CN108558899B - California xanthene mycin A glycosyl ligand, intermediate and preparation method thereof - Google Patents
California xanthene mycin A glycosyl ligand, intermediate and preparation method thereof Download PDFInfo
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- CN108558899B CN108558899B CN201810469176.XA CN201810469176A CN108558899B CN 108558899 B CN108558899 B CN 108558899B CN 201810469176 A CN201810469176 A CN 201810469176A CN 108558899 B CN108558899 B CN 108558899B
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- carixanthomycin
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- 125000003147 glycosyl group Chemical group 0.000 title claims abstract description 35
- 239000003446 ligand Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 title description 2
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 title description 2
- 239000000126 substance Substances 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 178
- 238000006243 chemical reaction Methods 0.000 claims description 60
- 238000007254 oxidation reaction Methods 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 239000002841 Lewis acid Substances 0.000 claims description 9
- 150000007517 lewis acids Chemical class 0.000 claims description 9
- 230000003647 oxidation Effects 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 6
- 125000003172 aldehyde group Chemical group 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000012380 dealkylating agent Substances 0.000 claims description 3
- 230000020335 dealkylation Effects 0.000 claims description 3
- 238000006900 dealkylation reaction Methods 0.000 claims description 3
- 238000006361 intramolecular Friedel-Crafts acylation reaction Methods 0.000 claims description 3
- DQDCGTUHSVXZIS-UHFFFAOYSA-N iodobenzene;2,2,2-trifluoroacetic acid Chemical group OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.IC1=CC=CC=C1 DQDCGTUHSVXZIS-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 3
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 abstract description 12
- 229930195731 calicheamicin Natural products 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 238000006206 glycosylation reaction Methods 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 147
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 68
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- 239000000243 solution Substances 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 239000003208 petroleum Substances 0.000 description 33
- 239000002904 solvent Substances 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- 238000012360 testing method Methods 0.000 description 19
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 17
- 239000007810 chemical reaction solvent Substances 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 14
- 238000001035 drying Methods 0.000 description 14
- 239000012046 mixed solvent Substances 0.000 description 14
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 239000003513 alkali Substances 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 239000012153 distilled water Substances 0.000 description 11
- -1 etc.) Substances 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 235000011181 potassium carbonates Nutrition 0.000 description 10
- 238000010791 quenching Methods 0.000 description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000007530 organic bases Chemical class 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 229910000019 calcium carbonate Inorganic materials 0.000 description 7
- 235000010216 calcium carbonate Nutrition 0.000 description 7
- 229960001701 chloroform Drugs 0.000 description 7
- 150000008282 halocarbons Chemical class 0.000 description 7
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 6
- 229940043279 diisopropylamine Drugs 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 6
- 150000002825 nitriles Chemical class 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 6
- 229960002218 sodium chlorite Drugs 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229930014626 natural product Natural products 0.000 description 5
- 239000011736 potassium bicarbonate Substances 0.000 description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical group COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 4
- 238000006192 iodination reaction Methods 0.000 description 4
- 239000012022 methylating agents Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- JNELGWHKGNBSMD-UHFFFAOYSA-N xanthone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3OC2=C1 JNELGWHKGNBSMD-UHFFFAOYSA-N 0.000 description 4
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical group FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- PPDJNZTUDFPAHX-UHFFFAOYSA-N benzyltrimethylammonium dichloroiodate Chemical group Cl[I-]Cl.C[N+](C)(C)CC1=CC=CC=C1 PPDJNZTUDFPAHX-UHFFFAOYSA-N 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
- 229940045803 cuprous chloride Drugs 0.000 description 3
- HKYGSMOFSFOEIP-UHFFFAOYSA-N dichloro(dichloromethoxy)methane Chemical compound ClC(Cl)OC(Cl)Cl HKYGSMOFSFOEIP-UHFFFAOYSA-N 0.000 description 3
- KZGWPHUWNWRTEP-UHFFFAOYSA-N ethynyl-tri(propan-2-yl)silane Chemical group CC(C)[Si](C#C)(C(C)C)C(C)C KZGWPHUWNWRTEP-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000026045 iodination Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 3
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 description 2
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 2
- 241000187759 Streptomyces albus Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
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- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical group BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000001035 methylating effect Effects 0.000 description 2
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- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 235000013824 polyphenols Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000005821 Claisen rearrangement reaction Methods 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920004482 WACKER® Polymers 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical group ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- FXORZKOZOQWVMQ-UHFFFAOYSA-L dichloropalladium;triphenylphosphane Chemical compound Cl[Pd]Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FXORZKOZOQWVMQ-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000012336 iodinating agent Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- HHVIBTZHLRERCL-UHFFFAOYSA-N methylsulphonylmethane Natural products CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 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
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical group 0.000 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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Abstract
The invention discloses a calicheamicin A glycosyl ligand, an intermediate and a preparation method thereof, wherein the calicheamicin A glycosyl ligand has a chemical structure shown in a formula 1:the preparation method of the carixanthomycin A glycosyl ligand comprises the following steps (2) or steps (1) to (2) in a synthetic route:the invention also discloses a carixanthomycin A glycosyl ligand intermediate which has the chemical structures shown in formulas 2, 4, 5 and 7 respectively:
Description
Technical Field
The invention relates to a carixanthomycin A glycosyl ligand, an intermediate and a preparation method thereof, belonging to the technical field of chemical drug synthesis.
Background
The kallidamycin A is a polycyclic xanthone natural product, is obtained by introducing an amplification gene sequence of a polyphenol natural product into Streptomyces albus by a Brady task group and separating the product from a culture solution of the Streptomyces albus, has strong inhibitory activity on human colon cancer cells, and has an IC50 value as low as 0.43nM (Hahk-Soo K.; Brady, S.; J.Am.chem.S.2014,136,18111-18119.), and has the following chemical structure:
as a novel polycyclic xanthone natural product, the kalifamycin A has a wide application prospect, but no reports related to chemical synthesis of the kalifamycin A exist at present due to the high oxidation state and complex six-ring structure of the kalifamycin A.
The inventor researches and discovers that if the carixanthomycin A glycosyl ligand is synthesized firstlyOnly one-step glycosylation is needed to synthesize the calicheamicin A, but no report related to the calicheamicin A glycosyl ligand exists at present, and no report related to the chemical synthesis of the calicheamicin A glycosyl ligand exists.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a carixanthomycin a glycosyl ligand, an intermediate thereof and a preparation method thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
a calicheamicin A glycosyl ligand has a chemical structure shown in formula 1:
a method for preparing a calicheamicin a glycosyl ligand represented by formula 1, comprising step (2) or steps (1) to (2) in the following synthetic scheme:
preferably, the step (1) is to selectively remove the carbonyl ortho-methyl and benzyl from the compound of formula 2 under the action of lewis acid to obtain the compound of formula 3.
In a further preferred embodiment, in the step (1), the lewis acid is selected from any one of boron trichloride, boron trifluoride and aluminum trichloride, and preferably boron trichloride.
As a further preferable mode, in the step (1), the reaction solvent is C1~C10And halogenated hydrocarbon solvents (for example, dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, etc.).
As a further preferred embodiment, in step (1), a compound of formula 2: the molar ratio of Lewis acid is 1: (3-8).
Preferably, the step (2) is to remove the methyl group at the para-position of the phenolic hydroxyl group in the compound of formula 3 selectively under the action of a dealkylation reagent to obtain the compound of formula 1 from the compound of formula 3.
As a further preferred embodiment, in step (2), the dealkylating agent is iodobenzene bistrifluoroacetate (also known as [ bis (trifluoroacetoxy) iodo ] benzene, CAS # 2712-78-9).
As a further preferred embodiment, in step (2), a compound of formula 3: the molar ratio of dealkylating agent is 1: (4-8).
As a further preferable mode, in the step (2), the reaction solvent is C1~C10A mixed solvent of a nitrile solvent (e.g., acetonitrile) or a ketone solvent (e.g., acetonitrile) and water.
A calicheamicin A glycosyl ligand intermediate has a chemical structure shown in formula 2:
a method for preparing a carixanthomycin A glycosyl ligand intermediate shown in a formula 2 comprises the following steps of firstly carrying out oxidation reaction on a compound shown in a formula 4 until aldehyde groups in the compound shown in the formula 4 are oxidized into carboxyl groups to obtain an oxidation product, and carrying out intramolecular Friedel-crafts acylation reaction on the obtained oxidation product to obtain a compound shown in the formula 2, wherein the chemical reaction formula is as follows:
as a preferred embodiment, the preparation of the compound of formula 2 is performed as follows: dissolving the compound shown in the formula 4 in a solvent A, and performing oxidation reaction with hydrogen peroxide and sodium chlorite under a neutral condition until aldehyde groups in the compound shown in the formula 4 are oxidized into carboxyl groups to obtain an oxidation product; the obtained oxidation product is directly dissolved in a solvent B, reacts with oxalyl chloride in the presence of a catalyst to obtain an acyl chloride intermediate, and then the obtained acyl chloride intermediate is subjected to intramolecular Friedel-crafts acylation reaction in a fluorinated solvent to obtain the compound shown in the formula 2.
As a further preferable mode, the solvent A is C1~C10A mixed solvent of water and a nitrile solvent (e.g., acetonitrile), the nitrile solvent: the volume ratio of water is (3-10): 1.
as a further preferred embodiment, the compound of formula 4: hydrogen peroxide: sodium chlorite: in a molar ratio of 1: (1-3): (1-3).
In a more preferred embodiment, the solvent B is a reaction solvent C1~C10And halogenated hydrocarbon solvents (for example, dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, etc.).
In a further preferred embodiment, the catalyst is N, N-dimethylformamide.
As a further preferred embodiment, the compound of formula 4: the molar ratio of the catalyst is 1: (2-4).
In a further preferred embodiment, the fluorinated solvent is hexafluoroisopropanol.
A calicheamicin A glycosyl ligand intermediate has a chemical structure shown in formula 4:
a method for preparing a carixanthomycin A glycosyl ligand intermediate shown in a formula 4 is to obtain a compound shown in the formula 4 by an aromatic nucleophilic substitution reaction of a compound shown in a formula 5 and a compound shown in a formula 6, wherein the chemical reaction formula is as follows:
as a preferred embodiment, the preparation of the compound of formula 4 is performed as follows: and (3) carrying out an aromatic nucleophilic substitution reaction on the compound of the formula 5 and the compound of the formula 6 at 110-130 ℃ in the presence of alkali to obtain the compound of the formula 4.
In a further preferred embodiment, the reaction solvent is N, N-dimethylformamide.
More preferably, the base is an inorganic base selected from any one of sodium carbonate, potassium carbonate, calcium carbonate and cesium carbonate.
Preferably, the compound of formula 5: alkali: the molar ratio of the compounds of formula 6 is 1: (1-2): (1-2).
A calicheamicin A glycosyl ligand intermediate has a chemical structure shown in formula 5:
a method for preparing a carixanthomycin A glycosyl ligand intermediate shown in formula 5 comprises the following steps of (c), (c) - (c) or (c) - (c):
preferably, the compound of formula 7 is subjected to a reduction reaction with hydrogen in the presence of a catalyst to obtain the compound of formula 8.
In a further preferred embodiment, in step (i), the catalyst is a palladium catalyst (e.g., palladium/barium sulfate).
As a further preferable mode, in the step (i), the reaction solvent used is C1~C10Ether solvents (e.g., tetrahydrofuran, dioxane, etc.).
As a further preferred embodiment, in step (i), the compound of formula 7: the molar ratio of the catalyst is 10: 1-10: 3.
Preferably, the step (II) is to perform an iodination reaction on the compound of the formula 8 with an iodination reagent in the presence of a base to obtain the compound of the formula 9.
In a further preferred embodiment, in the step (ii), the base used is an inorganic base selected from one or a mixture of two or more of sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and barium hydroxide.
As a further preferred embodiment, in step (II), the iodinating agent is benzyltrimethylammoniumdichloroiodate (CAS # 114971-52-7).
As a further preferable scheme, in the step (II), C1~C10Or a halogenated hydrocarbon solvent (e.g., dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, etc.), or a mixture thereof.
In the second step, the reaction temperature of iodination is 50-60 ℃.
As a further preferred embodiment, in step (ii), the compound of formula 8: iodination reagent: the molar ratio of the alkali is 1: (1-3): (5-12).
Preferably, the step (c) is to perform intramolecular radical cyclization reaction on the compound of the formula 9 in the presence of alkali under ultraviolet irradiation to obtain the compound of the formula 5.
In a further preferred embodiment, in step (c), the base used is an organic base selected from any one or a mixture of two or more of diisopropylamine, triethylamine, diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, 2-hydroxypyridine, piperidine, N-methylpiperidine, morpholine and N-methylmorpholine.
As a further preferable scheme, in the step (C), the reaction solvent used is C1~C10And (3) nitrile solvents (e.g., acetonitrile, etc.).
As a further preferred embodiment, in step (iii), the compound of formula 9: the molar ratio of the alkali is 1: (5-15).
A calicheamicin A glycosyl ligand intermediate has a chemical structure shown in formula 7:
a method for preparing a carixanthomycin A glycosyl ligand intermediate shown in a formula 7 is to obtain a compound shown in the formula 7 by a coupling reaction of a compound shown in a formula 10 and a compound shown in a formula 11 through sonogashira, wherein the chemical reaction formula is as follows:
as a preferred embodiment, the preparation of the compound of formula 7 is performed as follows: the compound shown in the formula 10 and the compound shown in the formula 11 are subjected to sonogashira coupling reaction at 90-100 ℃ in a mixed solvent of an organic solvent and an organic base under the catalysis of a palladium catalyst and cuprous iodide to obtain the compound shown in the formula 7.
More preferably, the volume ratio of the organic solvent to the organic base in the mixed solvent is (3-10): 1.
In a further preferred embodiment, the organic solvent is N, N-dimethylformamide.
In a further preferred embodiment, the organic base is selected from any one or a mixture of two or more of diisopropylamine, triethylamine, diisopropylethylamine, pyridine, 2-hydroxypyridine, piperidine, N-methylpiperidine, morpholine and N-methylmorpholine.
As a further preferred embodiment, the palladium catalyst is bis-triphenylphosphine palladium dichloride or tetrakis-triphenylphosphine palladium.
As a preferred embodiment, compounds of formula 10: the molar ratio of the compound of formula 11 is 1: 1-1: 2.
As a preferred scheme, the preparation of formula 10 comprises the steps h or g to h or f to g to h or e to f to g to h or d to e to f to g to h or c to d to e to f to g to h or b to c to d to e to f to g to h or a step a to b to c to d to e to f to g to h in the following synthetic routes:
as a further preferred embodiment, said step a is to obtain the compound of formula 10-2 by reacting the compound of formula 10-1 with allyl halide in the presence of a phase transfer catalyst and a base.
As a further preferred embodiment, in step a, the phase transfer catalyst is a quaternary ammonium salt (e.g., tetrabutylammonium iodide).
In a further preferred embodiment, in step a, the base is an inorganic base selected from any one or a mixture of two or more of sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate.
As a further preferred embodiment, in step a, the allyl halide is allyl bromide.
In a further preferred embodiment, in step a, the reaction solvent is a halogenated hydrocarbon solvent (e.g., dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, etc.) or a ketone solvent (e.g., acetone) having a carbon number of from C1 to C10; the reaction temperature is 40-60 ℃.
As a still further preferred embodiment, in step a, a compound of formula 10-1: alkali: the molar ratio of allyl halides is 1: (1-2): (1-1.5).
As a further preferable scheme, the compound of the formula 10-3 is obtained by reacting the compound of the formula 10-2 with 1, 1-dichloromethyl ether in the presence of Lewis acid.
As a further preferred embodiment, in step b, the Lewis acid is titanium tetrachloride.
As a still further preferred embodiment, in step b, the compound of formula 10-2: lewis acid: the mol ratio of 1, 1-dichloromethyl ether is 5: (8-10): (5-8).
In a more preferred embodiment, the reaction solvent in step b is a halogenated hydrocarbon solvent of C1-C10 (e.g., dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, etc.).
As a further preferred scheme, the step c is to perform an oxidation reaction on the compound of the formula 10-3 with hydrogen peroxide and sodium chlorite under a neutral condition until aldehyde groups in the compound of the formula 10-3 are oxidized into carboxyl groups to obtain the compound of the formula 10-4.
As a further preferred embodiment, in step C, the reaction solvent is C1~C10A mixed solvent of water and a nitrile solvent (e.g., acetonitrile), the nitrile solvent: the volume ratio of water is (3-10): 1.
As a still further preferred embodiment, in step c, a compound of formula 10-3: hydrogen peroxide: sodium chlorite: in a molar ratio of 1: (1-3): (1-3).
As a further preferred embodiment, said step d is to react the compound of formula 10-4 with a methylating agent in the presence of a base to obtain the compound of formula 10-5.
As a further preferred embodiment, in step d, the methylating agent is dimethyl sulphate.
In a further preferred embodiment, in step d, the base is an inorganic base selected from any one or a mixture of two or more of sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate.
In a further preferred embodiment, in step d, the reaction solvent is N, N-dimethylformamide.
As a still further preferred embodiment, in step d, the compound of formula 10-4: alkali: the molar ratio of the methylating agents is 1: (1-3): (1-2).
In a further preferable scheme, the compound of the formula 10-6 is obtained by performing a claisen rearrangement reaction on the compound of the formula 10-5 in an amine solvent at 180-220 ℃.
In a further preferred embodiment, in step e, the amine solvent is N-methylpyrrolidone.
As a further preferred embodiment, said step f is to react the compound of formula 10-6 with a methylating agent in the presence of a base to obtain the compound of formula 10-7.
As a further preferred embodiment, in step f, the methylating agent is dimethyl sulfate or methyl iodide.
In a further preferred embodiment, in step f, the base is an inorganic base selected from any one or a mixture of two or more of sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate and sodium hydride.
In a further preferred embodiment, in step f, the reaction solvent is N, N-dimethylformamide.
As a still further preferred embodiment, in step f, the compound of formula 10-6: alkali: the molar ratio of the methylating agents is 1: (1-3): (1-2).
As a further preferable scheme, the step g is that the compound of the formula 10-7 is subjected to a Wacker oxidation reaction with oxygen under the catalysis of palladium chloride and cuprous chloride to obtain the compound of the formula 10-8.
As a further preferred embodiment, in step g, the reaction solvent is C1~C10A mixed solvent of the ether solvent (e.g., dioxane, tetrahydrofuran, etc.) and water, ether solvent: the volume ratio of water is (3-10): 1.
As a still further preferred embodiment, in step g, the compound of formula 10-7: palladium chloride: the mol ratio of cuprous chloride is 10: (0.5-1.5): (8-15).
As a further preferable scheme, the step h is to perform hydroboration reduction reaction on the compound of the formula 10-8 and borohydride to obtain the compound of the formula 10.
As a further preferred embodiment, in step h, the borohydride is sodium borohydride.
As a still further preferred embodiment, in step h, the compound of formula 10-8: the molar ratio of borohydride is 1: (2-3).
Preferably, the preparation of the compound of formula 11 comprises steps E or steps D to E or steps C to D to E or steps B to C to D to E or steps A to B to C to D to E in the following synthetic routes:
as a further preferred scheme, the step A is to react the compound of the formula 11-1 with benzyl halide in the presence of alkali to obtain the compound of the formula 11-2.
In a further preferred embodiment, in step a, the base used is an inorganic base selected from any one or a mixture of two or more of sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate.
As a further preferred embodiment, in step A, the benzyl halide is benzyl chloride or benzyl bromide.
In a further preferred embodiment, in step A, the reaction solvent is N, N-dimethylformamide.
As a still further preferred embodiment, in step A, a compound of formula 11-1: alkali: the molar ratio of the halogenated benzyl is 1: (1-3): (1-2).
As a further preferred scheme, the step B is that the compound of the formula 11-2 is firstly reacted with the peroxy compound, and the obtained product intermediate is hydrolyzed in alkaline aqueous solution or acidic alcohol solution to obtain the compound of the formula 11-3.
In a further preferred embodiment, in step B, the peroxy compound is m-chloroperoxybenzoic acid.
More preferably, in the step B, when the compound of formula 11-2 is reacted with the peroxy compound, the reaction solvent is a halogenated hydrocarbon solvent of C1-C10 (e.g., dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane), and the reaction temperature is 40-60 ℃.
In a further preferred embodiment, in step B, the alkaline aqueous solution is an aqueous sodium hydroxide solution, and the acidic alcoholic solution is an alcoholic solution of hydrochloric acid.
As a still further preferred embodiment, in step B, a compound of formula 11-2: the molar ratio of the peroxy compound is 1: 1-2: 3.
In a further preferable embodiment, the step C is to perform the sonogashira coupling reaction of the compound of formula 11-3 in a mixed solvent of an organic solvent and an organic base and with triisopropylsilyl acetylene at 100-120 ℃ under the catalysis of a palladium catalyst and cuprous iodide to obtain the compound of formula 11-4.
In a further preferable embodiment, in the step C, the volume ratio of the organic solvent to the organic base in the mixed solvent is (3-10): 1.
In a further preferred embodiment, in step C, the organic solvent is toluene.
In a further preferred embodiment, in step C, the organic base is selected from any one or a mixture of two or more of diisopropylamine, triethylamine, diisopropylethylamine, pyridine, 2-hydroxypyridine, piperidine, N-methylpiperidine, morpholine and N-methylmorpholine.
As a still further preferred embodiment, in step C, the palladium catalyst is bis triphenylphosphine palladium dichloride.
As a still further preferred embodiment, in step C, a compound of formula 11-3: the molar ratio of triisopropyl silyl acetylene is 1: 1-1: 2.
As a further preferable mode, the step D is to remove the triisopropylsilyl group on the alkynyl group from the compound of the formula 11-4 under the action of a fluorine reagent to obtain the compound of the formula 11-5.
In a further preferred embodiment, in step D, the fluorine reagent is tetrabutylammonium fluoride or pyridine hydrofluoric acid.
As a further preferred embodiment, in step D, the reaction solvent is C1~C10Ether solvents (e.g., tetrahydrofuran, dioxane, etc.).
As a still further preferred embodiment, in step D, a compound of formula 11-4: the molar ratio of the fluorine reagent is 1: 1-1: 2.
As a further preferable scheme, the step E is to react the compound of the formula 11-5 with triisopropylchlorosilane under the action of alkali and a catalyst to obtain the compound of the formula 11.
In a more preferred embodiment, the reaction solvent in step E is a halogenated hydrocarbon solvent of C1-C10 (e.g., dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, etc.).
As a further preferred embodiment, in step E, the catalyst is DMAP.
In a further preferred embodiment, in step E, the base is an organic base, and the organic base is any one of diisopropylamine, triethylamine and diisopropylethylamine.
As a still further preferred embodiment, in step E, a compound of formula 11-5: catalyst: alkali: the molar ratio of triisopropyl chlorosilane is 10: (0.5-1.5): (10-20): (10-15).
Compared with the prior art, the invention has the following remarkable beneficial effects:
the invention realizes the chemical synthesis of the carixanthomycin A glycosyl ligand for the first time, the prepared carixanthomycin A glycosyl ligand can be used for preparing the carixanthomycin A through simple glycosylation reaction, and the preparation method has strong practical value for realizing the chemical synthesis of the carixanthomycin A, has the advantages of simple operation, safety, no pollution, no special requirement on equipment, low production cost and the like, and has significant progress compared with the prior art; in addition, the intermediate products such as the compounds shown in the formulas 2, 4, 5 and 7 generated in the process of preparing the carixanthomycin A glycosyl ligand have more modifiable sites, and provide a new chemical synthesis direction for derivatives of the carixanthomycin A or other natural products with similar structures.
Detailed Description
The technical scheme of the invention is further detailed and completely explained by combining the embodiment.
Example 1: preparation of Compounds of formula 10
Step a: preparing a compound of formula 10-2:
the compound of formula 10-1 (10.0g,49.2mmol) was dissolved in acetone (120ml), potassium carbonate (10.2g,73.9mmol) and tetrabutylammonium fluoride (182mg,0.49mmol) were added, the mixture was stirred and mixed uniformly, allyl bromide (5.1ml,59.1mmol) was added, the reaction was terminated at 55 ℃ for 12 hours, the reaction mixture was cooled to room temperature, filtered through celite, concentrated, and the residue was separated by column chromatography (5% ethyl acetate/petroleum ether) to give the compound of formula 10-2 (11.77g, yield 98%) and Rf ═ 0.54 (10% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,Chloroform-d)δ7.14(d,J=2.9Hz,1H),6.85(d,J=8.9Hz,1H),6.80(d,J=8.9Hz,1H),6.07(m,1H),5.48(dq,J=17.2,1.6Hz,1H),5.31(d,J=10.6Hz,1H),4.55(d,J=3.7Hz,2H),3.76(s,3H);
13C NMR(125MHz,CDCl3)δ154.3,149.3,133.1,118.9,117.6,115.1,113.6,112.2,70.7,55.9;
HRMS(EI):m/z calcd for[M]+:241.9942,found 241.9943。
step b: preparing a compound of formula 10-3:
the compound of formula 10-2 (12.10g,49.8mmol) was added to a dry dichloromethane solution (200ml) under nitrogen, adding 1, 1-dichloromethyl ether (8.1ml,89.6mmol) at 0 ℃, stirring and mixing uniformly, slowly dropwise adding a dichloromethane solution of titanium tetrachloride (1M dichloromethane, 59.7ml,59.7mmol), after dropwise adding, preserving heat and reacting for 2 hours, after the reaction was completed, the reaction solution was poured into an ice saturated sodium bicarbonate solution (200ml), stirred, separated, the aqueous phase was extracted 3 times with dichloromethane (80ml), the organic phases were combined, washed 1 time with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, the residue was separated by column chromatography (3-7% ethyl acetate/petroleum ether), to give a compound of formula 10-3 (6.09g, 45% yield), Rf ═ 0.56 (10% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,Chloroform-d)δ10.40(s,1H),7.35(s,1H),7.27(s,1H),6.11-6.03(m,1H),5.50(dd,J=17.2,1.7Hz,1H),5.33(dd,J=10.5,1.5Hz,1H),4.62(d,J=5.1Hz,2H),3.92(s,3H);
13C NMR(125MHz,CDCl3)δ188.7,156.3,149.4,132.3,124.1,121.0,118.1,117.6,111.4,70.3,56.4;
HRMS(EI):m/z calcd for[M]+:269.9892,found 269.9893。
step c: preparing a compound of formula 10-4:
adding a compound of a formula 10-3 (8.09g,29.80mmol) into a mixed solvent of acetonitrile (100ml) and water (20ml), uniformly stirring, then adding sodium dihydrogen phosphate dihydrate (930mg,5.96mmol), hydrogen peroxide (5.10ml, 30% v/v,44.70mmol), sodium chlorite (3.77g, dissolved in 20ml of water, 41.70mmol) at 0 ℃, keeping the temperature for reaction for 3 hours, then moving to room temperature for further reaction for 3 hours, finishing the reaction, quenching the reaction by using saturated sodium thiosulfate (10ml), decompressing and concentrating to remove excessive acetonitrile, adjusting the pH value of a residue to be about 4, extracting by using ethyl acetate for 3 times, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, and concentrating to obtain a compound of a formula 10-4, wherein the obtained compound of the formula 10-4 is directly used for the next reaction without further purification.
Step d: preparing a compound of formula 10-5:
directly dissolving the compound of formula 10-4 obtained in step c in N, N-dimethylformamide (50ml), adding potassium carbonate (6.60g,47.9mmol) and dimethyl sulfate (3.40ml,35.1mmol), reacting at room temperature for 10 hours, terminating the reaction, quenching the reaction with saturated ammonium chloride solution (20ml), extracting with ethyl acetate (60ml) 3 times, combining the organic phases, washing the organic phases with water 3 times, washing with saturated sodium chloride solution 1 time, drying, filtering, concentrating, and separating the residue with column chromatography (6-8% ethyl acetate/petroleum ether) to obtain the compound of formula 10-5 (7.84g, total yield in steps c and d is 81%), and Rf is 0.66 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(400MHz,Chloroform-d)δ7.38(s,1H),7.20(s,1H),6.11–6.00(m,1H),5.47(d,J=17.2Hz,1H),5.31(d,J=11.5Hz,1H),4.58(d,J=5.1Hz,2H),3.89(s,3H),3.87(s,3H);
HRMS(EI):m/z calcd for[M]+:299.9997,found:300.0001。
step e: preparing a compound of formula 10-6:
dissolving the compound of formula 10-5 (2.56g,8.50mmol) in dry N-methylpyrrolidone (20ml), reacting at 200 ℃ for 2 hours under nitrogen protection, cooling the reaction solution to room temperature, adding saturated ammonium chloride solution (10ml), quenching the reaction, extracting with ethyl acetate (40ml) for 3 times, combining organic phases, washing the organic phases with distilled water and saturated saline water in sequence, drying with anhydrous sodium sulfate, filtering, concentrating, and separating the residue with column chromatography (5% ethyl acetate/petroleum ether) to obtain the compound of formula 10-6 (2.16g, 83% yield), Rf ═ 0.68 (20% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,Chloroform-d)δ6.96(s,1H),5.97-5.93(m,1H),5.34(s,1H),5.12–5.03(m,2H),3.91(s,3H),3.79(s,3H),3.41(d,J=6.4Hz,2H);
13C NMR(125MHz,CDCl3)δ167.4,150.2,144.7,134.9,125.7,124.8,116.2,113.1,111.3,56.6,52.3,32.8;
MS(EI):300(M+,71),302(71),285(23),269(100)。
step f: preparing a compound of formula 10-7:
the compound of formula 10-6 (6.0g,19.0mmol,1.0equiv.) was dissolved in 30ml of DMF, potassium carbonate (4.13mg,29.9mmol,1.5equiv.) and Me2SO4(2.1ml,21.9mmol,1.1equiv.) were added, reaction was carried out at room temperature for 6 hours, the reaction was terminated, 5ml of saturated NH was added4Quenching the reaction with aqueous Cl, extracting with ethyl acetate, combining the organic phases, washing the organic phases with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating, and subjecting the residue to column chromatography (10% ethyl acetate)Ester/petroleum ether) to give a compound of formula 10-7 (5.07g, 81% yield), Rf ═ 0.55 (15% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,Chloroform-d)δ6.97(s,1H),5.89-5.79(m,1H),5.02–4.93(m,2H),3.81(s,3H),3.73(s,3H),3.72(s,3H),3.39(dt,J=6.4,1.7Hz,2H)ppm;
13C NMR(125MHz,CDCl3)δ167.1,152.8,149.2,135.6,133.1,124.3,118.9,116.2,114.4,61.3,56.3,52.1,32.3;
MS(EI):314(M+)。
step g: preparing a compound of formula 10-8:
dissolving the compound of formula 10-7 (4.96g,15.70mmol) in a mixed solvent of 1, 4-dioxane (70ml) and water (10ml), stirring well, adding palladium chloride (140mg,0.78mmol) and cuprous chloride (1.69g,18.8mmol), introducing oxygen, reacting at room temperature under oxygen atmosphere for 8 hours, ending the reaction, filtering the reaction solution with celite, extracting with ethyl acetate (40ml) three times, combining the organic phases, washing the organic phases with distilled water and saturated brine each once, drying, filtering, concentrating, separating the residue with column chromatography (5-15% ethyl acetate/petroleum ether) to obtain the compound of formula 10-8 (2.68g, 52% yield), Rf ═ 0.45 (30% ethyl acetate/petroleum ether).
Through the test:1H NMR(400MHz,Chloroform-d)δ7.07(s,1H),3.86(s,3H),3.81(s,3H),3.78(s,2H),3.75(s,3H),2.18(s,3H);
13C NMR(101MHz,CDCl3)δ204.64,167.10,153.32,149.46,129.16,123.86,119.32,115.65,61.18,56.52,52.46,43.09,29.44;
HRMS(EI):m/z calcd for[M]+:330.0103,found:330.0107。
step h: preparing a compound of formula 10:
the compound of formula 10-8 (2.13g,6.43mmol) was dissolved in methanol (30ml), sodium borohydride (243 × 3mg,19.3mmol) was added in portions at 0 ℃, after completion of the addition, the reaction was carried out for 2 hours at 0 ℃ and then moved to room temperature for 2 hours, the reaction was terminated, acetone (3ml) was added to quench the reaction, the excess acetone was removed by concentration under reduced pressure, the residue was dissolved in ethyl acetate (50ml), washed once with saturated brine, dried, filtered, concentrated, and the residue was separated by column chromatography (5-15% ethyl acetate/petroleum ether) to give the compound of formula 10 (1.52g, yield 78%), Rf ═ 0.4 (30% ethyl acetate/petroleum ether).
Through the test: 1H NMR (500MHz, Chloroform-d) δ 7.13(s,1H),4.51(ddd, J ═ 11.5,6.2,2.8Hz,1H),3.94(s,3H),3.79(s,3H),3.19(dd, J ═ 16.5,2.8Hz,1H),2.73(ddd, J ═ 16.5,11.4,0.8Hz,1H),1.53(d, J ═ 6.3Hz, 3H);
13C NMR(126MHz,CDCl3)δ161.9,157.5,146.8,135.8,123.8,115.6,113.8,73.9,61.1,56.7,30.5,20.7;
MS(EI):300(M+,71),302(71),269(100),253(94)。
example 2: preparation of Compounds of formula 11
Step A: preparing a compound of formula 11-2:
dissolving the compound of formula 11-1 (7.20g,30.9mmol,1.0equiv.) in 60ml DMF, adding potassium carbonate (6.40g,46.3mmol,1.5equiv.) and benzyl bromide (4.0ml,34.0mmol,1.1equiv.), reacting at room temperature for 2 hours, terminating the reaction, adding 20ml distilled water to quench the reaction, extracting with ethyl acetate (30ml) three times, combining the organic phases, washing the organic phases with distilled water 3 times, washing with saturated sodium chloride solution 1 time, drying with anhydrous sodium sulfate, filtering, concentrating, and separating the residue with column chromatography (5% ethyl acetate/petroleum ether) to obtain the compound of formula 11-2 (8.97g, yield 90%), Rf ═ 0.57 (10% ethyl acetate/petroleum ether).
Through the test:1H NMR(400MHz,CDCl3)δ10.04(s,1H),7.43(d,J=3.1Hz,1H),7.42–7.34(m,5H),7.24(d,J=3.1Hz,1H),5.06(s,2H),3.81(s,3H)ppm;
13C NMR(100MHz,CDCl3)δ188.9,156.5,152.5,135.3,131.2,128.9,128.9(2C),128.8(2C),126.6,118.8,110.0,78.1,56.0ppm;
MS(EI):320(M+)。
and B: preparing a compound of formula 11-3:
dissolving the compound of formula 11-2 (30.3g,94.3mmol,1.0equiv.) in 260ml of dichloromethane solution, slowly adding m-chloroperoxybenzoic acid (38.20g,122.6mmol,1.3equiv.), reacting at 50 ℃ for 15 hours after the completion of the addition, finishing the reaction, cooling the system temperature to room temperature, adding sodium bicarbonate solid (11.88g,141.4mmol,1.5equiv.), stirring for 30 minutes, filtering with diatomite, separating the filtrate, washing the separated organic phase twice with 30ml of saturated sodium thiosulfate solution, then washing once with 30ml of saturated sodium bicarbonate solution and 30ml of saturated sodium chloride solution, drying, filtering and concentrating; the resulting concentrate was directly dissolved in 80ml of THF solution, 20ml of 10% NaOH aqueous solution was added at 0 ℃, followed by reaction at room temperature for 15 minutes to terminate the reaction, the reaction solution was concentrated under reduced pressure to remove excess THF, 50ml of ethyl acetate was added to the residue, pH was adjusted to about 4, then liquid separation was performed, ethyl acetate (40ml) was extracted three times, the organic phases were combined, the organic phase was washed once with 50ml of distilled water, once with 50ml of saturated sodium bicarbonate solution, once with 50ml of saturated sodium chloride solution, dried, filtered, concentrated, and the residue was separated by column chromatography (8% ethyl acetate/petroleum ether) to obtain the compound of formula 11-3 (22.4g, yield 77%) having Rf of 0.39 (15% ethyl acetate/petroleum ether).
Through the test:1H NMR(400MHz,CDCl3)δ7.46–7.36(m,5H),6.65(d,J=2.9Hz,1H),6.44(d,J=2.9Hz,1H),5.55(br s,1H),4.99(s,2H),3.72(s,3H)ppm;
13C NMR(100MHz,CDCl3)δ157.1,150.6,137.4,136.5,128.9(2C),128.8,128.6(2C),116.3,109.9,101.3,76.1,55.7ppm;
MS(EI):308(M+,3),229(14),91(100)。
and C: preparing a compound of formula 11-4:
a compound of formula 11-3 (3.09g,9.99mmol,1.0equiv.), Pd (PhCN)2Cl2(268mg,0.7mmol,0.07equiv.), cuprous iodide (66.7mg,0.35mmol,0.035equiv.), and sodium iodide (2.24g,14.99mmol,1.5equiv.) A mixed solvent of toluene and diisopropylamine (48ml, 40ml of toluene, 8ml of diisopropylamine) was added under nitrogen protection, triisopropylsilylacetylene (3.36ml,14.99mmol,1.5equiv.) was finally added, after the addition, the reaction was terminated at 110 ℃ under nitrogen protection, the reaction system was cooled to room temperature, 15ml of saturated aqueous ammonium chloride solution was added to quench the reaction, the reaction solution was extracted three times with ethyl acetate (30ml), the organic phases were combined, the organic phase was washed three times with distilled water, washed once with saturated sodium chloride solution, dried, filtered, concentrated, and the residue was separated by column chromatography (2-5% ethyl acetate/petroleum ether) to obtain the compound of formula 11-4 (3.44g, yield 84%), rf 0.48 (15% ethyl acetate/petroleum ether).
Through the test:1H NMR(400MHz,Chloroform-d)δ7.46–7.30(m,5H),6.54(d,J=3.0Hz,1H),6.46(d,J=3.0Hz,1H),5.55(s,1H),5.21(s,2H),3.74(s,3H),1.13(d,J=2.2Hz,21H)ppm;
13C NMR(101MHz,CDCl3)δ155.9,149.7,140.9,137.0,128.7(2C),128.6,128.4(2C),116.7,110.0,102.8,102.8,96.3,75.9,55.7,18.7(3C),11.4(6C)。
step D: preparing a compound of formula 11-5:
the compound of formula 11-4 (3.44g,8.38mmol,1.0equiv.) was dissolved in 60ml of tetrahydrofuran, and then tetrabutylammonium iodide solution (10.9ml,10.9mmol,1.3equiv.) was added dropwise at 0 ℃, after completion of the addition, the reaction system was reacted at room temperature for 10 hours to terminate the reaction, 60ml of ethyl acetate was added for extraction, the organic phases were combined, washed once with 30ml of 1N hydrochloric acid aqueous solution, 30ml of distilled water and 30ml of saturated sodium chloride aqueous solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (2-5% ethyl acetate/petroleum ether) to obtain the compound of formula 11-5 (1.58 g), with a yield of 77% Rf ═ 0.37 (15% ethyl acetate/petroleum ether).
Through the test:1H NMR(400MHz,Chloroform-d)δ7.47–7.33(m,5H),6.56(d,J=3.0Hz,1H),6.51(d,J=3.0Hz,1H),5.57(s,1H),5.15(s,2H),3.74(s,3H),3.35(s,1H)ppm;
13C NMR(101MHz,CDCl3)δ156.1,149.7,141.4,136.8,128.8(2C),128.7,128.6(2C),115.4,109.7,103.3,82.1,79.8,76.3,55.6。
step E: preparing a compound of formula 11:
after 50ml of dried dichloromethane, triethylamine (1.26ml,9.07mmol,1.5equiv.), triisopropylchlorosilane (1.4ml,6.6mmol,1.1equiv.) and a compound of formula 11-5 (1.54g,6.05mmol,1.0equiv.) were added under nitrogen protection, the reaction was terminated by adding 15ml of saturated aqueous ammonium chloride solution under nitrogen protection, followed by liquid separation, washing of the organic phase with 20ml of saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, filtration, concentration, and separation of the residue by column chromatography (petroleum ether) to obtain a compound of formula 11 (2.05g, 82% yield), Rf ═ 0.87 (15% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,Chloroform-d)δ7.58–7.31(m,5H),6.59(d,J=2.9Hz,1H),6.53(d,J=3.0Hz,1H),5.06(s,2H),3.76(s,3H),3.23(s,1H),1.36–1.26(m,3H),1.13(d,J=7.4Hz,18H)ppm;
13C NMR(125MHz,CDCl3)δ155.4,150.2,145.9,137.6,128.4(2C),128.2(2C),127.8,117.5,109.1,109.1,80.9,80.4,75.2,55.6,18.0(3C),12.9(6C)。
example 3: preparation of the Compound of formula 7
Dissolving the compound of formula 10 (1.52g,5.05mmol,1.0equiv.) and the compound of formula 11 (2.70g,6.56mmol,1.3equiv.) in a mixed solvent of 40ml DMF and 8ml triethylamine, adding Ph (PPh3)4(577mg,0.5mmol,0.1equiv.) and CuI (95.3mg,0.5mmol,0.1equiv.), reacting at 95 ℃ for 10.5 hours under nitrogen protection after the completion of the addition, finishing the reaction, cooling the reaction system to room temperature, and reacting with 10ml saturated NH4The reaction was quenched with aqueous Cl solution, extracted three times with ethyl acetate (40ml), the organic phases were combined, washed twice with distilled water and saturated brine, respectively, dried, filtered, and concentrated to give the compound of formula 7(2.50g, yield 78%).
Through the test:1H NMR(500MHz,Chloroform-d)δ7.58–7.49(m,2H),7.32(q,J=6.2Hz,3H),6.85(s,1H),6.66(d,J=3.0Hz,1H),6.57(d,J=2.9Hz,1H),5.14(s,2H),4.52(ddd,J=11.6,6.2,2.8Hz,1H),3.84(s,3H),3.81(s,3H),3.80(s,3H),3.17(dd,J=16.6,2.8Hz,1H),2.67(dd,J=16.6,11.5Hz,1H),1.52(d,J=6.3Hz,3H),1.33(q,J=7.5Hz,3H),1.14(d,J=7.5Hz,18H)ppm;
13C NMR(125MHz,CDCl3)δ162.2,156.7,155.6,150.2,150.2,145.5,137.8,134.6,128.2(2C),127.9(2C),127.7,122.9,117.9,114.8,114.2,109.2,108.6,93.8,88.4,75.2,74.0,61.4,56.4,55.6,29.9,20.8,18.0(3C),12.9(6C);
MS(m/z):ESI[M+H]+calcd for 631.31,Found[M+H]+:631.22。
example 4: preparation of Compounds of formula 5
The method comprises the following steps: preparing a compound of formula 8:
dissolving the compound shown in the formula 7(2.50g,3.95mmol) in tetrahydrofuran (80ml), adding palladium/barium sulfate (500mg,0.2w/w, 5% Pd) under the protection of nitrogen, stirring uniformly, introducing hydrogen, reacting at 35 ℃ for 11 hours under the atmosphere of hydrogen to finish the reaction, filtering the reaction liquid by using kieselguhr, and concentrating the filtrate to obtain the compound shown in the formula 8, wherein the compound shown in the formula 8 is directly used for the next reaction without purification.
Step two: preparing a compound of formula 9:
directly dissolving the compound of the formula 8 prepared in the step (i) in a mixed solvent of methanol (60ml) and dichloromethane (60ml), adding benzyltrimethyl ammonium dichloroiodate (2.05g,5.9mmol) and calcium carbonate (3.9g,39mmol), reacting at 50 ℃ for 10 hours to finish the reaction, filtering reaction liquid by using kieselguhr, concentrating the filtrate, dissolving the concentrate by using ethyl acetate, washing the concentrate by using a saturated sodium thiosulfate solution and a saturated sodium chloride solution respectively, drying by using anhydrous sodium sulfate, filtering, concentrating, and separating residues by using column chromatography (10-25% ethyl acetate/petroleum ether) to obtain the compound of the formula 9 (2.12g, wherein the total yield of the two steps (i) and (ii) is 71%), and Rf is 0.50 (30% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,Chloroform-d)δ7.48–7.31(m,5H),6.68(s,1H),6.49(s,1H),5.07–4.95(m,2H),4.48-4.41(m,1H),3.85(s,3H),3.70(s,3H),3.61(s,3H),3.18–3.04(m,3H),2.93–2.78(m,2H),2.71–2.61(m,1H),1.50(d,J=6.3Hz,3H),1.40–1.27(m,3H),1.15(dd,J=7.5,0.8Hz,18H);
13C NMR(126MHz,CDCl3)δ162.8,157.4,154.5,150.1,147.8,141.9,141.9,139.4,137.8,134.5,128.3(2C),127.8,127.5(2C),112.3,112.2,102.3,82.0,74.6,73.9,61.5,56.7,56.1,36.6,30.2,30.2,20.8,18.0(3C),13.0(6C);
MS(m/z):ESI[M+H]+calcd for 761.24,Found[M+H]+:760.70。
step three: preparing a compound of formula 5:
placing the compound of formula 9 (10 × 200mg,2.76mmol) in 10 clean quartz tubes respectively, adding dry and oxygen-removed acetonitrile (10 × 10ml,20mg/ml) by bubbling under nitrogen protection, adding 2, 6-lutidine (10 × 300 μ l) into each quartz tube, shaking uniformly, placing the photoreaction tube under 300nm ultraviolet illumination for reaction for 5 hours, ending the reaction, combining and spin-drying the solvents to obtain a concentrate, dissolving the concentrate with ethyl acetate, washing with 1N hydrochloric acid, a saturated sodium thiosulfate solution and a saturated sodium chloride solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating, and separating the residue with column chromatography (5-15% ethyl acetate/petroleum ether) to obtain the compound of formula 5 (1.47 g), wherein the yield is 83% Rf ═ 0.55 (30% ethyl acetate/petroleum ether).
Through the test:1H NMR(400MHz,Chloroform-d)δ7.41–7.27(m,5H),6.53(d,J=3.7Hz,1H),5.01(s,2H),4.53(br s,1H),3.83(s,3H),3.65(s,3H),3.47(s,3H),3.19(dd,J=16.5,2.8Hz,1H),3.10–2.99(m,2H),2.74-2.59(m,1H),1.98(td,J=15.1,3.9Hz,1H),1.81(qd,J=14.7,3.6Hz,1H),1.52(d,J=6.1Hz,3H),1.42–1.31(m,3H),1.17(dd,J=7.5,3.9Hz,18H)ppm;
13C NMR(125MHz,CDCl3)δ163.0,156.3,153.4,149.5,148.3,140.5,139.1,137.6,135.2,131.6,128.7(2C),128.3(2C),127.9,127.7,117.2,114.2,102.8,74.9,73.8,61.0,56.1,30.7,23.9,23.2,20.9,18.0(3C),13.0(6C)ppm;
HRMS(EI):m/z calcd for[M]+:632.3169,found:632.3167。
example 5: preparation of the Compound of formula 4
Adding a compound of formula 5 (633mg, 1.0mmol), a compound of formula 6 (221mg,1.2mmol) and cesium carbonate (293mg,0.9mmol) into dry and frozen deoxygenated N, N-dimethylformamide (45ml) under nitrogen protection, reacting the reaction system at 120 ℃ for 4 hours under nitrogen protection, cooling to room temperature, adding a 1N hydrochloric acid (10ml) solution, performing extraction quenching reaction, extracting with ethyl acetate for 3 times, combining organic phases, washing the organic phases with distilled water for 3 times, washing with saturated brine for 1 time, drying with anhydrous sodium sulfate, filtering, concentrating, and separating the residue by column chromatography (20-60% ethyl acetate/petroleum ether) to obtain a compound of formula 4 (253mg, yield of 41%), wherein Rf is 0.33 (40% ethyl acetate/petroleum ether).
Through the test:1H NMR(300MHz,Chloroform-d)δ10.41(s,1H),7.42(s,1H),7.31(br s,5H),6.55(s,1H),6.42(s,1H),5.06-4.96(m,2H),4.63–4.53(m,1H),3.96(s,3H),3.79(s,6H),3.74(s,3H),3.64(s,3H),3.32–3.01(m,3H),2.83–2.62(m,1H),2.08(tt,J=28.4,14.5Hz,2H),1.56(d,J=5.9Hz,3H)ppm;
13C NMR(125MHz,CDCl3)δ187.5,162.9,157.4,156.5,155.7,153.8,149.1,148.4,145.7,140.4,139.4,136.7,136.3,132.6,128.6(2C),128.4(3C),126.9,119.2,118.0,117.2,116.1,108.3,102.2,101.3,76.2,73.9,61.6,61.1,56.3(2C),30.8,23.9,23.1,20.8ppm;
HRMS(EI):m/z calcd for[M]+:640.2308,found:640.2314。
example 6: preparation of the Compound of formula 2
Dissolving a compound (301.8mg,0.471mmol) of a formula 4 in a mixed solvent of acetonitrile (15ml) and distilled water (3ml), adding sodium dihydrogen phosphate dihydrate (29.4mg,0.18mmol), hydrogen peroxide (106ul, 30% v/v,0.94mmol) and sodium chlorite (85mg,0.94mmol) at 0 ℃, stirring and reacting for 2 hours at 0 ℃ after the addition is finished, and then continuing to react for 4 hours at room temperature to obtain an oxidation product;
directly dissolving the obtained oxidation product in dry dichloromethane (10ml), adding N, N-dimethylformamide (20ul,0.26mmol) and oxalyl chloride (99ul,1.17mmol) at 0 ℃, reacting at room temperature for 1 hour, reacting for 1 hour, finishing the reaction, and removing the solvent to obtain an acyl chloride intermediate;
the resulting acid chloride intermediate was directly dissolved in hexafluoroisopropanol (2.5ml) under nitrogen protection, reacted at room temperature for 3 hours, the reaction was terminated, hexafluoroisopropanol was removed by concentration under reduced pressure, and the residue was separated by column chromatography (40% ethyl acetate/petroleum ether-50% ethyl acetate/petroleum ether + 10% ethyl acetate/dichloromethane) to give a compound of formula 2 (123mg, yield 41%) with Rf ═ 0.21 (50% ethyl acetate/petroleum ether).
Through the test:1H NMR(500MHz,Chloroform-d)δ7.71(d,J=1.6Hz,1H),7.55–7.31(m,5H),6.83(s,1H),5.26–5.15(m,2H),4.67–4.56(m,1H),4.03(s,3H),4.02(s,3H),3.77(s,6H),3.68(s,3H),3.42–3.19(m,2H),3.13(ddd,J=24.9,15.8,3.2Hz,1H),2.77(dd,J=16.7,11.8Hz,1H),2.23–2.12(m,1H),2.10–1.98(m,1H),1.58(d,J=6.2Hz,3H)ppm;
13C NMR(125MHz,CDCl3)δ174.8,162.7,157.0,154.9,154.6,150.7,150.5,148.0,146.9,140.2,140.0,138.6,137.0,133.0,128.5(4c),128.4,126.3,120.7,117.1,115.9,115.0,105.7,99.2,76.3,73.9,62.5,62.1,61.2,56.6,56.3,31.0,23.8,23.7,20.8;
HRMS(m/z):ESI[M+H]+calcd for 639.2225,Found[M+H]+:629.2223。
example 6: preparation of the Compound of formula 1, a Glycosyl ligand of calicheaxanthomycin A
Step 1): preparing a compound of formula 3:
under the protection of nitrogen, dissolving the compound of formula 2 (46mg,0.072mmol,1.0equiv.) in 10ml of dichloromethane, slowly adding boron trichloride (360 μ l,1.0M in dichloromethane, 0.36mmol,5.0equiv.) dropwise at-78 ℃, reacting at room temperature for 2 hours after the dropwise addition is finished, ending the reaction, cooling to 0 ℃, adding 2ml of distilled water to quench the reaction, separating liquid, washing an organic phase with a saturated sodium chloride solution for 1 time, drying with anhydrous sodium sulfate, filtering, concentrating, and separating a residue by column chromatography (1% dichloromethane/methanol) to obtain the compound of formula 3 (26.1mg, the yield is 69%), Rf 0.22 (4% dichloromethane/methanol).
Through the test:1H NMR(400MHz,Chloroform-d)δ13.09(s,1H),11.85(s,1H),7.50(s,1H),6.93(s,1H),5.56(s,1H),4.72(br s,1H),4.03(s,3H),3.98(s,3H),3.69(s,3H),3.37(s,1H),3.20(br s,2H),2.88–2.72(m,1H),2.22(br s,2H),1.59(d,J=6.3Hz,3H)ppm;
13C NMR(125MHz,CDCl3)δ180.5,170.3,155.9,151.8,151.4,147.1,145.1,143.3,142.3,135.2,134.9,131.7,130.2,125.0,120.4,113.5,113.4,107.0,104.7,99.4.,75.8,61.4,56.6,56.4,29.7,23.2,22.8,20.9ppm;
HRMS(m/z):ESI[M+H]+calcd for 521.1442,Found[M+H]+:521.1434。
step 2): preparing a compound of formula 1, a calicheamicin a glycosyl ligand:
dissolving a compound (15.6mg,0.03mmol) of formula 3 in a mixed solution of acetonitrile and water (6ml, volume ratio is 5:1), adding iodobenzene bistrifluoroacetate (76.5mg,0.18mmol) at 0 ℃, reacting for 1 hour at 0 ℃, then reacting for 1 hour at room temperature after the addition is finished, finishing the reaction, adding sodium hydrosulfite to quench the reaction, decompressing and concentrating the reaction liquid to remove excessive acetonitrile, extracting the residue three times with ethyl acetate (5ml), combining organic phases, washing the organic phases for 1 time with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, separating the residue with a TLC plate (3% dichloromethane/methanol) to obtain a compound (2.8mg, 19%,) of formula 1, wherein Rf is 0.22 (4% dichloromethane/methanol).
Through the test:1H NMR(500MHz,DMSO-d6)δ13.02(s,1H),11.33(br s,1H),9.15(s,1H),8.55(s,1H),7.52(s,1H),7.21(s,1H),4.78(s,1H),4.00(s,3H),3.91(s,3H),3.44–3.36(m,1H),3.22(d,J=17.1Hz,1H),2.72(dd,J=16.9,11.6Hz,1H),2.40–2.32(m,1H),2.21–2.06(m,2H),1.49(d,J=6.3Hz,3H).13C NMR(125MHz,CDCl3)δ185.6,175.7,161.3,157.1,155.7,152.0,149.6,146.2,143.2,141.8,137.5,135.9,134.7,131.0,124.2,118.4,117.7,111.7,109.3,105.3,80.8,61.7,61.1,45.3,34.2,28.4,25.78;
HRMS(m/z):ESI[M+H]+calcd for 507.1286,Found[M+H]+:507.1280。
the prepared carixanthomycin A glycosyl ligand is subjected to glycosylation reaction according to a conventional method to obtain the carixanthomycin A, and the glycosylation reaction belongs to a relatively mature technology, so that the detailed description of the invention is omitted.
In conclusion, the kallidamycin A glycosyl ligand is provided, kallidamycin A can be prepared by using the kallidamycin A glycosyl ligand, a reference basis is provided for the chemical synthesis of the kallidamycin A, and the preparation method has the advantages of simple operation, safety, no pollution, no special requirement on equipment, low production cost and the like, and has significant progress compared with the prior art; in addition, the carixanthomycin A glycosyl ligand provided by the invention has more modifiable sites, and intermediate compounds shown in formulas 2, 4, 5 and 7 and the like generated in the process of preparing the carixanthomycin A glycosyl ligand, and provides a new chemical synthesis direction for derivatives of the carixanthomycin A or other natural products with similar structures.
Finally, it should be pointed out here that: the above is only a part of the preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention, and the insubstantial modifications and adaptations of the present invention by those skilled in the art based on the above description are intended to be covered by the present invention.
Claims (5)
1. A preparation method of carixanthomycin A glycosyl ligand is characterized in that the carixanthomycin A glycosyl ligand has a chemical structure shown in a formula 1, and the preparation method comprises the following steps (2) or steps (1) to (2) in a synthetic route:
the compound of the formula 2 is selectively removed of carbonyl ortho methyl and benzyl in the compound of the formula 2 under the action of Lewis acid to obtain a compound of the formula 3 in the step (1); the compound in the formula (3) is selectively removed from the methyl group at the para position of the phenolic hydroxyl group in the compound in the formula (3) under the action of a dealkylation reagent to obtain the compound in the formula (1);
in the step (1), the Lewis acid is boron trifluoride, and a compound shown in a formula 2: the molar ratio of Lewis acid is 1: (3-8);
in the step (2), the dealkylation reagent is iodobenzene bistrifluoroacetate, and the compound shown in the formula 3: the molar ratio of dealkylating agent is 1: (4-8).
2. The method of claim 1, wherein the compound of formula 2 is prepared by the following steps: the compound of formula 4 is firstly subjected to oxidation reaction until aldehyde group in the compound of formula 4 is oxidized into carboxyl to obtain an oxidation product, and the oxidation product is subjected to intramolecular Friedel-crafts acylation reaction to obtain the compound of formula 2, wherein the chemical reaction formula is as follows:
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