CN106188073B - A kind of ecteinascidin-743 alkaloid intermediate and its preparation method and application - Google Patents
A kind of ecteinascidin-743 alkaloid intermediate and its preparation method and application Download PDFInfo
- Publication number
- CN106188073B CN106188073B CN201610489181.8A CN201610489181A CN106188073B CN 106188073 B CN106188073 B CN 106188073B CN 201610489181 A CN201610489181 A CN 201610489181A CN 106188073 B CN106188073 B CN 106188073B
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- CN
- China
- Prior art keywords
- compound
- ecteinascidin
- general formula
- alkaloid
- preparation
- Prior art date
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- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical class C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229940126062 Compound A Drugs 0.000 claims abstract description 8
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 239000006096 absorbing agent Substances 0.000 claims abstract description 5
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 229930013930 alkaloid Natural products 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 9
- -1 ecteinascidin-743 class alkaloid Chemical class 0.000 claims description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 8
- 239000002808 molecular sieve Substances 0.000 claims description 7
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical group [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- HDFFVHSMHLDSLO-UHFFFAOYSA-M dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-M 0.000 claims 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 238000003541 multi-stage reaction Methods 0.000 claims 1
- 235000011152 sodium sulphate Nutrition 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
- 238000010189 synthetic method Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000007832 Na2SO4 Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 229960000977 trabectedin Drugs 0.000 description 5
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- LUSZGTFNYDARNI-UHFFFAOYSA-N Sesamol Natural products OC1=CC=C2OCOC2=C1 LUSZGTFNYDARNI-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000003797 alkaloid derivatives Chemical class 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 3
- VPAHZSUNBOYNQY-DLVGLDQCSA-N zalypsis Chemical compound C([C@H]1C2=C3OCOC3=C(C)C(OC(C)=O)=C2C[C@@H]2N1[C@@H](O)[C@@H]1CC3=CC(C)=C(C(=C3[C@H]2N1C)O)OC)NC(=O)\C=C\C1=CC=CC(C(F)(F)F)=C1 VPAHZSUNBOYNQY-DLVGLDQCSA-N 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BHINEHROXMLHMV-BVRLQDJESA-N C([C@H](N1C)[C@@H]2C#N)C3=CC(C)=C(OC)C(O)=C3[C@@H]1[C@H](C1)N2[C@@H](CNC(=O)[C@H](C)N)C2=C1C(=O)C(C)=C(OC)C2=O Chemical compound C([C@H](N1C)[C@@H]2C#N)C3=CC(C)=C(OC)C(O)=C3[C@@H]1[C@H](C1)N2[C@@H](CNC(=O)[C@H](C)N)C2=C1C(=O)C(C)=C(OC)C2=O BHINEHROXMLHMV-BVRLQDJESA-N 0.000 description 2
- HDFFVHSMHLDSLO-UHFFFAOYSA-N Dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)(O)OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229930190585 Saframycin Natural products 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229930188681 renieramycin Natural products 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- OROGUZVNAFJPHA-UHFFFAOYSA-N 3-hydroxy-2,4-dimethyl-2H-thiophen-5-one Chemical compound CC1SC(=O)C(C)=C1O OROGUZVNAFJPHA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 238000006407 Bischler-Napieralski reaction Methods 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910020889 NaBH3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229960001592 paclitaxel Drugs 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
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- PANBYUAFMMOFOV-UHFFFAOYSA-N sodium;sulfuric acid Chemical compound [Na].OS(O)(=O)=O PANBYUAFMMOFOV-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 229940004212 yondelis Drugs 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- 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
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- 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
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Abstract
The invention discloses a kind of ecteinascidin-743 Alkaloid intermediate and its synthetic method and applications, such compound is to occur what Pictet-Spengler cyclization obtained by aldehyde compound A and alkamine compound B in the case where being with or without catalyst and water absorbing agent；Synthesize ecteinascidin alkaloid with such intermediate, making entirely to synthesize has many advantages, such as that yield is ideal, step is succinct, source chemicals cheaply, mild condition, it is easy to operate, be easily industrialized.Compared with the synthesis of existing ecteinascidin Alkaloid, this method significantly reduces cost and improves efficiency, has a good application prospect.
Description
Technical field
The present invention relates to synthetic intermediate of a kind of ecteinascidin-743 Alkaloid and preparation method thereof and answer
With.
Background technique
The oceans such as Ecteinascidins, saframycins and renieramycins bis-tetrahydroisoquinoline alkaloid is one
The unique bioactive natural product of class formation contains similar five ring skeleton of feature (A-E ring).With saframycins and
Renieramycins's is different to quinoid A ring, and the A ring of ecteinascidin is a phenyl ring replaced entirely.This Alkaloid and
Its analog, due to having significant antitumor, antibacterial isoreactivity, in research fields such as chemistry, biology, medicine by extensive
Concern.Ecteinascidin 743 (Et-743) therein is soft as a variety of advanced stages are treated in Europe, South Korea etc. in 2007
The anticancer drug of tissue tumor uses (drug name: Trabectedin；Yondelis)[Nat.Rev.Drug Discovery
2009,8,69].Research shows that ecteinascidin 743 is than current clinically widely used camplotheca acuminata on anti-tumor activity
The famous anticancer drug such as alkali, taxol, adriamycin, bleomycin, mitomycin C, cis-platinum and etoposide is higher by 1~3 number
Magnitude, and there is unique multiple action mechanism.Since structure is complicated by Et-743, synthesis cost is high, and chemist attempts to tie it
Structure is transformed, and the extended structure of the ring of bridge containing thiolactone therein is saved, basic five ring skeleton is only remained, be prepared for be
The simplification analog of the Et-743 of column, and carry out screening active ingredients.Therefrom have found phthlascidin 650 (Pt-650)
[Proc.Natl.Acad.Sci.1999,96,3496] and zalypsis [Blood, 2009,113,3781；Molecules.,
The outstanding representative such as 2014,19,12328], they show the nanomole grade anticancer activity same with Et-743, and structure is but greatly
Simplify, successively enters clinical experimental stage.
Since Et-743 is extremely low in nature content, the needs such as clinical application and pharmacological research are unable to satisfy, are developed the economy
Practical synthetic method is particularly significant and urgent.The source of Et-743 and the like relies primarily on PharmaMar company at present
The semisynthesis of development, the alkaloid cyanosafracin B obtained from biofermentation, with total receipts of 21 steps 1.0%
Rate obtains Et-743 [WO0187895；Org Lett.2000,2,2545].This semi-synthetic gross production rate is not high, in addition raw material
Cyanosafracin B source itself is also restricted, and isolates and purifies difficulty, is still difficult to solve the problems, such as the supply of Et-743.
Develop the fully synthetic route of high-efficiency and economic, then may as it is semi-synthetic it is effective supplement and alternative route, acquisition compared with
Sufficient Et-743 meet demand.Between 1996 to 2006, it is completed there are three fully synthetic, respectively from Corey group
[J.Am.Chem.Soc.1996,118,9202；Org.Lett.2000,2,993], Fukuyama group
[J.Am.Chem.Soc.2002,124,6552] and Zhu group [J.Am.Chem.Soc.2006,128,87].Then have again
Danishefsky group [Angew.Chem.Int.Ed.2006,45,1754], Williams group [J.Org.Chem.2008,
73,9594] and Fukuyama group [J.Am.Chem.Soc.2013,135,13684] report Et-743 form synthesis.
Corey group developed in 1996 Et-743 it is first it is fully synthetic [J.Am.Chem.Soc.1996,118,
9202].As shown in reaction equation one, they have first synthesized left side amine segment (compound one) and the right aldehyde segment (compound two),
The coupling for realizing two segments of left and right is reacted by Strecker, then constructs C and D ring and obtains cyclization product (compound three), then
It modifies to obtain crucial five rings midbody compound four by introducing the conversions such as methyl on E ring and N.It is complete to possess target molecule
The compound four of five ring skeletons has just obtained Et-743 using extended structures and modifications such as the building big bridged rings of sulfur-bearing.
1999, Corey group was improved [Org.Lett.2000,2,993], Ta Mengai to synthesis above again
Aldehyde compound two is replaced with carboxylic acid fragment's (compound five), is attached by peptide formation and amine fragment compound one, is generated
Acid amide type coupled product, and then prepare known midbody compound three (reaction equation two).This improvement cause segment coupling and
C, the building of D ring and etc. yield significantly improve, the synthesis total recovery of Et-743 is had a surplus than being doubled originally finally, is reached
To 2% or so (being calculated from sesamol).This improved synthesis is that total recovery is most in the fully synthetic route of existing Et-743
High one has good application potential.
With the similar strategy in front, Corey etc. is by introducing required methyl etc. on the E ring and N to known compound three
Step has obtained the five rings advanced intermediate compound six very similar with key intermediate compound four, and compound six passes through again
A few step conversions have just synthesized Pt-650 (reaction equation three).
It can be seen that compound four and compound six etc. with complete five ring structures are to prepare Et-743 and the like
Key intermediate.Therefore this kind of intermediate preparation directly determines that the anticancers such as Et-743, Pt-650 and zalypsis are raw
The length and cost of alkaloids synthesis.Though the above synthetic route yields good result, but still has some local Shortcomings.Example
As longer in partially prepared transformation routes, some step yields are not ideal enough；Some are related to some more expensive reagents and raw material；It is some
Reaction condition requires harsh not easy to operate etc..These will lead to synthesis cost rising, be not easy to carry out fairly large preparation.Constantly change
Into strategy, develop more succinct cheap method to synthesize this kind of intermediate, for ecteinascidin Alkaloid and its derivative
The application prospect of object is most important.
Summary of the invention
The present invention provides a kind of double tetrahydro isoquinoline compounds and preparation method thereof with logical formula (I).This kind of chemical combination
Object can efficiently and easily be converted into the advanced synthetic intermediate in five rings of Et-743 and the like, so that the conjunction of this Alkaloid
At yield, in terms of more previous route be significantly improved.
Present invention obtains a kind of double tetrahydro isoquinoline compounds and its synthetic method with logical formula (I), lead to formula (I)
Closing object is prepared by a Pictet-Spengler cyclization between aldehyde compound A and alkamine compound B, knot
Structure formula and synthetic route are as follows:
R in each structural formula of route above1、R2、R3Definition it is all the same.
R1Following group: C can be represented1-C16Linear chain or branched chain saturated alkyl, C2-C16Containing the straight of double bond, three keys or aromatic ring
Chain or branch unsaturated alkyl, C3-C20Silylation, C1-C14Acyl group；Wherein there can be 0-3 fluorine in every kind of group,
Chlorine, bromine, iodine, oxygen, sulphur atom.
R2Following group: C can be represented1-C16Linear chain or branched chain saturated alkyl, C2-C16Containing the straight of double bond, three keys or aromatic ring
Chain or branch unsaturated alkyl, C3-C20Silylation, C1-C14Acyl group；Wherein there can be 0-3 fluorine in every kind of group,
Chlorine, bromine, iodine, oxygen, sulphur atom.
R3Following group: C can be represented1-C16Linear chain or branched chain alkoxy carbonyl group, C2-C16Linear chain or branched chain alkene oxygen carbonyl,
C6-C16Linear chain or branched chain aromatic hydrocarbons oxygen carbonyl, C1-C14Acyl group, C1-C14Sulfonyl；Wherein there can be 0-3 in every kind of group
A fluorine, chlorine, bromine, iodine atom.
The preparation of logical formula (I) compound:
Logical formula (I) compound is to be with or without catalyst (Bronsted acid, lewis acid) and water absorbing agent (molecular sieve, sulfuric acid
Sodium etc.) in the case where, occur what Pictet-Spengler cyclization obtained by aldehyde compound A and alkamine compound B.Change
Close R in object A1The preferred benzyl of protecting group or allyl, R2The preferred allyl of protecting group, R3The preferred Boc of protecting group.Cyclisation conditions are excellent
Selecting methylene chloride, trifluoroethanol and toluene is mixed solvent, and acetic acid and phosphate dibenzyl ester are catalyst,Molecular sieve is water suction
Agent, reaction temperature be -20~120 DEG C, the reaction time be 2~for 24 hours.
Known alkamine compound B can be from L- junket ammonia according to document [Tetrahedron:Asymmetry 2010,21,39]
Acid is prepared through 8 steps with 46% total recovery.
The preparation of compound A:
Compound A be by carrying out GPF (General Protection False to the amino in compound E after, then hydroxyl is oxidized to what aldehyde obtained.
The synthesis of compound E can refer to document [Tetrahedron Lett.2007,48,9163] similar approach, pass through amide compound
Bischler-Napieralski cyclisation occurs for D, restores the imine in intermediate product to obtain.And compound D is then
It is the hydroxyacetic acid generation peptide formation with known photolytic activity alkamine compound C [CN201610375613.2] with protection, then
What GPF (General Protection False obtained is carried out to phenolic hydroxyl group.
The present invention provides a kind of double tetrahydro isoquinoline compounds and its high efficiency preparation method with logical formula (I).Pass through
Formula (I) compound is led in the preparation of cyclization between aldehyde compound A and alkamine compound B, and yield is higher, and two couplings
Segment A and B can be prepared according to known references and similar approach by cheap chiral raw material economical and efficient.
Logical formula (I) compound can be according to pertinent literature [J.Nat.Prod.2013,76,1789；Org.Lett.2009,11,
5558], with synthetic strategy similar to known related double tetrahydroisoquinoline substrate, high productivity is converted into such as compound four and six
Etc advanced five rings intermediate.This kind of advanced five rings intermediate can be used to conveniently to be converted to including Et-743, Pt-650 and
Various ecteinascidin type alkaloids including zalypsis and the like.Using logical formula (I) compound as key intermediate
Ecteinascidin alkaloid is synthesized, making entirely to synthesize has yield is ideal, step is succinct (such as from sesamol, to pass through
Representative compound F in logical formula (I), totally 19 steps prepare five rings advanced intermediate J, total recovery can reach 12.4%), raw material
Reagent is cheap, mild condition, easy to operate, the advantages that being easily industrialized.And it is synthesized with the Et-743 that Corey group improves
Route is synthesized to similar advanced intermediate (compound four) from sesamol, then needs 24 steps altogether, and total recovery is about 7.3%.
Compared with the synthesis of existing ecteinascidin Alkaloid, this method significantly reduces cost and improves efficiency, has very
Good application prospect.
Specific embodiment
Embodiment is set forth below the present invention is described in more detail, but the present invention is not limited in these implementations
Example.
1. the synthesis of logical formula (I) representation compound F:
Embodiment 1: the preparation of logical formula (I) representation compound F:
Compound A1 and compound B are dissolved in toluene, methylene chloride and trifluoroethanol mixed liquor, acetic acid, phosphoric acid is added
Dibenzyl ester andMolecular sieve after 70 DEG C of reaction 10-16h, is added sodium bicarbonate, filters after stirring, through chromatographic column after filtrate concentration
Separate to obtain compound F.
Specific experimental data is set forth below:
Embodiment 1-1: 7.59mmol compound A1 and 9.90mmol compound B is dissolved in 20mL toluene, 8mL methylene chloride
In 7mL trifluoroethanol mixed liquor, 7.59mmol acetic acid, 0.76mmol phosphate dibenzyl ester and 4.4g is addedMolecular sieve.70℃
After reacting 14h, 10.0mmol sodium bicarbonate is added, is filtered after stirring.Compound F is obtained through chromatography post separation after filtrate concentration, is produced
Rate is 64%；[α]D 20–62.3(c 1.4,CHCl3)；IR(neat)vmax 3445,2974,2926,2859,1683,1651,
1455,1398,1294,1240,1168,1114,1091,1062,852,741cm-1；1H NMR(400MHz,CDCl3) δ: 7.76
(br s,0.5H),7.35(m,5H),6.44(s,1H),6.12-5.85(m,3H),5.78(m,1H),5.67(br s,0.5H),
5.12 (d, J=19.8Hz, 2H), 5.05 (d, J=10.0Hz, 2H), 4.80 (d, J=11.6Hz, 0.5H), 4.57 (m, 1H),
4.43(m,0.5H),4.34-3.90(m,3H),3.79(s,1.5H),3.77(s,1.5H),3.68-3.29(m,3H),3.14-
2.93(m,2H),2.67-2.29(m,5H),2.26(s,3H),2.11(s,3H),1.55(s,4.5H),1.53(s,4.5H)；13C
NMR(100MHz,CDCl3)δ156.8,149.3,149.0,146.9,146.0,144.3,144.2,143.2,139.2,
138.2,137.6,133.3,133.0,132.0,129.1,128.5,128.1,128.0,127.8,127.5,122.3,
121.4,121.3,121.1,120.4,119.7,118.2,117.8,114.7,114.4,112.8,112.5,101.3,81.3,
80.4,74.9,74.6,72.0,71.8,71.6,71.3,67.5,60.9,60.3,57.9,56.0,54.4,53.4,52.6,
49.4,47.7,33.0,28.7,28.6,20.7,19.8,15.7,9.5；MS(ESI+):m/z[M+H]+689.3。
2. the representation compound F of logical formula (I) is to the conversion of advanced five rings intermediate J:
Embodiment 2: the preparation of compound G:
Addition 3.89mmol compound F, the 22mL methylene chloride into 100mL round-bottomed flask, 22mL saturated sodium bicarbonate,
4.66mmol AllocCl.After reaction overnight, 20mL methylene chloride and 20mL water, liquid separation is added.Organic liquor saturated salt solution
Washing, anhydrous Na2SO4It is dry.Crude product after concentration is dissolved in 39mL acetonitrile, and 5.00mmol cesium carbonate, 0.39mmol iodate is added
Sodium, 7.78mmol allyl bromide, bromoallylene.50 DEG C are heated to, 6h is reacted, 55mL water is added after concentration, ethyl acetate extracts three times.It is organic
Liquid saturated common salt water washing, anhydrous Na2SO4It is dry.Compound G, yield 89% are obtained through chromatography post separation after concentration；[α]D 22
+14.3(c 1.5,CHCl3)；IR(neat)vmax 3456,2927,2861,1690,1455,1397,1305,1166,1124,
1094,994,935,864,771,737cm-1；1H NMR(400MHz,CDCl3)δ7.27(m,5H),6.71(s,1H),6.12
(br s, 1H), 6.03 (br s, 1H), 5.95-5.75 (m, 4H), 5.52 (br s, 1H), 5.42 (br d, J=17.2Hz,
1H), 5.35-5.23 (m, 3H), 5.17 (d, J=10.0Hz, 2H), 4.79-4.59 (m, 1H), 4.58-4.46 (m, 4H),
4.46-4.38(m,1H),4.37-4.15(m,4H),4.14-3.85(m,4H),3.77(s,3H),3.60(m,1H),3.53-
2.97(m,1H),2.90(m,2H),2.71(s,1H),2.24(s,2H),2.19(s,1H),2.17(s,3H),1.15(s,4H),
0.98(s,5H)；13C NMR(100MHz,CDCl3)δ157.7,155.8,149.7,148.6,144.4,140.4,140.0,
138.9,138.8,134.6,134.0,132.5,128.2,127.3,127.2,124.8,124.5,119.2,118.1,
117.3,112.1,101.2,80.4,79.7,74.8,74.6,72.4,70.9,70.5,67.1,60.3,57.4,56.9,
56.4,52.0,51.0,49.8,30.5,28.2,27.6,23.8,15.7,9.5；MS(ESI+):m/z[M+Na]+835.4。
Embodiment 3: the preparation of compound H:
6.76mmol compound G, 72mL MeOH, 4.8mL concentrated hydrochloric acid are added into 250mL round-bottomed flask.It is heated to 60
DEG C, after reacting 4h, saturated sodium bicarbonate is added after concentration, methylene chloride extracts three times.Organic liquor saturated common salt water washing, nothing
Water Na2SO4It is dry.Compound H, yield 94% are obtained through chromatography post separation after concentration；[α]D 21–79.4(c 1.4,CHCl3)；IR
(neat)vmax 3447,2926,2862,1694,1453,1419,1308,1271,1238,1098,994,927,807,771,
739cm-1；1H NMR(400MHz,CDCl3)δ7.25(m,3H),7.13(m,2H),6.79(s,1H),6.10(m,2H),5.93
(m, 1H), 5.84-5.68 (m, 3H), 5.48-5.35 (m, 2H), 5.35-5.16 (m, 3H), 5.20 (d, J=10.4Hz, 1H),
4.70 (m, 1H), 4.68-4.54 (m, 2H), 4.49 (d, J=12.4Hz, 1H), 4.40 (d, J=12.0Hz, 1H), 4.38 (m,
1H),4.27(m,1H),4.23-4.06(m,4H),3.97(m,1H),3.86(m,1H),3.82-3.60(m,4H),3.46-
3.06(m,3H),2.81(m,1H),2.35(m,1H),2.26(s,3H),2.13(s,3H)；13C NMR(100MHz,CDCl3)δ
156.7,149.8,149.6,148.5,144.2,139.3,138.4,134.3,134.1,132.8,131.8,130.6,
128.3,127.6,127.5,126.2,125.5,122.5,118.0,117.6,117.4,115.0,112.1,100.7,73.8,
73.6,73.2,71.7,71.2,70.6,66.6,65.8,64.9,60.0,58.4,58.0,55.2,54.6,54.4,54.2,
53.6,30.2,29.8,28.5,27.9,15.9,9.5；MS(ESI+):m/z[M+Na]+735.3。
Embodiment 4: the preparation of compound I:
100mL methylene chloride is added into 250mL round-bottomed flask, 5.56mmol oxalyl chloride is added at -78 DEG C
11.12mmol DMSO is stirred 20 minutes, and 2.78mmol compound G and 5mL methylene chloride mixed liquor is added.It is reacted at -78 DEG C
After 1h, 22.24mmol triethylamine is added.It is to slowly warm up to 0 DEG C, 50mL water is added, water phase is extracted with ethyl acetate three after liquid separation
It is secondary.Organic liquor saturated common salt water washing, anhydrous Na2SO4It is dry.Crude product after concentration is dissolved in 28mL methylene chloride, is added
The diethyl ether solution of 8.34mmol TMSCN, 8.34mL 1.0M zinc chloride.After reacting 3h, 30mL water, methylene chloride extraction three is added
It is secondary.Organic liquor saturated common salt water washing, anhydrous Na2SO4It is dry.Compound I is obtained through chromatography post separation after concentration, yield is
94%；[α]D 21+21.1(c 1.2,CHCl3)；IR(neat)vmax 3445,2924,2858,1707,1420,1338,1261,
1106,1020,928,740cm-1；1H NMR(400MHz,CDCl3)δ7.32(m,3H),7.24(m,2H),6.65(s,0.5H),
6.64(s,0.5H),6.26-6.06(m,2H),5.91(s,1H),5.95-5.82(m,1H),5.87(s,1H),5.56-5.34
(m, 3H), 5.34-5.15 (m, 4H), 4.82-4.58 (m, 3H), 4.56 (dd, J=5.6,1.2Hz, 1H), 4.51 (m, 2H),
4.47 (s, 1H), 4.34 (dd, J=12.0,5.0Hz, 1H), 4.24-4.10 (m, 3H), 3.80 (s, 1.5H), 3.78 (s,
1.5H), 3.56 (td, J=8.9,2.5Hz, 1H), 3.32 (ddd, J=15.4,10.1,2.1Hz, 1H), 3.23-3.04 (m,
3H), 2.79 (dd, J=17.4,4.4Hz, 1H), 2.25 (s, 3H), 2.12 (s, 3H), 1.84 (dt, J=15.2,11.9Hz,
1H)；13C NMR(100MHz,CDCl3)δ154.4,154.4,148.8,148.7,148.7,148.6,148.3,148.0,
144.5,139.3,139.2,138.2,138.2,134.5,134.4,133.8,132.6,132.5,131.2,131.1,
131.0,130.9,128.5,127.7,127.5,127.5,125.8,125.5,125.2,125.0,120.8,120.7,
118.3,118.0,117.9,117.7,117.3,117.2,112.5,112.5,112.2,112.1,101.2,76.7,76.5,
74.5,74.1,73.9,73.5,66.7,66.4,60.8,60.7,60.2,60.1,57.1,57.0,56.6,56.5,50.5,
49.8,49.7,48.9,30.4,29.8,26.3,26.2,16.0,9.4；MS(ESI+):m/z[M+Na]+742.3。
Embodiment 5: the preparation of compound J:
Addition 4.20mmol compound I, the 42mL methylene chloride into 100mL round-bottomed flask, 67.2mmol acetic acid,
1.68mmol Pd(Ph3P)4, 25.2mmol Bu3SnH.React 1h after, be added 10% sodium bicarbonate aqueous solution of 100mL and
100mL methylene chloride, liquid separation.Water phase is extracted with dichloromethane twice.Combined organic liquor saturated common salt water washing, it is anhydrous
Na2SO4It is dry.Crude product after concentration is dissolved in 40mL acetonitrile, and 37% formalin of 3.18mL, 8.10mmol is added
NaBH3CN, 8.40mmol acetic acid.After reacting 1h, 100mL methylene chloride and 50mL saturated sodium bicarbonate, liquid separation is added.Water phase is used
Ethyl acetate is extracted twice.Combined organic liquor saturated common salt water washing, anhydrous Na2SO4It is dry.Through chromatographic column point after concentration
From compound I, yield 94%；[α]D 21–26.3(c 1.2,CHCl3)；IR(neat)vmax 3441,2928,2857,
1620,1584,1497,1456,1361,1303,1235,1103,1027,954,881,739cm-1；1H NMR(400MHz,
CDCl3)δ7.35-7.18(m,5H),6.44(s,1H),5.93(s,1H),5.87(s,1H),5.81(s,1H),4.61(s,
1H), 4.50-4.40 (m, 2H), 4.33 (d, J=12.0Hz, 1H), 4.16 (d, J=8.0Hz, 1H), 4.13 (s, 1H), 3.77
(s, 3H), 3.51 (dd, J=9.1,2.3Hz, 1H), 3.27 (m, 2H), 3.06 (m, 2H), 2.93 (dd, J=17.8,8.1Hz,
1H), 2.59 (d, J=17.8Hz, 1H), 2.29 (s, 3H), 2.28 (s, 3H), 2.08 (s, 3H), 1.93 (m, 1H)13C NMR
(100MHz,CDCl3)δ146.6,145.0,144.3,142.7,138.4,136.9,131.7,128.5,128.4,127.6,
127.5,121.0,119.0,117.3,113.9,112.7,106.0,100.9,76.7,73.5,62.2,60.9,57.6,
57.1,57.0,55.6,41.8,29.8,25.6,16.0,9.0；MS(ESI+):m/z[M+H]+570.2。
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (9)
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| CN109912629B (en) * | 2017-12-13 | 2021-12-24 | 浙江中科创越药业有限公司 | Preparation of Natural product Trabectedin |
| CN112481649A (en) * | 2019-09-10 | 2021-03-12 | 南通诺泰生物医药技术有限公司 | Preparation method of trimebutine intermediate |
| CN113845478B (en) * | 2020-12-18 | 2023-11-21 | 四川大学 | An intermediate and its preparation method and application |
| CN116332932B (en) * | 2023-02-17 | 2024-07-09 | 四川大学 | Process for the preparation of Ecteinasticidin 743 and several higher intermediates of similar alkaloids |
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| CN104292237A (en) * | 2014-08-30 | 2015-01-21 | 云南民族大学 | Hexacyclic alkaloid compound, preparation method and application thereof |
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| CN104292237A (en) * | 2014-08-30 | 2015-01-21 | 云南民族大学 | Hexacyclic alkaloid compound, preparation method and application thereof |
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