JP2008501715A - ハリコンドリンbの調製用中間体 - Google Patents
ハリコンドリンbの調製用中間体 Download PDFInfo
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- JP2008501715A JP2008501715A JP2007515643A JP2007515643A JP2008501715A JP 2008501715 A JP2008501715 A JP 2008501715A JP 2007515643 A JP2007515643 A JP 2007515643A JP 2007515643 A JP2007515643 A JP 2007515643A JP 2008501715 A JP2008501715 A JP 2008501715A
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- 238000002360 preparation method Methods 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- -1 C 1-4 haloaliphatic Chemical group 0.000 claims description 103
- 125000006239 protecting group Chemical group 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 14
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 14
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 13
- 125000001931 aliphatic group Chemical group 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 150000002009 diols Chemical group 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 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 6
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 5
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical class [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 150000005676 cyclic carbonates Chemical class 0.000 claims description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 141
- 239000000543 intermediate Substances 0.000 abstract description 41
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 150000002678 macrocyclic compounds Chemical class 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- 230000002062 proliferating effect Effects 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 207
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 192
- 238000006243 chemical reaction Methods 0.000 description 183
- 239000000243 solution Substances 0.000 description 182
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 168
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 128
- 239000010410 layer Substances 0.000 description 125
- 239000012044 organic layer Substances 0.000 description 92
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 67
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 53
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 51
- 239000012267 brine Substances 0.000 description 49
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- 238000000034 method Methods 0.000 description 40
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 235000019439 ethyl acetate Nutrition 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 29
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 29
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- 239000000706 filtrate Substances 0.000 description 25
- 239000000047 product Substances 0.000 description 25
- 239000007787 solid Substances 0.000 description 24
- 239000000725 suspension Substances 0.000 description 23
- 239000000284 extract Substances 0.000 description 21
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 239000012071 phase Substances 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- 239000007864 aqueous solution Substances 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 0 CC(C*C1OC(C2)[C@](*)[C@](*)C[C@@]12O1)CC1=O Chemical compound CC(C*C1OC(C2)[C@](*)[C@](*)C[C@@]12O1)CC1=O 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 239000011780 sodium chloride Substances 0.000 description 17
- 229910004298 SiO 2 Inorganic materials 0.000 description 16
- 239000012065 filter cake Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 13
- 239000012298 atmosphere Substances 0.000 description 13
- 239000012141 concentrate Substances 0.000 description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- FXNFULJVOQMBCW-VZBLNRDYSA-N halichondrin b Chemical compound O([C@@H]1[C@@H](C)[C@@H]2O[C@@H]3C[C@@]4(O[C@H]5[C@@H](C)C[C@@]6(C[C@@H]([C@@H]7O[C@@H](C[C@@H]7O6)[C@@H](O)C[C@@H](O)CO)C)O[C@H]5C4)O[C@@H]3C[C@@H]2O[C@H]1C[C@@H]1C(=C)[C@H](C)C[C@@H](O1)CC[C@H]1C(=C)C[C@@H](O1)CC1)C(=O)C[C@H](O2)CC[C@H]3[C@H]2[C@H](O2)[C@@H]4O[C@@H]5C[C@@]21O[C@@H]5[C@@H]4O3 FXNFULJVOQMBCW-VZBLNRDYSA-N 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 238000004821 distillation Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 7
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 7
- 150000005215 alkyl ethers Chemical class 0.000 description 7
- 150000001540 azides Chemical class 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 238000011065 in-situ storage Methods 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- AAWZDTNXLSGCEK-WYWMIBKRSA-N (-)-quinic acid Chemical compound O[C@@H]1C[C@](O)(C(O)=O)C[C@@H](O)[C@H]1O AAWZDTNXLSGCEK-WYWMIBKRSA-N 0.000 description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 6
- 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 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 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 6
- 239000000843 powder Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- ZBLLGPUWGCOJNG-UHFFFAOYSA-N Halichondrin B Natural products CC1CC2(CC(C)C3OC4(CC5OC6C(CC5O4)OC7CC8OC9CCC%10OC(CC(C(C9)C8=C)C%11%12CC%13OC%14C(OC%15CCC(CC(=O)OC7C6C)OC%15C%14O%11)C%13O%12)CC%10=C)CC3O2)OC%16OC(CC1%16)C(O)CC(O)CO ZBLLGPUWGCOJNG-UHFFFAOYSA-N 0.000 description 5
- 238000010533 azeotropic distillation Methods 0.000 description 5
- 238000009739 binding Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 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 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 150000002367 halogens Chemical group 0.000 description 5
- 125000004043 oxo group Chemical group O=* 0.000 description 5
- 125000005547 pivalate group Chemical group 0.000 description 5
- 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 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 125000003107 substituted aryl group Chemical group 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- BJDCWCLMFKKGEE-CMDXXVQNSA-N chembl252518 Chemical compound C([C@@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-CMDXXVQNSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000013058 crude material Substances 0.000 description 4
- 239000010779 crude oil Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000002346 iodo group Chemical group I* 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 239000001301 oxygen Chemical group 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000005191 phase separation Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000011593 sulfur Chemical group 0.000 description 4
- 229910052717 sulfur Chemical group 0.000 description 4
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 4
- 239000010409 thin film Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- SODPIMGUZLOIPE-UHFFFAOYSA-N (4-chlorophenoxy)acetic acid Chemical compound OC(=O)COC1=CC=C(Cl)C=C1 SODPIMGUZLOIPE-UHFFFAOYSA-N 0.000 description 3
- ZOJKRWXDNYZASL-NSCUHMNNSA-N (e)-4-methoxybut-2-enoic acid Chemical compound COC\C=C\C(O)=O ZOJKRWXDNYZASL-NSCUHMNNSA-N 0.000 description 3
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 3
- 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 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical compound O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 3
- JOOXCMJARBKPKM-UHFFFAOYSA-M 4-oxopentanoate Chemical compound CC(=O)CCC([O-])=O JOOXCMJARBKPKM-UHFFFAOYSA-M 0.000 description 3
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Classifications
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/42—Halogenated unsaturated alcohols acyclic
- C07C33/423—Halogenated unsaturated alcohols acyclic containing only double bonds as unsaturation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
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Abstract
Description
本願は、2004年6月3日付けの米国仮特許出願第60/576,642号、2004年11月10日付けの第60/626,769号、並びに2005年3月18日付けの第60/663,300号に優先権を主張するものであり、参照することで、それら各々の全ての内容をここに取り入れることとする。
一実施形態によれば、本発明は、化合物F−1を提供する。
PG1及びPG2の各々は、個々独立して、水素又は適切なヒドロキシ保護基であり;
R1は、R又はORであり;
R2は、CHO又は-CH=CH2であり;且つ
各Rは、個々独立して、水素、C1-4ハロ脂肪族、ベンジル、又はC1-4脂肪族である。但し、R1がOMeのとき、PG1及びPG2はアセトニド基を形成しない。
他の実施形態によれば、本発明は、化合物F−2を提供する。
LG1は、適切な脱離基であり;
Xは、ハロゲン又は-OSO2(Ry)であり;
Ryは、C1-6脂肪族又は5〜7員の飽和環、部分的に未飽和の環、又は完全に未飽和の環であり、ここでRyは、ハロゲン、R、NO2、CN、OR、SR、又はN(R)2から選択された3つまでの基によって任意に置換されており;
各Rは、個々独立して、水素、C1-4ハロ脂肪族、又はC1-4脂肪族であり;且つ
PG3は、適切なヒドロキシ保護基である。
R'は、-CH=CH2又は-C(O)Hであり;
Alkは、C1-4の直鎖又は分岐脂肪族基であり;且つ
PG5は、適切なヒドロキシ保護基である。
R''は、OH、OPG3、又はLG4であり;
LG4は、適切な脱離基であり;且つ
各PG3は、個々独立して、適切なヒドロキシ保護基である。但し、PG3がt-ブチルジフェニルシリルのとき、R''はOMs以外である。
nは、1、2、又は3であり;
PG5及びPG6の各々は、個々独立して、適切なヒドロキシ保護基であり;
Wは、CH-A又はC(O)であり;
Aは、オキソ又はC1-6脂肪族基であり、ここでAは、1つ又は複数のQ1基で任意に置換されており;
各Q1は、個々独立して、シアノ、ハロ、アジド、オキソ、OR、SR、SO2R、OSO2R、N(R)2、NR(CO)R、NR(CO)(CO)R、NR(CO)N(R)2、NR(CO)OR、(CO)OR、O(CO)R、(CO)N(R)2、O(CO)N(R)2、O(CO)N(R)2、又はOPG1であり、ここでPG1は適切なヒドロキシ保護基であり;
任意に、A上の2つのQ1は一緒になって、窒素、酸素又は硫黄から個々独立して選択された0〜4個のヘテロ原子を有する、3〜8員の、飽和環、部分的に未飽和の環、又はアリール環を形成し;
各Rは、個々独立して、水素、又はC1-6脂肪族、5〜10員の飽和環、部分的に未飽和の環又はアリール炭素環、又は窒素、酸素又は硫黄から個々独立して選択された0〜4個のヘテロ原子を有する、4〜10員の、飽和環、部分的に未飽和の環又はアリール環から選択された任意に置換された基であり;
任意に、同一窒素原子上の2つのR基は、前記窒素原子と一緒になって、窒素、酸素又は硫黄から個々独立して選択された1〜4個のヘテロ原子を有する、3〜8員の飽和環、部分的に未飽和の環、又はアリール環を形成する。
(1)Aは、ヒドロキシ、アミノ、アジド、ハロ、及びオキソから選択される少なくとも1つの置換基を有する;
(2)Aは、ヒドロキシ、アミノ、及びアジドから選択される少なくとも1つの置換基を有するC1-6アルキル基である;
(3)Aは、ヒドロキシ、アミノ、及びアジドから個々独立して選択される少なくとも2つの置換基を有する;
(4)Aは、ヒドロキシ及びアミノから個々独立して選択される少なくとも2つの置換基を有する;
(5)Aは、少なくとも1つのヒドロキシ置換基と少なくとも1つのアミノ置換基を有する;
(6)Aは、少なくとも2つのヒドロキシ置換基を有する;
(7)Aは、置換されているC2-4脂肪族基である;
(8)Aは、置換されているC3脂肪族基である;
(9)Aは、Gを含有する環にAを連結させる炭素原子に対しアルファ位にある(S)-ヒドロキシを有するか、又は(R)-ヒドロキシを有する;
(10)Aは、ヒドロキシ及びシアノから選択される少なくとも1つの置換基を有するC1-6飽和脂肪族基である
用語「(S)-ヒドロキシ」とは、ヒドロキシ基を有する炭素原子の配置が(S)であることを意味する。本発明の実施形態にはまた、Aが結合している炭素原子に対し、(1)アルファ位及びガンマ位、(2)ベータ位及びガンマ位、又は(3)アルファ位及びベータ位にある各炭素原子が少なくとも1つ置換されているような化合物も含まれる。アルファ位、ベータ位及びガンマ位の各炭素原子は、個々独立して、(R)又は(S)の配置にある。ある実施形態では、本発明は、Aが結合している炭素原子に対しアルファ位及びベータ位にある各炭素原子が少なくとも1つ置換されているような化合物を提供する。
さらに他の実施形態によれば、本発明は、化合物F−3を提供する。
各PG4は、個々独立して、適切なヒドロキシ保護基から選択され;
R3は、CHO又はC(O)OR4であり;
R4は、適切なカルボキシ保護基であり;且つ
LG2は、適切な脱離基である。
断片F−1及びF−2の結合は、一般に、以下のスキームVIIIに記載のようにして達成することができる。
ハリコンドリンB類似体B-1939の調製を例示すべく、以下の実施例では、本発明の方法及び化合物を用いたハリコンドリンBの合成を説明する。
溶媒系: 96:4(vol/vol)ヘプタン:tert-ブタノール(移動相)
擬似移動相型
クロマトク゛ラフィ装置: Knauer SMG System CSEP C912
等温式(ラングミュア型、前面分析(frantal analysis)により決定):
望ましくない異性体: Qi*=2.8768xCi/(1+0.02327xCi)
所望の異性体: Qi=4.5320xCi/(1+0.0034595xCi)
*Qi=固相濃度(g/L)及びCi=液層濃度(g/L)
カラム空隙率: 0.658
温度: 27℃
EuroChrom 2000 for Windows. SMB Guide ver. 1.2(Wissenschaftliche Geratebau Dr.-Ing. Herbert Knauer GmbH, D-14163 Berlin;作者H. Kniep及びA. Seidel-Morgenstern)を用いたシミュレーションにより算出した流速等:
原料濃度: 36g/L(ER-806909)
原料流速(ポンプ1): 15mL/min
溶離剤流速(ポンプ2):76.4mL/min
領域IV(ポンプ3)流速:107mL/min
領域II(ポンプ4)流速:134.3mL/min(実流速143.5mL/min)
領域I流速: 183.4mL/min
領域III流速: 149.3mL/min
ラフィネート*流速: 42.3mL/min *ラフィネート=弱く結合した異性体
エキストラクト流速: 49.1mL/min *エキストラクト=強く結合した異性体
接触時間
(ポート切替時間): 0.8864min(53.18sec、実接触時間=54sec)
上記プロトコルを用いて、以下のようにして、ER-806909の鏡像異性体を分離した。11時間の運転の間、ER-806909を36g/Lにて含む10Lの移動相を、直径142mm、細孔径0.45μmのナイロンフィルタ(Cole-Parmer #2916-48)を通して原料タンクへと、ポンプ(Silog model Chemtec)を用いて流した。溶離剤タンクは、1μmグラスファイバから成る直径45mmのインラインフィルタ(Whatman GFC)によって濾過処理された36Lの移動相によって満たし、運転中、さらに追加した。SMG装置の内部温度は27℃に調節した。
HPLC充填部: Varian (Rainin) Dynamax Rampak 41/77 mm Column Packing Station
HPLCポンプ: Varian (Rainin) SD-1 Titanium Pump Heads
第1HPLC検出器: Waters R403 Refractive Index detector
第2HPLC検出器: 分取フローセルを備えたVarian (Rainin) UV-1 detector
クロマトグラフィ
制御ソフトウェア: Varian (Rainin) Dynamax DA version 1.4.6
クロマトグラフィ
処理ソフトウェア: Varian (Rainin) Dynamax R version 1.4.3
移動相: 28.5:63.7:7.85 (vol/vol) n-ヘプタン:メチルtert-ブチルエーテル:2-プロパノール
流速: 140mL/min
カラム温度: 室温(25℃)
検出: 屈折率、16×減衰及び215nm UVにおいて陰性
移動相勾配: 勾配なし(isocratic)
Run時間: 40min
インジェクタ容積: 0.8g/mLのER-807527を10ml
上記プロトコルを用いて、以下のようにして、ER-807527のジアステレオマーを分離した。ER-807527の各ロットを、まず、0.1g/mlとなるよう移動相中に希釈させ、47mm、細孔径1μmのグラスファイバーフィルタ(Whatman GFC)を用いて真空濾過した。次いで濾過液を、ロータリーエバポレータを用いて真空下で濃縮させた。SD-1 HPLCポンプA(呼び水を差され、移動相によってパージされている)を始動し、流速を徐々に140mL/minへと高めた。UV検出器及びRI検出器のベースラインが安定するまで、系を洗浄した。RI検出器の参照フローセルには、未使用の移動相を流した。
実施例4aでは、上述のスキームVに記載のスキームを用いて、F2への中間体であるところの式Aの化合物を調製する代替法が提供される。この方法では、上述の実施例3で調製された中間体ER-812935(化合物4)を利用する。
実施例4bでは、上述のスキームVb及びVcに記載のスキームを用いて、式F−2の化合物を調製する代替法が提供される。この方法では、実施例4aで調製した中間体ER-817664が利用される。
実施例4cでは、上述のスキームVIIに記載のスキームを用いて式F−2の化合物を調製する他の代替法が提供される。この方法では、実施例3で調製した中間体ER-811510が利用され、ここで、シクロヘキサノンの代わりにアセトンが用いられる。
A.(R)又は(S)型のN-[2-(4-イソプロピル-4,5-ジヒドロ-オキサゾール-2-イル)-6-メチル-フェニル]-メタンスルホンアミドの調製
Claims (12)
- R1がORであり、ここでRが、水素、メチル、又はベンジルである、請求項2に記載の化合物。
- PG1及びPG2が両方とも水素である、請求項2に記載の化合物。
- PG1及びPG2の各々が、個々独立して、適切なヒドロキシ保護基である、請求項2に記載の化合物。
- PG1及びPG2の一方又は両方が、その各々が結合している酸素原子と一緒になってシリルエーテル又はアリールアルキルエーテルとなる、請求項5に記載の化合物。
- PG1及びPG2が両方ともt-ブチルジメチルシリルである、請求項6に記載の化合物。
- PG1及びPG2が、それらが結合している酸素原子と一緒になってジオール保護基を形成している、請求項5に記載の化合物。
- 前記ジオール保護基が、環状アセタール又はケタール、シリレン誘導体、環状カーボネート、又は環状ボロネートである、請求項8に記載の化合物。
- LG1が、スルホニルオキシ、任意に置換されたアルキルスルホニルオキシ、任意に置換されたアルケニルスルホニルオキシ、又は任意に置換されたアリールスルホニルオキシである、請求項2に記載の化合物。
- LG1が、メシル又はトシルである、請求項10に記載の化合物。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US57664204P | 2004-06-03 | 2004-06-03 | |
US60/576,642 | 2004-06-03 | ||
US62676904P | 2004-11-10 | 2004-11-10 | |
US60/626,769 | 2004-11-10 | ||
US66330005P | 2005-03-18 | 2005-03-18 | |
US60/663,300 | 2005-03-18 | ||
PCT/US2005/019669 WO2005118565A1 (en) | 2004-06-03 | 2005-06-03 | Intermediates for the preparation of halichondrin b |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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JP2012255149A Division JP5705814B2 (ja) | 2004-06-03 | 2012-11-21 | ハリコンドリンb類似体の調製用中間体 |
Publications (2)
Publication Number | Publication Date |
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JP2008501715A true JP2008501715A (ja) | 2008-01-24 |
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