CN108341828B - Process for the preparation of eribulin and intermediates thereof - Google Patents
Process for the preparation of eribulin and intermediates thereof Download PDFInfo
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- CN108341828B CN108341828B CN201810063857.6A CN201810063857A CN108341828B CN 108341828 B CN108341828 B CN 108341828B CN 201810063857 A CN201810063857 A CN 201810063857A CN 108341828 B CN108341828 B CN 108341828B
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- 238000000034 method Methods 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 229960003649 eribulin Drugs 0.000 title claims abstract description 12
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 title claims abstract 4
- 239000000543 intermediate Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 145
- -1 p-methoxybenzyl Chemical group 0.000 claims abstract description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 238000005580 one pot reaction Methods 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 230000003301 hydrolyzing effect Effects 0.000 claims description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 2
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 claims description 2
- 229930195695 Halichondrin Natural products 0.000 abstract description 5
- 125000003172 aldehyde group Chemical group 0.000 abstract description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 4
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- UFNVPOGXISZXJD-JBQZKEIOSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-JBQZKEIOSA-N 0.000 description 9
- 150000004714 phosphonium salts Chemical class 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 150000004678 hydrides Chemical class 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000002009 diols Chemical class 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZBLLGPUWGCOJNG-UHFFFAOYSA-N Halichondrin B Natural products CC1CC2(CC(C)C3OC4(CC5OC6C(CC5O4)OC7CC8OC9CCC%10OC(CC(C(C9)C8=C)C%11%12CC%13OC%14C(OC%15CCC(CC(=O)OC7C6C)OC%15C%14O%11)C%13O%12)CC%10=C)CC3O2)OC%16OC(CC1%16)C(O)CC(O)CO ZBLLGPUWGCOJNG-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- FXNFULJVOQMBCW-VZBLNRDYSA-N halichondrin b Chemical compound O([C@@H]1[C@@H](C)[C@@H]2O[C@@H]3C[C@@]4(O[C@H]5[C@@H](C)C[C@@]6(C[C@@H]([C@@H]7O[C@@H](C[C@@H]7O6)[C@@H](O)C[C@@H](O)CO)C)O[C@H]5C4)O[C@@H]3C[C@@H]2O[C@H]1C[C@@H]1C(=C)[C@H](C)C[C@@H](O1)CC[C@H]1C(=C)C[C@@H](O1)CC1)C(=O)C[C@H](O2)CC[C@H]3[C@H]2[C@H](O2)[C@@H]4O[C@@H]5C[C@@]21O[C@@H]5[C@@H]4O3 FXNFULJVOQMBCW-VZBLNRDYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 3
- 238000007248 oxidative elimination reaction Methods 0.000 description 3
- 150000003003 phosphines Chemical class 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 2
- HCKNRHBSGZMOOF-UHFFFAOYSA-N 1-methoxy-2-methylperoxyethane Chemical compound COCCOOC HCKNRHBSGZMOOF-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 235000002597 Solanum melongena Nutrition 0.000 description 2
- 244000061458 Solanum melongena Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical group OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- OSQPUMRCKZAIOZ-UHFFFAOYSA-N carbon dioxide;ethanol Chemical compound CCO.O=C=O OSQPUMRCKZAIOZ-UHFFFAOYSA-N 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
- 238000001816 cooling Methods 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 2
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical class 0.000 description 1
- ACEKLXZRZOWKRY-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,5,5,5-undecafluoropentane-1-sulfonic acid Chemical group OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F ACEKLXZRZOWKRY-UHFFFAOYSA-N 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- QDZRKRKGYLBGRD-UHFFFAOYSA-N 2-bromo-1-phenylpropan-2-ol Chemical compound C(C1=CC=CC=C1)C(C)(O)Br QDZRKRKGYLBGRD-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 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
- 239000005909 Kieselgur Substances 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000004645 aluminates Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 150000008378 aryl ethers Chemical class 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 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
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229960000439 eribulin mesylate Drugs 0.000 description 1
- FGZJXVSDDHVZAH-UHFFFAOYSA-N ethoxyethane silane Chemical compound [SiH4].CCOCC FGZJXVSDDHVZAH-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- UQSQSQZYBQSBJZ-UHFFFAOYSA-M fluorosulfonate Chemical group [O-]S(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-M 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-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
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 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
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 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
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/12—Radicals substituted by oxygen atoms
-
- 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
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a process for the preparation of eribulin and intermediates thereof. In particular, the invention relates to a process for the preparation of compounds of formula 5, R3Selected from aldehyde groups OR OR1N is 0 or 1, R1Is a hydroxyl protecting group, preferably selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, p-methoxybenzyl or benzyl. Also provided are processes for the preparation of compounds of formula 5 useful for the preparation of halichondrin and derivatives thereof, such as eribulin.
Description
Technical Field
The invention relates to a method for preparing eribulin and a method for preparing an intermediate compound of formula 5.
Background
Halichondrin b (halichondrin b) is a natural product with anti-tumor activity, originally isolated from marine sponge black sponges. Eribulin is a first macrocyclic ketone analogue obtained by optimizing the structure of halichondrin B, and is currently marketed in a plurality of countries and used for treating metastatic breast cancer, but the eribulin mesylate injection is complex in structure, contains a plurality of chiral neutrals, and is relatively difficult to synthesize completely.
Therefore, it is necessary to develop a synthetic method for producing eribulin for use as an antitumor agent.
US6214865 and US5436238 report the synthesis of halichondrin and its derivatives using the compound 2, 5-disubstituted (2S,5S) -3-methylene-tetrahydrofuran (compound of formula B-12) as intermediate,
in 2003, L.Quintero et al developed a novel synthesis method of spiroketal compounds from 1,2,5, 6-diisopropylidenetogllucose (Tetrahedron Letters,44, Page 3919-,
CN104024237B discloses a process for obtaining a compound of formula B-12 starting from 1,2,5, 6-diisopropylidene glucose, wherein R is1、R2PG as described in the application text,
WO2014183211 discloses another process for the preparation of a compound of formula B-12 as follows:
disclosure of Invention
The present invention provides a process for preparing a compound of formula 5,
the method comprises the following steps: converting the compound of formula 2 into a compound of formula 4,
wherein R is2Is hydroxy or a Leaving Group (LG), R3Selected from aldehyde groups OR OR1N is 0 or 1, R1Is a hydroxyl protecting group, preferably selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, p-methoxybenzyl or benzyl. Further, the conversion of the compound of formula 2 to the compound of formula 4 may be a one-step process or a multi-step process, which may be performed stepwise, or may be a "one-pot" process or a "one-pot multi-step" process.
In embodiments, the compound of formula 2 undergoes a twisting or Horner-Wadsworth Emmons reaction with a phosphonium salt reagent of formula 9 or analog thereof to form a twisting or Horner-Wadsworth Emmons reaction product compound of formula 3, wherein n, R2、R3As has been described in the foregoing, the present invention,
further, the compound of formula 3 is converted into a compound of formula 4.
In some embodiments, a compound of formula 2a is reacted with a phosphonium salt reagent of formula 9 or an analog thereof to obtain a compound of formula 3a, followed by conversion of the hydroxyl group in the compound of formula 3a to a Leaving Group (LG) and elimination of the leaving group by reaction with a base to obtain a compound of formula 4, wherein n, R3As has been described in the foregoing, the present invention,
in some embodiments, the compound of formula 2b is reacted with a phosphonium salt reagent of formula 9 or the likeReacting the compound of formula 3b to obtain a compound of formula 3b, and subsequently reacting the compound of formula 3b with a base to eliminate said Leaving Group (LG) to obtain a compound of formula 4, wherein LG is a leaving group, n, R3As has been described in the foregoing, the present invention,
in some embodiments, however, the compound of formula 2 may be converted to the compound of formula 2d first,
followed by reaction of the compound of formula 2d with a phosphonium salt reagent of formula 9 or an analog thereof to form a compound of formula 4,
in some embodiments, the compound of formula 2b is first reacted with a base to eliminate the Leaving Group (LG) to obtain a compound of formula 2d, and then reacted with a phosphine salt reagent of formula 9 or an analog thereof to obtain a compound of formula 4, wherein LG is a leaving group and R is3As has been described in the foregoing, the present invention,
in some embodiments, a hydroxyl group in a compound of formula 2a is converted to a Leaving Group (LG), followed by reaction with a base to eliminate the Leaving Group (LG) to obtain a compound of formula 2d, which is then reacted with a phosphine reagent of formula 9 or an analog thereof to obtain a compound of formula 4, wherein LG is a leaving group and R is3As has been described in the foregoing, the present invention,
to obtain the compound of formula 5, in the embodiment of the present invention, the compound of formula 4 according to the present invention needs to be further subjected to a reduction reaction with a hydride source, and the compound of formula 5 can be obtained.
The hydride source of the present invention is well known or determinable to those skilled in the art and is selected from, but not limited to, at least one of lithium aluminum tetrahydride, lithium triethylborohydride, diisobutylaluminum hydride, sodium borohydride, sodium dihydrobis (2-methoxyethoxy) aluminate, hydrogen gas/metal catalyst. Further, the metal catalyst is selected from at least one of palladium carbon, palladium hydroxide, platinum oxide, palladium on alumina, platinum on activated carbon and raney nickel, but is not limited thereto, and preferably is palladium carbon, palladium hydroxide. Furthermore, the reduction reaction by using the hydride source can sequentially and respectively reduce olefin, ester group or deprotection group, and also can be carried out by a one-pot method or a one-pot multi-step method.
In the embodiment, the condition for reducing the double bond or aldehyde group of the olefin in the compound is preferably a metal catalyst/hydrogen condition, which can avoid the use of reducing agents such as lithium aluminum tetrahydride or sodium borohydride and the like, effectively avoid complex and tedious processes after reaction, is suitable for the requirements of large-scale production of the process, and can effectively improve the yield of the whole synthesis process and the quality of the final product.
In an embodiment of the invention, the 5, 6-isopropylidene protecting group in the compound of formula 1 is hydrolyzed and the diol is oxidatively cleaved to obtain the compound of formula 2,
the conditions for hydrolysis of the 5, 6-diisopropylidene protecting group should be known to those skilled in the art or can be determined. In embodiments, for example and without limitation, the 5, 6-isopropylidene protecting group is removed using an acid to produce a diol, which can then be oxidatively cleaved to form the compound of formula 2. The method for the oxidative cleavage of the diol is not particularly limited and should be known to those skilled in the art or can be determined. In embodiments, for example, but not limited to, periodate is usedNaIO4It can also be carried out as described in journal literature Synthesis, 1982, 28-29.
Further, hydrolysis of the 5, 6-diisopropylidene protecting group is carried out under the same reaction conditions as the oxidative cleavage of the diol, in embodiments such as, but not limited to, the removal of the 5, 6-isopropylidene protecting group using n-periodic acid, and the simultaneous oxidative cleavage of the resulting diol, to obtain the compound of formula 2, simplifying the reaction steps and obtaining a higher yield and quality of the compound of formula 2.
The Leaving Group (LG) according to the present invention is a molecular fragment that can function to protect a hydroxyl group or detach from the molecule during a bond breaking step, and is not particularly limited and known to those skilled in the art or can be determined. The ability of a leaving group to leave is related to the pKa of the conjugate acid, with lower Pka being related to better leaving group ability. Examples of leaving group forming include, but are not limited to, halides, which may include Cl, Br, or I; the sulfonic acid group may include, but is not limited to, a perfluorobutylmethanesulfonate group, a trifluoromethanesulfonate group, a fluorosulfonate group, a tosylate group, a methanesulfonate group (methylsulfonate group), or a benzenesulfonate group, preferably a methanesulfonate group and a trifluoromethanesulfonate group.
Bases used to eliminate leaving groups in the present invention are known to or can be determined by those skilled in the art, and in embodiments, elimination of a leaving group is performed using a base to form a compound having an olefinic bond. The base may be selected from, but is not limited to, inorganic bases or organic bases selected from, but is not limited to, tetrabutylammonium fluoride, 1, 8-diazabicycloundec-7-ene (DBU), Dicyclohexylurea (DCU), triethylamine (Et)3N), Diisopropylethylamine (DIPEA), pyridine; the inorganic base may be selected from, but is not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate.
In some embodiments, a method of making a compound of formula 5, comprises: hydrolyzing the 5, 6-isopropylidene group in the compound of formula 1 and oxidatively cleaving the diol to obtain the compound of formula 2, R1，R2As has been described in the foregoing, the present invention,
and then reacting the compound of formula 2 with a phosphine salt reagent of formula 9a or an analog thereof to obtain a compound of formula 3a, followed by converting the compound of formula 3a into a compound of formula 4a,
the compound of formula 4a is then reduced via a hydride source to provide the compound of formula 5.
In some embodiments, a method of making a compound of formula 5, comprises: hydrolyzing and oxidatively cleaving the 5, 6-isopropylidene group in the compound of formula 1a to obtain a compound of formula 2a,
and then reacting the compound of formula 2a with a phosphine salt reagent of formula 9a or the like, converting the hydroxyl group in the resulting 3da compound into a Leaving Group (LG), and reacting with a base to eliminate the Leaving Group (LG) to obtain a compound of formula 4a, wherein R is1As has been described in the foregoing, the present invention,
subsequent reduction of the compound of formula 4a via a hydride source affords the compound of formula 5.
In another embodiment, a method of preparing a compound of formula 5, comprising: hydrolyzing and oxidatively cleaving the 5, 6-isopropylidene in the compound of formula 1b to obtain the aldehyde compound of formula 2b,
reacting the compound of formula 2b with a phosphine reagent of formula 9a or an analog thereof, and then with a base to eliminate the reactionSaid Leaving Group (LG) to obtain a compound of formula 4a, wherein R1As has been described in the foregoing, the present invention,
the compound of formula 4a may then be converted to the compound of formula 5 by reduction with a hydride source.
In some embodiments, a method of making a compound of formula 5, comprises: hydrolyzing and oxidatively cleaving the 5, 6-isopropylidene group in the compound of formula 1a to obtain a compound of formula 2a,
subsequently converting the compound of formula 2a into a compound of formula 2b, i.e. converting the hydroxyl group in the compound of formula 2a into a Leaving Group (LG), and reacting with a base to eliminate the leaving group to obtain a compound of formula 2 d; and reacting the compound of formula 2d with a phosphonium salt reagent of formula 9a or the like to form the compound of formula 4, wherein R is1As has been described in the foregoing, the present invention,
the compound of formula 4 can then be converted to the compound of formula 5 by reduction with a hydride source.
In another embodiment, a method of preparing a compound of formula 5, comprising: hydrolyzing and oxidatively cleaving the 5, 6-isopropylidene in the compound of formula 1b to obtain the aldehyde compound of formula 2b,
then reacting the compound of formula 2b with a base to eliminate said Leaving Group (LG) to obtain a compound of formula 2d, followed by reaction with a phosphonium salt reagent of formula 9a or an analogue thereof to obtain a compound of formula 4a, wherein R is1The formula (I) is as defined above for LG,
the compound of formula 4a may then be converted to the compound of formula 5 by reduction with a hydride source.
Further, the conversion of the compound of formula 4a to the compound of formula 5 may be carried out by the following steps:
the invention also provides compounds of formula I, wherein R2Is hydroxy or a Leaving Group (LG), R3Selected from aldehyde groups OR OR1，R1Is a hydroxyl-protecting group selected, together with the oxygen atom to which it is bound, from the group consisting of silyl ethers, alkyl ethers, arylalkyl ethers and alkoxyalkyl ethers, esters, n-0 or 1,
further, the compounds of formula I have the structure wherein R is1As previously mentioned:
the present invention also provides a compound of formula 4aa having the structure:
wherein R is4Is alkyl or aryl.
Further, the compound of formula 4aa has the following structure:
the compound shown in the formula 1 is a derivative of natural sugar, and is easy to prepare and obtain, in addition, the compound shown in the formula 1 can exist as a single stereoisomer, and products obtained by using the compound shown in the formula 1 as a raw material all have single stereo configuration and high stereoisomer purity.
The compound of formula 5 of the present invention has a single stereoconfiguration with high stereoisomeric purity, preferably has the structure shown in the following, wherein R3As has been described in the foregoing, the present invention,
further, the compound of formula 5 has the structure wherein R is1As has been described in the foregoing, the present invention,
in some embodiments, a method of making eribulin intermediate a compound of formula 5a,
the method comprises the following steps: hydrolyzing and oxidatively cleaving the 5, 6-isopropylidene group in the compound of formula 1a to obtain a compound of formula 2a,
reacting the compound of formula 2a with Ph3P＝CHCO2R4Or an analog thereof, to form a compound of formula 3ac,
the compound of formula 3ac is subsequently converted into a compound of formula 4ac,
hydrogenating the olefinic double bond in the compound of formula 4ac, reducing the ester function to an alcohol, and protecting the resulting alcohol to obtain a compound of formula 5a,
wherein R is1Is a hydroxy protecting group, R4Is alkyl or aryl, and the hydroxyl protecting group is preferably selected from tert-butyl dimethyl silicon base, tert-butyl diphenyl silicon base, p-methoxybenzyl or benzyl. Further, the conversion of the hydroxyl group in the compound of formula 3ac into a Leaving Group (LG), followed by elimination of the Leaving Group (LG) by reaction with a base, to obtain the compound of formula 4ac is carried out by a "one-pot" or "one-pot multi-step" process, as described in example 6.
A process for preparing a compound of formula B-12, comprising the steps of preparing a compound of formula 5 as described above, followed by the steps shown below, wherein the reaction conditions are as described in WO2014183211, and the relevant reaction procedures are incorporated into the present specification,
a process for the preparation of a halichondrin analog, which may be eribulin or a pharmaceutically acceptable salt thereof, comprising the steps of preparing a compound of formula 5 as described above, followed by a process as described in US6214865 and US5436238, and incorporating the relevant reaction procedures into the specification.
A process for the preparation of a halichondrin analog comprising the step of synthesizing a halichondrin analog, which may be eribulin or a pharmaceutically acceptable salt thereof, using a compound of formula I as described above.
Eribulin according to the present invention may be salified with an acid known to or determinable by one skilled in the art selected from the group consisting of, but not limited to, hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, maleic acid, acetic acid, trifluoroacetic acid.
The content or purity of the related substances of the invention is determined by HPLC detection.
The diastereoisomeric excess value (d.e%: diasteroisomeric excess) as described herein refers to the diastereoisomeric excess in a compound having more than two chiral centers, and in embodiments, the d.e% value may be resolved from the nuclear magnetic data for that compound.
Analogs of the phosphonium salt reagent having formula 9 are not particularly limited, and in embodiments, for example, but not limited to, the use of a phosphate reagent (EtO)2P(＝O)-CH2(CH2)n R3Or (EtO)3P＝CH(CH2)n R3Wherein n and R3As previously described.
Ph according to the invention3P＝CHCO2R4In embodiments, for example, but not limited to (EtO)2P(＝O)-CHCO2R4，(EtO)3P＝CHCO2R4Wherein R is4Is alkyl or aryl.
As known to those skilled in the art, the one-pot method or the one-pot multi-step method can be used for directly obtaining molecules with complex structures from relatively simple and easily-obtained raw materials for multi-step reactions without separation of intermediates.
The "hydroxy-protecting Groups" described herein are those known in the art as being suitable for hydroxy-protection, as described in the literature ("Protective Groups in Organic Synthesis", 5th.ed.t.w.greene & p.g.m.wuts). The hydroxy protecting group used in the process for preparing the compound of formula 5 is not limited and is known or determined by the ordinarily skilled artisan, and together with the oxygen atom to which it is bound, forms an ester, ether, silane ether. The ester formed may be ethyl, methyl, benzyl or neopentyl ester; the ether formed may be an alkyl ether, aryl ether, alkoxyalkyl ether selected from, but not limited to, benzyl (Bn), Methoxyethoxymethyl Ether (MEM), p-methoxybenzyl, trityl (Tr), Dimethoxytrityl (DMT), methoxymethyl ether (MOM), or the like; the silyl ether may be tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), Triisopropylsilyloxymethyl (TOM), or Triisopropylsilyl (TIPS); the hydroxyl protecting group is preferably tert-butyldimethylsilyl, tert-butyldiphenylsilyl, p-methoxybenzyl or benzyl.
The length of the alkyl group or the number of atoms in the alkyl or aryl group in the present invention is not particularly limited and should be known to or can be determined by one of ordinary skill in the art. In one embodiment, for example and without limitation, the alkyl group is C1-6Alkyl or aryl-substituted C1-6Alkyl groups such as benzyl. In another embodiment, for example and without limitation, the aryl group is a C6-14And (4) an aryl group.
Term C1-6The alkyl group is not particularly limited and should be known to one of ordinary skill in the art. C1-6Alkyl may be, but is not limited to, any straight or branched chain alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, 1, 2-dimethylpropyl, 2-ethylpropyl, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1, 2-triethylpropyl, 1-dimethylbutyl, 2-dimethylbutyl, 2-ethylbutyl, 1, 3-dimethylbutyl, 2-methylpentyl, or 3-methylpentyl.
The aryl group is not particularly limited and should be known to one of ordinary skill in the art. The term "aryl" refers to an aromatic group having at least one ring with a conjugated pi-electron system and includes carbocyclic aryl, heterocyclic aryl (also known as heteroaryl) and biaryl, all of which may be optionally substituted. Aryl groups may include, for example, but are not limited to, six to fourteen atoms. Examples of aryl groups may include, but are not limited to, phenyl, pyridyl, or naphthyl.
The reagents used in the present invention are commercially available or can be prepared according to the prior art, for example, in CN 104024237B.
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and the spirit and scope of the present invention are not limited thereto.
Example 1
Benzyl bromoethanol (5.00g) was weighed in an eggplant type bottle, dissolved in acetonitrile (50mL), added with triphenylphosphine (9.21g), reacted at about 80 ℃ for 24h, cooled naturally to room temperature, evaporated under reduced pressure to remove the solvent, added with ethyl acetate (50mL), stirred for 30min, filtered, and washed with ethyl acetate to obtain 9.54g of a white solid with a yield of 86% and a purity of 96%.
Example 2
Weighing 9aa (4.76g) of quaternary phosphonium salt in an eggplant-shaped bottle, adding 300mL of anhydrous tetrahydrofuran, putting the reaction solution into dry ice-ethanol for cooling, dropwise adding 2.5M n-BuLi (4mL) into the reaction, keeping the temperature for reaction for 30min after the dropwise adding is finished, dropwise adding 1mL of THF solution of 2d compound (1.32g), stirring for 10min, naturally heating to room temperature, continuing the reaction for 1h, adding water (50mL) for quenching the reaction, evaporating the solvent under reduced pressure, adding 200mL of ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure. Separation and purification by column chromatography gave 1.80g of 4aa as an oily compound in 85% yield.
10mL of methanol and palladium on charcoal (0.33g) were placed in a reaction flask, and Compound C (1.80g) was added to replace hydrogen gas three times in the presence of H2(40Psi) for 24 hours, the reaction mixture was filtered through celite, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column separation to obtain 1.21g of an oily compound D, yield: 91%, purity 98%, d.e.>99.5％。
In a reaction flask, compound D (1.16g) was dissolved in 25mL of dichloromethane, N-lutidine (DMAP, 50mg) and triethylamine (0.80g) were added, tert-butyldiphenylchlorosilane (TBDPSCl, 2.10g) was further added in portions, the reaction was stirred at normal temperature, TLC detected for completion of the reaction, the reaction was quenched with water, diluted with dichloromethane (25mL), washed with water and saturated sodium chloride in this order, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Separation and purification by column chromatography gave 2.34g of compound 5aa, yield: 95%, purity 98%, d.e. > 99.5%.
Example 3
Compound E (10.37g), formylmethylenetriphenylphosphonium (12.21g) and THF (15ml) were weighed in an eggplant type bottle, dissolved and reacted at room temperature for 3 hours, and tetrabutylammonium fluoride trihydrate (36.89g) was added. After reacting for 6h at about 50 ℃, the reaction solution is naturally cooled, concentrated and separated and purified by silica gel column chromatography to obtain 4.66G of oily compound G with the yield of 61 percent and the purity of 95 percent.
100mL of ethanol, Raney nickel (1.66G) and Compound G (3.32G) were placed in a reaction flask, and hydrogen was replaced three times with hydrogen in H2(40Psi) for 24h, filtering through celite, evaporating the solvent under reduced pressure, and purifying by silica gel column separation to obtain 2.94g of oily compound D, yield: 87% and 97% purity d.e.>99.5％。
Example 4
Compound 2d (6.60G) and formylmethylenetriphenylphosphonium (12.22G) were weighed in an eggplant-shaped bottle, dissolved in THF (150 ml), reacted at room temperature for 3 hours, concentrated, and purified by silica gel column chromatography to give an oily compound G5.40G, yield 71%, purity 95%.
Example 5
Weighing 9aa (4.76g) of quaternary phosphonium salt in an eggplant-shaped bottle, adding anhydrous THF (300mL), putting the reaction bottle in a dry ice ethanol bath, stirring for 30min, dropwise adding 2.5M n-BuLi (4mL) into the reaction solution, keeping the temperature and stirring for 30min after dropwise adding, dropwise adding 10mL of THF solution of a raw material E (2.13g), stirring for 10min, naturally heating to about 10 ℃, continuing to react for 1h, adding water (50mL) into the reaction solution to quench the reaction, evaporating the solvent under reduced pressure, adding ethyl acetate (200mL), washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, separating and purifying by a silica gel column to obtain 1.15g of oily compound 4aa-1, wherein the purity is 50% and 97%.
Example 6
Weighing compound 1(20.0g) in a 250mL eggplant-shaped bottle, adding 750mL of anhydrous ethyl acetate, stirring for 10min, adding n-periodic acid (23.2g) at one time, stirring and reacting at 10 ℃ for 4h, performing suction filtration through a sand core funnel, and concentrating the filtrate to obtain 20.0g of brown oily matter which is directly used for the next reaction.
The product of 2a (20.0g, crede) from the previous step was dissolved in anhydrous tetrahydrofuran (400mL) and Wittig reagent Ph was added in one portion3P＝CHCO2Me (31.0g), then stirred at room temperature for 16h, the solvent was removed by evaporation, 400mL of anhydrous ether were added to the residue, stirred for 30min, the solid was removed by filtration, and the filtrate was concentratedThe residue was subjected to silica gel column chromatography to give 15.9g of a reddish brown oil in 85% yield in two steps and 98% purity.
Dissolving the product 3ac-1(14.5g) obtained in the previous step in anhydrous dichloromethane (200mL), cooling in an ice-water bath, adding pyridine (9.5mL), slowly dropwise adding trifluoromethanesulfonic anhydride (12.0mL), stirring at 0 ℃ for 1h after dropwise adding, dropwise adding 1, 8-diazabicycloundeca-7-ene (30mL), removing the ice bath, heating to room temperature, stirring for 15h, and performing silica gel column chromatography on the obtained residue after concentration to obtain 12.5g of colorless oil, the yield is 93%, and the purity is 98%.
The 4ac-1(11.0g) product obtained in the previous step was dissolved in isopropanol (200mL), 10% wet Pd/C (4.1g) was added in one portion, the system was replaced with hydrogen three times, and then the reaction was carried out for 12h while maintaining a hydrogen pressure of 40Psi, palladium on carbon was removed by filtration using celite, and the filtrate was concentrated to obtain 11.2g of an oil with a yield of 100% and a purity of 99%.
In N2Under protection, NaBH is weighed in a three-mouth bottle4(5.0g), ethanol (250ml) was added, cooled to 0-5 ℃ in an ice bath, and CaCl was added with stirring2(5.5g), stirred for 10min, added a tetrahydrofuran (250ml) solution of the compound (10.0g) obtained in the previous step, stirred for 10min after the addition, and stirred at room temperature for 10h after the ice bath was removed. The reaction solution was cooled and quenched by dropwise addition of 10% aqueous NaOH (100 ml). Filtering with thin layer of diatomaceous earth, concentrating the obtained solution to remove ethanol, extracting with ethyl acetate for 3 times, mixing the organic phases, and adding Na2SO4The residue obtained by drying and concentration was subjected to silica gel column chromatography to obtain 8.2g, yield 93% and purity 99%.
Example 7
Weighing Compound E (10.01g), Ph in an eggplant-shaped flask3P＝CHCO2Me (13.83 g) was dissolved by addition of tetrahydrofuran (80mL), and the reaction was stirred at room temperature for 3h, as indicated by TLC. Tetrabutylammonium fluoride trihydrate (35.51g) was added directly to the reaction solution, and the mixture was reacted at about 50 ℃ for 5 hours. The reaction solution was cooled, concentrated, and subjected to column chromatography to give 4 ac-17.33 g of an oily compound. The yield thereof was found to be 86%.
The obtained compound 4ac-1(6.8g) was dissolved in isopropanol (140mL), nitrogen was substituted three times, 10% Pd/C (2.7g) was added thereto, the mixture was stirred at room temperature, hydrogen was introduced into the reaction system to substitute three times, the reaction system was stirred at about 20 ℃ for 20 hours while maintaining the pressure of 40psi, then palladium/carbon was removed by filtration using celite, the filter cake was washed with methanol and dried by spin-drying under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to obtain colorless oily compound K6.71 g, yield 97%, purity 98%.
In N2Under protection, compound K (5.0g) is added with THF (50ml) in an eggplant-shaped bottle, cooled to about 10 ℃ in an ice bath, Lithium Aluminum Hydride (LAH) (1.6g) is slowly added with stirring, the air is obviously discharged, and the mixture is heated to room temperature for reaction for 30min after the addition. TLC showed the reaction was substantially complete. The reaction solution was cooled to about 0 ℃ and 1.6mL of water, 1.6mL of a 15% NaOH aqueous solution and 4.8mL of water were added dropwise thereto, anhydrous sodium sulfate was added to the reaction system, and the mixture was dried, filtered and concentrated, and the residue obtained was subjected to silica gel column chromatography to obtain D4.00 g, yield 91% and purity 98%.
Claims (5)
1. A process for preparing a compound of formula 5a,
the method comprises the following steps: hydrolyzing and oxidatively cleaving the 5, 6-isopropylidene group in the compound of formula 1a to obtain a compound of formula 2a,
reacting the compound of formula 2a with Ph3P＝CHCO2R4Reacting to form a compound of formula 3ac,
the compound of formula 3ac is subsequently converted into a compound of formula 4ac,
hydrogenating the olefinic double bond in the compound of formula 4ac, reducing the ester function to an alcohol, and protecting the resulting alcohol to obtain a compound of formula 5a,
wherein R is1Is a hydroxy protecting group, R4Is alkyl or aryl, and the hydroxyl protecting group is selected from tert-butyl dimethyl silicon base, tert-butyl diphenyl silicon base, p-methoxybenzyl or benzyl.
2. A process according to claim 1 for the preparation of a compound of formula 5a, characterized in that the process comprises: converting the hydroxyl group in the compound of formula 3ac to a leaving group, and subsequently reacting with a base to eliminate the leaving group to form the compound of formula 4 ac.
3. The process for the preparation of the compound of formula 5a according to claim 2, characterized in that the step of converting the compound of formula 3ac to the compound of formula 4ac is carried out in a "one-pot multi-step" manner.
4. A process for the preparation of a compound of formula B-12 comprising the steps of the process according to any one of claims 1 to 3,
5. a process for the preparation of eribulin or a pharmaceutically acceptable salt thereof, comprising the step of the process of any one of claims 1-4.
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