CN115043700A - Intermediate for preparing eribulin and preparation method thereof - Google Patents
Intermediate for preparing eribulin and preparation method thereof Download PDFInfo
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- CN115043700A CN115043700A CN202210580144.3A CN202210580144A CN115043700A CN 115043700 A CN115043700 A CN 115043700A CN 202210580144 A CN202210580144 A CN 202210580144A CN 115043700 A CN115043700 A CN 115043700A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 229960003649 eribulin Drugs 0.000 title claims abstract description 20
- 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
- 150000001875 compounds Chemical class 0.000 claims abstract description 233
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 34
- 125000003118 aryl group Chemical group 0.000 claims abstract description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 108
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 239000007800 oxidant agent Substances 0.000 claims description 23
- 230000009471 action Effects 0.000 claims description 22
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 21
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- 239000003960 organic solvent Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 14
- 238000005811 Corey-Fuchs synthesis reaction Methods 0.000 claims description 14
- 229910052740 iodine Inorganic materials 0.000 claims description 14
- 239000011630 iodine Substances 0.000 claims description 14
- 238000006722 reduction reaction Methods 0.000 claims description 14
- 230000001590 oxidative effect Effects 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 10
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical group C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 10
- 238000007259 addition reaction Methods 0.000 claims description 9
- 238000003379 elimination reaction Methods 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 8
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- 239000002841 Lewis acid Substances 0.000 claims description 7
- 150000007517 lewis acids Chemical class 0.000 claims description 7
- 235000009518 sodium iodide Nutrition 0.000 claims description 7
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 6
- 238000007112 amidation reaction Methods 0.000 claims description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 6
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 229910000043 hydrogen iodide Inorganic materials 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 5
- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical compound [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 235000011054 acetic acid Nutrition 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 235000011148 calcium chloride Nutrition 0.000 claims description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 235000011147 magnesium chloride Nutrition 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims 6
- 229910000085 borane Inorganic materials 0.000 claims 3
- 238000006192 iodination reaction Methods 0.000 claims 2
- 238000006467 substitution reaction Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 80
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 238000004809 thin layer chromatography Methods 0.000 description 34
- 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 21
- 238000010791 quenching Methods 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 15
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 14
- 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 14
- -1 lithium aluminum hydride Chemical compound 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000007858 starting material Substances 0.000 description 9
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical group CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 230000002083 iodinating effect Effects 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 150000001345 alkine derivatives Chemical class 0.000 description 5
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 5
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 229940118951 halaven Drugs 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 206010055113 Breast cancer metastatic Diseases 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 125000005366 cycloalkylthio group Chemical group 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-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
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 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
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 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
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 241000353756 Halichondria okadai Species 0.000 description 1
- 229930195695 Halichondrin Natural products 0.000 description 1
- 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 1
- 206010021143 Hypoxia Diseases 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical class CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 description 1
- 208000032594 Vascular Remodeling Diseases 0.000 description 1
- OZQXEOSNFMMMRD-UHFFFAOYSA-M [Cl-].CC(C)[Mg+].C1CCOC1 Chemical compound [Cl-].CC(C)[Mg+].C1CCOC1 OZQXEOSNFMMMRD-UHFFFAOYSA-M 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000004645 aluminates Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical group ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- AXAZMDOAUQTMOW-UHFFFAOYSA-N dimethylzinc Chemical compound C[Zn]C AXAZMDOAUQTMOW-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 229960000439 eribulin mesylate Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 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 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor 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
- 239000003446 ligand Substances 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 230000008880 microtubule cytoskeleton organization Effects 0.000 description 1
- 230000001617 migratory effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 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
- 239000002547 new drug Substances 0.000 description 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 150000003839 salts Chemical class 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
- 238000011519 second-line treatment Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 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
- 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 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/013—Preparation of halogenated hydrocarbons by addition of halogens
- C07C17/04—Preparation of halogenated hydrocarbons by addition of halogens to unsaturated halogenated hydrocarbons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to a preparation method of an eribulin intermediate. In particular, the invention relates to a compound shown as a formula III, a formula IV or a formula X, wherein R is 1 Is alkyl, or substituted or unsubstituted aryl. The invention also particularly relates to a preparation method of the compound shown as the formula III, the formula IV or the formula X, and the method has mild reaction conditionsSimple operation, low synthesis cost and the like, and is suitable for large-scale production.
Description
Technical Field
The invention relates to an intermediate for preparing eribulin and a preparation method thereof.
Background
Eribulin (shown as formula I) is a derivative for optimizing the structure of macrolide compound halichondrin B extracted from marine natural product Halichondria okadai, and is a halichondrin microtubule dynamics inhibitor. Since the first FDA approval of eribulin mesylate (Halaven) injection for the treatment of metastatic breast cancer patients who received at least two chemotherapy regimens in 2010, 11/15 days, the wei material company has actively developed a new indication for eribulin. The FDA approved for second-line treatment of nonsurgical resection or metastatic liposarcoma at 28/1/2016, and became the first new anticancer agent worldwide that could significantly prolong the survival of patients with advanced soft tissue sarcoma. The drug is currently approved for the treatment of metastatic breast cancer in more than 60 countries worldwide, and for unresectable or metastatic soft tissue sarcoma in the united states, japan and the european union. In addition, waive also filed new drug applications by Halaven for the treatment of locally advanced or metastatic breast cancer in 2016 to the central office of food and drug administration in china. Recent non-clinical and transformation studies have shown that, in addition to having antimitotic effects, Halaven is able to induce tumor vascular remodeling in advanced breast cancer tumor tissues, increase vascular perfusion and permeability in the core region of the tumor, and decrease the degree of hypoxia in the tumor microenvironment. In addition, Halaven can improve the state of epithelial cells and reduce the migratory capacity of breast cancer cells.
The compound shown in formula II is an important chiral small fragment for synthesizing eribulin, by which eribulin can be synthesized in a convergent manner, thereby reducing the number of linear reaction steps and improving the synthesis efficiency (Organic letters,2002,4,4435, 4438; Journal of the American Chemical Society,2009,131, 15636-. Therefore, the synthesis of this compound attracts many synthetic chemists' attention.
The Kishi project group at Harvard university used benzyl-protected chiral alkynes to synthesize compound II in 2002 (org. Lett.2002,4, 4435-4438). The use of expensive B-I-9-BBN is required during the iodine addition. Although the synthetic route of the raw material alkyne is not disclosed in the literature, obviously, the alkyne cannot be purchased from the market at a relatively low price, and the hydroxyl protecting group is changed for many times in the route, so that the total efficiency of the synthesis is reduced, and the alkyne is not suitable for large-scale production.
The Kishi project group subsequently published two additional synthetic routes in 2009 (JACS 2009,131, 15636-H15641). One of the two needs to adopt a specially synthesized chiral ligand and a dangerous dimethyl zinc reagent, and the ee value of the obtained product is only 98 percent. The other route requires the use of hazardous trimethylaluminum reagents and the final step of enzymatic resolution to obtain the chiral product, resulting in loss of overall yield.
Alphora, Canada, discloses a route to the TBDPS group in patent (WO2013078559A1) and repeated replacement of the hydroxyl protecting group still exists. Meanwhile, the reaction route uses a low-temperature condition lower than-65 ℃ in the ester reduction process; the cost of reagent B-I-9-BBN in the iodine addition process is also very high and is not available in large quantities on the market.
In summary, the synthesis method of the compound of formula II reported in the above publication is not only harsh in reaction conditions, tedious in steps, and high in synthesis cost, but also has potential safety hazards, and is not suitable for large-scale production.
Disclosure of Invention
Aiming at the defects of the existing synthetic method of eribulin key intermediate shown as formula II, the invention provides a new eribulin intermediate and a synthetic method thereof, and the route directly adopts substituted sulfonate with leaving effect as a hydroxyl protecting group, thereby avoiding frequent replacement of the protecting group in the overall process and improving the synthetic efficiency; provides a mild method for synthesizing aldehyde, eliminates harsh low-temperature conditions; the alkyne is mildly obtained by adopting Corey-Fuchs reaction and elimination reaction under the alkaline condition, so that the use of dangerous diazotization reagent is avoided; in the iodine addition step, a very cheap iodine reagent is adopted, and the use of a very expensive B-I-9-BBN reagent is avoided. The method has the advantages of simple whole reaction route, mild conditions, simple and convenient operation and low synthesis cost, and is suitable for large-scale production and synthesis of eribulin intermediates shown in formula II.
The invention provides an eribulin intermediate shown in a synthetic formula (II) and a novel preparation method thereof,
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl;
R 2 is hydrogen, alkyl, or substituted or unsubstituted aryl.
Specifically, the synthesis method comprises the following steps:
1) carrying out a reduction reaction on the compound shown as the formula VI under the condition of a reducing agent to obtain a compound shown as a formula V;
2) the compound of the formula V is subjected to a Corey-Fuchs reaction under the action of carbon tetrabromide and triphenylphosphine to obtain a compound shown as a formula IV;
3) the compound shown in the formula IV undergoes elimination reaction under the action of alkali to obtain a compound shown in a formula III;
4) carrying out iodine addition reaction on the compound of the formula III under the action of an iodinating reagent to obtain a compound shown as a formula IX;
5) carrying out nucleophilic substitution reaction on the compound of the formula IX under the action of an iodinating reagent to obtain a compound shown as a formula II;
wherein, the compound VI can be prepared according to the literature (Chemistry-A European Journal,2010,16, 11530-11534).
In a preferred embodiment of the invention, R 1 Is p-methylphenyl; r 2 Is methyl.
The invention also provides another eribulin intermediate shown in the synthetic formula (II) and a novel preparation method thereof,
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl;
R 2 is hydrogen, alkyl, or substituted or unsubstituted aryl;
R 3 and R 4 Independently is alkyl or alkyloxy, or R 3 ，R 4 Form a cyclic structure containing 1-3 heteroatoms with the attached N atom.
Specifically, the synthesis method comprises the following steps:
1) carrying out amidation reaction on the compound shown as the formula VI and substituted amine to obtain a compound shown as a formula VII;
2) carrying out a reduction reaction on the compound shown as the formula VII under the action of a reducing agent to obtain a compound shown as a formula V;
3) the compound of the formula V is subjected to a Corey-Fuchs reaction under the action of carbon tetrabromide and triphenylphosphine to obtain a compound shown as a formula IV;
4) the compound shown in the formula IV undergoes elimination reaction under the action of alkali to obtain a compound shown in a formula III;
5) carrying out iodine addition reaction on the compound of the formula III under the action of an iodinating reagent to obtain a compound shown as a formula IX;
6) carrying out nucleophilic substitution reaction on the compound of the formula IX under the action of an iodinating reagent to obtain a compound shown as a formula II;
among them, the compound VI can be prepared according to the literature (Chemistry-A European Journal,2010,16, 11530-11534).
In a preferred embodiment of the invention, R 1 Is p-methylphenyl; r 2 Is methyl; r 3 Is methyl; r 4 Is methoxy.
The invention also provides another eribulin intermediate shown in the synthetic formula (II) and a novel preparation method thereof,
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl;
R 2 is hydrogen, alkyl, or substituted or unsubstituted aryl.
Specifically, the synthesis method comprises the following steps:
1) carrying out a reduction reaction under the action of a compound reducing agent shown as a formula VI to obtain a compound shown as a formula VIII;
2) the compound shown as the formula VIII is subjected to oxidation reaction under the action of an oxidant to obtain a compound shown as a formula V;
3) the compound of the formula V is subjected to a Corey-Fuchs reaction under the action of carbon tetrabromide and triphenylphosphine to obtain a compound shown as a formula IV;
4) the compound shown in the formula IV undergoes elimination reaction under the action of alkali to obtain a compound shown in a formula III;
5) carrying out iodine addition reaction on the compound of the formula III under the action of an iodinating reagent to obtain a compound shown as a formula IX;
6) carrying out nucleophilic substitution reaction on the compound of the formula IX under the action of an iodinating reagent to obtain a compound shown as a formula II;
wherein, the compound VI can be prepared according to the literature (Chemistry-A European Journal,2010,16, 11530-11534).
In a preferred embodiment of the invention, R 1 Is p-methylphenyl; r is 2 Is methyl.
The invention also provides another eribulin intermediate shown in the synthetic formula (II) and a novel preparation method thereof,
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl;
R 2 is hydrogen, alkyl, or substituted or unsubstituted aryl.
Specifically, the synthesis method comprises the following steps:
1) carrying out a reduction reaction under the action of a compound reducing agent shown as a formula VI to obtain a compound shown as a formula VIII;
2) the compound shown as the formula VIII is subjected to oxidation reaction under the action of an oxidant to obtain a compound shown as a formula V;
3) the compound of the formula V is subjected to a Corey-Fuchs reaction under the action of carbon tetrabromide and triphenylphosphine to obtain a compound shown as a formula IV;
4) the compound shown in the formula IV undergoes elimination reaction under the action of alkali to obtain a compound shown in a formula III;
5) carrying out nucleophilic substitution reaction on the compound of the formula III under the action of an iodinating reagent to obtain a compound shown as a formula X;
6) reacting the compound in the formula X with an iodinating reagent to perform iodine addition reaction to obtain a compound shown in a formula II;
wherein, the compound VI can be prepared according to the literature (Chemistry-A European Journal,2010,16, 11530-11534).
In a preferred embodiment of the invention, R 1 Is p-methylphenyl; r 2 Is a methyl group.
The invention also provides another eribulin intermediate shown in the synthetic formula (II) and a novel preparation method thereof,
in a preferred embodiment of the present invention, the method comprises the following steps:
dissolving X, iodide and TMSCl in an organic solvent, reacting at 20-90 ℃, stirring for 1-24 hours, detecting by TLC to complete the reaction, adding saturated sodium bicarbonate aqueous solution to quench the reaction, extracting by ethyl acetate, concentrating and purifying to obtain a compound II.
In the scheme, the iodide is preferably selected from hydrogen iodide, lithium iodide, sodium iodide, potassium iodide, tetraethylammonium iodide, tetrabutylammonium iodide and the like;
in the scheme, the organic solvent is preferably acetonitrile, ethyl acetate, dimethylformamide, toluene, tetrahydrofuran, acetone, 2-butanone and the like.
The invention also provides a compound shown as the formula X,
the invention also provides a preparation method of the compound shown in the formula X, wherein the compound X is prepared by nucleophilic substitution reaction of the compound shown in the formula III under the condition of iodide;
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl.
In a preferred embodiment of the present invention, the method comprises the following steps:
dissolving a compound III and an iodide in an organic solvent, stirring for 2-24 h in an oil bath at 30-120 ℃, cooling to room temperature after TLC detection reaction is completed, adding water for quenching reaction, extracting with ethyl acetate, concentrating and purifying to obtain a compound X.
In the scheme, the iodide is preferably selected from hydrogen iodide, lithium iodide, sodium iodide, potassium iodide, tetraethylammonium iodide, tetrabutylammonium iodide and the like;
the organic solvent in the scheme is preferably acetone, 2-butanone, tetrahydrofuran, methyl tert-butyl ether, dimethylformamide, dimethylacetamide, toluene, ethyl acetate, acetonitrile and the like.
The invention also provides a preparation method of the compound shown in the formula IX, wherein the compound IX is prepared by the compound shown in the formula III through iodine addition reaction;
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl.
In a preferred embodiment of the present invention, the method comprises the following steps:
dissolving III, iodide and TMSCl in an organic solvent, reacting at 20-90 ℃ for 1-24 hours under stirring, detecting by TLC to complete the reaction, adding saturated sodium bicarbonate aqueous solution to quench the reaction, extracting with ethyl acetate, concentrating and purifying to obtain a compound IX.
In the scheme, the iodide is preferably hydrogen iodide, lithium iodide, sodium iodide, potassium iodide, tetraethylammonium iodide, tetrabutylammonium iodide and the like.
The invention also provides a compound shown as the formula III,
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl.
In a preferred embodiment of the invention, R 1 Is p-methylphenyl.
The invention also provides a preparation method of the compound shown in the formula III, the compound shown in the formula III is prepared by the elimination reaction of the compound shown in the formula IV,
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl.
In a preferred embodiment of the present invention, the method comprises the following steps:
dissolving a compound IV in THF, adding alkali at-50-20 ℃, and continuously stirring for 1-6 h at-40-60 ℃ for reaction. And (3) detecting the reaction by TLC (thin layer chromatography), adding saturated aqueous sodium bicarbonate solution to quench the reaction, extracting with ethyl acetate, concentrating and purifying to obtain a compound III.
The base in this embodiment is preferably butyllithium, lithium diisopropylamide, tetrabutylammonium fluoride, cesium carbonate, potassium carbonate, DBU, or the like.
The invention also provides a compound shown as the formula IV,
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl.
In a preferred embodiment of the invention, R 1 Is p-methylphenyl.
The invention also provides a preparation method of the compound shown in the formula IV, the compound IV is prepared by the compound shown in the formula V through the Corey-Fuchs reaction,
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl.
In a preferred embodiment of the present invention, the method comprises the following steps:
dissolving triphenylphosphine into a dichloromethane solution, adding carbon tetrabromide at one time, reacting at-30-0 ℃, stirring for 20 min-2 h, adding a dichloromethane solution of a compound V, reacting at-20-30 ℃, stirring for 30 min-3 h, detecting by TLC for complete reaction, adding water, quenching, extracting with ethyl acetate, concentrating, and purifying to obtain a compound IV.
The invention also provides a compound shown as the formula VII,
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl;
R 3 and R 4 Independently is alkyl or alkyloxy, or R 3 ，R 4 Form a cyclic structure containing 1-3 heteroatoms with the attached N atom.
In a preferred embodiment of the invention, R 1 Is p-methylphenyl; r is 3 Is methyl; r 4 Is methoxy.
The invention also provides a preparation method of the compound shown in the formula V, the compound shown in the formula VII is prepared by carrying out amidation reaction on the compound shown in the formula VI,
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl;
R 2 is hydrogen, alkyl, or substituted or unsubstituted aryl;
R 3 and R 4 Independently is alkyl or alkyloxy, or R 3 ，R 4 Form a cyclic structure containing 1-3 heteroatoms with the attached N atom.
In a preferred embodiment of the present invention, the method comprises the following steps:
weighing VI and MeONHME or chemically acceptable salts thereof into a flask, adding an organic solvent for suspension, and adding a base into the mixture at the temperature of-30-80 ℃. After the reaction is stirred for 30 min-12 h at-30-80 ℃, TLC shows that the raw materials are completely converted. Adding saturated ammonium chloride aqueous solution to quench reaction, extracting with ethyl acetate, concentrating and purifying to obtain a compound VII.
The base in the scheme is preferably trimethylaluminum, diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, isopropylmagnesium chloride, isopropylmagnesium bromide, diisopropyllithium amide and the like;
the organic solvent in this embodiment is preferably THF, DMF or toluene.
The invention also provides a preparation method of the compound shown as the formula IV, which is characterized by comprising the following steps:
1) carrying out reduction reaction on the compound shown as the formula VI to obtain a compound shown as the formula V;
2) carrying out Corey-Fuchs reaction on the compound shown in the formula V to obtain a compound shown in a formula IV;
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl;
R 2 is hydrogen, alkyl, or substituted or unsubstituted aryl.
In a preferred embodiment of the present invention, the step 1) is:
dissolving a compound VI in an organic solvent, slowly dripping a reducing agent, and controlling the internal temperature of the system to be-65 to-30 ℃ in the dripping process. After the addition is finished, the reaction is continuously stirred for 30 min-2 h at the temperature. And (3) after TLC detection reaction is completed, quenching, extracting with ethyl acetate, concentrating and purifying to obtain a compound V.
In the scheme, the reducing agent is preferably diisobutylaluminum hydride (DIBAL-H) or lithium aluminum hydride.
In this embodiment, the organic solvent is preferably CH 2 Cl 2 Tetrahydrofuran, acetonitrile.
The invention also provides a preparation method of the compound shown as the formula IV, which is characterized by comprising the following steps:
1) carrying out amidation reaction on the compound shown as the formula VI to obtain a compound shown as the formula VII;
2) carrying out reduction reaction on the compound shown as the formula VII to obtain a compound shown as a formula V;
3) carrying out Corey-Fuchs reaction on the compound shown in the formula V to obtain a compound shown in a formula IV;
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl;
R 2 is hydrogen, alkyl, or substituted or unsubstituted aryl;
R 3 and R 4 Independently is alkyl or alkyloxy, or R 3 ，R 4 Form a cyclic structure containing 1-3 heteroatoms with the attached N atom.
In a preferred embodiment of the present invention, the step 2) is:
dissolving a compound VI in an organic solvent, adding a reducing agent at-30-0 ℃, reacting at-30-25 ℃, stirring for 1-4 h, performing TLC to show that the raw material is completely converted, adding citric acid or sodium hydroxide to quench the reaction, extracting with ethyl acetate, concentrating, and purifying to obtain a compound V.
In the scheme, the organic solvent is preferably dichloromethane, tetrahydrofuran, methyl tert-butyl ether, toluene, n-hexane, n-heptane and the like;
in the scheme, the reducing agent is preferably Dibal-H, lithium aluminum hydride, Red-Al and the like.
The invention also provides a preparation method of the compound shown as the formula IV, which is characterized by comprising the following steps:
1) carrying out reduction reaction on the compound shown as the formula VI to obtain a compound shown as the formula VIII;
2) carrying out oxidation reaction on the compound shown as the formula VIII to obtain a compound shown as a formula V;
3) carrying out Corey-Fuchs reaction on the compound shown in the formula V to obtain a compound shown in a formula IV;
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl;
R 2 is hydrogen, alkyl, or substituted or unsubstituted aryl.
In a preferred embodiment of the present invention, the step 1) is:
dissolving a compound VI and sodium borohydride in an organic solvent, then adding Lewis acid, reacting for 1-8 h at-20-80 ℃, and displaying complete conversion of the raw materials by TLC. And adding water to quench the reaction, separating and extracting by ethyl acetate, concentrating and purifying to obtain the compound VIII.
In the scheme, the organic solvent is preferably tetrahydrofuran, dichloromethane, methyl tert-butyl ether, toluene, 2-methyl-tetrahydrofuran and the like;
the reducing agent described in this scheme is preferably a combination of sodium borohydride and a lewis acid; the Lewis acid is preferably boron trifluoride diethyl etherate, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, butyric acid, calcium dichloride, zinc dichloride, magnesium dichloride and the like.
In another preferred embodiment of the present invention, the step 2) is:
dissolving a compound VIII in an organic solvent, adding an oxidant at 0-40 ℃, reacting at 25-80 ℃, stirring for 1-24 hours, detecting by TLC to complete the reaction, adding water to quench the reaction, extracting by ethyl acetate, concentrating and purifying to obtain a compound V.
The organic solvent in the scheme is preferably dichloromethane, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, acetone, N, N-dimethylformamide, methyl tert-butyl ether and the like;
the oxidant in the scheme is preferably TEMPO-oxidant combination, Dess-Martin oxidant, IBX oxidant, Swern oxidation, sulfur trioxide-pyridine and the like; the oxidizing agent of the TEMPO-oxidizing agent combination is preferably PhI (OAc) 2 、PhI(OCOCF 3 ) 2 、NaClO、NaBrO、FeCl 3 、CuCl、CuCl 2 、CuBr 2 CuBr, CuI, NMO, potassium peroxodisulfate, Oxone, oxygen, and the like.
If commercially available, a portion of the product of the above reaction step may also be used to prepare the compound of formula II in a shorter route; for example, the compound of formula II can be prepared by purchasing intermediates of formula III and formula IV as described above and then following the procedures provided in the above-described method.
In another aspect, the present invention also provides a method for preparing eribulin, comprising preparing a compound of formula II according to the methods provided herein, and then preparing eribulin from the compound of formula II according to known methods, wherein reference is made to the following references: org Lett 2002,4, 4435-4438; j.am.chem.soc.2009,131, 15636-15641; j.am.chem.soc.2009,131, 15387-15393; angew. chem. Intl.Ed.2009,48, 2346-
The terms used in the present invention have the following meanings, unless otherwise stated:
"alkyl" refers to a saturated aliphatic hydrocarbon group, straight and branched chain groups comprising 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo.
The hydroxyl-protecting Groups of the present invention are suitable Groups known in the art for hydroxyl protection, see the literature ("Protective Groups in Organic Synthesis",5 Th Ed.T.W.Greene&p.g.m.wuts).
"aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, more preferably phenyl and naphthyl, most preferably phenyl. The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The substituent in the substituted aryl group in the present invention means a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and the like.
Abbreviation table:
| abbreviations | Full scale |
| OTs | P-toluenesulfonate group |
| DIBAL-H | Diisobutylaluminum hydride |
| Red-Al | Sodium dihydrobis (2-methoxyethoxy) aluminate |
| Me | Methyl radical |
| TEMPO | Tetramethyl piperidine nitroxide |
| DMP | Dess-martin oxidizer |
| IBX | 2-iodoxybenzoic acid |
| PhI(OAc) 2 | Diacetyliodobenzene |
| DMF | N, N-dimethylformamide |
The following table shows the structural formulae of the compounds mentioned in the examples
Detailed Description
The present invention will be explained in detail below with reference to specific examples so that those skilled in the art can more fully understand the present invention, and the specific examples are only for illustrating the technical scheme of the present invention and do not limit the present invention in any way.
Examples 1-3 are syntheses of compounds of formula VIIa
Example 1: preparation of Compound VIIa
VIa (10g, 36.7mmol) and MeONHME & HCl (4.6g) were weighed into a flask, 100mL of THF was added to suspend, and 2.0M isopropyl magnesium chloride-tetrahydrofuran solution (30mL) was slowly added thereto at-30 to 0 ℃. After the reaction is stirred for 30 minutes at the temperature of-30-0 ℃, TLC shows that the raw materials are completely converted. The reaction was quenched by addition of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and purified after concentration to give compound VIIa (10.3 g).
MS(ESI)m/z:302(M+H + )
1 H NMR(400MHz,Chloroform-d)δ7.87–7.73(m,2H),7.36(d,J＝8.2Hz,2H),4.22(dd,J＝9.5,8.2Hz,1H),3.99(dd,J＝9.5,6.1Hz,1H),3.72(s,3H),3.35-3.30(m,1H),3.17(s,3H),2.46(s,3H),1.11(d,J＝7.0Hz,3H).
Example 2: preparation of Compound VIIa
VIa (10g, 36.7mmol), MeONHME & HCl (4.6g) and potassium carbonate (3.2g) were weighed into the flask, added to 100mL DMF and suspended, stirred at 50 ℃ for 6h, TLC indicated complete conversion of the starting material. The reaction was quenched by addition of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and purified after concentration to give compound VIIa (9.8 g).
Example 3: preparation of Compound VIIa
VIa (10g, 36.7mmol), MeONHME (6.5g) and diisopropylethylamine (4.9mL) were weighed into the flask, 200mL of toluene was added, and after stirring at 80 ℃ for 12h, TLC showed complete conversion of the starting material. The reaction was quenched by addition of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and purified after concentration to give compound VIIa (9.6 g).
Examples 4-8 are syntheses of compounds of formula VIIIa
Example 4: preparation of Compound VIIIa
Compound VIa (40g, 147mmol) was dissolved in 400mL tetrahydrofuran, and sodium borohydride solid (10.12g) was added under ice-water bath, followed by boron trifluoride diethyl etherate (30.6mL) added dropwise. The reaction was allowed to warm to room temperature and after 3h, TLC showed complete conversion of starting material. Water was added to quench the reaction, and the mixture was subjected to liquid-separation extraction with ethyl acetate, followed by concentration and purification to give Compound VIIIa (33.3 g).
MS(ESI)m/z:245(M+H + )
1 H NMR(400MHz,Chloroform-d)δ7.88–7.75(m,2H),7.43–7.33(m,2H),4.11–3.95(m,2H),3.64-3.51(m,2H),2.47(s,3H),2.10–1.92(m,1H),1.68-1.66(m,1H),0.94(d,J＝7.0Hz,3H).
Example 5: preparation of Compound VIIIa
Dissolve compound VIa (40g, 147mmol) in 200mL dichloromethane, add sodium borohydride solid (29.3g) at room temperature, then add trifluoroacetic acid (36mL) dropwise, after 6h TLC showed complete conversion of starting material. Water was added to quench the reaction, and the mixture was subjected to liquid separation extraction with ethyl acetate, followed by concentration and purification to obtain Compound VIIIa (32.6 g).
Example 6: preparation of Compound VIIIa
Dissolve compound VIa (40g, 147mmol) in 300mL methyl tert-butyl ether and add borane dimethylsulfide (27mL) at room temperature, after 1h TLC indicated complete conversion of starting material. Water was added to quench the reaction, and the mixture was subjected to liquid-separation extraction with ethyl acetate, followed by concentration and purification to give Compound VIIIa (32.1 g).
Example 7: preparation of Compound VIIIa
Compound VIa (40g, 147mmol) was dissolved in 400mL of toluene, sodium borohydride solid (29.3g) was added at room temperature, followed by calcium dichloride (37.8g), and after 8h of reaction at 60 ℃, TLC showed complete conversion of the starting material. Water was added to quench the reaction, and the mixture was subjected to liquid-separation extraction with ethyl acetate, followed by concentration and purification to give Compound VIIIa (29.7 g).
Example 8: preparation of Compound VIIIa
Dissolve Compound VIa (40g, 147mmol) in 350mL 2-methyl-tetrahydrofuran, add sodium borohydride solid (29.3g) at-20 deg.C, then add acetic acid (32mL) dropwise, after stirring for 2h at 40 deg.C, TLC shows complete conversion of the starting material. Water was added to quench the reaction, and the mixture was subjected to liquid-separation extraction with ethyl acetate, followed by concentration and purification to give Compound VIIIa (31.5 g).
Examples 9-16 Synthesis of Compounds represented by formula Va
Example 9: preparation of Compound Va
Dissolve Compound VIa (23.01g,84.50mmol) in 300mL CH 2 Cl 2 In the process, DIBAL-H n-hexane solution (1.0M,120mL) was slowly added dropwise while controlling the internal temperature of the system to be lower than-65 ℃. After the addition was complete, the reaction was allowed to continue stirring at this temperature for 1 hour. After the TLC detection reaction is completed, potassium sodium tartrate solution is added for quenching, ethyl acetate extraction is carried out, and after concentration, the compound Va (19.5g) is obtained through purification.
MS(ESI)m/z:243(M+H + )
1 H NMR(400MHz，CDCl 3 )：δ9.61(d,J＝0.8Hz,1H),7.79(d,J＝8.3Hz,2H),7.37(d,J＝8.0Hz,2H),4.25(dd,J＝6.2,10.0Hz,1H),4.15(dd,J＝5.6,10.0Hz,1H),2.80-2.71(m,1H),2.46(s,3H),1.17(d,J＝7.4Hz,3H).
Example 10: preparation of Compound Va
Compound VIa (10.3g, 34.2mmol) was dissolved in 100mL of dichloromethane, 1.0M diisobutylaluminum hydride in n-hexane (51mL) was added at-30 deg.C, the reaction was stirred at-30 deg.C for 2h, TLC showed complete conversion of the starting material, the reaction was quenched by addition of aqueous citric acid, extracted with ethyl acetate, and purified after concentration to give Compound Va (7.86 g).
Example 11: preparation of Compound Va
Compound VIIa (30g, 99.6mmol) was dissolved in 100mL of tetrahydrofuran, 1.0M diisobutylaluminum hydride in n-hexane (150mL) was added at 0 deg.C, the reaction was stirred at 25 deg.C for 4h, TLC showed complete conversion of the starting material, the reaction was quenched by addition of aqueous sodium hydroxide, filtered, washed with ethyl acetate, and concentrated to give compound Va (21.7 g).
Example 12: preparation of Compound Va
Compound VIIIa (20g, 82mmol) was dissolved in 200mL of DMSO, IBX oxidant (49.2g) was added at room temperature, the reaction was stirred at 40 ℃ for 4h, TLC checked for completion, water was added to quench the reaction, ethyl acetate was extracted, and compound Va (18.7g) was purified after concentration.
Example 13: preparation of Compound Va
Compound VIIIa (10g, 42mmol) was dissolved in 100mL of dichloromethane, TEMPO (101mg) and NaClO solution (48mL) were added at 0 ℃, the reaction was stirred at room temperature for 1h, TLC detection of completion of the reaction was performed, water was added to quench the reaction, dichloromethane extraction was performed, and compound Va (9.8g) was purified after concentration.
Example 14: preparation of Compound Va
Dissolve Compound VIIIa (16g, 65mmol) in 110mL of dichloromethane, TEMPO (223mg) and PhI (OAc) are added at room temperature 2 (23.03g), the reaction was stirred at 50 ℃ for 6h, TLC checked for completion, quenched with water, and dichloromethaneExtraction with alkane, concentration and purification gave compound Va (14.33 g).
Example 15: preparation of Compound Va
Compound VIIIa (20g, 82mmol) was dissolved in 200mL acetonitrile, TEMPO (223mg) and Oxone (56g) were added at 20 deg.C, the reaction was stirred at 70 deg.C for 8h, TLC detected complete, the reaction was quenched by addition of water, extracted with ethyl acetate, concentrated and purified to give compound Va (14.33 g).
Example 16: preparation of Compound Va
Compound VIIIa (16g, 65mmol) was dissolved in 160mL acetonitrile, TEMPO (358mg) and CuCl (32g) were added at 40 deg.C, the reaction was stirred at 80 deg.C for 24h, TLC checked for completion, water was added to quench the reaction, extracted with ethyl acetate, concentrated and purified to give compound Va (12.7 g).
Example 17: preparation of Compound IVa
Triphenylphosphine (86.6g) was dissolved in 300mL dichloromethane, carbon tetrabromide (76.043g) was added in one portion, after stirring at 30 ℃ for 20 minutes, compound Va (20.5g) in dichloromethane (30mL) was added, the reaction was stirred at-20 ℃ for 3 hours, TLC was performed to detect completion of the reaction, water was added to quench the reaction, ethyl acetate was used for extraction, and compound IVa (25.76g) was purified after concentration.
MS(ESI)m/z:421(M+Na + )
1 H NMR(400MHz，CDCl 3 )：δ7.79(d,J＝8.3Hz,2H),7.36(d,J＝8.0Hz,2H),6.14(d,J＝9.1Hz,1H),3.92(S,1H),3.90(s,1H),2.84-2.75(m,1H),2.46(s,3H),1.04(d,J＝6.9Hz,3H).
Example 18: preparation of Compound IVa
Triphenylphosphine (86.6g) was dissolved in 300mL dichloromethane solution, carbon tetrabromide (76.043g) was added in one portion, after stirring at 10 ℃ for 2h, compound Va (20.5g) in dichloromethane (30mL) was added, the reaction was stirred at 30 ℃ for 30min, TLC was performed to detect completion of the reaction, water was added to quench the reaction, ethyl acetate was used for extraction, and compound IVa (23.86g) was purified after concentration.
Example 19: preparation of Compound IIIa
Compound IVa (25.76g,64.71mmol) was dissolved in 250mL of THF, and an n-hexane solution of n-butyllithium (2.5M,79.8mL) was slowly added dropwise while controlling the internal temperature of the system to be lower than-20 ℃ during the addition. The reaction is continuously stirred for 1h at the temperature of minus 40 to 0 ℃. TLC detection of the reaction was complete, and the reaction was quenched by addition of saturated aqueous sodium bicarbonate, extracted with ethyl acetate, concentrated and purified to give Compound IIIa (13.61 g).
MS(ESI)m/z:261(M+Na + )
1 H NMR(400MHz，CDCl 3 )：δ7.81(d,J＝8.4Hz,2H),7.35(d,J＝8.0Hz,2H),4.03(dd,J＝6.0,9.4Hz,1H),3.88(dd,J＝7.6,9.5Hz,1H),2.83-2.78(m,1H),2.46(s,3H),2.04(d,J＝2.4Hz,1H),1.19(d,J＝6.9Hz,3H).
Example 20: preparation of Compound IIIa
Dissolve compound IVa (25g,62.8mmol) and tetrabutylammonium fluoride (25.3g) in 250mL THF, stir the reaction at 25-60 ℃ for 6 h. TLC detection of the reaction was complete, and the reaction was quenched by addition of saturated aqueous sodium bicarbonate, extracted with ethyl acetate, concentrated and purified to give Compound IIIa (12.73 g).
Example 21: preparation of the Compound IXa
IIIa (13.61g,57.11mmol), sodium iodide (16.3g) and TMSCl (10.5g) were dissolved in 200mL acetonitrile, the reaction was stirred at 30 ℃ for 7 hours, TLC checked for completion, quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, and purified after concentration to give compound IXa (19.66 g).
MS(ESI)m/z:389(M+Na + )
1 H NMR(400MHz，CDCl 3 )：δ7.80(d,J＝8.4Hz,2H),7.35(d,J＝8.4Hz,2H),6.20(dd,J＝1.2Hz,1.2Hz,1H),5.81(d,J＝1.2Hz,1H),3.89-3.86(m,1H),2.45(s,3H),2.36-2.31(m,1H),1.00(d,J＝2.8Hz,3H)
Example 22: preparation of Compound X
Compound IIIa (2.38g, 10mmol) and potassium iodide (21g) were dissolved in acetone (30mL), stirred in an oil bath at 60 ℃ for 24h, after completion of the TLC check reaction, cooled to room temperature, quenched by addition of water, extracted with ethyl acetate, concentrated and purified to give compound X (1.86 g).
1 H NMR(400MHz，CDCl 3 )：δ3.29(dd,J＝9.6Hz,2.4Hz,1H),3.22(dd,J＝9.6Hz,2.8Hz,1H),2.73-2.70(m,1H),2.24(d,J＝2.8Hz,1H,1.31(d,J＝6.4Hz,3H).
Example 23: preparation of Compound II
Compound IXa (25g,68.3mmol) and sodium iodide (15.6g) were dissolved in 150mL of 2-butanone and stirred in an oil bath at 90 ℃ for 18 hours, after completion of the TLC detection reaction, the reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, and purified after concentration to give Compound IIa (19.48 g).
1 H NMR(400MHz，CDCl 3 )：δ6.25-6.15(m,1H),5.86-5.81(m,1H),3.23-3.11(m,2H),2.28-2.21(m,1H),1.17(d,8.0Hz,3H)
Example 24: preparation of Compound II
After dissolving X (19.3g,100mmol), potassium iodide (56g) and TMSCl (23g) in 200mL of toluene and stirring the reaction at 110 ℃ for 12 hours, the completion of the reaction was checked by TLC, and the reaction was quenched by addition of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, concentrated and purified to give Compound II (30.2 g).
Since the present invention has been described in terms of specific embodiments thereof, certain modifications and equivalent variations will be apparent to those of ordinary skill in the art and are intended to be included within the scope of the present invention.
Claims (23)
1. A preparation method of a compound shown as a formula II is characterized in that the compound is prepared by an iodine addition reaction of a compound shown as a formula X under the action of TMSCl, iodide and an organic solvent;
2. the method according to claim 1, wherein the iodide is one or more of hydrogen iodide, lithium iodide, sodium iodide, potassium iodide, tetraethyl ammonium iodide, and tetrabutyl ammonium iodide.
3. The method according to claim 1, wherein the organic solvent is one or more of acetonitrile, ethyl acetate, dimethylformamide, toluene, tetrahydrofuran, acetone, and 2-butanone.
4. A preparation method of a compound shown as a formula II is characterized by comprising the following steps:
1) carrying out amidation reaction on the compound shown as the formula VI to obtain a compound shown as the formula VII;
2) carrying out reduction reaction on the compound shown as the formula VII to obtain a compound shown as a formula V;
3) carrying out Corey-Fuchs reaction on the compound shown in the formula V to obtain a compound shown in a formula IV;
4) carrying out elimination reaction on the compound shown as the formula IV to obtain a compound shown as a formula III;
5) carrying out iodine addition reaction on the compound shown as the formula III to obtain a compound shown as the formula IX;
6) performing iodination reaction on the compound shown in the formula IX to obtain a compound shown in the formula II;
wherein R is 1 Is C 1-6 Alkyl, or substituted or unsubstituted aryl;
R 2 is hydrogen, alkyl, or substituted or unsubstituted aryl;
R 3 and R 4 Independently is alkyl or alkyloxy, or R 3 ，R 4 Form a cyclic structure containing 1-3 heteroatoms with the attached N atom.
5. The process of claim 4, wherein R is a compound of formula II 1 Is substituted or unsubstituted phenyl.
6. Preparation of a compound of formula II according to claim 4Method characterized in that R 2 Is C 1-6 An alkyl group.
7. The process of claim 4, wherein R is a compound of formula II 3 And R 4 Independently is C 1-6 Alkyl or C 1-6 An alkyloxy group.
8. The process of claim 4, wherein R is a compound of formula II 1 Is substituted or unsubstituted phenyl; r 2 Is C 1-6 An alkyl group; r 3 And R 4 Independently is C 1-6 Alkyl or C 1-6 An alkyloxy group.
9. The process of claim 4, wherein R is a compound of formula II 1 Is p-methylphenyl; r 2 Is methyl; r is 3 Is methyl; r 4 Is methoxy.
10. A preparation method of a compound shown as a formula II is characterized by comprising the following steps:
1) the compound shown as the formula VI is subjected to reduction reaction to obtain a compound shown as the formula VIII, and the reduction reaction adopts one or more of borane or sodium borohydride and Lewis acid;
2) the compound shown in the formula VIII is subjected to oxidation reaction to obtain a compound shown in the formula V, wherein the reagent adopted in the oxidation reaction is one or more of TEMPO-oxidant combination, Dess-Martin oxidant, IBX oxidant, Swern oxidant or sulfur trioxide-pyridine;
3) carrying out Corey-Fuchs reaction on the compound shown in the formula V to obtain a compound shown in a formula IV;
4) carrying out elimination reaction on the compound shown as the formula IV to obtain a compound shown as a formula III;
5) carrying out iodine substitution reaction on the compound shown as the formula III to obtain a compound shown as the formula X;
6) the compound shown in the formula X is subjected to iodine addition reaction under the action of TMSCl, iodide and an organic solvent to obtain a compound shown in the formula II, wherein the iodide is one or more of hydrogen iodide, lithium iodide, sodium iodide, potassium iodide, tetraethylammonium iodide and tetrabutylammonium iodide, and the organic solvent is one or more of acetonitrile, ethyl acetate, dimethylformamide, toluene, tetrahydrofuran, acetone and 2-butanone;
wherein R is 1 、R 2 As defined in any one of claims 4-6, 8-9.
11. A preparation method of a compound shown as a formula II is characterized by comprising the following steps:
1) carrying out reduction reaction on the compound shown as the formula VI to obtain a compound shown as the formula VIII;
2) carrying out oxidation reaction on the compound shown as the formula VIII to obtain a compound shown as a formula V;
3) carrying out Corey-Fuchs reaction on the compound shown in the formula V to obtain a compound shown in a formula IV;
4) carrying out elimination reaction on the compound shown as the formula IV to obtain a compound shown as a formula III;
5) carrying out iodine addition reaction on the compound shown as the formula III to obtain a compound shown as the formula IX;
6) performing iodination reaction on the compound shown in the formula IX to obtain a compound shown in the formula II;
wherein R is 1 、R 2 As defined in any one of claims 4-6, 8-9.
12. A method for preparing a compound shown as a formula IV is characterized by comprising the following steps:
1) carrying out amidation reaction on the compound shown as the formula VI to obtain a compound shown as the formula VII;
2) carrying out reduction reaction on the compound shown as the formula VII to obtain a compound shown as a formula V;
3) carrying out Corey-Fuchs reaction on the compound shown in the formula V to obtain a compound shown in a formula IV;
wherein R is 1 、R 2 、R 3 、R 4 As defined in any one of claims 4 to 9.
13. A compound shown as a formula VII is provided,
wherein R is 1 、R 3 And R 4 As defined in any one of claims 4-5, 7-9.
14. A preparation method of a compound shown in a formula VII is characterized in that the compound is prepared by amidation reaction of a compound shown in a formula VI,
wherein R is 1 、R 2 、R 3 、R 4 As defined in any one of claims 4 to 9.
15. A method for preparing a compound shown as a formula IV is characterized by comprising the following steps:
1) carrying out reduction reaction on the compound shown as the formula VI to obtain a compound shown as the formula VIII;
2) carrying out oxidation reaction on the compound shown as the formula VIII to obtain a compound shown as a formula V;
3) carrying out Corey-Fuchs reaction on the compound shown in the formula V to obtain a compound shown in a formula IV;
wherein R is 1 、R 2 As defined in any one of claims 1 to 6, 8 to 9.
16. The method of claim 15, wherein the reduction reaction in step 1) is performed with one or more of borane or a combination of sodium borohydride and a lewis acid as a reducing agent.
17. The method of claim 16, wherein the reducing agent in step 1) is borane.
18. The method according to claim 16, wherein the step 1) comprises using sodium borohydride and a lewis acid selected from boron trifluoride diethyl etherate, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, butyric acid, calcium dichloride, zinc dichloride and magnesium dichloride.
19. The method of claim 18, wherein the lewis acid is one or more of boron trifluoride diethyl etherate, trifluoroacetic acid, calcium dichloride, or acetic acid.
20. The process of claim 15, wherein the oxidation reaction in step 2) is carried out using one or more of a TEMPO-oxidant combination, Dess-Martin oxidant, IBX oxidant, Swern oxidant, or sulfur trioxide-pyridine.
21. The process of claim 20, wherein the oxidizing agent of the TEMPO-oxidizing agent combination is PhI (OAc) 2 、PhI(OCOCF 3 ) 2 、NaClO、NaBrO、FeCl 3 、CuCl、CuCl 2 、CuBr 2 One or more of CuBr, CuI, NMO, potassium peroxodisulfate or Oxone, oxygen.
22. The process of claim 21, wherein the oxidizing agent of the TEMPO-oxidizing agent combination is PhI (OAc) 2 One or more of NaClO, CuCl or Oxone.
23. A method for preparing eribulin, comprising the steps of preparing a compound represented by formula II according to any one of claims 1 to 11; and a step of preparing eribulin via the compound represented by formula III or formula IV.
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| CN104053645A (en) * | 2011-11-30 | 2014-09-17 | 阿方拉研究股份有限公司 | Process for preparation of (3R)-2,4-di-leaving group-3-methylbut-1-ene |
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| CN105330686A (en) * | 2014-07-10 | 2016-02-17 | 上海源力生物技术有限公司 | Preparation method of eribulin intermediate |
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| Title |
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| DAE-SHIK KIM ET AL.: "New Syntheses of E7389 C14-C35 and Halichondrin C14-C38 Building Blocks: Double-Inversion Approach", 《JOURNAL OF AMERICAN CHEMICAL SOCIETY》, vol. 131, pages 15636 - 15641 * |
| R. KARL DIETER ET AL.: "Fe/Cu-Mediated One-Pot Ketone Synthesis", 《TETRAHEDRON》, vol. 61, pages 3221 - 3230 * |
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