR(film):2251,1254cm-1;1H NMR(400MHz,CDCl3)δ6.06(ddd,J=17.2,10.8,2.8Hz,1H),5.88-5.74(m,1H),5.28(d,J=16.8Hz,1H),5.07(d,J=10.4Hz,1H),4.98(dd,J=17.2,1.2Hz,1H),4.91(d,J=10.0Hz,1H),4.55-4.48(m,1H),3.91-3.79(m,1H),3.60(dd,J=8.0,3.2Hz,1H),3.56(s,3H),3.26(s,3H),2.90(dd,J=17.2,3.2Hz,1H),2.55(dd,J=17.2,8.4Hz,1H),2.14-1.94(m,3H),1.86-1.80(m,1H),1.72-1.58(m,2H),1.56-1.46(m,1H),1.22-1.15(m,1H),1.12(d,J=6.0Hz,3H),0.92(s,9H),0.06(s,3H),0.04(s,3H);13C NMR(100MHz,CDCl3)δ140.1,139.3,119.1,114.3,113.3,100.6,81.1,70.4,63.0,59.9,49.9,45.8,35.4,32.9,32.8,28.8,26.1,21.9,18.6,18.4,-4.5,-4.6;HRMS calcd for C24H43O4NNaSi[M+Na]:460.2854;found:460.2849.
步骤(i):将2.0g式15所示化合物溶于80mL二甲亚砜中,然后加入1.26g碳酸钾,4.7mL双氧水(30%质量分数)并将反应置于室温搅拌过夜,然后缓慢加入100ml水淬灭反应,乙酸乙酯(3x60mL)萃取,二次水和饱和食盐水洗涤有机相,有机相用MgSO4干燥,过滤,浓缩过快速色谱柱纯化得到0.73g式16所示化合物(94%)。无色液体;[α]D 25=-68.7(c1.01,CHCl3);IR(film):3332,3193,1673,1252cm-1;1H NMR(400MHz,CDCl3)δ6.12(ddd,J=17.2,10.4,2.4Hz,1H),5.87-5.68(m,3H),5.26(d,J=17.2Hz,1H),5.04(d,J=10.8Hz,1H),4.97(d,J=17.2Hz,1H),4.90(d,J=10.0Hz,1H),4.68-4.61(m,1H),3.86-3.73(m,2H),3.47(s,3H),3.20(s,3H),2.78(dd,J=14.8,2.4Hz,1H),2.32(dd,J=15.2,8.8Hz,1H),2.12-1.97(m,3H),1.79-1.73(m,1H),1.73-1.59(m,2H),1.59-1.48(m,1H),1.21-1.14(m,1H),1.12(d,J=6.4Hz,3H),0.92(s,9H),0.06(s,3H),0.03(s,3H);13C NMR(100MHz,CDCl3)δ174.4,140.7,139.6,114.1,112.6,101.6,81.0,70.6,62.7,59.7,48.8,47.0,37.3,35.7,33.0,32.9,28.9,26.1,22.0,18.4,-4.4,-4.5;HRMS calcd for C24H45O5NNaSi[M+Na]:478.2959;found:478.2954.
步骤(j):将0.9g式16所示化合物溶于30mL无水四氢呋喃中,加入分子筛0.2g,反应于室温搅拌10分钟后加入3.95ml四丁基氟化铵(1.0M的四氢呋喃溶液),然后将反应置于55℃油浴中反应23小时,将反应冷却至室温,加水淬灭反应,乙酸乙酯(3x40mL)萃取,二次水和饱和食盐水洗涤有机相,有机相用MgSO4干燥,过滤,浓缩过快速色谱柱纯化得到0.62g式17所示化合物(92%)。白色固体;mp.104-106℃;[α]D 25=-49.2(c 1.01,CHCl3);IR(film):3367,1668cm-1;1H NMR(400MHz,CDCl3)δ5.92-5.70(m,3H),5.56(br s,1H),5.21(d,J=16.8Hz,1H),5.11(d,J=10.0Hz,1H),4.98(d,J=17.2Hz,1H),4.93(d,J=10.0Hz,1H),4.74(d,J=3.6Hz,1H),4.44-4.35(m,1H),3.96(dd,J=10.4,2.4Hz,1H),3.85-3.73(m,1H),3.58(s,3H),3.20(s,3H),2.71(dd,J=15.2,10.4Hz,1H),2.56(dd,J=15.2,2.4Hz,1H),2.06-1.96(m,2H),1.90-1.82(m,1H),1.79-1.68(m,1H),1.65-1.51(m,2H),1.46-1.34(m,1H),1.23-1.15(m,1H),1.19(d,J=6.4Hz,3H);13C NMR(100MHz,CDCl3)δ173.9,140.1,139.3,115.1,114.5,102.7,80.7,72.8,63.3,61.3,47.1,46.6,37.2,34.4,33.2,32.7,32.0,22.0;HRMS calcd for C18H31O5NNa[M+Na]:364.2094;found:364.2091.
步骤(k):将0.39g式17所示化合物溶于27mL二氯甲烷和3mL乙腈的混合液中,加入0.21gN-甲基吗啡啉氮氧化物和1.14g分子筛,反应置于0℃反应30分钟,然后加入0.04g四丙基高钌酸铵,并将反应拿到室温反应3小时,旋干溶剂,把粗产品混合物溶于乙酸乙酯,并过一段硅胶柱滤掉分子筛,浓缩过快速色谱柱纯化得到0.62g式6所示化合物(80%)。无色液体;[α]D 25=-22.3(c 0.90,CHCl3);IR(film):3349,3198,1674,1612cm-1;1HNMR(400MHz,CDCl3)δ6.58(dd,J=17.2,10.4Hz,1H),6.12(d,J=17.2Hz,1H),5.90(br s,1H),5.82-5.69(m,1H),5.59(d,J=10.4Hz,1H),5.64-5.52(m,1H),4.99(d,J=17.2Hz,1H),4.94(d,J=10.0Hz,1H),3.98-3.86(m,1H),3.75(dd,J=8.0,3.6Hz,1H),3.26(s,3H),3.21(s,3H),2.85(d,J=2.8Hz,1H),2.69(dd,J=15.2,3.6Hz,1H),2.30(dd,J=15.2,8.0Hz,1H),2.12-2.00(m,2H),1.89-1.75(m,2H),1.74-1.62(m,1H),1.62-1.50(m,1H),1.40-1.31(m,1H),1.23(d,J=6.4Hz,3H);13C NMR(100MHz,CDCl3)δ198.5,174.2,138.5,137.2,125.6,115.1,101.8,80.5,63.9,58.6,51.1,49.0,37.1,34.3,32.4,32.3,32.1,21.8;HRMS calcd for C18H29O5NNa[M+Na]:362.1938;found:362.1935.
实施例1、式1所示五环吡咯类生物碱的制备
一、制备方法
按照图2所示流程示意图,制备式1所示五环吡咯类生物碱,包括如下步骤:
(1)式5所示化合物的制备:将3-乙基-5-(2-羟乙基)-4-甲基噻唑溴化物(0.30g)加入100mL两口瓶,抽真空通氮气3次,将0.31g式6所示化合物(对应式VI所示化合物)和(0.36g)5-己烯醛溶于30mL1,4-二氧六环中并加入反应体系,然后加入0.76mL三乙胺,将反应置于78℃油浴反应18小时,然后冷却至室温,加水淬灭反应,乙酸乙酯(3x30mL)萃取,二次水和饱和食盐水洗涤有机相,有机相用MgSO4干燥,过滤,浓缩过快速色谱柱纯化得到0.29g式5所示化合物(73%)。无色液体;[α]D 25=-8.6(c 0.93,CHCl3);IR(film):3350,3194,1707,1684,1640cm-1;1H NMR(400MHz,CDCl3)δ5.92(br s,1H),5.83-5.68(m,2H),5.49(br s,1H),5.06-4.90(m,4H),3.94-3.82(m,1H),3.69(dd,J=7.6,4.0Hz,1H),3.25(s,3H),3.19(s,3H),2.90-2.76(m,2H),2.74-2.52(m,4H),2.47(t,J=7.2Hz,2H),2.32(dd,J=14.8,7.6Hz,1H),2.13-1.98(m,4H),1.97-1.88(m,1H),1.87-1.76(m,1H),1.72-1.57(m,3H),1.56-1.44(m,1H),1.38-1.30(m,1H),1.20(d,J=6.0Hz,3H);13C NMR(100MHz,CDCl3)δ210.1,207.1.174.2,138.6,138.2,115.4,115.0,101.7,80.5,64.2,58.6,52.0,48.6,42.3,37.5,36.8,36.4,34.3,33.3,32.6,32.1,31.8,23.0,21.7;HRMS calcd forC24H39O6NNa[M+Na]:460.2670;found:460.2665.
(2)式4所示化合物的制备:将0.29g式5所示化合物(对应式V所示化合物)溶于40mL无水二氯甲烷中,加入0.25mL三氟化硼乙醚,反应于室温反应15小时,加入1mL三乙胺淬灭反应,浓缩,过快速色谱柱纯化得到0.20g式4所示的化合物(产率75%)。无色液体;[α]D 25=-34.0(c 0.80,CHCl3);IR(film):3233,1707,1640cm-1;1HNMR(400MHz,CDCl3)δ6.84(s,1H),5.88-5.68(m,2H),5.14-4.90(m,4H),3.80-3.67(m,2H),3.10(s,3H),3.02-2.90(m,1H),2.84-2.71(m,2H),2.65-2.38(m,5H),2.26-2.14(m,3H),2.13-1.98(m,3H),1.76-1.58(m,4H),1.57-1.45(m,1H),1.38-1.30(m,1H),1.13(d,J=6.0Hz,3H);13C NMR(100MHz,CDCl3)δ209.6,205.9,177.5,138.2,137.5,116.0,115.4,91.7,82.8,62.5,56.3,50.3,42.3,35.7,33.8,33.3,32.3,31.9,31.7,23.0,21.8;HRMS calcd for C23H35O5NNa[M+Na]:428.2407;found:428.2404.
(3)式3所示化合物的制备:将41.9g Grubbs II催化剂加入1000mL两口瓶,抽真空通氮气3次,将式4所示的化合物(对应式IV所示化合物)溶于490mL二氯甲烷并加入反应瓶中,将反应置于回流条件下反应36小时后,冷却至室温,加入5ml乙烯基乙醚并与室温反应30分钟,浓缩,过快速色谱柱纯化得到0.0965g式3所示化合物。白色固体;mp.192-193℃;[α]D 25=-90.4(c 0.59,CHCl3);IR(film):3247,1706cm-1;1H NMR(500MHz,CDCl3)δ6.69(brs,1H),5.28-5.20(m,2H),3.77-3.66(m,2H),3.12(s,3H),2.94-2.83(m,1H),2.66-2.46(m,5H),2.45-2.32(m,2H),2.28-2.12(m,3H),1.96-1.84(m,3H),1.83-1.73(m,2H),1.70-1.52(m,2H),1.40-1.25(m,2H),1.16(d,J=6.0Hz,3H);13C NMR(125MHz,CDCl3)δ209.5,205.3,177.2,133.6,129.9,91.6,82.8,62.3,56.2,51.0,41.2,38.8,38.0,34.0,33.7,33.3,30.0,29.7,27.7,21.8,21.2;HRMS calcd for C21H31O5NNa[M+Na]:400.2094;found:400.2092.
(4)式2所示化合物的制备:将63.2mg式3所示化合物(对应式III所示化合物)溶于15mL四氢呋喃中,加入35.7mg钯碳(10%钯),置于氢气条件下(气球)反应12小时后,浓缩,过快速色谱柱纯化得60.1mg式2所示化合物(产率94%)。白色固体。mp.192-193℃;[α]D 25=-40.3(c 1.04,CHCl3);IR(film):3189,1704,1645cm-1;1H NMR(500MHz,CDCl3)δ7.01(brs,1H),3.85-3.75(m,1H),3.73-3.66(m,1H),3.11(s,3H),2.95-2.85(m,1H),2.78-2.69(m,2H),2.69-2.57(m,3H),2.54-2.42(m,2H),2.22(d,J=17.0Hz,1H),1.87-1.71(m,2H),1.69-1.57(m,2H),1.50-1.29(m,8H),1.28-1.11(m,3H),1.18(d,J=6.0Hz,3H);13C NMR(125MHz,CDCl3)δ210.8,207.2,177.4,92.1,82.8,63.0,55.9,52.5,41.4,39.6,37.4,34.3,31.3,31.0,29.7,27.1,24.9,24.8,23.7,21.8,21.1;HRMS calcd for C21H33O5NNa[M+Na]:402.2251;found:402.2249.
(5)式1所示化合物的制备:将30.2mg式2所示化合物(对应式II所示化合物)溶解于5mL甲醇中并加入微波管,而后加入245.6mg醋酸铵,然后将微波管置于140℃微波下反应25分钟,冷却至室温,然后加入245.6mg醋酸铵,再次将微波管置于140℃微波下反应25分钟,冷却至室温,加水淬灭反应,二氯甲烷(3x20mL)萃取,二次水和饱和食盐水洗涤有机相,有机相用Na2SO4干燥,过滤,浓缩,粗产品直接溶于3mL新蒸馏的吡咯中并于氮气保护下加入10mL反应管中,将反应体系冷却至0℃,加入27微升三氟甲磺酸酐,然后将反应拿到室温反应3小时,加如饱和碳酸氢钠淬灭反应,二氯甲烷(3x20mL)萃取,二次水和饱和食盐水洗涤有机相,有机相用Na2SO4干燥,过滤,浓缩过快速色谱柱纯化得到10.8mg式1所示化合物(两步总产率33%)。白色固体;mp.120-121℃;[α]D 25=62.6(c 0.16,MeOH),[α]D 25=190.0(c0.05,Acetone);IR(film):3397,3367,2920,2848,1645,1470,1421cm-1;1H NMR(500MHz,Acetone-d6)δ8.71(br s,1H),6.99(s,1H),6.50(d,J=3.5Hz,1H),6.15(s,1H),5.77(s,1H),5.56(s,1H),4.27-4.18(m,1H),3.92(dd,J=8.0,7.5Hz,1H),3.42(s,3H),2.80(dd,J=16.0,7.5Hz,1H),2.73(d,J=12.0Hz,1H),2.71(dd,J=15.5,8.0Hz,1H),2.56-2.42(m,2H),2.38-2.28(m,1H),1.83-1.71(m,2H),1.67-1.54(m,2H),1.52-1.34(m,4H),1.34(d,J=6.5Hz,3H),1.22-1.11(m,1H),1.10-1.01(m,1H),0.99-0.91(m,1H),0.85-0.73(m,2H),0.65-0.52(m,1H);13C NMR(125MHz,Acetone-d6)δ165.2,132.8,130.4,129.3,123.0,114.0,110.2,105.8,101.6,83.7,69.7,58.5,49.4,39.9,38.2,32.8,28.9,27.6,25.8,25.7,25.4,23.5;HRMS calcd for C25H36O2N3[M+H]:410.2802;found:410.2797.
式1所示化合物单晶结构如图3所示。由图3可知,该化合物结构正确,为目标化合物。
二、抗肿瘤活性测定
采用MTT法,以下面代表细胞为例:A549人肺癌细胞、HCT116人结肠癌细胞、HepG2人肝癌细胞、MCF-7人乳腺癌细胞、Hela人子宫颈癌细胞,具体步骤如下:
将上述制备得到的式1所示化合物命名为5号化合物,式2所示化合物命名为3号化合物,式3所示化合物命名为2号化合物,式4所示化合物命名为1号化合物,将1~5号化合物以DMSO配制成10mM的储备液,-20℃分装冻存,临用前用相应的培养基配制成25、5、1、0.3、0.04μM的工作液。
(1)消化对数生长期的贴壁肿瘤细胞,用培养基稀释并细胞计数,以5×103个/孔接种于96孔板中,每孔加入100μl细胞悬液,放置于CO2培养箱中培养24h。
(2)培养24h后,对照组,加入100μl培养液;给药组,加入不同浓度梯度的样品溶液,即:25、5、1、0.2、0.04μM,继续培养48h。
(3)每孔加入20μl MTT(四甲基偶氮唑蓝,5mg/ml,用PBS缓冲液配制),继续在CO2培养箱培养4h。
(4)小心吸弃上清,每孔各加入150μl DMSO(二甲基亚砜),震荡8min,酶标仪570nm处测定OD(吸光度)值。细胞存活率=给药组OD570/对照组OD570×100%
用Excel计算药物处理后肿瘤细胞存活率,并用GraphPad Prism 6软件计算IC50值。
4种化合物处理后肿瘤细胞的IC50值如表1和图4所示。1号-5号化合物处理肿瘤细胞后的存活率如表2-表5所示。由此可以看出,本发明五环吡咯类生物碱及制备得到的中间产物具有抗肿瘤活性,尤其是本发明五环吡咯类生物碱具有显著的抗肿瘤活性。
表1、4种化合物处理后肿瘤细胞的IC50值(48h)
表2、1号化合物处理后肿瘤细胞的存活率(%)
细胞株 | control | 0.04μM | 0.2μM | 1μM | 5μM | 25μM |
A549 | 100±0 | 104.48±7.76 | 99.48±8.94 | 101.81±6.17 | 100.21±4.35 | 93.88±5.68 |
MCF-7 | 100±0 | 87.21±19.14 | 85.06±23.48 | 84.79±20.94 | 82.99±19.81 | 78.44±21.25 |
HepG2 | 100±0 | 93.73±9.25 | 91.89±3.72 | 91.46±4.06 | 91.13±1.64* | 80.17±2.44** |
HCT116 | 100±0 | 92.3±9.26 | 95.66±7.24 | 97.08±10.87 | 93.38±734 | 87.35±2.91* |
He1a | 100±0 | 109.95±9.99 | 109.93±9.33 | 107.71±9.87 | 105.12±7.56 | 103.98±12.65 |
表3、2号化合物处理后肿瘤细胞的存活率(%)
细胞株 | control | 0.04μM | 0.2μM | 1μM | 5μM | 25μM |
A549 | 100±0 | 10235±6.91 | 105.44±4.54 | 102.86±3.51 | 101.48±335 | 92.28±1.95* |
MCF-7 | 100±0 | 83.81±23.04 | 82.93±21.07 | 80.71±18.87 | 81.53±19.96 | 73.95±16.99 |
HepG2 | 100±0 | 92.33±4.67 | 94.76±5.08 | 94.44±2.11* | 9033±3.37* | 894±3.51* |
HCT116 | 100±0 | 98.09±9.28 | 98.8±10.68 | 97.65±12.33 | 9732±14.03 | 90.91±12.08 |
Hela | 100±0 | 105.87±10.9 | 108.54±10.19 | 107.6±9.24 | 10649±938 | 102.96±7.18 |
表4、3号化合物处理后肿瘤细胞的存活率(%)
表5、5号化合物处理后肿瘤细胞的存活率(%)
注:表2-表5中,*p<0.05,**p<0.01 vs control.
Claims (12)
1.一种制备式I所示化合物的方法,包括如下步骤:
(1)将式VI所示化合物在催化剂存在的条件下与5-己烯醛进行Stetter反应,反应完毕得到式V所示化合物;
(2)将式V所示化合物在酸存在的条件下进行关螺环反应,反应完毕得到式IV所示化合物;
(3)将式IV所示化合物在催化剂存在的条件下进行烯烃复分解反应,反应完毕得到式III所示化合物;
(4)将式III所示十三元大环骨架化合物在催化剂存在的条件下和氢气条件下进行选择性氢化反应,反应完毕得到式II所示化合物;
(5)将式II所示化合物先在Paal-Knorr反应条件下与氮源反应,然后置于Vilsmeier-Haack反应条件下与反应,反应完毕得到式I所示化合物;所述氮源为醋酸铵、碳酸铵或R3-NH2;
其中,
式I中,R1和R3为氢原子;
R2和R4为甲基;
中,R1为氢原子;
式II中,R2和R4的定义同式I;
式III中,R2和R4的定义同式I;
式IV中,R2和R4的定义同式I;
式V中,R2和R4的定义同式I,R5为C1-C12烷基;
式VI中,R2、R4和R5的定义同式V;
所述式VI所示化合物是由包括如下步骤的方法制备得到的:
B1)式VII所示化合物和格氏试剂进行迈克尔加成反应,得到式VIII所示化合物;
B2)将步骤B1)所得式VIII所示化合物在三氟甲磺酸二丁硼、二异丙基乙胺和丙烯醛存在的条件下经行羟醛缩合反应,得到式IX所示化合物;
B3)在有机碱存在下,将步骤B2)所得式IX所示化合物与保护基试剂反应,对式IX所示化合物中的羟基进行保护,得到式X所示化合物;所述保护基试剂为R6-Cl或R6-CF3SO3;
B4)将步骤B3)所得式X所示化合物在甲酰基前体和强碱存在的条件下进行反应,得到式XI所示化合物;所述甲酰基前体为R7-H;
B5)将步骤B4)所得式XI所示化合物在酸存在的条件下与醇进行关环反应,反应完毕得到式XII所示化合物;所述醇为R5-OH;
B6)将步骤B5)所得式XII所示化合物经过转化,可以得到式XIII所示化合物;
B7)将步骤B6)所得式XIII所示化合物在乙腈、强碱的存在条件下进行反应,反应完毕得到式XIV所示化合物;
B8)将步骤B7)所得式XIV所示化合物中的羟基在保护基试剂和碱的存在下进行保护,反应完毕得到式XV所示化合物;
B9)将步骤B8)所得式XV所示化合物在双氧水、碳酸钾、二甲亚砜存在下把氰基水解为酰胺,反应完毕得到式XVI所示化合物;
B10)将步骤B9)所得式XVI所示化合物在碱存在的条件下脱R6保护,反应完毕得到式XVII所示化合物;
B11)将步骤B10)所得式XVII所示化合物在氧化剂存在的条件下进行氧化,反应完毕得到式VI所示化合物;
所述式VI至式XVII中,R2为甲基;
R4为甲基;
R5为C1-C12烷基;
R6为叔丁基二甲基硅基、三乙基硅基、叔丁基二苯基硅基或三异丙基硅基;
R7为2-噻唑基、1,3-二硫代坊基或1,3-二噻烷基。
2.根据权利要求1所述的方法,其特征在于:步骤(5)中,所述Paal-Knorr反应在催化剂的条件下进行;所述催化剂选自沸石、三氧化铝、对甲苯磺酸、樟脑磺酸、磷酸锆、四异丙氧基钛和微波条件中的至少一种;所述Paal-Knorr反应中,所述式II所示化合物和所述氮源的投料摩尔比为(1.0):(1.0~100.0);所述Paal-Knorr反应在溶剂中进行;所述溶剂选自甲醇、乙醇、水、甲苯、N,N-二甲基甲酰胺和离子液体中的任一种;所述Paal-Knorr反应的温度为-100℃~200℃;时间为1分钟~1000分钟;
所述Vilsmeier-Haack反应在氮气条件下进行;所述Vilsmeier-Haack反应在试剂的条件下进行;所述试剂选自三氯氧磷、三溴氧磷、草酰氯和三氟甲磺酸酐中的任一种;所述Vilsmeier-Haack反应中,所述式II所示化合物、所述和所述试剂的投料摩尔比为(1.0):(1.0~1000):(1.0~10.0);所述Vilsmeier-Haack反应的温度为-20℃~100℃;所述Vilsmeier-Haack反应的时间为0.1小时~50小时。
3.根据权利要求2所述的方法,其特征在于:所述Paal-Knorr反应在微波条件下进行;所述Paal-Knorr反应的温度为25℃~150℃;时间为10分钟~100分钟;
所述Vilsmeier-Haack反应中,所述式II所示化合物、所述和所述试剂的投料摩尔比为1.0:540.0:2.0;所述Vilsmeier-Haack反应的温度为25℃;所述Vilsmeier-Haack反应的时间为3小时。
4.根据权利要求1所述的方法,其特征在于:步骤(4)中,所述氢气的压力为1.0~50bar;所述催化剂为钯碳、威尔金森催化剂或氧化铂;所述选择性氢化反应步骤中,温度为0℃~100℃,时间为0.01小时~24小时;所述催化剂与所述式III所示化合物的投料摩尔比为(0.01~1.0):1.0;所述选择性氢化反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、乙酸乙酯、四氢呋喃、二氯甲烷和二氧六环中的至少一种。
5.根据权利要求1所述的方法,其特征在于:步骤(3)中,所述催化剂为Grubbs一代催化剂、Grubbs二代催化剂、Grubbs-Hoveyda一代催化剂、Grubbs-Hoveyda二代催化剂、Schrock催化剂、Zhan-1B催化剂、Zhan-1C一代催化剂或Zhan二代催化剂;所述烯烃复分解反应步骤中,温度为0℃~100℃;所述反应步骤中,时间为0.01小时~48小时;所述催化剂与所述式IV所示化合物的投料摩尔比为(0.01~1.0):1.0;所述烯烃复分解反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、四氢呋喃和二氯甲烷中的至少一种。
6.根据权利要求5所述的方法,其特征在于:所述烯烃复分解反应步骤中,温度为25~60℃;所述反应步骤中,时间为12~40小时。
7.根据权利要求1所述的方法,其特征在于:步骤(2)中,所述酸选自对甲苯磺酸、对甲苯磺酸吡啶盐、樟脑磺酸、三氟化硼乙醚、三氟甲磺酸镱、三氟甲磺酸铕、三氟甲磺酸钇、氯化铁、氯化锌和氯化锡中的任一种;所述反应步骤中,温度为-20℃~100℃;时间为0.01小时~48小时;所述酸与所述式V所示化合物的投料摩尔比为(0.01~10):1.0;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、四氢呋喃和二氯甲烷中的至少一种。
8.根据权利要求7所述的方法,其特征在于:所述反应步骤中,温度为0~30℃;时间为5~24小时;所述酸与所述式V所示化合物的投料摩尔比为3.0:1。
9.根据权利要求1所述的制备方法,其特征在于:步骤(1)中,所述催化剂选自氰化钾、氰化钠、3-乙基-5-(2-羟乙基)-4-甲基噻唑溴化物和3-苄基3-乙基-5-(2-羟乙基)-4-甲基噻唑氯化物中的任一种;所述反应中,温度为0℃~200℃;所述反应中,时间为0.01小时~48小时;所述催化剂、所述5-己烯醛和所述式VI所示化合物的投料摩尔比为(0.01~10):(1.0~10.0):1.0;所述反应在溶剂中进行;所述溶剂选自甲醇、乙醇、N,N-二甲基甲酰胺、四氢呋喃、二甲亚砜和1,4-二氧六环中的至少一种。
10.根据权利要求9所述的方法,其特征在于:所述反应中,温度为50~100℃;所述反应中,时间为5~24小时;所述催化剂、所述5-己烯醛和所述式VI所示化合物的投料摩尔比为1.3:4.0:1。
11.根据权利要求1所述的方法,其特征在于:步骤B1)中,所述格氏试剂为高烯丙基溴化镁;所述迈克尔加成反应在催化剂的条件下进行;所述催化剂为碘化亚铜;所述格氏试剂、所述催化剂、所述式VII所示化合物的投料摩尔比为(1~10):(0.01~10):1;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚和四氢呋喃中的至少一种;所述迈克尔加成反应的温度为-78~0℃;时间可为1~10小时;
所述步骤B2)反应步骤中,温度为-78℃~0℃,时间为5~24小时;所述反应的溶剂选自甲苯、二甲苯、四氢呋喃和二氯甲烷中的至少一种;
所述步骤B3)中,所述保护基试剂为叔丁基二甲基硅基氯、叔丁基二甲基硅基三氟甲磺酸酯、三乙基硅基氯、叔丁基二苯基硅基氯和三异丙基硅基氯中的任一种;所述有机碱为三乙胺、二异丙基乙胺、吡啶和2,6-二甲基吡啶中的一种;温度为0℃~25℃,时间为0.1小时~50小时;所述保护基试剂与式IX所示化合物的投料摩尔比为(1~10):1.0;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、四氢呋喃和二氯甲烷中的至少一种;
所述步骤B4)中,所述甲酰基前体选自噻唑、1,3-二噻烷和1,3-二硫代坊中的任一种;所述强碱选自正丁基锂、叔丁基锂、二异丙氨基锂、六甲基二硅胺基锂、六甲基二硅胺基钠和六甲基二硅胺基钾中的至少一种;所述甲酰基前体与式X所示化合物的投料摩尔比为(1~10):1.0;所述步骤B4)反应步骤中,温度为-78℃~-35℃,时间为3~10小时;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、四氢呋喃和二氯甲烷中的至少一种;
所述步骤B5)中,所述酸选自对甲苯磺酸、对甲苯磺酸吡啶盐、樟脑磺酸、三氟化硼乙醚、三氯化铁中的至少一种;所述醇为C1-C12的烷基醇;所述酸与式XI所示化合物的投料摩尔比为(0.01~10):1.0;所述步骤B5)反应步骤中,温度为10℃~40℃,时间为2~10小时;所述反应在溶剂中进行;所述溶剂选自甲醇、乙醇、乙醚、四氢呋喃、二氯甲烷中的至少一种;
所述步骤B6)中,所述转化条件选自三氟甲磺酸甲酯、硼氢化钠、硝酸银体系或者三氟甲磺酸甲酯、硼氢化钠、氧化铜、氯化铜体系以及硝酸铈铵体系;所述三氟甲磺酸甲酯、硼氢化钠、硝酸银与式XII所示化合物的投料摩尔比为(1~10):(1~10):(1~10):1.0;所述反应中,温度为0℃~30℃,时间为1~2小时;
所述步骤B7)中,所述强碱选自正丁基锂、叔丁基锂、二异丙氨基锂、六甲基二硅胺基锂、六甲基二硅胺基钠和六甲基二硅胺基钾中的至少一种;所述乙腈、强碱与式XIII所示化合物的投料摩尔比为(1~10):(1~10):1.0;所述反应中,温度为-78℃,时间为2~5小时;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚和四氢呋喃中的至少一种;
所述步骤B8)中,所述保护基试剂选自C1-烷基卤化物;所述碱选自氢化钠、氧化银、2,6-二叔丁基-4-甲基吡啶、2,6-二叔丁基吡啶和碳酸铯中的至少一种;所述保护基试剂与式XIV所示化合物的投料摩尔比为(1~10):1.0;所述步骤B8)反应步骤中,温度为0℃~25℃,时间为2~10小时;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、四氢呋喃、二氯甲烷中的至少一种;
所述步骤B9)中,所述双氧水、碳酸钾与式XV所示化合物的投料摩尔比为(1~50):(1~10):1.0;所述反应步骤中,温度为20℃~40℃,时间为10~18小时;所述反应在溶剂中进行;所述溶剂选自二甲基亚砜;
所述步骤B10)中,所述碱选自四丁基氟化铵、氟化钾、氟化氢吡啶、三氧化铝、氟化铯中的一种;所述碱与式XVI所示化合物的投料摩尔比为(1~10):1.0;温度为0℃~100℃,时间为18~30小时;所述反应在溶剂中进行;所述溶剂选自甲苯、二甲苯、乙醚、四氢呋喃和二氯甲烷中的至少一种;所述反应在分子筛的条件下进行,所述分子筛为分子筛、分子筛和分子筛中的任一种;所述分子筛的量为:每1mmol式XVI所示化合物加入分子筛50mg~200mg;
所述步骤B11)中,所述氧化剂选自高锰酸钾、二氧化锰、二氯二氰对苯醌、邻碘酰苯甲酸、戴斯-马丁氧化剂、氧气、四氯对苯醌、四丙基高钌酸铵和氮甲基吗啉氧化物中的至少一种;所述氧化反应步骤中,温度为-100℃~50℃;所述氧化反应步骤中,时间为0.01小时~50小时;所述四丙基高钌酸铵和氮甲基吗啉氧化物与所述式XVII化合物的投料摩尔比为(0.01~1.0):(1.0~10):1.0;所述反应在溶剂中进行;所述溶剂选自二氯甲烷、乙腈、四氢呋喃和乙醚中的至少一种;所述反应在分子筛的条件下进行,所述分子筛为分子筛、分子筛和分子筛中的任一种,所述分子筛的量为:每1mmol式XVII所示化合物加入分子筛50mg~2000mg。
12.根据权利要求1所述的方法,其特征在于:步骤B8)中,所述保护基试剂选自碘甲烷、硫酸二甲酯、三甲基氧鎓四氟硼酸盐和三氟甲磺酸甲酯中的一种。
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Towards the Total Synthesis of Marineosin A: Construction of the Macrocyclic Pyrrole and an Advanced, Functionalized Spiroaminal Model;Dr. Leslie N. Aldrich et al.;《European J Org Chem.》;20130701;第20卷;第1-9页,第5页Scheme 1,第8页Scheme 4 * |
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