WO2016038624A1 - "process for the preparation of macrocyclic ketone analogs of halichondrin b or pharmaceutically acceptable salts and intermediates thereof" - Google Patents
"process for the preparation of macrocyclic ketone analogs of halichondrin b or pharmaceutically acceptable salts and intermediates thereof" Download PDFInfo
- Publication number
- WO2016038624A1 WO2016038624A1 PCT/IN2015/000354 IN2015000354W WO2016038624A1 WO 2016038624 A1 WO2016038624 A1 WO 2016038624A1 IN 2015000354 W IN2015000354 W IN 2015000354W WO 2016038624 A1 WO2016038624 A1 WO 2016038624A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- vii
- eribulin
- iii
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 65
- 230000008569 process Effects 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 150000003839 salts Chemical class 0.000 title claims abstract description 23
- 239000000543 intermediate Substances 0.000 title abstract description 27
- 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 title abstract description 25
- 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 title abstract description 8
- 150000002576 ketones Chemical class 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 199
- 238000006243 chemical reaction Methods 0.000 claims description 56
- 229960003649 eribulin Drugs 0.000 claims description 32
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 27
- 125000006239 protecting group Chemical group 0.000 claims description 18
- 238000005859 coupling reaction Methods 0.000 claims description 17
- 150000002009 diols Chemical group 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 230000008878 coupling Effects 0.000 claims description 12
- 238000010168 coupling process Methods 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 7
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002346 iodo group Chemical group I* 0.000 claims description 4
- 239000003223 protective agent Substances 0.000 claims description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 4
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 4
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000006405 Nozaki-Hiyama-Kishi reaction Methods 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 230000000640 hydroxylating effect Effects 0.000 claims description 2
- VMESOKCXSYNAKD-UHFFFAOYSA-N n,n-dimethylhydroxylamine Chemical compound CN(C)O VMESOKCXSYNAKD-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims 12
- 239000000126 substance Substances 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound 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 1
- -1 chloro, bromo, fluoro, iodo Chemical group 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- 239000000243 solution Substances 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 24
- 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 22
- 239000000203 mixture Substances 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 239000012300 argon atmosphere Substances 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000008052 alkyl sulfonates Chemical class 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 5
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 4
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 4
- 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 4
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 3
- 229910021554 Chromium(II) chloride Inorganic materials 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229930195695 Halichondrin Natural products 0.000 description 3
- 150000001345 alkine derivatives Chemical class 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 description 3
- 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 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 230000033444 hydroxylation Effects 0.000 description 3
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 3
- 239000003880 polar aprotic solvent Substances 0.000 description 3
- HNDXKIMMSFCCFW-UHFFFAOYSA-M propane-2-sulfonate Chemical compound CC(C)S([O-])(=O)=O HNDXKIMMSFCCFW-UHFFFAOYSA-M 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- 150000003456 sulfonamides Chemical class 0.000 description 3
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 3
- 229940086542 triethylamine Drugs 0.000 description 3
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- 0 C*C1(*)[C@](C[C@]2O[C@@](CC[C@@]3OC(CCCO)CC3=C)C[C@@](C)C2=C)O[C@](CC(*)C*)C1O* Chemical compound C*C1(*)[C@](C[C@]2O[C@@](CC[C@@]3OC(CCCO)CC3=C)C[C@@](C)C2=C)O[C@](CC(*)C*)C1O* 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940072107 ascorbate Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- 238000005828 desilylation reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 150000002440 hydroxy compounds Chemical class 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 2
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 239000011572 manganese Substances 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 2
- 229910052762 osmium Inorganic materials 0.000 description 2
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 2
- 239000012285 osmium tetroxide Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-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
- 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 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 150000003871 sulfonates Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- SODPIMGUZLOIPE-UHFFFAOYSA-N (4-chlorophenoxy)acetic acid Chemical compound OC(=O)COC1=CC=C(Cl)C=C1 SODPIMGUZLOIPE-UHFFFAOYSA-N 0.000 description 1
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 1
- ZOJKRWXDNYZASL-NSCUHMNNSA-N (e)-4-methoxybut-2-enoic acid Chemical compound COC\C=C\C(O)=O ZOJKRWXDNYZASL-NSCUHMNNSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- GPAAEZIXSQCCES-UHFFFAOYSA-N 1-methoxy-2-(2-methoxyethoxymethoxymethoxy)ethane Chemical compound COCCOCOCOCCOC GPAAEZIXSQCCES-UHFFFAOYSA-N 0.000 description 1
- HCKNRHBSGZMOOF-UHFFFAOYSA-N 1-methoxy-2-methylperoxyethane Chemical compound COCCOOC HCKNRHBSGZMOOF-UHFFFAOYSA-N 0.000 description 1
- JDIIGWSSTNUWGK-UHFFFAOYSA-N 1h-imidazol-3-ium;chloride Chemical compound [Cl-].[NH2+]1C=CN=C1 JDIIGWSSTNUWGK-UHFFFAOYSA-N 0.000 description 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- FFFIRKXTFQCCKJ-UHFFFAOYSA-M 2,4,6-trimethylbenzoate Chemical compound CC1=CC(C)=C(C([O-])=O)C(C)=C1 FFFIRKXTFQCCKJ-UHFFFAOYSA-M 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- JUSXLWAFYVKNLT-UHFFFAOYSA-N 2-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1Br JUSXLWAFYVKNLT-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- GPVOTFQILZVCFP-UHFFFAOYSA-N 2-trityloxyacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(=O)O)C1=CC=CC=C1 GPVOTFQILZVCFP-UHFFFAOYSA-N 0.000 description 1
- BVVXTLWKNXVYDS-UHFFFAOYSA-M 3-benzyl-1,3-thiazol-3-ium;bromide Chemical compound [Br-].C1=CSC=[N+]1CC1=CC=CC=C1 BVVXTLWKNXVYDS-UHFFFAOYSA-M 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-M 4-bromobenzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-M 0.000 description 1
- SPXOTSHWBDUUMT-UHFFFAOYSA-M 4-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=C(S([O-])(=O)=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-M 0.000 description 1
- JOOXCMJARBKPKM-UHFFFAOYSA-M 4-oxopentanoate Chemical compound CC(=O)CCC([O-])=O JOOXCMJARBKPKM-UHFFFAOYSA-M 0.000 description 1
- HWTDMFJYBAURQR-UHFFFAOYSA-N 80-82-0 Chemical compound OS(=O)(=O)C1=CC=CC=C1[N+]([O-])=O HWTDMFJYBAURQR-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- MWQGSJRDPQOJIO-QVDQXJPCSA-N CC(C[C@@H](CCC=C)O)C(N(C)OC)=O Chemical compound CC(C[C@@H](CCC=C)O)C(N(C)OC)=O MWQGSJRDPQOJIO-QVDQXJPCSA-N 0.000 description 1
- QWYZRLNNNKMABE-CUUXFQNZSA-N CCC(C[C@H]1C)OC(C)C1=C Chemical compound CCC(C[C@H]1C)OC(C)C1=C QWYZRLNNNKMABE-CUUXFQNZSA-N 0.000 description 1
- TYSZPVDNWFPOAP-ZOCYIJKUSA-N CC[C@@H](C[C@H]1C#C)OC(C)C1=C Chemical compound CC[C@@H](C[C@H]1C#C)OC(C)C1=C TYSZPVDNWFPOAP-ZOCYIJKUSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 238000005811 Corey-Fuchs synthesis reaction Methods 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 101100050026 Enterobacteria phage T4 y01J gene Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 241000353756 Halichondria okadai Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 229910013594 LiOAc Inorganic materials 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- QANDQRKVQCIBES-BTJKTKAUSA-N OC(=O)\C=C/C(O)=O.CCCCCCCCCCCCCCCCCC(O)=O Chemical compound OC(=O)\C=C/C(O)=O.CCCCCCCCCCCCCCCCCC(O)=O QANDQRKVQCIBES-BTJKTKAUSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 241000243142 Porifera Species 0.000 description 1
- 229910052772 Samarium Inorganic materials 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 238000007329 Woodward reaction Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- UZEDIBTVIIJELN-UHFFFAOYSA-N chromium(2+) Chemical compound [Cr+2] UZEDIBTVIIJELN-UHFFFAOYSA-N 0.000 description 1
- 229940109126 chromous chloride Drugs 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003426 co-catalyst Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-M crotonate Chemical compound C\C=C\C([O-])=O LDHQCZJRKDOVOX-NSCUHMNNSA-M 0.000 description 1
- 150000003997 cyclic ketones Chemical class 0.000 description 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 235000019524 disodium tartrate Nutrition 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- UQSQSQZYBQSBJZ-UHFFFAOYSA-M fluorosulfonate Chemical compound [O-]S(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-M 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 229960004279 formaldehyde Drugs 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940118951 halaven Drugs 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-M methoxyacetate Chemical compound COCC([O-])=O RMIODHQZRUFFFF-UHFFFAOYSA-M 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- FAQJJMHZNSSFSM-UHFFFAOYSA-N phenylglyoxylic acid Chemical compound OC(=O)C(=O)C1=CC=CC=C1 FAQJJMHZNSSFSM-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 description 1
- 125000005547 pivalate group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 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 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 1
- UAWABSHMGXMCRK-UHFFFAOYSA-L samarium(ii) iodide Chemical compound I[Sm]I UAWABSHMGXMCRK-UHFFFAOYSA-L 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 229940095064 tartrate Drugs 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
- 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 description 1
- 238000006257 total synthesis reaction Methods 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
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical compound CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 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
- C07D493/22—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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- 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
Definitions
- the present invention relates to a novel process for the preparation of macrocyclic ketone analogs of halichondrin B or pharmaceutically acceptable salts thereof and to novel intermediates which are produced during the course of carrying out the novel process.
- Halichondrin B is a large naturally occurring polyether macrolide originally isolated from the marine sponge Halichondria okadai with potent antiproliferative activities.
- Halichondrin B A total synthesis of Halichondrin B was published in 1992 (Aicher, T. D. et al. , J. Am. Chem. Soc. 1 14:3162-3164).
- Eribulin a synthetic macrocyclic ketone analogs of halichondrin B with potent antiproliferative activities is an anticancer drug marketed by Eisai Co ⁇ under the trade name Halaven and it is also known as E7389, B1939 and ER-086526.
- the object of the present invention is to provide a novel process for preparation of halichondrin B analogs or pharmaceutically acceptable salts thereof.
- Yet another object of the present invention is to provide a novel process via new intermediates for the synthesis of halichondrin B analogs or pharmaceutically acceptable salts thereof.
- Yet another object of the present invention is to provide a process which is simple, economical and suitable for industrial scale-up.
- the invention provides compound of Formula (I):
- the invention rovides compound of Formula (III):
- the invention provides compound of Formula (VII);
- the invention provides a process to prepare halichondrin analogs and particularly, eribulin or pharmaceutically acceptable salts thereof, from the compound ofFormula I, III, V and VII.
- halichondrin analogs and particularly, eribulin or pharmaceutically acceptable salts thereof, so prepared may be formulated with one or more pharmaceutically acceptable excipients to provide a pharmaceutical composition.
- excipients and compositions are well known to those skilled in the art.
- the present invention provides a process for the preparation of halichondrin B analogs and particularly, eribulin or pharmaceutically acceptable salts thereof, which process is economical, fast and which results in a high purity halichondrin B analogs.
- CI -6 alkyl is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
- leaving group include halide such as chloro, bromo, fluoro, iodo and a sulfonate such as mesylate, besylate, easylate, tosylate, triflate, nonaflate or fluorosulfonate.
- hydroxyl protecting groups include, but are not limited to the protecting groups for hydroxy delineated in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, (2007), which is incorporated herein by reference in its entirety.
- PG is benzyloxycarbonyl (Cbz), 2,2,2- trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-20 trifluoro methyl phenyl sulfonyl) ethoxycarbonyl (Tsc ), t-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc ), 2- adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxy carbonyl (Hoc), l,l-dimethyl-2,2,2- trichloro ethoxycarbonyl (TcBOC), vinyl, 2- chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl- 4-pyrid
- PG is tri(Cl-4 alkyl)silyl (e.g., tri(isopropyl)silyl). In some embodiments, PG is 1,1- diethoxymethyl. In some embodiments, PG is 2-(trimethylsilyl)ethoxymethyl (SEM). In some embodiments, PG is N-pivaloyloxymethyl (POM). In some embodiments, PG forms an ester, such as acetyl, benzoyl or pivaloyl.
- PG forms an ether such as ⁇ - methoxyethoxymethyl ether (MEM), trityl (Tr), dimethoxy trityl( DMT),methoxymethyl ether ( MOM), P-toluenesulphonyl ( Ts), tert-butylsilyl (TBS).
- PG forms silyl protection such as tert-butyldimethylsilyl (TBDMS), tri-isoprolylsilyloxy methyl (TOM), tri-isopropylsilyl (TIPS).
- the present invention provides processes for preparing intermediate compounds useful for producing halichondrin B analogs and particularly, eribulin or pharmaceutically acceptable salts thereof.
- the present invention provides intermediate compounds of any of the intermediates described herein.
- each of PGi, PG 2 and PG 3 are independently hydrogen or a hydroxyl protecting group and Xi is leaving group.
- one, two, or three of PGi, PG 2 and PG3, taken with the oxygen atom(s) to which they are bound, are silyl ethers or arylalkyl ether.
- one, two, or three of PGi, PG 2 and PG 3 are t-butyldimethylsilyl (TBS), benzyl (Bz) or tosyl (Ts), or all of Pd, PG 2 and PG 3 are t-butyldimethylsilyl (TBS) or tosyl (Ts).
- Xi is a halogen, such as iodide.
- Xi is (Cl- C6)alkylsulfonate, (C6-C10 aryl or C1-C6 heteroaryl)sulfonate, (C6-C 15)aryl(Cl- C6)alkyl sulfonate, or (CI -C6)heteroaryl(C 1 -C6)alkylsulfonate.
- Specific leaving groups include mesylate, toluenesulfonate, isopropylsulfonate, phenylsulfonate, or benzylsulfonate.
- compound of Formula (I) is prepared by a process which comprises steps of (i) reacting compound of Formula (la)
- X 2 and X3 are leaving group, preferably halide, more preferably bromo.
- the process further comprises preparing the compound of Formula (la); by reacting compound of Formula Ila)
- lactone of Formula (Ila) is treated with ⁇ , ⁇ -dimethylhydroxylamine hydrochloride [MeO(Me)NH*HCl] in presence of AlMe 3 or AlMe 2 Cl to afford the corresponding Weinreb amide of Formula (la).
- Reaction may be performed in a non-polar solvents, such as halogenated solvents like dichloromethane (DCM) and dichloroethane ( EDC).
- DCM dichloromethane
- EDC dichloroethane
- the reaction is carried out at a temperature in the range of from about - 10°C to about 40°C for about 1 hour to about 24 hours. More preferably the reaction step is carried out at a temperature in the range from about 0 to about 30°C, for about 3 hours to about 6 hours.
- Preparation of compounds can involve the protection and deprotection of various chemical groups.
- the need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
- the chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4d. Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. Adjustments to the protecting groups and formation and cleavage methods described herein may be adjusted as necessary in light of the various substituents.
- the protective groups are independently selected from esters, carbonates, carbamates, sulfonates, and ethers.
- the protection reaction is performed under anhydrous conditions in the presence of a polar protic solvent such as THF using mesyl chloride or tosyl chloride.
- a polar protic solvent such as THF using mesyl chloride or tosyl chloride.
- Hydroxylation of compound of Formula (lb) is carried out using dilute potassium permanganate (KMn04) or osmium catalyst.
- a preferred osmium catalyst is osmium tetroxide (Os04).
- a stoichiometric amount of an oxidant e.g. K 3 Fe(CN) 6 or N-methylmorpholine oxide (NMO)
- a buffered solution may be added to ensure a stable pH, since the reaction proceeds more rapidly under slightly basic conditions.
- hydroxylation may be carried out by the Woodward Reaction to give corresponding diol of Formula (Ic) which is further protected using suitable protecting group to give compound of Formula (Id).
- the hydroxylation is performed in the presence of aqueous solvents at a temperature in the range of from about -10°C to about 30°C for about 1 hour to about 24 hours.
- Weinreb amide of Formula (Id) is further reduced with DIB AL-H or an excess of lithium aluminum hydride to aldehyde of Formula ( Ie).
- the reduction step is performed in the presence of polar aprotic solvent such as THF under inert atmosphere at a temperature in the range of from about -10°C to about 10°C for about 30 minutes to about 5 hours.
- polar aprotic solvent such as THF
- Suitable halogenating agent include but not limited to CBr 4 in combination with triphenyl phosphine (Corey-Fuchs reaction ) to transform an aldehyde of Formula (Ie) into 1,1-dibromoolefins of Formula (If), which is further converted to an alkyne.
- the halogenation step is performed in the presence of halogenated solvents such as DCM at a temperature in the range of from about -10°C to about 30°C for about 30 minutes to about 5 hours. In one aspect, it is carried out at a temperature in the range of from about 10°C to about 20°C for about 1 to about 2 hours.
- halogenated solvents such as DCM
- the deprotonation reaction step is performed under anhydrous conditions in the presence of polar aprotic solvent such as THF at a temperature in the range of from about -78 °C to about -70°C for about 1 to 2 hours.
- polar aprotic solvent such as THF
- the intermediate alkyne is not isolated and undergoes haloboration reaction at room temperature for about 1 to 5 hours to yield compound (I).
- the compound (I) obtained by the process of the invention includes compound of formula (I)-A:
- the invention rovides compound of Formula (III).
- each of PG 4 and PG 5 are independently H or CI -6 alkyl; or PG 4 and PG 5 , together with the oxygen atoms to which they are attached, form a diol protecting 5- to 6- membered heterocyclic ring, which is optionally substituted with CI -4 alkyl groups.
- Diol protecting groups are well known in the art and include cyclohexylidene and benzylidene diol protecting group.
- one or both of PG 4 and PG 5 of Formula (III), taken with the oxygen atom(s) to which they are bound, are silyl ethers or arylalkyl ethers.
- one or both of PG 4 and PG 5 are TBS or benzyl, or both PG 4 and PG 5 are TBS;
- R is H, CI -6 alkyl or CI -6 haloalkyl. In a further embodiment R is CI -6 alkyl. In a preferred embodiment R is methyl.
- compound of Formula (III) is prepared by a process which comprises steps of;
- an intramolecular coupling reaction of halide of Formula (I) and aldehyde of Formula (II) is a chromium- induced redox reaction.
- the coupling reaction is, Cr-Ni bimetallic catalyst-promotes redox addition of vinyl halides to aldehydes.
- a key advantage is the high chemoselectivity toward aldehydes.
- catalytic amount of chromium(II) which is regenerated by reduction with manganese or via electrochemical reduction, or palladium acetate may be added as co-catalyst to enhance the rate of the reaction.
- the catalyst used for the coupling reaction is NiCk/CrCk.
- the coupling is preferably carried in the presence of a ligand and polar aprotic solvent such as THF, DMSO, and acetonitrile at room temperature for about 5 to 10 hours.
- a ligand and polar aprotic solvent such as THF, DMSO, and acetonitrile at room temperature for about 5 to 10 hours.
- the ligand used is preferably selected from sulfonamide ligands such as sulfonamide-A, sulfo
- compound of Formula (Ilia) is treated with potassium hexamethyldisilazide to give tetrahydropyran of compound Formula (Illb).
- the hydroxyl protecting groups of compound Formula (Illb) are removed by appropriate means to afford compound Formula (Illc).
- One of the ordinary skilled in the art would recognize that the methods appropriate to achieve removal of the protecting groups of compound Formula (Illb) depend upon the actual protecting groups used and include those described in the "Greene”. For example, when each of the protecting groups of compound Formula (Illb) is a TBS group, then removal may be achieved by treating with TBAF.
- vicinal diol compound of Formula (IIIc) is then treated with sodium periodate to form aldehyde compound Formula (III). Addition of 2,6-lutidine can suppress the side reactions and improve the yield of the reaction.
- vicinal diol compound of Formula (IIIc) may be treated with oxidants like periodic acid (HI04) and lead tetraacetate [Pb(OAc) 4 ] to form carbonyl compound of Formula (III).
- R is methyl
- Ri and R 2 together form CH2SO2PI1
- Pd is methane sulfonyl (mesyl/ Ms)
- PG2 and PG3 are t-butyldimethyl silyl (TBS)
- PG 4 and PG together with the oxygen atoms to which they are attached, form a diol protecting 5 membered heterocyclic ring, which is optionally substituted with methyl groups
- the compound (III) obtained by the process of the invention includes compound of formula (III)-A:
- the compounds of Formula Ilia, Illb, IIIc and III-A are hitherto unreported intermediates useful in the process for the preparation of halichondrin B analogs as described herein.
- the invention provides compound of Formula (V).
- compound of Formula (V) is prepared by a process which comprises; intramolecular coupling (NHK coupling) of compound of Formula (III) with compound of Formula (IV)
- PG 4 , PG 5 , R, Ri and R 2 are as defined above and each of PG 6 and PG7 are independently hydrogen or a hydroxyl protecting group and X 4 is a leaving group.
- compound of Formula V is hitherto unreported intermediate useful in the process for the preparation of halichondrin B analogs as described herein.
- compound of Formula (III) is subjected to an intramolecular coupling reaction with compound of Formula (IV) in the presence of a base and a suitable solvent, under conditions similar to those involved in the coupling of compound of Formula (I) with (II).
- R is methyl
- Ri and R 2 together form CH 2 S0 2 Ph
- PG 4 and PG 5 together with the oxygen atoms to which they are attached, form a diol protecting 5 membered heterocyclic ring optionally substituted with methyl groups
- PG 6 is mesyl (Ms)
- PG 7 is t-butyl diphenyl silyl (TBDPS)
- the compound (V) obtained by the process of the invention includes compound of formula (V)-A:
- the invention provides compound of Formula (VII).
- the invention provides a process for converting compound Formula (V) into compound of Formula (VII);
- compound of Formula (V) is treated with either S1O2 or PPTS in presence of a suitable solvent such as isopropyl alcohol and a base such as pyridine for a period of' 2 hours to 4 days at 25-50°C to obtain cyclic ketone of Formula (VI).
- a suitable solvent such as isopropyl alcohol and a base such as pyridine
- the hydroxyl protective group is then chemoselectively deprotected using HO, TTAF, LiOAc or DBU using suitable polar solvent like THF and IPA to obtain compound of Formula (VII).
- R is methyl
- Ri and R 2 together form CH 2 S0 2 Ph
- PG 4 and PG 5 together with the oxygen atoms to which they are attached, form a diol protecting 5 membered heterocyclic ring optionally substituted with methyl groups
- the compound (VII) obtained by the process of the invention includes compound of formula (VII)-A:
- V (V)-A (Vl)-A (Vll)-A
- R is methyl
- Ri and R 2 together form CHbSChPh
- PG 4 and PG 5 together with the oxygen atoms to which they are attached, form a diol protecting 5 membered heterocyclic ring which is optionally substituted with methyl groups
- PG 6 is mesyl (Ms)
- PG 7 is t- butyl diphenyl silyl (TBDPS).
- the invention provides a process for converting compound of Formula (VII) prepared by the process of the present invention into halichondrin analogs and particularly, eribulin or pharmaceutically acceptable salts thereof.
- R is methyl; PG 4 , PG 5 , ,Ri and R 2 , are as defined above, and wherein each of PG 8 , PG9, and PG10 are each independently H or Cl-6 alkyl or a hydroxyl protecting group; and X 5 is a leaving group.
- one, two, or three of PG 8 , PG9, and PG 10 of Formula (VIII), taken with the oxygen atom(s) to which they are bound, are silyl ethers or arylalkyl ethers.
- one, two, or three of PG 8 , PG9, and PG10 of Formula (VIII) are t- butyldimethylsilyl (TBS) or benzyl, or all of PG 8 , PG9, and PG 10 of Formula (VIII) are t- butyldimethylsilyl (TBS).
- X3 is a halogen, (Cl-C6)alkylsulfonate, (C6-C10 aryl or CI -C6 heteroaryl) sulfonate, (C6-C15)aryl(Cl-C6)alkylsulfonate, or (CI- C6)heteroaryl (Cl-C6)alkyl sulfonate.
- X 3 include iodide, mesylate, toluenesulfonate, isopropylsulfonate, phenylsulfonate, nitro-phenylsulfonate (nosylate), and bromo-phenylsulfonate (brosylate ),
- one or both of PG 8 , PG9, and PG10 of Formula (VIII), taken with the oxygen atom(s) to which they are bound, are independently selected from esters, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
- esters include formates, acetates, carbonates, and sulfonates.
- formate benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chloro phenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-( ethylenedithio )pentanoate,
- pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2- trichloro ethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p- nitrobenzyl.
- silyl ethers examples include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
- Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
- Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta(trimethylsilyl) ethoxymethyl, and tetrahydro pyranyl ethers.
- arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, o-nitrobenzyl, pnitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl.
- one, two, or three of PG 8 , PG9, and PG10 are t- butyldimethylsilyl (TBS), benzyl(Bz) or tos ' yl (Ts), or all of PG 8 , PG 9 , and PG10 are t- butyldimethylsilyl (TBS) or tosyl (Ts).
- PG 8 and PG9 together with the oxygen atoms to which they are attached, form a diol protecting 5- to 6-membered heterocyclic ring, which is optionally substituted with CI -4 alkyl groups.
- PG 8 and PG 9 are taken together to form a cyclohexylidene protecting group.
- X 5 is halogen, such as iodide.
- X 5 is (Cl- C6)alkylsulfonate, (C6-C10 aryl or C1-C6 heteroaryl)sulfonate, (C6-C15)aryl(Cl- C6)alkyl sulfonate, or (CI -C6)heteroaryl(C 1 -C6)alkylsulfonate.
- Specific leaving groups include mesylate, toluenesulfonate, isopropylsulfonate, phenylsulfonate, or benzylsulfonate.
- compound of Formula (VII) is coupled with compound of Formula (VIII) in the presence of a base and a suitable solvent, similar to those as noted herein and disclosed in US Patent Number 6,214,865 Bl (incorporated herein by reference) to form an intermediate alcohol.
- a base and a suitable solvent similar to those as noted herein and disclosed in US Patent Number 6,214,865 Bl (incorporated herein by reference) to form an intermediate alcohol.
- oxidation of the alcohol using reagents to give the compound of Formula (IX).
- compound of Formula (VII) is treated with n-butyllithium then with the aldehyde of Formula (VIII).
- the resulting diol intermediate is then oxidized with Dess-Martin reagent to form the ketone-aldehyde intermediate of Formula (IX).
- the compound of Formula (IX) is subjected to the reduction of the arylsulfonyl moiety using a reducing agent, for example and without limitation, Sml 2 ; followed by an intramolecular coupling reaction, under conditions similar to those involved in the coupling of compound of Formula (I) with (II) in trivalent chromium, nickel and zinc.
- a reducing agent for example and without limitation, Sml 2
- the intramolecular coupling is performed in the presence of the chiral oxazole ligand, such as Ph-NMS-oxazole or sulfonamide to impart a higher yield and greater efficiency for the reaction.
- the subsequent oxidation using reagents as described above, can be performed to obtain compound of Formula (X).
- Deprotection of the compound of Formula (X) can be performed using reagents known to a skilled person, for example, desilylation is performed using a fluoride source to give triol compound which is subjected to the intramolecular cyclization to result into the protected diol compound of Formula (XI).
- the desilylation is performed using tetra-butyl ammonium fluoride (TBAF).
- TBAF tetra-butyl ammonium fluoride
- the intramolecular cyclization is performed using PPTS.
- suitable deprotecting agents such as PTSA results in the diol compound of Formula (XII).
- Diol compound of Formula (XII) is useful intermediate for preparing various Halichondrin B analogs and particularly, eribulin or pharmaceutically acceptable salts thereof.
- a selective protection of terminal alcohol of compound of Formula (XII) is carried out by converting the alcohol into a leaving group to form an intermediate compound followed by substitution of the leaving group by an amine or other nitrogen based nucleophile which results in eribulin.
- selective protection is carried out by using Ts 2 0, TsCl, TMSOTf or MsCl in presence of a base such as collidine or lutidine.
- the amine or other nitrogen based nucleophile used is not limited to ammonia gas or a solution of ammonia in an organic solvent.
- the nitrogen based nucleophile is an azide for example, trimethylsilyl azide (TMSN3).
- Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
- a given reaction can be carried out in one solvent or a mixture of more than one solvent.
- suitable solvents for a particular reaction step can be selected.
- reactions can be carried out in the absence of solvent, such as when at least one of the reagents is a liquid or gas.
- Suitable solvents can include halogenated solvents, ether solvents, protic solvents, aprotic solvents, hydrocarbon solvents and the like.
- the reactions of the processes described herein can be carried out at appropriate temperatures which can be readily determined by the skilled artisan. Reaction temperatures will depend on, for example, the melting and boiling points of the reagents and solvent, if present; the thermodynamics of the reaction (e.g., vigorously exothermic reactions may need to be carried out at reduced temperatures); and the kinetics of the reaction (e.g., a high activation energy barrier may need elevated temperatures).
- Elevated temperature refers to temperatures above room temperature (about 22°C). In some embodiments reaction may be performed below room temperature (below 22°C) or under subzero temperature ( below 0°C).
- reactions of the processes described herein can be carried out in air or under an inert atmosphere.
- reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan.
- R is methyl, R ⁇ and R 2 together form CH 2 S0 2 Ph, PG 4 and PG 5 together with the oxygen atoms to which they are attached, form a diol protecting 5 membered heterocyclic ring which is optionally substituted with methyl groups, PG 8 , PG 9 , PG 10 are TBS and X5 is iodo.
- Eribulin obtained by the process of the present invention may subsequently be converted to the corresponding pharmaceutically accepted salts by reacting with corresponding acid in suitable solvents.
- the pharmaceutically acceptable salt of eribulin prepared according to the present invention are selected from inorganic acid salt or organic acid salt.
- the inorganic acid salts may be selected from but not limited to hydrochloride, sulfate, hydrobromide, hydroiodide, nitrate, bisulfate and phosphate salts.
- the organic acid salts may be selected from but not limited to ascorbate, malonate, citrate, cinnamate , malate, isonicotinate, acetate, lactate, salicylate, tartrate, pantotenate, ascorbate, succinate, stearate maleate, fumarate, gluconate, saccharate, formate, benzoate, glutamate, mesyalte, esylate, benzenesulfonate , p-toluenesulfonate, pamoate, lactate, oleate, tannate and oxalate salts.
- eribulin is converted to mesylate salt.
- reaction mass was quenched with 1.3 M disodium tartrate at 0°C, organic layer was extracted with ethyl acetate (3 x 50 ml), washed with water (10 ml) followed by brine (10 ml), dried over sodium sulphate and evaporated under reduced pressure to afford the compound la (0.4 g ) which was used for the next step without any further purification.
- reaction mass was quenched with aq.Na 2 S0 3 and extracted with 10% MeOH/DCM (2x 50 ml), washed with water (25 ml) followed by brine (25 ml), dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain the compound Ic which was taken for the next step without further purification.
- Sulfonamide-C (53.0 mg, 0.22 eq) was weighed outside a glove box and put in a flask. In a glove box, proton sponge (30 mg, 0.22 eq), CrCl 2 (12 mg, 0.20 eq) and MeCN (1.5 ml) were added and the resulting mass was then stirred at 25-30°C for 1 h.
- the resulting solution was added to a reaction vial containing mixture of compound (II) (200 mg, 1 eq), compound (I) (506 mg, 1.5 eq), LiCl (41 mg, 2.0 eq), Mn powder (53 mg, 2.0 eq), Zr(Cp) 2 Cl 2 (212 mg, 1.5 eq) and NiCl 2 »dmp (3.1 mg, 0.05 eq).
- the resulting mass was stirred at 25-30°C in the glove box for 6 h.
- the reaction mixture was diluted with ethyl acetate (10 ml), and treated with florisil (0.5g).
- the resulting suspension was stirred for lh at 25-30°C and then passed through a short pad of silica gel. The solvent evaporated and the compound (Ilia) was taken for next step without purification.
- reaction mass was allowed to stir at RT for 16 h, the reaction mass was diluted with THF (5 ml) and filtered over celite pad. The filtrate was concentrated under reduced pressure to obtain the compound (V)-A which was used in the next step without any further purification.
- the reaction was quenched with potassium carbonate/ Rochelle's Salts/ water (1/10/100; w/w/v, 5 ml) and MTBE (15 ml) such that internal temperature did not exceed -65° C.
- the reaction was warmed to room temperature.
- the organic layer was separated, evaporated under reduced pressure.
- Crude was purified by column chromatography to afford de-sulfonyl compound (Keto-aldehyde) (Yield 25 mg, 55%).
- the material was stored under inert gas atmosphere at -20° C.
- Compound (XII) (40 mg, 0.05 mmol) was stripped off with anhydrous toluene ( 2 x 3 ml) and then diluted with anhydrous DCM (3 ml) under argon atmosphere. Collidine (0.054 ml, 0.4mmol) was added, followed by anhydrous DCM containing catalytic amount of pyridine (1.5 ml). The resulting mixture was cooled to an internal temperature of -20 to -25°C.
- p-Toluenesulfonic anhydride (18 mg, 0.055 mmol) in anhydrous DCM (0.5 ml) under argon atmosphere was added slowly maintaining internal temperature below -16°C.
- the reaction was stirred at -20 to-25°C for 90 minutes then warmed to 0°C over 20 minutes and stirred for an additional 30 minutes.
- the reaction mixture was quenched with water (2 ml). The bath was removed and reaction mixture was allowed to warm to room temperature and stirred for 30 min.
- the reaction mixture was transferred to another flask containing IPA (20 ml) and aqueous ammonium hydroxide (20 ml) at room temperature, stirred for 24 hours.
- the reaction was concentrated to dryness or near dryness at reduced pressure.
- the resulting material was diluted with DCM (20 ml) and washed pH 10 buffer (NaHC0 3 /Na 2 C0 3 (aq), 20 ml).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a novel process for the preparation of macrocyclic ketone analogs of halichondrin B or pharmaceutically acceptable salts thereof and to novel intermediates which are produced during the course of carrying out the novel process.
Description
"PROCESS FOR THE PREPARATION OF MACROCYCLIC KETONE ANALOGS OF HALICHONDRIN B OR PHARMACEUTICALLY ACCEPTABLE SALTS AND INTERMEDIATES THEREOF"
Field of the Invention:
The present invention relates to a novel process for the preparation of macrocyclic ketone analogs of halichondrin B or pharmaceutically acceptable salts thereof and to novel intermediates which are produced during the course of carrying out the novel process.
Background of the Invention:
Halichondrin B is a large naturally occurring polyether macrolide originally isolated from the marine sponge Halichondria okadai with potent antiproliferative activities.
Halichondrin B
A total synthesis of Halichondrin B was published in 1992 (Aicher, T. D. et al. , J. Am. Chem. Soc. 1 14:3162-3164).
Eribulin, a synthetic macrocyclic ketone analogs of halichondrin B with potent antiproliferative activities is an anticancer drug marketed by Eisai Co^ under the trade name Halaven and it is also known as E7389, B1939 and ER-086526.
It was first reported in U.S. Patent No. 6214865. Accordingly, new methods for the synthesis of halichondrin B analogs and particularly, eribulin useful as anti-cancer agents are desirable.
Objects of the Invention:
The object of the present invention is to provide a novel process for preparation of halichondrin B analogs or pharmaceutically acceptable salts thereof.
Yet another object of the present invention is to provide a novel process via new intermediates for the synthesis of halichondrin B analogs or pharmaceutically acceptable salts thereof.
Yet another object of the present invention is to provide a process which is simple, economical and suitable for industrial scale-up.
Statements of Invention:
According to a first aspect of the present invention, there is provided compounds useful in the synthesis of halichondrin B analogs and particularly, eribulin or pharmaceutically acceptable salts thereof.
(I)
wherein PGi, PG2, PG3 and Xi are as described herein.
In yet another aspect, the invention rovides compound of Formula (III):
(III)
wherein PG4, PG5, R, R!and R2 are as described herein.
In yet another aspect, the invention rovides compound of Formula (V):
wherein PG4, PG5, PG6, PG7, R, Ri and R2 are as described herein.
In another aspect, the invention provides compound of Formula (VII);
(VII)
In yet another aspect, the invention provides a process to prepare halichondrin analogs and particularly, eribulin or pharmaceutically acceptable salts thereof, from the compound ofFormula I, III, V and VII.
The halichondrin analogs and particularly, eribulin or pharmaceutically acceptable salts thereof, so prepared may be formulated with one or more pharmaceutically acceptable excipients to provide a pharmaceutical composition. Such excipients and compositions are well known to those skilled in the art.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of halichondrin B analogs and particularly, eribulin or pharmaceutically acceptable salts thereof, which process is economical, fast and which results in a high purity halichondrin B analogs.
At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual sub combination of the members of such groups and ranges.
For example, the term "CI -6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
The term " leaving group " include halide such as chloro, bromo, fluoro, iodo and a sulfonate such as mesylate, besylate, easylate, tosylate, triflate, nonaflate or fluorosulfonate.
The term " hydroxyl protecting groups" include, but are not limited to the protecting groups for hydroxy delineated in Wuts and Greene, Protective Groups in Organic
Synthesis, 4th ed., John Wiley & Sons: New Jersey, (2007), which is incorporated herein by reference in its entirety.
In some embodiments, PG is benzyloxycarbonyl (Cbz), 2,2,2- trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-20 trifluoro methyl phenyl sulfonyl) ethoxycarbonyl (Tsc ), t-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc ), 2- adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxy carbonyl (Hoc), l,l-dimethyl-2,2,2- trichloro ethoxycarbonyl (TcBOC), vinyl, 2- chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl- 4-pyridylmethyl, Ν',Ν'-dimethylhydrazinyl, methoxymethyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM), or 2-tetrahydropyranyl (THP). In some embodiments, PG is tri(Cl-4 alkyl)silyl (e.g., tri(isopropyl)silyl). In some embodiments, PG is 1,1- diethoxymethyl. In some embodiments, PG is 2-(trimethylsilyl)ethoxymethyl (SEM). In some embodiments, PG is N-pivaloyloxymethyl (POM). In some embodiments, PG forms an ester, such as acetyl, benzoyl or pivaloyl. In some embodiments, PG forms an ether such as β- methoxyethoxymethyl ether (MEM), trityl (Tr), dimethoxy trityl( DMT),methoxymethyl ether ( MOM), P-toluenesulphonyl ( Ts), tert-butylsilyl (TBS). In some embodiments, PG forms silyl protection such as tert-butyldimethylsilyl (TBDMS), tri-isoprolylsilyloxy methyl (TOM), tri-isopropylsilyl (TIPS).
In one aspect, the present invention provides processes for preparing intermediate compounds useful for producing halichondrin B analogs and particularly, eribulin or pharmaceutically acceptable salts thereof.
In another aspect, the present invention provides intermediate compounds of any of the intermediates described herein.
(I)
wherein each of PGi, PG2 and PG3 are independently hydrogen or a hydroxyl protecting group and Xi is leaving group.
In certain embodiment's one, two, or three of PGi, PG2 and PG3, taken with the oxygen atom(s) to which they are bound, are silyl ethers or arylalkyl ether. For example, in other embodiments, one, two, or three of PGi, PG2 and PG3are t-butyldimethylsilyl (TBS), benzyl (Bz) or tosyl (Ts), or all of Pd, PG2 and PG3are t-butyldimethylsilyl (TBS) or tosyl (Ts).
In some embodiments, Xi is a halogen, such as iodide. In other embodiments, Xi is (Cl- C6)alkylsulfonate, (C6-C10 aryl or C1-C6 heteroaryl)sulfonate, (C6-C 15)aryl(Cl- C6)alkyl sulfonate, or (CI -C6)heteroaryl(C 1 -C6)alkylsulfonate. Specific leaving groups include mesylate, toluenesulfonate, isopropylsulfonate, phenylsulfonate, or benzylsulfonate.
In an embodiment, compound of Formula (I), is prepared by a process which comprises steps of (i) reacting compound of Formula (la)
(la)
with a protecting agent in the presence of a base to obtain compound of Formula (lb).
(ii) reacting with a suitable hydroxylating agent, to form vicinal diol of Formula ( Ic)
(iii) protecting using suitable protecting agent to form compound of Formula (Id):
(Id)
(iv) reducing with suitable reducing agent to form compound of Formula (Ie):
(le)
(V) reacting with suitable halogenating agent to form compound of Formula (If):
(If)
and
(vi) alkynetion and haloboration to form compound of Formula (I); wherein PGl5 PG2 and PG3are as defined above;
and ,
X2 and X3 are leaving group, preferably halide, more preferably bromo.
In some embodiments, the process further comprises preparing the compound of Formula (la); by reacting compound of Formula Ila)
with dimethyl hydroxyl amine.
Accordingly, an embodiment of the process for the preparation of compound of Formula (I) is as shown in Scheme A.
Scheme A
The compounds of Formula la, lb, Ic, Id, Ie, If and I are hitherto unreported intermediates useful in the process for the preparation of halichondrin B analogs as described herein.
In an embodiment lactone of Formula (Ila) is treated with Ν,Ο-dimethylhydroxylamine hydrochloride [MeO(Me)NH*HCl] in presence of AlMe3 or AlMe2Cl to afford the corresponding Weinreb amide of Formula (la). Reaction may be performed in a non-polar solvents, such as halogenated solvents like dichloromethane (DCM) and dichloroethane ( EDC). Preferably, the reaction is carried out at a temperature in the range of from about - 10°C to about 40°C for about 1 hour to about 24 hours. More preferably the reaction step is carried out at a temperature in the range from about 0 to about 30°C, for about 3 hours to about 6 hours.
The hydroxyl group on Weinreb amide of Formula (la) is further protected. using suitable protecting group to obtain compound of Formula (lb).
Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4d. Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. Adjustments to the protecting groups and formation and cleavage methods described herein may be adjusted as necessary in light of the various
substituents. The protective groups are independently selected from esters, carbonates, carbamates, sulfonates, and ethers.
Preferably, the protection reaction is performed under anhydrous conditions in the presence of a polar protic solvent such as THF using mesyl chloride or tosyl chloride.
Hydroxylation of compound of Formula (lb) is carried out using dilute potassium permanganate (KMn04) or osmium catalyst. A preferred osmium catalyst is osmium tetroxide (Os04). Optionally, a stoichiometric amount of an oxidant [e.g. K3Fe(CN)6 or N-methylmorpholine oxide (NMO)] and a buffered solution may be added to ensure a stable pH, since the reaction proceeds more rapidly under slightly basic conditions. Alternatively, hydroxylation may be carried out by the Woodward Reaction to give corresponding diol of Formula (Ic) which is further protected using suitable protecting group to give compound of Formula (Id).
Preferably, the hydroxylation is performed in the presence of aqueous solvents at a temperature in the range of from about -10°C to about 30°C for about 1 hour to about 24 hours.
Weinreb amide of Formula (Id) is further reduced with DIB AL-H or an excess of lithium aluminum hydride to aldehyde of Formula ( Ie).
The reduction step is performed in the presence of polar aprotic solvent such as THF under inert atmosphere at a temperature in the range of from about -10°C to about 10°C for about 30 minutes to about 5 hours.
Suitable halogenating agent include but not limited to CBr4 in combination with triphenyl phosphine (Corey-Fuchs reaction ) to transform an aldehyde of Formula (Ie) into 1,1-dibromoolefins of Formula (If), which is further converted to an alkyne.
The halogenation step is performed in the presence of halogenated solvents such as DCM at a temperature in the range of from about -10°C to about 30°C for about 30 minutes to about 5 hours. In one aspect, it is carried out at a temperature in the range of from about 10°C to about 20°C for about 1 to about 2 hours.
Deprotonation of 1,1-dibromoolefins of Formula (If) with butyllithium gives rise to internal alkyne, which further undergoes haloboration with B- Bromo- or B-iodo-9- borabicyclo[3.3.1]-nonane (B-X-9-BBN) and other haloboranes to give corresponding 1- halo-l-alkenes of Formula (I).
The deprotonation reaction step is performed under anhydrous conditions in the presence of polar aprotic solvent such as THF at a temperature in the range of from about -78 °C to about -70°C for about 1 to 2 hours. The intermediate alkyne is not isolated and undergoes haloboration reaction at room temperature for about 1 to 5 hours to yield compound (I).
In one preferred embodiment, when XI is iodo, X2 and X3 are bromo, PG1 is methane sulfonyl (mesyl/ Ms), PG2 and PG3 are t-butyldimethyl silyl (TBS) , the compound (I) obtained by the process of the invention includes compound of formula (I)-A:
(l)-A
Accordingly, a process for preparing a compound of formula (I)-A according to the present invention is exemplified in Scheme Al .
Scheme Al
The compounds of Formula la, lb, Ic, Id, Ie, If and I-A are hitherto unreported intermediates useful in the process for the preparation of halichondrin B analogs as described herein.
In yet another aspect, the invention rovides compound of Formula (III).
(III)
wherein each of PG4 and PG5 are independently H or CI -6 alkyl; or PG4 and PG5, together with the oxygen atoms to which they are attached, form a diol protecting 5- to 6- membered heterocyclic ring, which is optionally substituted with CI -4 alkyl groups. Diol protecting groups are well known in the art and include cyclohexylidene and benzylidene diol protecting group.
In certain embodiments, one or both of PG4 and PG5 of Formula (III), taken with the oxygen atom(s) to which they are bound, are silyl ethers or arylalkyl ethers. For example, one or both of PG4 and PG5 are TBS or benzyl, or both PG4 and PG5 are TBS;
Ri and R2 each independently is H, -CH2OR3 or -CH2S02Ar, or Ri and R2 together form =CH2S02Ar, wherein R3 is H or a hydroxyl protecting group; and Ar is an aryl group;
In one embodiment R is H, CI -6 alkyl or CI -6 haloalkyl. In a further embodiment R is CI -6 alkyl. In a preferred embodiment R is methyl.
In an embodiment, compound of Formula (III), is prepared by a process which comprises steps of;
(i) intramolecular coupling (Nozaki-Hiyama-Kishi [NHK] coupling) of compound of Formula (I) with compound of Formula (II)
to form compound of Formula(IIIa) :
(ii) intramolecular cyclization (oxy- Michael ring closure) to form compound of Formula (Illb) :
(iii) removal of protecting group to form compound of Formula (IIIc)
(IIIc) and
(iv) reducing with suitable reducing agent to form compound of Formula (III)
(III)
wherein PGi, PG2, PG3, PG4, PG5, Xi, R, Riand R2 are as defined above
Accordingly, an embodiment of the process for the preparation of compound of Formula (III) is as shown in Scheme B.
Scheme B
(1Mb) (lllc) (III)
The compounds of Formula Ilia, Illb, IIIc and III are hitherto unreported intermediates useful in the process for the preparation of halichondrin B analogs as described herein.
In an embodiment, an intramolecular coupling reaction of halide of Formula (I) and aldehyde of Formula (II), is a chromium- induced redox reaction. The coupling reaction is, Cr-Ni bimetallic catalyst-promotes redox addition of vinyl halides to aldehydes. A key
advantage is the high chemoselectivity toward aldehydes. Alternatively, catalytic amount of chromium(II) which is regenerated by reduction with manganese or via electrochemical reduction, or palladium acetate may be added as co-catalyst to enhance the rate of the reaction. In a preferred embodiment the catalyst used for the coupling reaction is NiCk/CrCk.
The coupling is preferably carried in the presence of a ligand and polar aprotic solvent such as THF, DMSO, and acetonitrile at room temperature for about 5 to 10 hours. The ligand used is preferably selected from sulfonamide ligands such as sulfonamide-A, sulfo
Sulfonamide-A Sulfonamide-B Sulfonamide-C
In an embodiment compound of Formula (Ilia) is treated with potassium hexamethyldisilazide to give tetrahydropyran of compound Formula (Illb). The hydroxyl protecting groups of compound Formula (Illb) are removed by appropriate means to afford compound Formula (Illc).One of the ordinary skilled in the art would recognize that the methods appropriate to achieve removal of the protecting groups of compound Formula (Illb) depend upon the actual protecting groups used and include those described in the "Greene". For example, when each of the protecting groups of compound Formula (Illb) is a TBS group, then removal may be achieved by treating with TBAF.
The details of which are set forth in the examples infra.
The vicinal diol compound of Formula (IIIc) is then treated with sodium periodate to form aldehyde compound Formula (III). Addition of 2,6-lutidine can suppress the side reactions and improve the yield of the reaction. Alternatively, vicinal diol compound of Formula (IIIc) may be treated with oxidants like periodic acid (HI04) and lead tetraacetate [Pb(OAc)4] to form carbonyl compound of Formula (III).
In one preferred embodiment, when Xi is iodo, R is methyl, Ri and R2 together form CH2SO2PI1, Pd is methane sulfonyl (mesyl/ Ms), PG2 and PG3 are t-butyldimethyl silyl (TBS), PG4 and PG together with the oxygen atoms to which they are attached, form a diol protecting 5 membered heterocyclic ring, which is optionally substituted with methyl groups; the compound (III) obtained by the process of the invention includes compound of formula (III)-A:
(lll)-A
Accordingly, a process for preparing a compound of formula (III)-A according to the present invention is exemplified in Scheme Bl
Scheme Bl
The compounds of Formula Ilia, Illb, IIIc and III-A are hitherto unreported intermediates useful in the process for the preparation of halichondrin B analogs as described herein.
In yet another aspect, the invention provides compound of Formula (V).
(V)
In an embodiment, compound of Formula (V), is prepared by a process which comprises; intramolecular coupling (NHK coupling) of compound of Formula (III) with compound of Formula (IV)
wherein PG4, PG5, R, Ri and R2 are as defined above and each of PG6 and PG7 are independently hydrogen or a hydroxyl protecting group and X4 is a leaving group.
Accordingly, an embodiment of the process for the preparation of compound of Formula (V) is as shown in Scheme C.
Scheme C
The compound of Formula V is hitherto unreported intermediate useful in the process for the preparation of halichondrin B analogs as described herein.
In an embodiment, compound of Formula (III) is subjected to an intramolecular coupling reaction with compound of Formula (IV) in the presence of a base and a suitable solvent, under conditions similar to those involved in the coupling of compound of Formula (I) with (II).
In one preferred embodiment, when X4 is bromo, R is methyl, Ri and R2 together form CH2S02Ph, PG4 and PG5 together with the oxygen atoms to which they are attached, form a diol protecting 5 membered heterocyclic ring optionally substituted with methyl groups, PG6 is mesyl (Ms) and PG7 is t-butyl diphenyl silyl (TBDPS); the compound (V) obtained by the process of the invention includes compound of formula (V)-A:
(V)-A
Accordingly, a process for preparing a compound of formula (V)-A according to the present invention is exemplified in Scheme CI
Scheme CI
In yet another aspect, the invention provides compound of Formula (VII).
In yet another aspect, the invention provides a process for converting compound Formula (V) into compound of Formula (VII);
(VII)
comprising steps of:
(i) intramolecular cyclization
(oxy- Michael ring closure) of compound of Formula (V) to form compound of Formula (VI) :
(VI)
and
(ii) removal of protecting group to form compound of Formula (VII);
wherein PG4, PG5, PG6, PG , R, Riand R2 are as defined above.
Accordingly, an embodiment of the process for the preparation of compound of Formula (VII) is as shown in Scheme D.
Scheme D
The compounds of Formula VI and VII are hitherto unreported intermediates useful in the process for the preparation of halichondrin B analogs as described herein.
In an embodiment, compound of Formula (V) is treated with either S1O2 or PPTS in presence of a suitable solvent such as isopropyl alcohol and a base such as pyridine for a period of' 2 hours to 4 days at 25-50°C to obtain cyclic ketone of Formula (VI). The hydroxyl protective group is then chemoselectively deprotected using HO, TTAF, LiOAc or DBU using suitable polar solvent like THF and IPA to obtain compound of Formula (VII).
In one preferred embodiment, R is methyl, Ri and R2 together form CH2S02Ph, PG4 and PG5 together with the oxygen atoms to which they are attached, form a diol protecting 5 membered heterocyclic ring optionally substituted with methyl groups; the compound (VII) obtained by the process of the invention includes compound of formula (VII)-A:
(Vll)-A
In a preferred embodiment compound (V)-A is converted to compound (VII)-A as shown in Scheme Dl
Scheme Dl
(V)-A (Vl)-A (Vll)-A wherein R is methyl, Ri and R2 together form CHbSChPh, PG4 and PG5 together with the oxygen atoms to which they are attached, form a diol protecting 5 membered heterocyclic ring which is optionally substituted with methyl groups, PG6 is mesyl (Ms) and PG7 is t- butyl diphenyl silyl (TBDPS).
The compounds of Formula (VI)-A and (VII)-A are hitherto unreported intermediates useful in the process for the preparation of halichondrin B analogs as described herein.
In yet another aspect, the invention provides a process for converting compound of Formula (VII) prepared by the process of the present invention into halichondrin analogs and particularly, eribulin or pharmaceutically acceptable salts thereof.
Accordingly, an embodiment of the process for the preparation of eribulin is as shown in Scheme E.
Scheme E
wherein R is methyl; PG4, PG5, ,Ri and R2, are as defined above, and wherein each of PG8, PG9, and PG10 are each independently H or Cl-6 alkyl or a hydroxyl protecting group; and X5 is a leaving group.
The compounds of Formula IX, X and XI are hitherto unreported intermediates useful in the process for the preparation of halichondrin B analogs as described herein.
In certain embodiments, one, two, or three of PG8, PG9, and PG10 of Formula (VIII), taken with the oxygen atom(s) to which they are bound, are silyl ethers or arylalkyl ethers. For example, one, two, or three of PG8, PG9, and PG10 of Formula (VIII) are t- butyldimethylsilyl (TBS) or benzyl, or all of PG8, PG9, and PG10 of Formula (VIII) are t- butyldimethylsilyl (TBS). In other embodiments, X3 is a halogen, (Cl-C6)alkylsulfonate, (C6-C10 aryl or CI -C6 heteroaryl) sulfonate, (C6-C15)aryl(Cl-C6)alkylsulfonate, or (CI- C6)heteroaryl (Cl-C6)alkyl sulfonate. Specific examples of X3 include iodide,
mesylate, toluenesulfonate, isopropylsulfonate, phenylsulfonate, nitro-phenylsulfonate (nosylate), and bromo-phenylsulfonate (brosylate ),
and benzylsulfonate.
In certain embodiments, one or both of PG8, PG9, and PG10 of Formula (VIII), taken with the oxygen atom(s) to which they are bound, are independently selected from esters, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chloro phenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-( ethylenedithio )pentanoate,
pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2- trichloro ethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p- nitrobenzyl.
Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta(trimethylsilyl) ethoxymethyl, and tetrahydro pyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, o-nitrobenzyl, pnitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl.
For example, in other embodiments, one, two, or three of PG8, PG9, and PG10 are t- butyldimethylsilyl (TBS), benzyl(Bz) or tos'yl (Ts), or all of PG8, PG9, and PG10 are t- butyldimethylsilyl (TBS) or tosyl (Ts).
In some embodiments PG8 and PG9 , together with the oxygen atoms to which they are attached, form a diol protecting 5- to 6-membered heterocyclic ring, which is optionally substituted with CI -4 alkyl groups. In other embodiments, PG8 and PG9 are taken together to form a cyclohexylidene protecting group.
In some embodiments X5 is halogen, such as iodide. In other embodiments, X5 is (Cl- C6)alkylsulfonate, (C6-C10 aryl or C1-C6 heteroaryl)sulfonate, (C6-C15)aryl(Cl- C6)alkyl sulfonate, or (CI -C6)heteroaryl(C 1 -C6)alkylsulfonate. Specific leaving groups include mesylate, toluenesulfonate, isopropylsulfonate, phenylsulfonate, or benzylsulfonate.
In an embodiment, compound of Formula (VII) is coupled with compound of Formula (VIII) in the presence of a base and a suitable solvent, similar to those as noted herein and disclosed in US Patent Number 6,214,865 Bl (incorporated herein by reference) to form an intermediate alcohol. This is followed by oxidation of the alcohol using reagents to give the compound of Formula (IX). Preferably, compound of Formula (VII) is treated with n-butyllithium then with the aldehyde of Formula (VIII). The resulting diol intermediate is then oxidized with Dess-Martin reagent to form the ketone-aldehyde intermediate of Formula (IX).
The compound of Formula (IX) is subjected to the reduction of the arylsulfonyl moiety using a reducing agent, for example and without limitation, Sml2; followed by an intramolecular coupling reaction, under conditions similar to those involved in the coupling of compound of Formula (I) with (II) in trivalent chromium, nickel and zinc. In an alternate method, the intramolecular coupling is performed in the presence of the chiral oxazole ligand, such as Ph-NMS-oxazole or sulfonamide to impart a higher yield and greater efficiency for the reaction. The subsequent oxidation using reagents as described above, can be performed to obtain compound of Formula (X).
Deprotection of the compound of Formula (X) can be performed using reagents known to a skilled person, for example, desilylation is performed using a fluoride source to give triol compound which is subjected to the intramolecular cyclization to result into the protected diol compound of Formula (XI). In one embodiment, for example and without limitation, the desilylation is performed using tetra-butyl ammonium fluoride (TBAF). In one embodiment, for example and without limitation, the intramolecular cyclization is performed using PPTS.
The deprotection of protected diol using suitable deprotecting agents such as PTSA results in the diol compound of Formula (XII).
Diol compound of Formula (XII) is useful intermediate for preparing various Halichondrin B analogs and particularly, eribulin or pharmaceutically acceptable salts thereof.
A selective protection of terminal alcohol of compound of Formula (XII) is carried out by converting the alcohol into a leaving group to form an intermediate compound followed by substitution of the leaving group by an amine or other nitrogen based nucleophile which results in eribulin.
In an embodiment, selective protection is carried out by using Ts20, TsCl, TMSOTf or MsCl in presence of a base such as collidine or lutidine.
In an embodiment, the amine or other nitrogen based nucleophile used is not limited to ammonia gas or a solution of ammonia in an organic solvent. In another embodiment, the nitrogen based nucleophile is an azide for example, trimethylsilyl azide (TMSN3).
The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. In some embodiments, reactions can be carried out in the absence of solvent, such as when at least one of the reagents is a liquid or gas.
Suitable solvents can include halogenated solvents, ether solvents, protic solvents, aprotic solvents, hydrocarbon solvents and the like.
The reactions of the processes described herein can be carried out at appropriate temperatures which can be readily determined by the skilled artisan. Reaction temperatures will depend on, for example, the melting and boiling points of the reagents and solvent, if present; the thermodynamics of the reaction (e.g., vigorously exothermic reactions may need to be carried out at reduced temperatures); and the kinetics of the reaction (e.g., a high activation energy barrier may need elevated temperatures). "Elevated temperature" refers to temperatures above room temperature (about 22°C). In some embodiments reaction may be performed below room temperature (below 22°C) or under subzero temperature ( below 0°C).
The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan.
In a preferred embodiment compound (VII)-A is converted to eribulin as shown in Scheme El
Scheme El
wherein R is methyl, R\ and R2 together form CH2S02Ph, PG4 and PG5 together with the oxygen atoms to which they are attached, form a diol protecting 5 membered heterocyclic ring which is optionally substituted with methyl groups, PG8 , PG9 , PG10 are TBS and X5 is iodo.
The compounds of Formula IX, X and XI are hitherto unreported intermediates useful in the process for the preparation of halichondrin B analogs as described herein.
Eribulin obtained by the process of the present invention may subsequently be converted to the corresponding pharmaceutically accepted salts by reacting with corresponding acid in suitable solvents.
The pharmaceutically acceptable salt of eribulin prepared according to the present invention, preferably having purity at least 98%, more preferably at least 99%, are selected from inorganic acid salt or organic acid salt. The inorganic acid salts may be
selected from but not limited to hydrochloride, sulfate, hydrobromide, hydroiodide, nitrate, bisulfate and phosphate salts.
The organic acid salts may be selected from but not limited to ascorbate, malonate, citrate, cinnamate , malate, isonicotinate, acetate, lactate, salicylate, tartrate, pantotenate, ascorbate, succinate, stearate maleate, fumarate, gluconate, saccharate, formate, benzoate, glutamate, mesyalte, esylate, benzenesulfonate , p-toluenesulfonate, pamoate, lactate, oleate, tannate and oxalate salts. Preferably, eribulin is converted to mesylate salt.
While emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.
The details of the invention given in the examples which are provided below are for illustration only and therefore these examples should not be construed to limit the scope of the invention.
Examples :-
Example 1 : Preparation of Compound (Ia):-
To a stirred solution of N, O-dimethyl hydroxyl amine hydrochloride (1.10 g, 0.011 mol) in DCM (20 ml), was added very slowly a solution of trimethyl alumina (2 M in toluene) (0.011 mol, 5.7 ml) at 0°C under argon atmosphere and the reaction mass was allowed to stir at same temp for 10 min. Compound Ila (0.7 g, 0.004 mol) was taken in dry DCM (10 ml) and added slowly to the above reaction mixture. Reaction mass was stirred at RT for 5 hr. Reaction mass was quenched with 1.3 M disodium tartrate at 0°C, organic layer was
extracted with ethyl acetate (3 x 50 ml), washed with water (10 ml) followed by brine (10 ml), dried over sodium sulphate and evaporated under reduced pressure to afford the compound la (0.4 g ) which was used for the next step without any further purification.
Example 2: Preparation of Compound (Ib :-
Compound la (0.4 g, Crude) was stirred in anhydrous THF (4 ml) and cooled to 0-5°C. Triethylamine (0.3 ml) was added followed by Methanesulfonyl Chloride (0.22 g). Stirred the reaction mass at 0-5 °C for 15 min. The reaction mixture was diluted with n-Heptane (100 ml). Organic layer was washed with brine (20 ml) solution and dried over sodium sulphate, evaporated under reduced pressure to give compound lb (0.45 g) which was used in the next step without further purification.
Example 3: Preparation of Compound (Ic and Id):-
To a stirred solution of compound lb (2 g, 6 mmol) in THF-H2O (4:1, 26 ml) at 0°C was added osmium tetroxide (4 ml, 1% t-BuOH solution) at 0°C and stirred for 5 min, followed by addition of NMO(1.2g,9.1mmol) under nitrogen atmosphere, RM stirred for 1 h at RT. After completion of the reaction, the reaction mass was quenched with aq.Na2S03 and extracted with 10% MeOH/DCM (2x 50 ml), washed with water (25 ml) followed by brine (25 ml), dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain the compound Ic which was taken for the next step without further purification.
Compound Ic, was dissolved in 10 ml anhydrous THF and was treated with 2,6-lutidine (3.6 ml, 30.5 mmol) and TBSOTf (3.33 ml, 18.3 mmol) at 0°C. The reaction mass was
allowed to warm to ambient temperature and stirred for 1 h. The reaction mass was quenched with MeOH (1 ml). The mixture was diluted with MTBE and the organic layer washed twice with saturated aqueous CuS04, dried over MgS04, filtered, and evaporated under reduced pressure to give crude compound Id. Crude compound Id was purified by column chromatography using Si02 and eluted with MTBE /hexanes mixture to give pure compound Id (yield 2g, 80%).
Example 4: Preparation of Compound (le):-
To a stirred solution of Id (2.0 g, 3.6 mmol) in anhydrous THF (80 ml) was treated with DIBAL-H (1.0 M in toluene, 3.6 ml at 0-5°C slowly over 30 min and stirred the reaction, mixture at same temperature for lh. Reaction mixture was quenched with MeOH (0.5 ml). MTBE (100 ml) was added followed by aqueous Rochelle's salt (50 ml), and stirred at room temperature for 30 min. The organic layer was separated, and the organic layer was washed with saturated aqueous Rochelle's salt (10 ml), water (20 ml), saturated NaHC03 (20 ml), and brine (20 ml). The organic layer was dried over MgS04, filtered, and concentrated to give Ie (Yield 1 g, 60%) as a colorless oil, which was taken onto the next step without further purification.
Example 5: Preparation of Compound (I)-A:-
le If Ί-Α
To a solution of triphenylphosphine (1.0 g, 8.0 mmol) in CH2CI2 (20 ml) was added a solution of carbon tetrabromide (1.3 g, 4 mmol) in CH2CI2 (10 ml) at 0-5°C and the resultant suspension was stirred for 15 min. A solution of compound (Ie) (lg, 2.0 mmol)
in CH2Cb (2 ml) was added via syringe at 0-5 °C over 30 min. The reaction mixture was stirred at 10-15°C for 1 h and then evaporated. The residue was passed through a short pad of silica gel and the solvent evaporated. The residue (If) was taken for next step without purification.
To a stirred solution of (If) (1.1 g, 1.69 mmol) in anhydrous THF (20 ml) at -78°C was added under nitrogen a solution of BuLi (1.6 M in hexane 2.1 ml, 3.38 mmol). The reaction mixture was further stirred at -78 °C for 1 h and then the temperature raised to 20-25°C. A 1.0 M solution of Iodo-9-BBN in hexane (3.5 ml, 3.5 mmol) was added. After being stirred at room temperature for 2 h, the reaction mixture was quenched with saturated aqueous NH4C1 solution and extracted with MTBE (3X 50 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na2S04, and evaporated under reduced pressure. Crude compound I-A was purified by column chromatography using Si02 and eluted with a mixture of MTBE: Hexane to give pure compound I-A (Yield 550 mg, 52%).
Example 6: Preparation of Compound (II):
Compound (A) (500 mg, 1 eq) was dissolved in Acetone (10 Vol) and DM water (8 Vol). The reaction mixture was cooled to 10-15°C. Then Charged NMO (0.214 g, 1.5 eq) in one portion into the reaction mass and stirred for 15 min. Os04 (4% solution in water) (0.01 eq) was added drop wise by keeping internal temp below 20°C. The temperature was raised to 20-25°C and stirred for 2 hrs. Reaction was monitored by TLC (10% Ethyl acetate in Hexane, KMn04 active). Poured the reaction mass into 10% sodium bisulphite solution (15 Vol) and extracted with Ethyl acetate (3x 5 Vol). The combined organic layers were washed with brine solution (5 Vol), dried over Na2S04 and evaporated under reduced pressure below 45°C to get 300 mg Di-ol intermediate.
Di-ol intermediate (300 mg) was dissolved in Methanol (3.0 ml, 10.0 Vol) and DM water (1.2 ml, 4.0 Vol) at 20-25°C. NaI04 (0.296 g, 2.0 eq) was charged in one portion
into the reaction mass at 20-25°C and stirred for 1 hr at the same temp. Reaction was monitored by TLC (10% Ethyl acetate in Hexane, KMn04 active). Reaction mass was quenched with water (10 Vol) and extracted with Chloroform (3x 8 Vol). The combined organic layer was washed with brine solution (5 Vol), dried (Na2S04) and evaporated under reduced pressure below 45°C to get the crude compound-(II). The crude compound was purified by column chromatography over silica gel (100-200 mesh) by eluting with 5-40% Ethyl acetate in Hexane. Desired fraction was concentrated to afford 150 mg (30%) of pure compound (II).
Example 7: Preparation of Compound (HI b):
Sulfonamide-C (53.0 mg, 0.22 eq) was weighed outside a glove box and put in a flask. In a glove box, proton sponge (30 mg, 0.22 eq), CrCl2 (12 mg, 0.20 eq) and MeCN (1.5 ml) were added and the resulting mass was then stirred at 25-30°C for 1 h. The resulting solution was added to a reaction vial containing mixture of compound (II) (200 mg, 1 eq), compound (I) (506 mg, 1.5 eq), LiCl (41 mg, 2.0 eq), Mn powder (53 mg, 2.0 eq), Zr(Cp)2Cl2 (212 mg, 1.5 eq) and NiCl2»dmp (3.1 mg, 0.05 eq). The resulting mass was stirred at 25-30°C in the glove box for 6 h. The reaction mixture was diluted with ethyl acetate (10 ml), and treated with florisil (0.5g). The resulting suspension was stirred for lh at 25-30°C and then passed through a short pad of silica gel. The solvent evaporated and the compound (Ilia) was taken for next step without purification.
Compound (Ilia) was stirred in anhydrous THF (106 ml) under argon atmosphere and cooled the reaction mixture to -15 -20° C, Then a solution of 0.5 M KHMDS in toluene (2 ml) was added at rate such that internal temperature did not exceed -12° C. Reaction
mixture was quenched with saturated ammonium chloride solution below 0°C. MTBE was added, stirred for 5 -10 min and the layers separated. Combined all the organic layers and washed with saturated ammonium chloride solution (10 ml) followed by brine solution (10 ml) and dried over sodium sulphate and evaporated under reduced pressure. The product was purified by column chromatography by using Si02 by eluting with Hexane / MTBE mixture. The fractions collected and evaporated to give (Illb) (Yield 170 mg, 43%).
Example 8: Preparation of Compound (Hie):
(Illb) (lllc)
To a stirred solution of (0.15 g, 0.18 mmol) compound (ΪΠ b) in anhydrous THF (20 ml), was added slowly a solution of tetrabutylammonium fluoride (0.7 ml, 0.7 mmol) (1.0 M solution in THF) at 0-5°C under argon atmosphere. Reaction mass was allowed to stirr at room temperature for 1 hour and the disappearance of the target compound was checked by TLC. The reaction mass was concentrated and the residue was purified by S1O2 column chromatography using Hexane/ MTBE, respective fractions were evaporated to give (IIIc) (Yield 70 mg, 70%).
Example 9: Preparation of Compound (III)-A:
Compound (IIIc) (0.1 g, 0.17 mmol) was dissolved in a mixture of ethyl acetate (2 ml) and water (2 ml). NaI04 (0.04 g, 0.19 mmol) was added portion wise over 1 hour at 0-5° C. The reaction mass was further stirred at 0-5 °C for 1 hour. The reaction mixture was treated with NaCl solid (1 g) at 0-5 °C and further stirred at same temperature for 30 min. The reaction mixture was filtered and the cake was washed with ethyl acetate (10 ml). Separated the organic layer, aqueous layer was extracted with ethyl acetate (3X 5 ml). The combined organic layers were washed with brine solution (5 ml). The organic layer was concentrated and the residue was stripped off with toluene (20 ml) and DCM (20 ml) and used for the next step without further purification.
Example 10: Preparation of Compound (V)-A :
Anhydrous chromous chloride (200 mg, 1.62 mmol) was taken in clean dry RBF under argon atmosphere in glove box. Sulfonamide A (500 mg, 1.62 mmol) was dissolved in dry THF (20 ml) and added to it followed by triethyl amine (0.23 ml, 1.62 mmol). The resulting light green solution was heated at 40°C for 1 hr and then cooled to 0°C. NiCI2 (23mg, 0.695 mmol) was added to the reaction mass under argon atmosphere followed by
the addition of compound (IV) (91 mg, 0.43 mmol) and compound (III) (200 mg, 0.36 mmol) in dry THF(2 ml). The reaction mass was allowed to stir at RT for 16 h, the reaction mass was diluted with THF (5 ml) and filtered over celite pad. The filtrate was concentrated under reduced pressure to obtain the compound (V)-A which was used in the next step without any further purification.
Example 1 1 : Preparation of Compound (VP:
To a stirred solution of crude compound (V)-A in Isopropyl Alcohol (3 ml), was added pyridine (0.15 ml) and PPTS (50 mg) and the reaction mass was stirred at room temperature under argon atmosphere for 16 hr. The reaction mass was evaporated under reduced pressure to afford the crude compound which was purified via column chromatography using 230-400 silica gel eluting with MTBE: Hexane mixture to afford compound (VI) (Yield 100 mg, 0.31%)
Example 12: Preparation of Compound (VII)-A:
(VI) (Vll)-A
Compound (VI) (150 mg, 0.166 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml), at room temperature under nitrogen atmosphere. Tetrabutylammonium fluoride (1M
in THF) (0.25 ml, 0.25 mmol) was added at 0-5°C over 30 min. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (5 ml) and the mixture was extracted with MTBE (3x 15 ml). The combined organic layers were dried over sodium sulphate, and evaporated under reduced pressure to give crude compound of (VII)-A. Crude was purified by column chromatography using MTBE: Hexane mixture as an eluent. The compound (VII)-A was afforded as a white foam (Yield 80 mg, 80%).
Example 13: Preparation of Compound ( IX):
Compound (VII) (50 mg, 0.075 mmol) was stirred in anhydrous tetrahydrofuran (2.5 ml) cooled to -75° C, and treated with n-butyl lithium (1.6M in hexane) of (0.24 ml) at same temperature and stirred for 30 min. A solution of Compound (VIII) (68 mg, 0.092 mmol) in n-hexane (3 ml) was added slowly at -75 °C over 10 min. The reaction mixture was stirred at -70 to -75° C for 30 min. The reaction mixture was quenched with saturated ammonium chloride (5 ml) and diluted with MTBE (15 ml) and water (5 ml). The organic layer was separated and dried over sodium sulphate, evaporated under reduced pressure to get crude compound. Crude was purified by column chromatography to give Hydroxy compound (Yield 75 mg, 71%) which was taken for the next step.
Hydroxy compound (75 mg, 0.05 mmol) was dissolved in dichloromethane (2 ml, moisture content~400 ppm) at rt. Dess-Martin (50 mg, 0.125mmol) was added in one portion at 20-25° C and stirred for 10 min. The reaction mixture was quenched with saturated sodium bicarbonate (2 ml) and 10 % aqueous sodium sulfite (2 ml) and stirred for 30 minutes. The mixture was diluted with saturated sodium chloride (5 ml) and extracted with MTBE (2X 15 ml). The aqueous layer was discarded and the organic layer
concentrated and purified by silica gel chromatography to afford compound (IX) (Yield 55 mg, 73%). The material was stored under inert gas atmosphere at -20° C.
Example 14: Preparation of Compound (X):
Samarium di-iodide solution (0.089 ml, 0.089 mmol) was taken in a pre-dried RBF under argon atmosphere and the solution cooled to internal temperature -70° C. Compound (IX) (50 mg, 0.035 mmol) was dissolved in a mixture of anhydrous methanol (0.5 ml) and anhydrous THF (0.5 ml) and cooled to -70°C. Compound (IX) was added to the cold samarium solution at a rate such that the internal temperature did not exceed -70°C. The reaction was quenched with potassium carbonate/ Rochelle's Salts/ water (1/10/100; w/w/v, 5 ml) and MTBE (15 ml) such that internal temperature did not exceed -65° C. Upon complete addition of the workup solution, the reaction was warmed to room temperature. The organic layer was separated, evaporated under reduced pressure. Crude was purified by column chromatography to afford de-sulfonyl compound (Keto-aldehyde) (Yield 25 mg, 55%). The material was stored under inert gas atmosphere at -20° C.
Sulfonamide-B (42 mg, 0.14 mmol) was weighed in a glove box under argon atmosphere. The CrCl2 (37 mg, 0.3 mmol) was added in one portion followed by anhydrous acetonitrile (2 ml) and the mixture was warmed and maintained temperature between 30- 35° C. Triethylamine (0.043 ml, 0.3mmol) was added in one portion and the mixture stirred for 1 h. The NiCl2 (4 mg, 0.03mmol) was added in one portion, followed by a solution of keto-aldehyde (50 mg, 0.03 mmol) in anhydrous THF (1.5 ml) over 30 minutes. The warm was removed, then heptane (20 ml) and Celite (0.5 g) were added. The mixture was stirred for 5 minutes and filtered over a pad of Celite (1.5 g) and the
Celite pad rinsed with heptane (20 ml) and acetonitrile (3 ml). Separated the heptane layers, combined and washed with acetonitrile (5 ml). The heptane layer was evaporated under reduced pressure and the product purified by silica gel chromatography to afford Cyclized-Hydroxy compound (Yield 28 mg, 68%).
Cyclized-Hydroxy compound (50 mg, 0.044 mmol) was dissolved in dichloromethane (3 ml, moisture content~400 ppm) at rt. Dess-Martin (28 mg, 0.066mmol) was added, stirred for 10 min at rt. The reaction mixture was quenched with saturated sodium bicarbonate (3 ml) and 10 % aqueous sodium sulfite (3 ml) and stirred for 30 minutes. The mixture was diluted with saturated sodium chloride (5 ml) and extracted with DCM (2X 15 ml). The aqueous layer was discarded and the organic layer concentrated and purified by silica gel chromatography to afford compound (X) (Yield 35 mg, 73%). The material was stored under inert gas atmosphere at -20° C.
Example 15: Preparation of Compound (XI):
To a solution of imidazole hydrochloride (60 mg, 0.56 mmol), 1 M TBAF in THF (1.4 ml, 1.4 mmol) was taken in anhydrous THF (0.5 ml) at ambient temperature under nitrogen atmosphere, The resulting mixture was stirred for 20-30 min until it is homogenous. Into another RBF, compound (X) (80 mg, 0.07 mmol) was taken in anhydrous THF (4 ml) and stirred for 10-15 min until compound dissolve completely. The TBAF/Imidazole mixture was charged as single portion into the reaction mixture and stirred at rt for 3-4 days. Crude was purified by silica gel chromatography to afford pure TBS de-protected compound.
TBS de-protected compound was dissolved in anhydrous dichloromethane (4 ml) under a nitrogen atmosphere and treated with PPTS (105 mg, 0.42 mmol). After 40-60 minutes, the reaction mixture was directly purified by column chromatography. Collected all the fractions and evaporated under reduced pressure, strip off toluene (2X10 ml) to give compound (XI) (Yield 26 mg, 46%).
Example 16: Preparation of Compound (XII):
To a solution of compound (XI) (50 mg, 0.06mmol) in a mixture of isopropyl acetate (3 ml) and propionic acid (1 ml), after the addition of water (0.5 ml), was added at 0-5° C p- toluene sulfonic acid (3mg, cat amount) in 0.1ml in water under nitrogen atmosphere. Then, the reaction mixture was stirred at room temperature for 3 h. After complete conversion of (XI) diluted the reaction mixture with isopropyl acetate (15 ml) and washed with water (2X 5 ml) and brine solution (5 ml). The organic layer was dried over sodium sulphate and evaporated under reduced pressure to afford the crude compound (XII) which was used for the next step without any further purification.
Example 17: Preparation of Eribulin:
Accordingly, Compound (XII) (40 mg, 0.05 mmol) was stripped off with anhydrous toluene ( 2 x 3 ml) and then diluted with anhydrous DCM (3 ml) under argon atmosphere. Collidine (0.054 ml, 0.4mmol) was added, followed by anhydrous DCM containing catalytic amount of pyridine (1.5 ml). The resulting mixture was cooled to an internal temperature of -20 to -25°C. p-Toluenesulfonic anhydride (18 mg, 0.055 mmol) in anhydrous DCM (0.5 ml) under argon atmosphere was added slowly maintaining internal temperature below -16°C. The reaction was stirred at -20 to-25°C for 90 minutes then warmed to 0°C over 20 minutes and stirred for an additional 30 minutes. The reaction mixture was quenched with water (2 ml). The bath was removed and reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was transferred to another flask containing IPA (20 ml) and aqueous ammonium hydroxide (20 ml) at room temperature, stirred for 24 hours. The reaction was concentrated to dryness or near dryness at reduced pressure. The resulting material was diluted with DCM (20 ml) and washed pH 10 buffer (NaHC03/Na2C03 (aq), 20 ml). The aqueous phase was back extracted with DCM (2X25 ml) and the combined organic layers were concentrated to dryness. The resulting free amine (eribulin crude) was purified by Reverse phase column chromatography. The pooled fractions were evaporated under reduced pressure below 30°C and lyophilized the material to afford Eribulin (Yield 26 mg, 65 %).
Claims
We claim;
1. A process for the preparation of compound of formula I
comprising steps of :
(ii) reacting with a suitable hydroxylating agent, to form vicinal diol of Formula ( Ic)
(iii) protecting using suitable protecting agent to form compound of Formula (Id):
(Id)
(le)
(V) reacting with suitable halogenatin agent to form compound of Formula (If):
and
(vi) alkynetion and haloboration to form compound of Formula (I);
wherein PGi, PG2 and PG3 are independently hydrogen or a hydroxyl protecting groups, preferably mesyl, tosyl, t-butyldimethyl silyl (TBS) and t-butyldiphenyl silyl (TBDPS); and Xi, X2 and X3 are leaving group, preferably halide, more preferably bromo and iodo.
3. A process for the preparation of com ound of formula III
(III)
which comprises, converting compound of formula I into compound of formula III; wherein PGi, PG2 , PG3 , X2 and X3 are as defined above and each of PG4 and PG5 are independently H or CI -6 alkyl; or PG4 and PG5, together with the oxygen atoms to which they are attached, form a diol protecting 5- to 6-membered
heterocyclic ring, which is optionally substituted with CI -4 alkyl groups; Ri and R2 each independently is H, -CH2OR3 or -CH2S02Ar, or Ri and R2 together form =CH2S02Ar, wherein R3 is H or a hydroxyl protecting group; and Ar is an aryl group; and R is H, CI -6 alkyl or CI -6 haloalkyl.
4. The process according to claim 3, wherein said conversion comprises steps of : (i) intramolecular coupling (Nozaki-Hiyama-Kishi [NHK] coupling) of compound of Formula (I) with compound of Formula II)
(Ilia)
intramolecular cyclization (oxy- Michael ring closure) to form compound of Formula (Illb) :
(Illb)
(iv) reducing with suitable reducing agent to form compound of Formula (III); wherein PGi, PG2, PG3, PG4, PG5, R , Ri and R2 are as defined above.
5. The process according to claim 3 or 4,. wherein the compound of formula III is a compound of formula (I -A )
(lll)-A
6. A process for the preparation of compound of formula V
(V)
which comprises, converting compound of formula III into compound of formula V; wherein PG4, PG5, R, Ri and R2 are as defined above and each of PG6 and PG7 are independently hydrogen or a hydroxyl protecting group.
7. The process according to claim 6, wherein said conversion comprises steps of : intramolecular coupling (NHK coupling) of compound of Formula (III) with compound of Formula (IV
wherein PG4, PG5, PG6 , PG7, R, Ri and R2 are as defined above and X4 is a leaving group.
8. The process according to claim 6 or 7, wherein the compound of formula V is a compound of formula ( V-A )
(V)-A
9. A process for the reparation of compound of formula VII
(VII)
which comprises, converting compound of formula V into compound of formula VII; wherein PG4, PG5, PG6 , PG7, R, Ri and R2 are as defined above.
. The process according to claim 9, wherein said conversion comprises steps of : (i) intramolecular cyclization
(oxy- Michael ring closure) of compound of Formula (V) to form com ound of Formula (VI) :
and
(ii) removal of protecting group to form compound of Formula (VII);
wherein PG4, PG5, PG6, PG7, R, Riand R are as defined above.
11. The process according to claim 9 or 10, wherein the compound of formula VII is a compound of formula -A )
(Vll)-A
12. A process for preparing eribulin, or a pharmaceutically acceptable salt thereof, said process comprising the steps of:
(a) producing a compound of Formula (VII) or (VII-A) by the method of any one of claims 1-1 1 ;
(b) reacting the compound of Formula (VII) or (VII-A) under suitable conditions to produce eribulin, or the pharmaceutically acceptable salt thereof.
13. A process for preparing eribulin substantially as described herein with reference to the examples.
14. Eribulin in substantially pure form.
15. Eribulin according to claim 14, having a chemical purity of greater than about 99% by weight.
16. Eribulin according to claim 14 or claim 15, prepared according to the process of claim 12.
17. Novel intermediate compound of formula (I);
(I) wherein PGi, PG2, PG3 and Xi are as defined above.
18. Novel intermediate compound of formula I-A;
(l)-A
19. Novel intermediate compound of formula (III);
20. Novel intermediate compound of formula III-A
(lll)-A
21. Novel intermediate compound of formula (V);
wherein PG4, PGs ,PG6, PG7, R, Ri and R2 are as defined above.
22. Novel intermediate compound of formula (V-A);
(V)-A
23. Novel intermediate com ound of formula VII;
(VII)
wherein PG4, PG5, R, Ri and R2 are as defined above. 24. Novel intermediate compound of formula VII-A;
(Vll)-A
25. Use of compound according to any one of claims 17 to 24 for preparing eribulin or pharmaceutically acceptable salts thereof.
26. Process for preparing eribulin or pharmaceutically acceptable salts thereof using at least one compound according to any one of the claims 17 to 24
27. The process according to claim 1, further comprises preparing the compound of Formula (la); by reacting compound of Formula Ila)
with dimethyl hydroxyl amine.
28. A process for preparing a pharmaceutical composition containing eribulin or pharmaceutically acceptable salts thereof comprising, preparing eribulin or pharmaceutically acceptable salts thereof in accordance with a process of any claims 1 to 16 or 25 and converting eribulin or pharmaceutically acceptable salts thereof into the pharmaceutical composition.
29. Eribulin or pharmaceutically acceptable salts thereof substantially as herein described with reference to the examples.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/510,077 US10208058B2 (en) | 2014-09-09 | 2015-09-09 | Process for the preparation of macrocyclic ketone analogs of halichondrin B or pharmaceutically acceptable salts and intermediates thereof |
EP15805635.8A EP3191479B1 (en) | 2014-09-09 | 2015-09-09 | "process for the preparation of macrocyclic ketone analogs of halichondrin b or pharmaceutically acceptable salts and intermediates thereof" |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN2869/MUM/2014 | 2014-09-09 | ||
IN2869MU2014 | 2014-09-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016038624A1 true WO2016038624A1 (en) | 2016-03-17 |
Family
ID=54834881
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2015/000354 WO2016038624A1 (en) | 2014-09-09 | 2015-09-09 | "process for the preparation of macrocyclic ketone analogs of halichondrin b or pharmaceutically acceptable salts and intermediates thereof" |
Country Status (3)
Country | Link |
---|---|
US (1) | US10208058B2 (en) |
EP (1) | EP3191479B1 (en) |
WO (1) | WO2016038624A1 (en) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9938288B1 (en) | 2017-04-05 | 2018-04-10 | President And Fellows Of Harvard College | Macrocyclic compound and uses thereof |
WO2018187331A1 (en) | 2017-04-05 | 2018-10-11 | President And Fellows Of Harvard College | Macrocyclic compound and uses thereof |
WO2018217894A1 (en) * | 2017-05-24 | 2018-11-29 | Eisai R&D Management Co., Ltd. | Fluorine-labelled halichondrin derivatives and related methods of synthesis |
WO2019099646A1 (en) | 2017-11-15 | 2019-05-23 | President And Fellows Of Harvard College | Macrocyclic compounds and uses thereof |
US10344038B2 (en) | 2015-04-30 | 2019-07-09 | President And Fellows Of Harvard College | Chromium-mediated coupling and application to the synthesis of halichondrins |
US10392400B2 (en) | 2016-11-11 | 2019-08-27 | President And Fellows Of Harvard College | Palladium-mediated ketolization |
WO2019211877A1 (en) * | 2018-05-03 | 2019-11-07 | Cipla Limited | Process for the preparation of macrocyclic ketone analogs of halichondrin b |
US10556910B2 (en) | 2014-06-30 | 2020-02-11 | President And Fellows Of Harvard College | Synthesis of halichondrin analogs and uses thereof |
US10611773B2 (en) | 2013-11-04 | 2020-04-07 | Eisai R&D Management Co., Ltd. | Macrocyclization reactions and intermediates and other fragments useful in the synthesis of analogs of halichondrin B |
US10676481B2 (en) | 2016-02-12 | 2020-06-09 | Eisai R&D Management Co., Ltd. | Intermediates in the synthesis of eribulin and related methods of synthesis |
US10717743B2 (en) | 2007-10-03 | 2020-07-21 | Eisai R&D Management Co., Ltd. | Intermediates and methods for the synthesis of halichondrin B analogs |
US10913749B2 (en) | 2015-05-07 | 2021-02-09 | Eisai R&D Management Co., Ltd. | Macrocyclization reactions and intermediates and other fragments useful in the synthesis of halichondrin macrolides |
US11136335B2 (en) | 2016-06-30 | 2021-10-05 | Eisai R&D Management Co., Ltd. | Prins reaction and intermediates useful in the synthesis of halichondrin macrolides and analogs thereof |
US11498892B2 (en) | 2017-07-06 | 2022-11-15 | President And Fellows Of Harvard College | Fe/Cu-mediated ketone synthesis |
US11542269B2 (en) | 2018-01-03 | 2023-01-03 | Eisai R&D Management Co., Ltd. | Prins reaction and compounds useful in the synthesis of halichondrin macrolides and analogs thereof |
US11548898B2 (en) | 2017-07-06 | 2023-01-10 | President And Fellows Of Harvard College | Synthesis of halichondrins |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113527146B (en) * | 2021-08-19 | 2023-04-18 | 广东药科大学 | Method for preparing beta-hydroxy-difluoro sulfonyl ester compound by promoting hydroxylation sulfonyl esterification reaction of difluoro alkene by molecular oxygen |
WO2023212746A2 (en) * | 2022-04-30 | 2023-11-02 | William Marsh Rice University | A unified strategy for the total syntheses of eribulin and a macrolactam analogue of halichondrin b |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6214865B1 (en) | 1998-06-17 | 2001-04-10 | Eisai Co., Ltd. | Macrocyclic analogs and methods of their use and preparation |
WO2005118565A1 (en) * | 2004-06-03 | 2005-12-15 | Eisai Co., Ltd. | Intermediates for the preparation of halichondrin b |
WO2009046308A1 (en) * | 2007-10-03 | 2009-04-09 | Eisai R & D Management Co., Ltd. | Intermediates and methods for the synthesis of halichondrin b analogs |
-
2015
- 2015-09-09 US US15/510,077 patent/US10208058B2/en not_active Expired - Fee Related
- 2015-09-09 EP EP15805635.8A patent/EP3191479B1/en active Active
- 2015-09-09 WO PCT/IN2015/000354 patent/WO2016038624A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6214865B1 (en) | 1998-06-17 | 2001-04-10 | Eisai Co., Ltd. | Macrocyclic analogs and methods of their use and preparation |
WO2005118565A1 (en) * | 2004-06-03 | 2005-12-15 | Eisai Co., Ltd. | Intermediates for the preparation of halichondrin b |
WO2009046308A1 (en) * | 2007-10-03 | 2009-04-09 | Eisai R & D Management Co., Ltd. | Intermediates and methods for the synthesis of halichondrin b analogs |
Non-Patent Citations (11)
Title |
---|
"Compound Summary for CID 68014084", 30 November 2012 (2012-11-30), pages 1 - 11, XP055241226, Retrieved from the Internet <URL:http://pubchem.ncbi.nlm.nih.gov/compound/68014084#x304> [retrieved on 20160114] * |
"Synthesis", 2007, JOHN WILEY & SONS |
AICHER, T. D. ET AL., J. AM. CHEM. SOC., vol. 114, pages 3162 - 3164 |
BRIAN AUSTAD ET AL: "Commercial Manufacture of Halaven : Chemoselective Transformations En Route to Structurally Complex Macrocyclic Ketones", SYNLETT, vol. 24, no. 03, 5 February 2013 (2013-02-05), DE, pages 333 - 337, XP055241364, ISSN: 0936-5214, DOI: 10.1055/s-0032-1318026 * |
GREENE ET AL.: "Protective Groups in Organic Synthesis", 2007, WILEY & SONS |
LEI LIU ET AL: "Supporting Information for Synthesis of Alcohols from m-Fluorophenylsulfones and Di-alkylboranes: Application to the C14-C35 Building Block of E7389", 24 April 2012 (2012-04-24), pages S1 - S55, XP055242304, Retrieved from the Internet <URL:http://pubs.acs.org/doi/suppl/10.1021/ol300672q/suppl_file/ol300672q_si_001.pdf> [retrieved on 20160118] * |
LEI LIU ET AL: "Synthesis of Alcohols from m -Fluorophenylsulfones and Dialkylboranes: Application to the C14-C35 Building Block of E7389", ORGANIC LETTERS, vol. 14, no. 9, 4 May 2012 (2012-05-04), US, pages 2262 - 2265, XP055241188, ISSN: 1523-7060, DOI: 10.1021/ol300672q * |
THEODORA W GREENE ET AL: "CHAPTER 2: PROTECTION FOR THE HYDROXYLGROUP, INCLUDING 1,2- AND 1,3-DIOLS", 1 January 1999, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, JOHN WILEY & SONS, INC, NEW YORK, NY [U.A.], PAGE(S) 17 - 245, ISBN: 978-0-471-16019-9, XP009107105 * |
XIANG LIU ET AL: "Dramatic Improvement in Catalyst Loadings and Molar Ratios of Coupling Partners for Ni/Cr-Mediated Coupling Reactions: Heterobimetallic Catalysts", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 131, no. 46, 25 November 2009 (2009-11-25), US, pages 16678 - 16680, XP055241186, ISSN: 0002-7863, DOI: 10.1021/ja9079308 * |
ZHAO-KUI WAN ET AL: "Asymmetric Ni(II)/Cr(II)-Mediated Coupling Reaction:? Stoichiometric Process", ORGANIC LETTERS, vol. 4, no. 25, 1 December 2002 (2002-12-01), pages 4431 - 4434, XP055040186, ISSN: 1523-7060, DOI: 10.1021/ol0269805 * |
ZHAO-KUI WAN ET AL: "Supporting Information Asymmetric Ni(II)/Cr(II)-mediated Coupling Reaction: Stoichiometric Process", 9 November 2002 (2002-11-09), XP055241344, Retrieved from the Internet <URL:http://pubs.acs.org/doi/suppl/10.1021/ol0269805/suppl_file/ol0269805si20021026_071534.pdf> [retrieved on 20160114] * |
Cited By (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10717743B2 (en) | 2007-10-03 | 2020-07-21 | Eisai R&D Management Co., Ltd. | Intermediates and methods for the synthesis of halichondrin B analogs |
US11643418B2 (en) | 2013-11-04 | 2023-05-09 | Eisai R&D Management Co., Ltd. | Macrocyclization reactions and intermediates and other fragments useful in the synthesis of analogs of halichondrin B |
US10934307B2 (en) | 2013-11-04 | 2021-03-02 | Eisai R&D Management Co., Ltd. | Macrocyclization reactions and intermediates and other fragments useful in the synthesis of analogs of halichondrin B |
US10611773B2 (en) | 2013-11-04 | 2020-04-07 | Eisai R&D Management Co., Ltd. | Macrocyclization reactions and intermediates and other fragments useful in the synthesis of analogs of halichondrin B |
US11155562B2 (en) | 2014-06-30 | 2021-10-26 | President And Fellows Of Harvard College | Synthesis of halichondrin analogs and uses thereof |
US10556910B2 (en) | 2014-06-30 | 2020-02-11 | President And Fellows Of Harvard College | Synthesis of halichondrin analogs and uses thereof |
US11220513B2 (en) | 2015-04-30 | 2022-01-11 | President And Fellows Of Harvard College | Chromium-mediated coupling and application to the synthesis of halichondrins |
US10344038B2 (en) | 2015-04-30 | 2019-07-09 | President And Fellows Of Harvard College | Chromium-mediated coupling and application to the synthesis of halichondrins |
US10633392B2 (en) | 2015-04-30 | 2020-04-28 | President And Fellows Of Harvard College | Chromium-mediated coupling and application to the synthesis of halichondrins |
US10913749B2 (en) | 2015-05-07 | 2021-02-09 | Eisai R&D Management Co., Ltd. | Macrocyclization reactions and intermediates and other fragments useful in the synthesis of halichondrin macrolides |
US10676481B2 (en) | 2016-02-12 | 2020-06-09 | Eisai R&D Management Co., Ltd. | Intermediates in the synthesis of eribulin and related methods of synthesis |
US11136335B2 (en) | 2016-06-30 | 2021-10-05 | Eisai R&D Management Co., Ltd. | Prins reaction and intermediates useful in the synthesis of halichondrin macrolides and analogs thereof |
US10844073B2 (en) | 2016-11-11 | 2020-11-24 | President And Fellows Of Harvard College | Palladium-mediated ketolization |
US10392400B2 (en) | 2016-11-11 | 2019-08-27 | President And Fellows Of Harvard College | Palladium-mediated ketolization |
US9938288B1 (en) | 2017-04-05 | 2018-04-10 | President And Fellows Of Harvard College | Macrocyclic compound and uses thereof |
US11725015B2 (en) | 2017-04-05 | 2023-08-15 | President And Fellows Of Harvard College | Macrocyclic compound and uses thereof |
US10954249B2 (en) | 2017-04-05 | 2021-03-23 | President And Fellows Of Harvard College | Macrocyclic compound and uses thereof |
WO2018187331A1 (en) | 2017-04-05 | 2018-10-11 | President And Fellows Of Harvard College | Macrocyclic compound and uses thereof |
EP4119563A2 (en) | 2017-04-05 | 2023-01-18 | President And Fellows Of Harvard College | Macrocyclic compound and uses thereof |
WO2018217894A1 (en) * | 2017-05-24 | 2018-11-29 | Eisai R&D Management Co., Ltd. | Fluorine-labelled halichondrin derivatives and related methods of synthesis |
US11548898B2 (en) | 2017-07-06 | 2023-01-10 | President And Fellows Of Harvard College | Synthesis of halichondrins |
US11498892B2 (en) | 2017-07-06 | 2022-11-15 | President And Fellows Of Harvard College | Fe/Cu-mediated ketone synthesis |
US11407762B2 (en) | 2017-11-15 | 2022-08-09 | President And Fellows Of Harvard College | Macrocyclic compounds and uses thereof |
WO2019099646A1 (en) | 2017-11-15 | 2019-05-23 | President And Fellows Of Harvard College | Macrocyclic compounds and uses thereof |
US11814398B2 (en) | 2017-11-15 | 2023-11-14 | President And Fellows Of Harvard College | Macrocyclic compounds and uses thereof |
US11542269B2 (en) | 2018-01-03 | 2023-01-03 | Eisai R&D Management Co., Ltd. | Prins reaction and compounds useful in the synthesis of halichondrin macrolides and analogs thereof |
WO2019211877A1 (en) * | 2018-05-03 | 2019-11-07 | Cipla Limited | Process for the preparation of macrocyclic ketone analogs of halichondrin b |
Also Published As
Publication number | Publication date |
---|---|
EP3191479B1 (en) | 2020-04-08 |
US20170240561A1 (en) | 2017-08-24 |
US10208058B2 (en) | 2019-02-19 |
EP3191479A1 (en) | 2017-07-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3191479B1 (en) | "process for the preparation of macrocyclic ketone analogs of halichondrin b or pharmaceutically acceptable salts and intermediates thereof" | |
JP6511613B2 (en) | Synthetic methods for the preparation of macrocyclic C1-keto analogues of halichondrin B and intermediates useful in said methods, such as intermediates containing -SO2- (p-tolyl) group | |
CA2567984C (en) | Intermediates for the preparation of analogs of halichondrin b | |
EP2797945B1 (en) | 2-((2s,3s,4r,5r)-5-((s)-3-amino-2-hydroxyprop-1-yl)-4-methoxy-3-(phenylsulfonylmethyl)tetrahydrofuran-2-yl)acetaldehyde derivatives and process for their preparation | |
JP5791636B2 (en) | Process for preparing entecavir and its intermediates | |
WO2008055814A2 (en) | Process for the preparation of (s)-4-fluoromethyl-dihydro-furan-2-one | |
WO2019211877A1 (en) | Process for the preparation of macrocyclic ketone analogs of halichondrin b | |
US20130296558A1 (en) | Preparation process of an antiviral drug (entecavir) and intermediates thereof | |
JP5960130B2 (en) | Preparation of tesetaxel and related compounds and corresponding synthetic intermediates | |
HoRITA et al. | Synthetic studies of halichondrin B, an antitumor polyether macrolide isolated from a marine sponge. 6. Synthesis of the C1-C15 unit via stereoselective construction of the B and A rings by kinetically and thermodynamically controlled Michael reactions with the aid of computational search for dominant conformers | |
US5508397A (en) | Activated macrolactams | |
JP3808735B2 (en) | Intermediates for synthesizing vinblastine, methods for producing them, and methods for synthesizing vinblastine | |
JP6528251B2 (en) | Crystalline derivatives of (S) -1-((2R, 3R, 4S, 5S) -5-allyl-3-methoxy-4- (tosylmethyl) tetrahydrofuran-2-yl) -3-aminopropan-2-ol | |
JP3037965B2 (en) | 2-Alkoxycarbonyl-2-methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative | |
JPH05229975A (en) | Cyclopentenol derivative | |
JP4406406B2 (en) | Intermediate for producing vinblastine by coupling reaction with bindrin | |
CN114057793A (en) | Tacrolimus derivative | |
JPH0977772A (en) | Epoxyketofuranoside derivative and intermediate for producing the same | |
JPH0761951A (en) | Biphenylcarboxylic acid ester derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15805635 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15510077 Country of ref document: US |
|
REEP | Request for entry into the european phase |
Ref document number: 2015805635 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015805635 Country of ref document: EP |