JP2005068064A - Method for producing bongkrekic acid and precursor compound thereof - Google Patents
Method for producing bongkrekic acid and precursor compound thereof Download PDFInfo
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- JP2005068064A JP2005068064A JP2003299382A JP2003299382A JP2005068064A JP 2005068064 A JP2005068064 A JP 2005068064A JP 2003299382 A JP2003299382 A JP 2003299382A JP 2003299382 A JP2003299382 A JP 2003299382A JP 2005068064 A JP2005068064 A JP 2005068064A
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 71
- RGOJCHYYBKMRLL-UHFFFAOYSA-N 4-(trifluoromethoxy)benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(OC(F)(F)F)C=C1 RGOJCHYYBKMRLL-UHFFFAOYSA-N 0.000 title claims abstract description 22
- SHCXABJSXUACKU-XTXDISFPSA-N isobongkrekic acid Natural products COC(CC=C/C=C/CCC=CCC(C)C=CC(=C/C(=O)O)CC(=O)O)C(=C/C=C(C)/C(=O)O)C SHCXABJSXUACKU-XTXDISFPSA-N 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 title claims description 303
- 239000002243 precursor Substances 0.000 title abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 69
- 239000002253 acid Substances 0.000 claims description 82
- -1 dibromomethylidene Chemical group 0.000 claims description 65
- 125000003808 silyl group Chemical class [H][Si]([H])([H])[*] 0.000 claims description 53
- 125000003118 aryl group Chemical group 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 43
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 38
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims description 19
- 239000007800 oxidant agent Substances 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 16
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 16
- 125000003172 aldehyde group Chemical group 0.000 claims description 14
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 11
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 239000012351 deprotecting agent Substances 0.000 claims description 10
- 230000001590 oxidative effect Effects 0.000 claims description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 9
- 150000001340 alkali metals Chemical class 0.000 claims description 9
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 claims description 8
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 8
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 8
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 8
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 8
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 8
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 7
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 7
- 229960002218 sodium chlorite Drugs 0.000 claims description 7
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 150000008065 acid anhydrides Chemical class 0.000 claims description 5
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 claims description 5
- 239000012022 methylating agents Substances 0.000 claims description 5
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 4
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 4
- DDKMFOUTRRODRE-UHFFFAOYSA-N chloromethanone Chemical compound Cl[C]=O DDKMFOUTRRODRE-UHFFFAOYSA-N 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 4
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 4
- 230000005588 protonation Effects 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 3
- 235000019800 disodium phosphate Nutrition 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 239000011981 lindlar catalyst Substances 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- MJGFBOZCAJSGQW-UHFFFAOYSA-N mercury sodium Chemical compound [Na].[Hg] MJGFBOZCAJSGQW-UHFFFAOYSA-N 0.000 claims description 3
- 229910001023 sodium amalgam Inorganic materials 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 150000002440 hydroxy compounds Chemical group 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 138
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 230000008878 coupling Effects 0.000 abstract description 3
- 238000010168 coupling process Methods 0.000 abstract description 3
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 68
- 239000000243 solution Substances 0.000 description 64
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- 239000002904 solvent Substances 0.000 description 56
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- 239000012043 crude product Substances 0.000 description 40
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 38
- 238000003786 synthesis reaction Methods 0.000 description 38
- 230000015572 biosynthetic process Effects 0.000 description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 238000004440 column chromatography Methods 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 19
- 235000019341 magnesium sulphate Nutrition 0.000 description 19
- 230000035484 reaction time Effects 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 238000000746 purification Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 239000012230 colorless oil Substances 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 238000006138 lithiation reaction Methods 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000000605 extraction Methods 0.000 description 11
- 239000012046 mixed solvent Substances 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000007796 conventional method Methods 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 9
- 0 C[C@]1C(CC2)C2CC*1 Chemical compound C[C@]1C(CC2)C2CC*1 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- SIJBDWPVNAYVGY-UHFFFAOYSA-N 2,2-dimethyl-1,3-dioxolane Chemical compound CC1(C)OCCO1 SIJBDWPVNAYVGY-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000011261 inert gas Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical compound CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 description 4
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229910003849 O-Si Inorganic materials 0.000 description 4
- 229910003872 O—Si Inorganic materials 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 238000006859 Swern oxidation reaction Methods 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 150000002148 esters Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- YCOMFYACDCWMMD-WCTZXXKLSA-N (1r)-1-[(4r,5r)-5-[(1r)-1,2-dihydroxyethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]ethane-1,2-diol Chemical compound CC1(C)O[C@H]([C@H](O)CO)[C@@H]([C@H](O)CO)O1 YCOMFYACDCWMMD-WCTZXXKLSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229940043279 diisopropylamine Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 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 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- VBYOTISTNZJGRH-UHFFFAOYSA-N deca-2,6,8-trienoic acid Chemical compound CC=CC=CCCC=CC(O)=O VBYOTISTNZJGRH-UHFFFAOYSA-N 0.000 description 2
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride 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
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- MLIWQXBKMZNZNF-KUHOPJCQSA-N (2e)-2,6-bis[(4-azidophenyl)methylidene]-4-methylcyclohexan-1-one Chemical compound O=C1\C(=C\C=2C=CC(=CC=2)N=[N+]=[N-])CC(C)CC1=CC1=CC=C(N=[N+]=[N-])C=C1 MLIWQXBKMZNZNF-KUHOPJCQSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- TYISXKCAFNKLQV-UHFFFAOYSA-N 2,2-dimethyl-4,5-bis(oxiran-2-yl)-1,3-dioxolane Chemical compound C1OC1C1OC(C)(C)OC1C1CO1 TYISXKCAFNKLQV-UHFFFAOYSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910000497 Amalgam Inorganic materials 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241001135516 Burkholderia gladioli Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- ZWZUFQPXYVYAFO-UHFFFAOYSA-N Tert-butyl (triphenylphosphoranylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC(C)(C)C)C1=CC=CC=C1 ZWZUFQPXYVYAFO-UHFFFAOYSA-N 0.000 description 1
- GMTMQELZTNWUAC-UHFFFAOYSA-K [Pb+3].CC([O-])=O.[O-]C([O-])=O Chemical compound [Pb+3].CC([O-])=O.[O-]C([O-])=O GMTMQELZTNWUAC-UHFFFAOYSA-K 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- FXCLIEYDXXVEAI-UHFFFAOYSA-N benzene;dichloromethane Chemical compound ClCCl.C1=CC=CC=C1 FXCLIEYDXXVEAI-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- KPUNOVLMCQQCSK-UHFFFAOYSA-N diazomethane;ethoxyethane Chemical compound C=[N+]=[N-].CCOCC KPUNOVLMCQQCSK-UHFFFAOYSA-N 0.000 description 1
- CMMUKUYEPRGBFB-UHFFFAOYSA-L dichromic acid Chemical compound O[Cr](=O)(=O)O[Cr](O)(=O)=O CMMUKUYEPRGBFB-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000007789 gas Substances 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000019645 odor Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- AAGZZSXOPTZNPS-UHFFFAOYSA-M sodium periodic acid periodate Chemical compound [Na+].OI(=O)(=O)=O.[O-]I(=O)(=O)=O AAGZZSXOPTZNPS-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 125000002130 sulfonic acid ester group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
本発明は、アポトーシスの阻害活性を有することからアポトーシスに関する研究に必須の化合物として有用性の高いボンクレキン酸の前駆化合物であるボンクレキン酸のＣ１１〜Ｃ２２セグメントの製造法、並びに該セグメントを用いたボンクレキン酸の製造法に関する。 INDUSTRIAL APPLICABILITY The present invention has a method for producing C 11 to C 22 segments of boncrekinic acid, which is a precursor compound of boncrekinic acid, which is highly useful as an essential compound for research on apoptosis because of having an inhibitory activity on apoptosis, and using the segment The present invention relates to a method for producing boncrekinic acid.
ボンクレキン酸はボンクレク酸ともよばれ、一般にＡＴＰ−ＡＤＰ交換輸送体の阻害剤として知られており、下記構造式で示される。
ボンクレキン酸は、Pseudomonas cocovenenansという細菌が、ココナッツを培地とした場合に産生する化合物として単離されたが、既にその菌はボンクレキン酸を産生せず、現存する当該化合物は１ｇを切っている。
ボンクレキン酸の化学的合成法としては、２０年前に１例だけ速報で報告されているが（非特許文献１）、その詳細な実験方法は明らかでない。また、その合成法は、極めて高価な原料や試薬、及び高速液体クロマトグラフィーによる光学分割など大量供給には多くの問題があり、到底実用的とは言えない。最近、米国で市販品が出てきているが（製造方法は不明）、とてつもなく高価で実用性にはほど遠い。また、本発明者らは先に、ボンクレキン酸のＣ１〜Ｃ１０セグメントの効果的な製造法を確立すると共にボンクレキン酸のＣ１１〜Ｃ２２セグメントの製造法についても研究を行ない、その成果についても発表したが（特許文献１）、その後の研究で、このボンクレキン酸のＣ１１〜Ｃ２２セグメントの製造法に関しては再現性に問題があることが判明した。
化学合成によるボンクレキン酸の大量供給はアポトーシスの研究推進に必須であり、その効果的な製造法の確立が待たれている現状にある。
Bonglequinic acid is also called boncrecic acid and is generally known as an inhibitor of ATP-ADP exchange transporter, and is represented by the following structural formula.
Bonglequinic acid was isolated as a compound produced by a bacterium called Pseudomonas cocovenenans when coconut was used as a medium, but the bacterium already did not produce boncrekinic acid, and the existing compound was cut in 1 g.
As a chemical synthesis method of boncrekinic acid, only one case was reported 20 years ago (Non-Patent Document 1), but the detailed experimental method is not clear. In addition, the synthesis method has many problems in mass supply such as extremely expensive raw materials and reagents, and optical resolution by high performance liquid chromatography, and cannot be said to be practical at all. Recently, a commercial product has appeared in the United States (the manufacturing method is unknown), but it is extremely expensive and far from practical. In addition, the present inventors previously established an effective production method for the C 1 to C 10 segment of boncrekinic acid and also conducted research on the production method for the C 11 to C 22 segment of boncrekinic acid, and the results thereof. (Patent Document 1), however, in subsequent studies, it was found that there was a problem in reproducibility with respect to the method for producing the C 11 to C 22 segment of this boncrekinic acid.
Mass supply of boncrekinic acid by chemical synthesis is essential for promoting the research of apoptosis, and the establishment of an effective production method is awaited.
本発明は、ボンクレキン酸の実用的な合成方法を提供するためのボンクレキン酸前駆体であるボンクレキン酸のＣ１１〜Ｃ２２セグメント（ボンクレキン酸分子の右半分）の実用的で、且つ効果的な製造方法と、該ボンクレキン酸のＣ１１〜Ｃ２２セグメントを用いたボンクレキン酸の実用的で、且つ効果的な製造方法を提供することを目的とする。 INDUSTRIAL APPLICABILITY The present invention provides a practical and effective production of the C 11 to C 22 segment (the right half of the boncrekinic acid molecule) of boncrekinic acid, which is a boncrequinic acid precursor for providing a practical method for synthesizing boncrequinic acid. and methods, practical for bongkrekic acid with C 11 -C 22 segments of the bongkrekic acid, and an object thereof is to provide an and effective manufacturing process.
本発明は、下記（１）〜（１３）の工程を含んでなるボンクレキン酸のＣ１１〜Ｃ２２セグメントの製造法に関する。
（１）一般式［１］
で示される化合物を一般式［２］
で示される化合物と反応させて、一般式［３］
で示される化合物とする工程。
（２）上記（１）で得られた一般式［３］で示される化合物をメチル化剤と反応させて、一般式［４］
で示される化合物とする工程。
（３）上記（２）で得られた一般式［４］で示される化合物の三重結合を部分水素化して一般式［５］
で示される化合物とする工程。
（４）上記（３）で得られた一般式［５］で示される化合物を酸で加水分解処理して、一般式［６］
で示される化合物とする工程。
（５）上記（４）で得られた一般式［６］で示される化合物を酸化して、一般式［７］
で示される化合物とする工程。
（６）上記（５）で得られた一般式［７］で示される化合物をジブロモメチリデン化して、一般式［８］
で示される化合物とする工程。
（７）上記（６）で得られた一般式［８］で示される化合物を一般式［９］
ＣｌＣＯ２Ｒ４ ［９］
（式中、Ｒ４はアルキル基、アリール基、アラルキル基又はトリ置換シリル基を表す。）
で示される化合物と反応させて、一般式［１０］
で示される化合物とする工程。
（８）上記（７）で得られた一般式［１０］で示される化合物の三重結合に有機銅を１，４−付加させた後、プロトン化して一般式［１１］
で示される化合物とする工程。
（９）上記（８）で得られた一般式［１１］で示される化合物の８位の水酸基の保護基Ｒ３を脱保護剤で処理することにより脱保護して、一般式［１２］
で示される化合物とする工程。
（１０）上記（９）で得られた一般式［１２］で示される化合物を酸化剤で処理した後、一般式［１３］
Ｐｈ３Ｐ＝ＣＨＣＯ２Ｒ５
（式中、Ｒ５は、ｔｅｒｔ−ブチル基又はトリ置換シリル基を表す。）
で示される化合物と反応させて、一般式［１４］
で示される化合物とする工程。
（１１）上記（１０）で得られた一般式［１４］で示される化合物の１位のカルボキシル基の保護基Ｒ５を、脱保護剤で処理することにより脱保護して、一般式［１５］
で示される化合物とする工程。
（１２）上記（１１）で得られた一般式［１５］で示される化合物の１位のカルボキシル基を還元して、一般式［１６］
で示されるヒドロキシ体とする工程。
（１３）上記（１２）で得られた一般式［１６］で示されるヒドロキシ体の１０位の水酸基をスルホン酸エステル化又はハロゲン置換して、一般式［１７］
で示される化合物とする工程。
The present invention relates to a method for producing a C 11 to C 22 segment of boncrekinic acid comprising the following steps (1) to (13).
(1) General formula [1]
The compound represented by general formula [2]
Is reacted with a compound represented by the general formula [3]
The process made into the compound shown by these.
(2) The compound represented by the general formula [3] obtained in the above (1) is reacted with a methylating agent to give a general formula [4].
The process made into the compound shown by these.
(3) Partial hydrogenation of the triple bond of the compound represented by the general formula [4] obtained in the above (2) to give a general formula [5]
The process made into the compound shown by these.
(4) The compound represented by the general formula [5] obtained in the above (3) is hydrolyzed with an acid to give a general formula [6].
The process made into the compound shown by these.
(5) The compound represented by the general formula [6] obtained in the above (4) is oxidized to give a general formula [7].
The process made into the compound shown by these.
(6) The compound represented by the general formula [7] obtained in the above (5) is converted to a dibromomethylidene to give a general formula [8]
The process made into the compound shown by these.
(7) The compound represented by the general formula [8] obtained in the above (6) is converted to the general formula [9].
ClCO 2 R 4 [9]
(In the formula, R 4 represents an alkyl group, an aryl group, an aralkyl group or a tri-substituted silyl group.)
Is reacted with a compound represented by the general formula [10]
The process made into the compound shown by these.
(8) 1,4-addition of organic copper to the triple bond of the compound represented by the general formula [10] obtained in the above (7), followed by protonation to give the general formula [11]
The process made into the compound shown by these.
(9) The protecting group R 3 of the hydroxyl group at the 8-position of the compound represented by the general formula [11] obtained in the above (8) is deprotected by treatment with a deprotecting agent, and the general formula [12]
The process made into the compound shown by these.
(10) After treating the compound represented by the general formula [12] obtained in the above (9) with an oxidizing agent, the general formula [13]
Ph 3 P = CHCO 2 R 5
(In the formula, R 5 represents a tert-butyl group or a tri-substituted silyl group.)
And a compound represented by the general formula [14]
The process made into the compound shown by these.
(11) The protecting group R 5 of the carboxyl group at the 1-position of the compound represented by the general formula [14] obtained in the above (10) is deprotected by treatment with a deprotecting agent, and the general formula [15 ]
The process made into the compound shown by these.
(12) The carboxyl group at the 1-position of the compound represented by the general formula [15] obtained in the above (11) is reduced to give the general formula [16]
The process made into the hydroxy body shown by these.
(13) The hydroxy group at the 10-position of the hydroxy compound represented by the general formula [16] obtained in the above (12) is sulfonated or substituted with a halogen to give a general formula [17]
The process made into the compound shown by these.
また、本発明は、上記ボンクレキン酸のＣ１１〜Ｃ２２セグメントの製造法に於ける各中間体とそれら中間体の製造法に関する。 The present invention also relates to the intermediates and production method thereof intermediates in the preparation of C 11 -C 22 segments of the bongkrekic acid.
更に、本発明は、下記（１４）〜（２３）の工程を含んでなるボンクレキン酸の製造法に関する。
（１４）一般式［１８］
で示される化合物と一般式［１７］
で示される化合物とを反応させて、一般式［１９］
で示される化合物とする工程。
（１５）上記（１４）で得られた一般式［１９］で示される化合物を還元して、一般式［２０］
で示されるヒドロキシ体とする工程。
（１６）上記（１５）で得られた一般式［２０］で示される化合物の１１位の−ＳＯ２Ａｒ基を脱離させて、一般式［２１］
で示される化合物とする工程。
（１７）上記（１６）で得られた一般式［２１］で示される化合物を酸化剤で処理した後、一般式［２２］
Ｐｈ３Ｐ＝Ｃ（ＣＨ３）ＣＯ２Ｒ９ ［２２］
（式中、Ｒ９はアルキル基、アリール基、アラルキル基又はトリ置換シリル基を表す。）
で示される化合物と反応させて、一般式［２３］
で示される化合物とする工程。
（１８）上記（１７）で得られた一般式［２３］で示される化合物の水酸基の保護基Ｒ７，Ｒ８を酸で処理することにより脱離させて、一般式［２４］
で示されるジヒドロキシ体とする工程。
（１９）上記（１８）で得られた一般式［２４］で示される化合物をアルカリで加水分解して、式［２５］
（２０）上記（１９）で得られた式［２５］で示される化合物の−ＣＨ２ＯＨ基の一つを酸化して、式［２６］
（２１）上記（２０）で得られた式［２６］で示されるアルデヒド体のアルデヒド基を更に酸化して、式［２７］
（２２）上記（２１）で得られた式［２７］で示されるヒドロキシジカルボン酸のヒドロキシ基を酸化して、式［２８］
（２３）上記（２２）で得られた式［２８］で示されるアルデヒド体のアルデヒド基を更に酸化して、下式
(14) General formula [18]
And a compound of the general formula [17]
And a compound represented by the general formula [19]
The process made into the compound shown by these.
(15) The compound represented by the general formula [19] obtained in the above (14) is reduced to obtain the general formula [20].
The process made into the hydroxy body shown by these.
(16) The —SO 2 Ar group at the 11-position of the compound represented by the general formula [20] obtained in the above (15) is eliminated, and the general formula [21]
The process made into the compound shown by these.
(17) After treating the compound represented by the general formula [21] obtained in the above (16) with an oxidizing agent, the general formula [22]
Ph 3 P═C (CH 3 ) CO 2 R 9 [22]
(Wherein R 9 represents an alkyl group, an aryl group, an aralkyl group or a tri-substituted silyl group.)
Is reacted with a compound represented by the general formula [23]
The process made into the compound shown by these.
(18) The hydroxyl-protecting groups R 7 and R 8 of the compound represented by the general formula [23] obtained in the above (17) are eliminated by treatment with an acid, and the general formula [24]
The process made into the dihydroxy body shown by these.
(19) The compound represented by the general formula [24] obtained in the above (18) is hydrolyzed with an alkali to obtain the formula [25].
(20) One of the —CH 2 OH groups of the compound represented by the formula [25] obtained in the above (19) is oxidized to obtain the formula [26]
(21) The aldehyde group of the aldehyde compound represented by the formula [26] obtained in the above (20) is further oxidized to obtain the formula [27]
(22) The hydroxy group of the hydroxydicarboxylic acid represented by the formula [27] obtained in the above (21) is oxidized to obtain the formula [28]
(23) The aldehyde group represented by the formula [28] obtained in the above (22) is further oxidized to give the following formula:
更にまた、本発明は、上記ボンクレキン酸の製造法に於ける各中間体とそれら中間体の製造法に関する。 Furthermore, this invention relates to each intermediate body in the manufacturing method of the said boncrekinic acid, and the manufacturing method of those intermediate bodies.
本発明は、ボンクレキン酸の実用的で且つ効果的な製造方法を提供するためのボンクレキン酸前駆体であるボンクレキン酸Ｃ１１〜Ｃ２２セグメント（ボンクレキン酸分子の右半分）の実用的で且つ効果的な製造方法と、これを用いたボンクレキン酸の実用的で且つ効果的な製造方法を提供するものであり、本発明の方法によれば、ボンクレキン酸の大量供給が可能となるので、今後アポトーシスの研究が飛躍的に進展することが予想され、また、誘導体合成により多くの疾患の治療薬にも発展しうる可能性も充分考えられるので、斯業に貢献するところ甚だ大なる発明である。 INDUSTRIAL APPLICABILITY The present invention provides a practical and effective boncrekinic acid C 11 to C 22 segment (the right half of the boncrekinic acid molecule) which is a boncrekinic acid precursor for providing a practical and effective method for producing boncrekinic acid. And a practical and effective method for producing boncrequinic acid using the same, and according to the method of the present invention, a large amount of boncrekinic acid can be supplied. The research is expected to make dramatic progress, and it is considered that it can be developed into a therapeutic drug for many diseases by synthesis of derivatives. Therefore, it is a very large invention that contributes to this business.
本発明に係る上記工程（１）において、一般式［１］で示される化合物のＲ１，Ｒ２で示されるアルキル基としては、例えば、炭素数が１〜２０、好ましくは１〜１０、より好ましくは１〜６の直鎖状又は分枝状のアルキル基が挙げられ、より具体的には、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ペンチル基、ヘキシル基などが挙げられる。
アリール基としては、例えば、炭素数６〜３０、好ましくは６〜２０、より好ましくは６〜１５の単環、多環又は縮合環式の芳香族炭化水素基が挙げられ、より具体的には、例えば、フェニル基、トリル基、キシリル基、ナフチル基、メチルナフチル基等が挙げられる。
アラルキル基としては、例えば、炭素数７〜３０、好ましくは７〜２０、より好ましくは７〜１５の単環、多環又は縮合環式のアラルキル基が挙げられ、より具体的には、例えば、ベンジル基、フェネチル基、ナフチルメチル基、ナフチルエチル基等が挙げられる。
また、一般式［２］で示される化合物のＲ３で示される水酸基の保護基としては、例えば、４−メトキシフェニルメチル（ＭＰＭ）基、ベンジル基、ｔｅｒｔ−ブチルジフェニルシリル（ＴＢＤＰＳ）基、トリイソプロピルシリル（ＴＩＰＳ）基等が挙げられる。
In the step (1) according to the present invention, the alkyl group represented by R 1 and R 2 of the compound represented by the general formula [1] has, for example, 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms. Preferably, a linear or branched alkyl group having 1 to 6 is exemplified, and more specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group. , Tert-butyl group, pentyl group, hexyl group and the like.
Examples of the aryl group include a monocyclic, polycyclic or condensed cyclic aromatic hydrocarbon group having 6 to 30 carbon atoms, preferably 6 to 20 carbon atoms, more preferably 6 to 15 carbon atoms, and more specifically. Examples thereof include a phenyl group, a tolyl group, a xylyl group, a naphthyl group, and a methylnaphthyl group.
Examples of the aralkyl group include a monocyclic, polycyclic or condensed cyclic aralkyl group having 7 to 30 carbon atoms, preferably 7 to 20 carbon atoms, more preferably 7 to 15 carbon atoms. Examples include a benzyl group, a phenethyl group, a naphthylmethyl group, and a naphthylethyl group.
Examples of the protecting group for the hydroxyl group represented by R 3 of the compound represented by the general formula [2] include a 4-methoxyphenylmethyl (MPM) group, a benzyl group, a tert-butyldiphenylsilyl (TBDPS) group, And isopropylsilyl (TIPS) group.
一般式［１］で示される化合物を一般式［２］で示される化合物と反応させるに際しては、例えば、先ず一般式［２］で示される化合物をリチオ化又はマグネシウム化した後、一般式［１］で示される化合物と反応させるのが好ましい。
リチオ化は、例えばジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン（ＴＨＦ）等のエーテル系溶媒中、ｎ−ブチルリチウム、フェニルリチウム、リチウムジイソプロピルアミド、或いはｎ−ブチルリチウムとジイソプロピルアミンとの組み合わせ等のリチオ化試薬を用いて、−５０℃以下、好ましくは−７０℃以下で、常法に従ってリチオ化反応させればよく、リチオ化後、同温度でこれに三弗化ホウ素−ジエチルエーテル錯体を反応させた後、一般式［１］で示される化合物と反応させれば、一般式［３］で示される化合物が容易に得られる。
一般式［１］で示される化合物を反応させる際の反応温度は、リチオ化の反応温度と同じでよく、反応時間は、通常１〜５時間程度である。
When the compound represented by the general formula [1] is reacted with the compound represented by the general formula [2], for example, first, the compound represented by the general formula [2] is lithiated or magnesiumated, and then the general formula [1] It is preferable to make it react with the compound shown by this.
Lithiation is a lithiation reagent such as n-butyllithium, phenyllithium, lithium diisopropylamide, or a combination of n-butyllithium and diisopropylamine in an ether solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), etc. May be used for the lithiation reaction at -50 ° C. or lower, preferably −70 ° C. or lower in accordance with a conventional method. After lithiation, after reacting this with boron trifluoride-diethyl ether complex at the same temperature. , A compound represented by the general formula [3] can be easily obtained by reacting with the compound represented by the general formula [1].
The reaction temperature for reacting the compound represented by the general formula [1] may be the same as the reaction temperature for lithiation, and the reaction time is usually about 1 to 5 hours.
また、マグネシウム化は、例えばＴＨＦ、ジエチルエーテル、ジイソプロピルエーテル等のエーテル系溶媒中、例えば塩化メチルマグネシウム、臭化メチルマグネシウム、ヨウ化メチルマグネシウム等のマグネシウム化剤を用いて、−５０℃以下、好ましくは−７０℃以下で、常法に従ってマグネシウム化反応させればよく、マグネシウム化後、これに三弗化ホウ素−ジエチルエーテルを反応させた後、一般式［１］で示されるエポキシ体を反応させれば、一般式［３］で示される化合物が容易に得られる。
リチオ化、マグネシウム化の何れにてもよいが、リチオ化がより好ましい。
Further, the magnesiumation is performed at a temperature of −50 ° C. or less using a magnesium agent such as methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide in an ether solvent such as THF, diethyl ether, diisopropyl ether and the like. May be magnesium-reacted at a temperature of −70 ° C. or less according to a conventional method. After magnesiumation, this is reacted with boron trifluoride-diethyl ether, and then reacted with an epoxy compound represented by the general formula [1]. Then, the compound represented by the general formula [3] can be easily obtained.
Either lithiation or magnesiumation may be used, but lithiation is more preferred.
本発明に係る上記工程（２）において、一般式［３］で示される化合物のメチル化に用いられるメチル化剤としては、例えば、ジメチル硫酸や沃化メチル等が挙げられる。
メチル化剤の使用量は、一般式［３］で示される化合物の二つの水酸基をメチル化し得る量であればよいが、通常、一般式［３］で示される化合物に対して２〜４倍モル用いられる。反応は、通常、アルゴン、窒素等の不活性ガス雰囲気下、例えば、ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）、テトラヒドロフラン（ＴＨＦ）等の極性非プロトン系溶媒中、水素化ナトリウム等の強塩基の存在下に行われる。反応温度は通常−１０℃〜１０℃位、反応時間は通常数十分〜数時間である。
In the above step (2) according to the present invention, examples of the methylating agent used for methylation of the compound represented by the general formula [3] include dimethyl sulfate and methyl iodide.
The amount of the methylating agent used may be an amount that can methylate the two hydroxyl groups of the compound represented by the general formula [3], but is usually 2 to 4 times that of the compound represented by the general formula [3]. Used in moles. The reaction is usually carried out under an inert gas atmosphere such as argon or nitrogen, for example, a strong base such as sodium hydride in a polar aprotic solvent such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF). Done in the presence of. The reaction temperature is usually about −10 ° C. to 10 ° C., and the reaction time is usually several tens of minutes to several hours.
本発明に係る上記工程（３）において、一般式［４］で示される化合物の三重結合を部分水素化して一般式［５］で示される化合物とする反応に用いられる試薬としては、例えば、水素ガス、リンドラー触媒［Ｐｄ−ＣａＣＯ３−Ｐｂ（ＣＨ３ＣＯ２）２］、キノリンの組み合わせが挙げられる。この場合の反応溶媒としては例えばｎ−ヘキサン等の脂肪族炭化水素系溶媒が好ましく用いられる。反応は、水素ガス雰囲気下（１気圧）、通常３０分〜１時間程度の撹拌で充分である。
本工程において、反応後、常法に従い後処理を行って得られる一般式［５］で示される化合物の粗生成物は、これを更にカラムクロマトグラフィー等により精製することなく、次の工程に使用することが可能である。
In the above step (3) according to the present invention, the reagent used for the reaction in which the triple bond of the compound represented by the general formula [4] is partially hydrogenated to obtain the compound represented by the general formula [5] is, for example, hydrogen A combination of gas, Lindlar catalyst [Pd—CaCO 3 —Pb (CH 3 CO 2 ) 2 ], and quinoline can be used. In this case, an aliphatic hydrocarbon solvent such as n-hexane is preferably used as the reaction solvent. For the reaction, stirring in a hydrogen gas atmosphere (1 atm) is usually sufficient for about 30 minutes to 1 hour.
In this step, after the reaction, the crude product of the compound represented by the general formula [5] obtained by post-treatment according to a conventional method is used in the next step without further purification by column chromatography or the like. Is possible.
本発明に係る上記工程（４）において、一般式［５］で示される化合物を加水分解して一般式［６］で示される化合物とする反応に用いられる酸としては、例えば、塩酸、硫酸等が好ましいものとして挙げられるが、通常この種の反応に用いられる酸であれば、当然のことながら何れも使用可能である。
反応は、通常、例えばメタノール等の親水性溶媒に一般式［５］で示される化合物を溶解し、これに上記した如き酸の水溶液を加えて、室温乃至要すれば若干加温下で数時間乃至十数時間撹拌することにより容易に進行し、一般式［６］で示される化合物が好収率で得られる。
In the above step (4) according to the present invention, examples of the acid used for the reaction of hydrolyzing the compound represented by the general formula [5] to obtain the compound represented by the general formula [6] include hydrochloric acid, sulfuric acid and the like. Although it is mentioned as a preferable thing, naturally, as long as it is an acid normally used for this kind of reaction, all can be used.
The reaction is usually carried out by dissolving the compound represented by the general formula [5] in a hydrophilic solvent such as methanol and adding an aqueous solution of the acid as described above to room temperature to several hours under slight heating if necessary. The reaction proceeds easily by stirring for tens of hours or more, and the compound represented by the general formula [6] is obtained in good yield.
本発明に係る上記工程（５）において、一般式［６］で示される化合物を酸化して一般式［７］で示される化合物とする反応に用いられる酸化剤としては、例えば、過ヨウ素酸ナトリウム、過ヨウ素酸カリウム等の過ヨウ素酸塩が好ましいものとして挙げられる。
反応は、通常、例えばＴＨＦ−水混合溶媒等の溶媒中で行われる。反応温度は、通常、室温でよく、反応時間は、数十分〜１時間程度で十分である。
本工程において、反応後、常法に従い後処理を行って得られる一般式［７］で示される化合物の粗生成物は、これを更にカラムクロマトグラフィー等により精製することなく、次の工程に使用することが可能である。
In the above step (5) according to the present invention, examples of the oxidizing agent used in the reaction of oxidizing the compound represented by the general formula [6] into the compound represented by the general formula [7] include sodium periodate Periodate such as potassium periodate is preferable.
The reaction is usually performed in a solvent such as a THF-water mixed solvent. The reaction temperature may usually be room temperature, and the reaction time is about several tens of minutes to one hour.
In this step, after the reaction, the crude product of the compound represented by the general formula [7] obtained by post-treatment according to a conventional method is used in the next step without further purification by column chromatography or the like. Is possible.
本発明に係る上記工程（６）において、一般式［７］で示される化合物をジブロモメチリデン化して、一般式［８］で示される化合物とする反応に用いられる試薬としては、例えば、四臭化炭素、トリフェニルホスフィン及びジイソプロピルエチルアミンの組み合わせ等が好ましいものとして挙げられる。
反応は、通常、例えば塩化メチレン等の溶媒中で行われる。反応温度は、通常、室温でよく、反応時間は、数十分〜数時間程度で十分である。
In the step (6) according to the present invention, the reagent used in the reaction of dibromomethylidene conversion of the compound represented by the general formula [7] into the compound represented by the general formula [8] includes, for example, four odors A combination of carbonized carbon, triphenylphosphine and diisopropylethylamine is preferable.
The reaction is usually performed in a solvent such as methylene chloride. The reaction temperature may usually be room temperature, and the reaction time is about several tens of minutes to several hours.
本発明に係る上記工程（７）において、一般式［８］で示される化合物と反応させる一般式［９］
ＣｌＣＯ２Ｒ４ ［９］
（式中、Ｒ４はアルキル基、アリール基、アラルキル基又はトリ置換シリル基を表す。）
で示される化合物のＲ４で表されるアルキル基、アリール基、アラルキル基としては、上記Ｒ１、Ｒ２で表されるアルキル基、アリール基、アラルキル基と同様のものが挙げられる。また、トリ置換シリル基の具体例としては、例えば、トリメチルシリル基、トリエチルシリル基、ｔｅｒｔ−ブチルジメチルシリル基、トリフェニルシリル基等が挙げられる。
一般式［８］で示される化合物を一般式［９］で示される化合物と反応させるに際しては、一般式［８］で示される化合物を先ずリチオ化した後、一般式［９］で示される化合物と反応させるのが好ましい。
リチオ化は、通常、アルゴン、窒素等の不活性ガス雰囲気下、例えばジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン（ＴＨＦ）等のエーテル系溶媒中、ｎ−ブチルリチウム、フェニルリチウム、リチウムジイソプロピルアミド、或いはｎ−ブチルリチウムとジイソプロピルアミンとの組み合わせ等のリチオ化試薬を用いて、−５０℃以下、好ましくは−７０℃以下で、常法に従ってリチオ化反応させればよい。リチオ化後、同温度でこれにクロロ炭酸エステルのＴＨＦ溶液等を加えて数時間反応させれば、一般式［１０］で示される化合物が好収率で得られる。
In the step (7) according to the present invention, the general formula [9] is reacted with the compound represented by the general formula [8].
ClCO 2 R 4 [9]
(In the formula, R 4 represents an alkyl group, an aryl group, an aralkyl group or a tri-substituted silyl group.)
Examples of the alkyl group, aryl group, and aralkyl group represented by R 4 of the compound represented by the same as those described above for the alkyl group, aryl group, and aralkyl group represented by R 1 , R 2 can be given. Specific examples of the tri-substituted silyl group include a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, and a triphenylsilyl group.
When the compound represented by the general formula [8] is reacted with the compound represented by the general formula [9], the compound represented by the general formula [8] is first lithiated and then the compound represented by the general formula [9]. It is preferable to make it react with.
Lithiation is usually performed in an inert gas atmosphere such as argon or nitrogen, for example, in an ether solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), n-butyllithium, phenyllithium, lithium diisopropylamide, or n- A lithiation reagent such as a combination of butyllithium and diisopropylamine may be used to carry out a lithiation reaction according to a conventional method at −50 ° C. or lower, preferably −70 ° C. or lower. After lithiation, a solution of chlorocarbonate in THF at the same temperature is added and allowed to react for several hours to obtain a compound represented by the general formula [10] in good yield.
本発明に係る上記工程（８）において、一般式［１０］で示される化合物の三重結合に有機銅を１，４−付加させた後プロトン化して一般式［１１］で示される化合物とする反応に用いられる試薬としては、ヨウ化銅又は臭化銅と、メチルリチウム等との組み合わせがより一般的で好ましいものとして挙げられる。なお、臭化銅を使用する場合には、ＣｕＢｒ・Ｍｅ２Ｓの形で使用するのが好ましい。
反応は、通常、アルゴン、窒素等の不活性ガス雰囲気下、例えばジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン（ＴＨＦ）等のエーテル系溶媒中で行われる。反応温度は、通常−５０℃以下、好ましくは−７０℃以下で 、反応時間は、通常、数十分〜１時間程度で十分である。
In the step (8) according to the present invention, 1,4-addition of organocopper to the triple bond of the compound represented by the general formula [10], followed by protonation to obtain a compound represented by the general formula [11] As a reagent used for the above, a combination of copper iodide or copper bromide with methyl lithium is more general and preferable. In addition, when using copper bromide, it is preferable to use it in the form of CuBr · Me 2 S.
The reaction is usually performed in an ether solvent such as diethyl ether, diisopropyl ether or tetrahydrofuran (THF) under an inert gas atmosphere such as argon or nitrogen. The reaction temperature is usually −50 ° C. or lower, preferably −70 ° C. or lower, and the reaction time is usually from several tens of minutes to about 1 hour.
本発明に係る上記工程（９）において、一般式［１１］で示される化合物の８位の水酸基の保護基Ｒ３を脱保護剤で処理することにより脱保護して一般式［１２］で示される化合物とする反応に用いられる脱保護剤としては、例えば、ジクロロジシアノベンゾキノン（ＤＤＱ）、硝酸第二セリウムアンモニウム（ＣＡＮ）、アルカリ金属と液体アンモニア、或いはアルカリ金属とナフタレン等が挙げられる。
反応は、例えば、塩化メチレン−水混合溶媒等の混合溶媒中で行われる。反応温度は、通常、室温でよく、反応時間は、数十分〜１時間程度で十分である。
In the above step (9) according to the present invention, the protecting group R 3 of the hydroxyl group at the 8-position of the compound represented by the general formula [11] is deprotected by treating with a deprotecting agent and represented by the general formula [12]. Examples of the deprotecting agent used in the reaction to form a compound include dichlorodicyanobenzoquinone (DDQ), ceric ammonium nitrate (CAN), alkali metal and liquid ammonia, or alkali metal and naphthalene.
The reaction is performed, for example, in a mixed solvent such as a methylene chloride-water mixed solvent. The reaction temperature may usually be room temperature, and the reaction time is about several tens of minutes to one hour.
本発明に係る上記工程（１０）において、一般式［１２］で示される化合物を酸化剤で処理した後、反応させる一般式［１３］
Ｐｈ３Ｐ＝ＣＨＣＯ２Ｒ５
（式中、Ｒ５は、ｔｅｒｔ−ブチル基又はトリ置換シリル基を表す。）
で示される化合物のＲ５で表されるトリ置換シリル基の具体例としては、上記Ｒ４で表されるトリ置換シリル基のそれと同様のものが挙げられる。
また、一般式［１２］で示される化合物と反応させる酸化剤としては、アルコールを酸化してアルデヒドにする酸化剤であれば何れの酸化剤でもよいが、例えば、二酸化マンガン、クロロクロム酸ピリジニウム（ＰＣＣ）、二クロム酸ピリジニウム（ＰＤＣ）、Ｓｗｅｒｎ酸化試薬（Ｓｗｅｒｎ酸化に用いられる試薬：オキサリルクロリド、ジメチルスルフィド及びトリエチルアミンの組み合わせからなる）等が挙げられる。
酸化反応は、通常、例えば塩化メチレン等の溶媒中で行われる。反応温度は、通常、室温でよく、反応時間は、通常、数十分〜数時間程度で十分である。
一般式［１３］で示される化合物を反応させる際には、通常、上記酸化反応後の系に、例えば、ベンゼン等の溶媒を加えた後、一般式［１３］で示される化合物を加えて、通常、加熱還流下に、数時間〜１０時間位反応させればよい。
In the step (10) according to the present invention, the compound represented by the general formula [12] is treated with an oxidant and then reacted.
Ph 3 P = CHCO 2 R 5
(In the formula, R 5 represents a tert-butyl group or a tri-substituted silyl group.)
Specific examples of the tri-substituted silyl group represented by R 5 of the compound represented by the above include those similar to those of the tri-substituted silyl group represented by R 4 above.
Moreover, as an oxidizing agent to be reacted with the compound represented by the general formula [12], any oxidizing agent may be used as long as it is an oxidizing agent that oxidizes alcohol into an aldehyde. For example, manganese dioxide, pyridinium chlorochromate ( PCC), pyridinium dichromate (PDC), Swern oxidation reagent (reagent used for Swern oxidation: composed of a combination of oxalyl chloride, dimethyl sulfide and triethylamine).
The oxidation reaction is usually performed in a solvent such as methylene chloride. The reaction temperature is usually room temperature, and the reaction time is usually about several tens of minutes to several hours.
When reacting the compound represented by the general formula [13], usually, for example, after adding a solvent such as benzene to the system after the oxidation reaction, the compound represented by the general formula [13] is added, Usually, the reaction may be performed for several hours to 10 hours under heating and reflux.
本発明に係る上記工程（１１）において、一般式［１４］で示される化合物の１位のカルボキシル基の保護基Ｒ５を、脱保護剤で処理することにより脱保護して一般式［１５］で示される化合物とする反応に用いられる脱保護剤としては、例えば、三弗化ホウ素−ジエチルエーテル錯体や酸などが挙げられる。好ましい酸の具体例としては、例えば、塩酸、臭化水素酸等の無機酸や、例えば、酢酸、トリフルオロ酢酸等の有機酸等が挙げられる。
反応は、例えば三弗化ホウ素−ジエチルエーテル錯体を使用する場合は、通常、塩化メチレン等の溶媒中で行われる。反応温度は、通常、室温でよく、反応時間は、数十分〜１時間程度で十分である。
In the step (11) according to the present invention, the protecting group R 5 of the carboxyl group at the 1-position of the compound represented by the general formula [14] is deprotected by treatment with a deprotecting agent, and the general formula [15] Examples of the deprotecting agent used for the reaction represented by the compound represented by the above include boron trifluoride-diethyl ether complex and acid. Specific examples of preferable acids include inorganic acids such as hydrochloric acid and hydrobromic acid, and organic acids such as acetic acid and trifluoroacetic acid.
For example, when a boron trifluoride-diethyl ether complex is used, the reaction is usually performed in a solvent such as methylene chloride. The reaction temperature may usually be room temperature, and the reaction time is about several tens of minutes to one hour.
本発明に係る上記工程（１２）において、一般式［１５］で示される化合物の１位のカルボキシル基を還元して一般式［１６］で示される化合物とするに際しては、先ず、一般式［１５］で示される化合物をクロロ炭酸エステル又は酸無水物と反応させてカルボキシル基を活性化した後、これを還元するのが好ましい。ここで用いられるクロロ炭酸エステルとしては、例えば、上記一般式［９］で示される化合物等が挙げられる。また、酸無水物としては、例えば、無水酢酸、無水コハク酸等の通常この種の反応において用いられる各種酸無水物が挙げられる。
反応は、通常、トリエチルアミン等の塩基の存在下、ＴＨＦ等のエーテル系溶媒中で行われる。反応温度は、通常、−１０℃〜１０℃、好ましくは０℃前後で、反応時間は、通常、数十分〜１時間程度である。
次いで行われる還元工程で用いられる還元剤としては、例えば、水素化ホウ素ナトリウムや水素化ホウ素リチウム等が好ましいものとして挙げられる。
反応は、通常、ＴＨＦ等のエーテル系溶媒中で行われる。反応温度は、通常、室温でよく、反応時間は、数十分〜１時間程度で十分である。
In the step (12) according to the present invention, when the carboxyl group at the 1-position of the compound represented by the general formula [15] is reduced to obtain the compound represented by the general formula [16], first, the general formula [15] It is preferable to reduce the compound after reacting the compound represented by the above formula with a chlorocarbonate or acid anhydride to activate the carboxyl group. As a chloro carbonate used here, the compound shown by the said General formula [9] etc. are mentioned, for example. Examples of the acid anhydride include various acid anhydrides usually used in this type of reaction, such as acetic anhydride and succinic anhydride.
The reaction is usually carried out in an ether solvent such as THF in the presence of a base such as triethylamine. The reaction temperature is usually −10 ° C. to 10 ° C., preferably around 0 ° C., and the reaction time is usually several tens of minutes to about 1 hour.
Preferred examples of the reducing agent used in the subsequent reduction step include sodium borohydride and lithium borohydride.
The reaction is usually performed in an ether solvent such as THF. The reaction temperature may usually be room temperature, and the reaction time is about several tens of minutes to one hour.
本発明に係る上記工程（１３）において、一般式［１６］で示される化合物の１０位の水酸基をスルホン酸エステル化又はハロゲン置換して得られる、一般式［１７］で示される化合物のＸで表されるスルホン酸エステル基又はハロゲンとしては、例えば、メタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、塩素、臭素、ヨウ素等が挙げられる。
反応は、例えば、一般式［１６］で示される化合物の１０位の水酸基を臭素で置換する場合を例にすると、一般式［１６］で示される化合物を塩化メチレン等の溶媒に溶解し、これに、イミダゾール、トリフェニルホスフィン及び四臭化炭素を加えて、室温で数十分〜数時間撹拌することにより、目的とする一般式［１７］において、ＸがＢｒの化合物が容易に得られる。
In the step (13) according to the present invention, X of the compound represented by the general formula [17] obtained by sulfonated or halogen-substituted the hydroxyl group at the 10-position of the compound represented by the general formula [16] Examples of the sulfonic acid ester group or halogen represented include methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, chlorine, bromine, iodine and the like.
In the reaction, for example, when the hydroxyl group at the 10-position of the compound represented by the general formula [16] is substituted with bromine, the compound represented by the general formula [16] is dissolved in a solvent such as methylene chloride. In addition, imidazole, triphenylphosphine and carbon tetrabromide are added, and the mixture is stirred for several tens of minutes to several hours at room temperature, whereby a compound having X as Br in the desired general formula [17] can be easily obtained.
本工程で得られた一般式［１７］で示される化合物は、ボンクレキン酸前駆体であるボンクレキン酸のＣ１１〜Ｃ２２セグメント（ボンクレキン酸分子の右半分）であり、該化合物を、本発明者らが先に創製した（特許文献１参照。）ボンクレキン酸のＣ１〜Ｃ１０セグメント（ボンクレキン酸分子の左半分）とカップリングさせることにより、ボンクレキン酸の化学的合成が可能となる。 The compound represented by the general formula [17] obtained in this step is the C 11 to C 22 segment (the right half of the boncrekinic acid molecule) of the boncrekinic acid precursor that is the boncrequinic acid precursor. Coupling with the C 1 to C 10 segment (left half of the boncrekinic acid molecule) of boncrekinic acid, which was previously created (see Patent Document 1), enables chemical synthesis of boncrekinic acid.
本発明のボンクレキン酸のＣ１１〜Ｃ２２セグメントの製造方法に於いて、出発物質として用いられる一般式［１］で示される化合物は、Ｄ−マンニトールから、例えば下記合成スキームに従って容易に合成することが出来る。なお、合成スキーム中のｐ−ＴｓＣｌはｐ−トルエンスルホニルクロリドの略号である。 The compound represented by the general formula [1] used as a starting material in the method for producing C 11 to C 22 segments of boncrechinic acid of the present invention can be easily synthesized from D-mannitol, for example, according to the following synthesis scheme. I can do it. Note that p-TsCl in the synthesis scheme is an abbreviation for p-toluenesulfonyl chloride.
即ち、本発明の方法によれば、安価なＤ−マンニトールから１７工程（平均収率８０％）でボンクレキン酸のＣ１１〜Ｃ２２セグメントを製造することが出来る。 That is, according to the method of the present invention, C 11 to C 22 segments of boncrekinic acid can be produced from inexpensive D-mannitol in 17 steps (average yield 80%).
以下、本発明者らが先に創製した（特許文献１参照。）ボンクレキン酸のＣ１〜Ｃ１０セグメント（ボンクレキン酸分子の左半分）と、上で得られたボンクレキン酸のＣ１１〜Ｃ２２セグメント（ボンクレキン酸分子の右半分）からボンクレキン酸を製造する方法について順を追って述べる。 Hereinafter, the present inventors have previously created (see Patent Document 1) C 1 to C 10 segment of boncrekinic acid (left half of the boncrekinic acid molecule) and C 11 to C 22 of boncrekinic acid obtained above. A method for producing boncrequinic acid from the segment (the right half of the boncrekinic acid molecule) will be described step by step.
本発明に係る上記工程（１４）において用いられる一般式［１８］で示される化合物のＲ７，Ｒ８で表されるトリ置換シリル基の具体例としては、上記Ｒ４，Ｒ５で表されるトリ置換シリル基の具体例と同様、例えば、トリメチルシリル基、トリエチルシリル基、ｔｅｒｔ−ブチルジメチルシリル基、トリフェニルシリル基等が挙げられる。
本発明に係る上記工程（１４）において、一般式［１８］で示される化合物と一般式［１７］で示される化合物とを反応させて、一般式［１９］で示される化合物とする際には、先ず、一般式［１８］で示される化合物をヘキサメチルホスホルアミド（ＨＭＰＡ）の存在下で、リチオ化した後、一般式［１７］で示される化合物と反応させるのが好ましい。
反応は、通常、アルゴン、窒素等の不活性ガス雰囲気下、ＴＨＦ等のエーテル系溶媒中、例えば、ｎ−ブチルリチウム、フェニルリチウム、リチウムジイソプロピルアミド、或いはｎ−ブチルリチウムとジイソプロピルアミンとの組み合わせ等のリチオ化試薬を用いて、で行われる。反応温度は、通常、−５０℃以下、好ましくは−７０℃以下で、反応時間は、数十分〜１時間程度で十分である。
なお、リチオ化の代りにマグネシウム化やナトリウム化でもよく、更には、所謂、強塩基の使用も可能である。
次いで、上記反応液に一般式［１７］で示される化合物を加えて、−５０℃以下、好ましくは−７０℃以下で、数十分撹拌反応を行えば一般式［１９］で示される化合物が得られる。
Specific examples of the trisubstituted silyl group represented by R 7 and R 8 of the compound represented by the general formula [18] used in the step (14) according to the present invention are represented by the above R 4 and R 5. Examples of the trisubstituted silyl group include trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, and triphenylsilyl group.
In the step (14) according to the present invention, when the compound represented by the general formula [18] is reacted with the compound represented by the general formula [17] to obtain a compound represented by the general formula [19] First, a compound represented by the general formula [18] is preferably lithiated in the presence of hexamethylphosphoramide (HMPA) and then reacted with a compound represented by the general formula [17].
The reaction is usually performed in an ether solvent such as THF under an inert gas atmosphere such as argon or nitrogen, for example, n-butyllithium, phenyllithium, lithium diisopropylamide, or a combination of n-butyllithium and diisopropylamine. Using a lithiation reagent of The reaction temperature is usually −50 ° C. or lower, preferably −70 ° C. or lower, and the reaction time is about several tens of minutes to 1 hour.
Note that magnesiumation or sodiumation may be used instead of lithiation, and so-called strong bases can also be used.
Next, the compound represented by the general formula [17] can be obtained by adding the compound represented by the general formula [17] to the reaction solution and carrying out a tens of minutes stirring reaction at −50 ° C. or lower, preferably −70 ° C. or lower. can get.
本発明に係る上記工程（１５）において、一般式［１９］で示される化合物を還元して、一般式［２０］で示されるヒドロキシ体とする反応において用いられる還元剤としては、例えば、水素化ジイソブチルアルミニウム、水素化リチウムアルミニウム等が挙げられる。
反応は、通常、アルゴン、窒素等の不活性ガス雰囲気下、ＴＨＦ等のエーテル系溶媒中で行われる。反応温度は、通常、−１０℃〜１０℃、好ましくは０℃前後で、反応時間は、通常、数十分〜１時間程度である。
本工程において、反応後、常法に従い後処理を行って得られる一般式［２０］で示される化合物の粗生成物は、これを更にカラムクロマトグラフィー等により精製することなく、次の工程に使用することが可能である。
In the above-mentioned step (15) according to the present invention, the reducing agent used in the reaction of reducing the compound represented by the general formula [19] to give a hydroxy form represented by the general formula [20] includes, for example, hydrogenation Examples include diisobutylaluminum and lithium aluminum hydride.
The reaction is usually carried out in an ether solvent such as THF under an inert gas atmosphere such as argon or nitrogen. The reaction temperature is usually −10 ° C. to 10 ° C., preferably around 0 ° C., and the reaction time is usually several tens of minutes to about 1 hour.
In this step, after the reaction, the crude product of the compound represented by the general formula [20] obtained by post-treatment according to a conventional method is used in the next step without further purification by column chromatography or the like. Is possible.
本発明に係る上記工程（１６）において、一般式［２０］で示される化合物の１１位の−ＳＯ２Ａｒ基を脱離させて、一般式［２１］で示される化合物とする反応に用いられる試薬としては、例えば、ナトリウムアマルガム及びリン酸水素ナトリウムの組み合わせ、或いはアルカリ金属及びナフタレンの組み合わせ等が挙げられる。
反応は、通常、メタノール等の溶媒中、室温で行われる。反応時間は、通常、数十分〜数時間である。撹拌は、超音波による撹拌が特に好ましい。
In the step (16) according to the present invention, the compound represented by the general formula [20] is used for a reaction in which the 11-position —SO 2 Ar group is eliminated to obtain a compound represented by the general formula [21]. Examples of the reagent include a combination of sodium amalgam and sodium hydrogen phosphate, or a combination of alkali metal and naphthalene.
The reaction is usually performed at room temperature in a solvent such as methanol. The reaction time is usually several tens of minutes to several hours. The stirring is particularly preferably ultrasonic stirring.
本発明に係る上記工程（１７）においては、一般式［２１］で示される化合物を先ず酸化剤で処理するが、ここで用いられる酸化剤としては、上記工程（１０）において、一般式［１２］で示される化合物と反応させる酸化剤と同様、アルコールを酸化してアルデヒドにする酸化剤であれば何れの酸化剤でもよいが、例えば、二酸化マンガン、クロロクロム酸ピリジニウム（ＰＣＣ）、二クロム酸ピリジニウム（ＰＤＣ）、Ｓｗｅｒｎ酸化試薬（Ｓｗｅｒｎ酸化に用いられる試薬：オキサリルクロリド、ジメチルスルフィド及びトリエチルアミンの組み合わせからなる）等が挙げられる。
酸化反応は、通常、例えば塩化メチレン等の溶媒中で行われる。反応温度は、通常、室温でよく、反応時間は、通常、数十分〜数時間程度で十分である。
反応生成物に一般式［２２］
Ｐｈ３Ｐ＝Ｃ（ＣＨ３）ＣＯ２Ｒ９ ［２２］
（式中、Ｒ９はアルキル基、アリール基、アラルキル基又はトリ置換シリル基を表す。）
で示される化合物を反応させる際には、通常、上記酸化反応後の系に、例えば、ベンゼン等の溶媒を加えた後、一般式［２２］で示される化合物を加えて、通常、加熱還流下に、数時間反応させればよい。
なお、上記一般式［２２］において、Ｒ９で表されるアルキル基、アリール基、アラルキル基、トリ置換シリル基の具体例としては、上記Ｒ４で表されるアルキル基、アリール基、アラルキル基及びトリ置換シリル基の具体例と同様のものが挙げられる。
In the step (17) according to the present invention, the compound represented by the general formula [21] is first treated with an oxidizing agent. The oxidizing agent used here is the general formula [12] in the step (10). Any oxidizing agent may be used as long as it is an oxidizing agent that oxidizes alcohol to form an aldehyde, such as manganese dioxide, pyridinium chlorochromate (PCC), dichromic acid. Pyridinium (PDC), Swern oxidation reagent (reagent used for Swern oxidation: composed of a combination of oxalyl chloride, dimethyl sulfide and triethylamine).
The oxidation reaction is usually performed in a solvent such as methylene chloride. The reaction temperature is usually room temperature, and the reaction time is usually about several tens of minutes to several hours.
The reaction product is represented by the general formula [22].
Ph 3 P═C (CH 3 ) CO 2 R 9 [22]
(Wherein R 9 represents an alkyl group, an aryl group, an aralkyl group or a tri-substituted silyl group.)
When the compound represented by general formula (2) is reacted, usually, for example, a solvent such as benzene is added to the system after the oxidation reaction, and then the compound represented by the general formula [22] is added. The reaction may be performed for several hours.
In the general formula [22], specific examples of the alkyl group, aryl group, aralkyl group, and tri-substituted silyl group represented by R 9 include the alkyl group, aryl group, and aralkyl group represented by R 4. And the thing similar to the specific example of a tri-substituted silyl group is mentioned.
本発明に係る上記工程（１８）において、一般式［２３］で示される化合物の水酸基の保護基Ｒ７，Ｒ８を酸で処理することにより脱離させて、一般式［２４］で示されるジヒドロキシ体とする反応に用いられる酸としては、例えば、塩酸、硫酸等の鉱酸の水溶液が通常用いられるが、例えば、テトラブチルアンモニウムフルオリド等のフッ素イオン等もこれらの酸と同様に使用可能である。
反応は、通常、ＴＨＦ等のエーテル系溶媒中で行われる。反応温度は、通常、室温でよく、反応時間は、通常、１０分〜数十分程度で十分である。
In the step (18) according to the present invention, the hydroxyl-protecting groups R 7 and R 8 of the compound represented by the general formula [23] are eliminated by treatment with an acid, and represented by the general formula [24]. For example, an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid is usually used as the acid used for the reaction to form a dihydroxy compound. For example, fluorine ions such as tetrabutylammonium fluoride can be used in the same manner as these acids. It is.
The reaction is usually performed in an ether solvent such as THF. The reaction temperature may usually be room temperature, and the reaction time is usually about 10 minutes to several tens of minutes.
本発明に係る上記工程（１９）において、一般式［２４］で示される化合物をアルカリで加水分解して、式［２５］で示される化合物とする反応に用いられるアルカリとしては、例えば、水酸化カリウム、水酸化ナトリウム、水酸化リチウム等の強アルカリが挙げられる。
反応は、通常、一般式［２４］で示される化合物をメタノール等の溶媒に溶解し、これに上記したアルカリの水溶液を加えて、室温で数時間撹拌することにより行われる。
本工程において、反応後、常法に従い後処理を行って得られる一般式［２５］で示される化合物の粗生成物は、これを更にカラムクロマトグラフィー等により精製することなく、次の工程に使用することが可能である。
In the step (19) according to the present invention, the alkali used in the reaction of hydrolyzing the compound represented by the general formula [24] with an alkali to obtain the compound represented by the formula [25] is, for example, hydroxylation Strong alkalis such as potassium, sodium hydroxide, lithium hydroxide and the like can be mentioned.
The reaction is usually performed by dissolving the compound represented by the general formula [24] in a solvent such as methanol, adding the above-mentioned aqueous alkali solution thereto, and stirring the mixture at room temperature for several hours.
In this step, after the reaction, the crude product of the compound represented by the general formula [25] obtained by post-treatment according to a conventional method is used in the next step without further purification by column chromatography or the like. Is possible.
本発明に係る上記工程（２０）において、一般式［２５］で示される化合物の−ＣＨ２ＯＨ基の一つを酸化して、式［２６］で示される化合物とする反応に用いられる酸化剤としては、例えば二酸化マンガン等が好ましいものとして挙げられる。
反応は、通常、塩化メチレン等の溶媒中で行われる。反応温度は、通常、室温でよく、反応時間は、通常、１０〜数十分程度で十分である。
本工程においても、反応後、常法に従い後処理を行って得られる一般式［２６］で示される化合物の粗生成物は、これを更にカラムクロマトグラフィー等により精製することなく、次の工程に使用することが可能である。
In the step (20) according to the present invention, an oxidizing agent used for the reaction of oxidizing one of the —CH 2 OH groups of the compound represented by the general formula [25] to form the compound represented by the formula [26] For example, manganese dioxide is preferable.
The reaction is usually performed in a solvent such as methylene chloride. The reaction temperature is usually room temperature, and the reaction time is usually about 10 to several tens of minutes.
Also in this step, after the reaction, the crude product of the compound represented by the general formula [26] obtained by post-treatment according to a conventional method is used in the next step without further purification by column chromatography or the like. It is possible to use.
本発明に係る上記工程（２１）において、一般式［２６］で示される化合物のアルデヒド基を酸化して、式［２７］で示される化合物とする反応に用いられる酸化試薬としては、例えば、亜塩素酸ナトリウムとリン酸二水素ナトリウムの組み合わせ等が挙げられる。
反応は、通常、２−メチル−ブテン/２−メチルプロパノール/ＴＨＦ（１：３：１）混合溶媒等の溶媒中で行われる。反応温度は、通常、室温でよく、反応時間は、通常、１０分〜数十分程度で十分である。
本工程においても、反応後、常法に従い後処理を行って得られる一般式［２７］で示される化合物の粗生成物は、これを更にカラムクロマトグラフィー等により精製することなく、次の工程に使用することが可能である。
In the step (21) according to the present invention, an oxidizing reagent used for the reaction to oxidize the aldehyde group of the compound represented by the general formula [26] to obtain the compound represented by the formula [27] is, for example, Examples include a combination of sodium chlorate and sodium dihydrogen phosphate.
The reaction is usually performed in a solvent such as a 2-methyl-butene / 2-methylpropanol / THF (1: 3: 1) mixed solvent. The reaction temperature may usually be room temperature, and the reaction time is usually about 10 minutes to several tens of minutes.
Also in this step, after the reaction, the crude product of the compound represented by the general formula [27] obtained by post-treatment according to a conventional method is used in the next step without further purification by column chromatography or the like. It is possible to use.
本発明に係る上記工程（２２）において、一般式［２７］で示される化合物のヒドロキシ基を酸化して、式［２８］で示される化合物とする反応に用いられる試薬としては、例えば、１，１，１−トリアセトキシ−１，１−ジヒドロ−１，２−ベンズイオドキソル−３（１Ｈ）−オン（Ｄｅｓｓ−Ｍａｒｔｉｎ試薬）等が挙げられる。
反応は、通常、塩化メチレン−ベンゼン（１：１）混合溶媒等の溶媒中で行われる。反応温度は、通常、５０〜７０℃、反応時間は、通常、１０分〜数十分程度で十分である。
本工程においても、反応後、常法に従い後処理を行って得られる一般式［２８］で示される化合物の粗生成物は、これを更にカラムクロマトグラフィー等により精製することなく、次の工程に使用することが可能である。
In the step (22) according to the present invention, the reagent used for the reaction to oxidize the hydroxy group of the compound represented by the general formula [27] to obtain the compound represented by the formula [28] includes, for example, 1, 1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one (Dess-Martin reagent) and the like.
The reaction is usually performed in a solvent such as a methylene chloride-benzene (1: 1) mixed solvent. The reaction temperature is usually 50 to 70 ° C., and the reaction time is usually about 10 minutes to several tens of minutes.
Also in this step, after the reaction, the crude product of the compound represented by the general formula [28] obtained by post-treatment according to a conventional method is used in the next step without further purification by column chromatography or the like. It is possible to use.
本発明に係る上記工程（２３）において、一般式［２８］で示される化合物のアルデヒド基を酸化して、ボンクレキン酸とする反応に用いられる酸化試薬としては、前記工程（２１）における場合と同様、例えば、亜塩素酸ナトリウムとリン酸二水素ナトリウムの組み合わせ等が挙げられる。
反応は、通常、２−メチル−ブテン/２−メチルプロパノール/ＴＨＦ（１：３：１）混合溶媒等の溶媒中で行われる。反応温度は、通常、室温でよく、反応時間は、通常、１０分〜数十分程度で十分である。
反応後は、必要に応じてカラムクロマトグラフィー等により適宜精製すればよい。
In the step (23) according to the present invention, the oxidizing reagent used for the reaction to oxidize the aldehyde group of the compound represented by the general formula [28] to obtain boncrekinic acid is the same as in the step (21). Examples thereof include a combination of sodium chlorite and sodium dihydrogen phosphate.
The reaction is usually performed in a solvent such as a 2-methyl-butene / 2-methylpropanol / THF (1: 3: 1) mixed solvent. The reaction temperature may usually be room temperature, and the reaction time is usually about 10 minutes to several tens of minutes.
After the reaction, it may be appropriately purified by column chromatography or the like as necessary.
斯くして、ボンクレキン酸のＣ１〜Ｃ１０セグメント（ボンクレキン酸分子の左半分）とボンクレキン酸のＣ１１〜Ｃ２２セグメント（ボンクレキン酸分子の右半分）両セグメントの結合から１０工程でボンクレキン酸が比較的高収率（１０工程の平均収率６０〜７０％）で得られる。
本発明者らは、得られたボンクレキン酸の構造を確認するため上記で得られたボンクレキン酸の粗生成物をトリメチルエステル化してその確認を行った。
なお、ボンクレキン酸のトリメチルエステル体は、ボンクレキン酸の粗生成物をジエチルエーテルに溶解し、これにジアゾメタンのジエチルエーテル溶液を加えて室温で１０分間撹拌した後、低沸点物を減圧留去し、得られた残渣をプレパラティブ薄層板（溶媒：酢酸エチル／ヘキサン）に付すことにより、これを得た。なお、得られたボンクレキン酸トリメチルエステルの構造確認データ等は以下の参考例２に示す。
Thus to, the C 1 -C 10 segments (left half of bongkrekic acid molecule) and C 11 -C 22 segments (the right half of bongkrekic acid molecules) of bongkrekic acid bongkrekic acid in 10 steps from the coupling of both segments of bongkrekic acid A relatively high yield (average yield of 10 steps 60-70%) is obtained.
In order to confirm the structure of the obtained boncrekinic acid, the present inventors performed trimethylesterification of the crude boncrekinic acid product obtained above and confirmed it.
In addition, the trimethyl ester form of boncrequinic acid was prepared by dissolving a crude product of boncrequinic acid in diethyl ether, adding a diethyl ether solution of diazomethane to this and stirring for 10 minutes at room temperature, and then distilling off low-boiling substances under reduced pressure. This was obtained by subjecting the obtained residue to a preparative thin layer plate (solvent: ethyl acetate / hexane). In addition, the structure confirmation data etc. of the obtained boncrekinic acid trimethyl ester are shown in Reference Example 2 below.
以下、参考例、実施例により本発明をより具体的に説明するが、本発明はこれら参考例、実施例により何ら限定されるものではない。 Hereinafter, the present invention will be described more specifically with reference examples and examples. However, the present invention is not limited to these reference examples and examples.
参考例１ １，２；５，６−ジアンヒドロ−３，４−Ｏ−イソプロピリデン−Ｄ−マンニトール（２，２−ジメチル−４，５−ビス（オキシラニル）−［１，３］ジオキソラン）の合成
（１）１，２；３，４；５，６−トリ−Ｏ−イソプロピリデン−Ｄ−マンニトールの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．３５（６Ｈ，ｓ，(ＣＨ ３)２Ｃ），１．３９（６Ｈ，ｓ，(ＣＨ ３)２Ｃ），１．４２（６Ｈ，ｓ，(ＣＨ ３)２Ｃ），３．９７（４Ｈ，ｄｄ，Ｊ＝５．６，８．４Ｈｚ，Ｏ−ＣＨ ２−ＣＨ），４．０７（２Ｈ，ｄｄ，Ｊ＝６．４，８．４Ｈｚ，ＣＨ２−ＣＨ−ＣＨ−），４．１８（２Ｈ，ｍ，ＣＨ２−ＣＨ−ＣＨ−）。
１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ：１１０．４（ｓ），１０９．８（ｓ），７９．７（ｄ），７６．６（ｄ），６６．６（ｔ），２７．８（ｑ），２６．８（ｑ），２５．７（ｑ）。
ＩＲ（ＫＢｒ，ＣＨＣｌ３）１３８２，１３７３，１０７２ｃｍ−１。
Ｍｐ．７０℃。
（文献：C.Morpain, M, M.Tisserand, J. C. S. Perkin 1, 1979, 1379-1383）
Reference Example 1 Synthesis of 1,2; 5,6-dianhydro-3,4-O-isopropylidene-D-mannitol (2,2-dimethyl-4,5-bis (oxiranyl)-[1,3] dioxolane) (1) Synthesis of 1,2; 3,4; 5,6-tri-O-isopropylidene-D-mannitol
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.35 (6H, s, (C H 3 ) 2 C), 1.39 (6H, s, (C H 3 ) 2 C), 1.42 ( 6H, s, (C H 3 ) 2 C), 3.97 (4H, dd, J = 5.6, 8.4 Hz, O—C H 2 —CH), 4.07 (2H, dd, J = 6.4,8.4Hz, CH 2 -C H -CH - ), 4.18 (2H, m, CH 2 -CH-C H -).
13 C-NMR (100 MHz, CDCl 3 ) δ: 110.4 (s), 109.8 (s), 79.7 (d), 76.6 (d), 66.6 (t), 27.8 (Q), 26.8 (q), 25.7 (q).
IR (KBr, CHCl 3 ) 1382, 1373, 1072 cm −1 .
Mp. 70 ° C.
(Reference: C. Morpain, M, M. Tisserand, JCS Perkin 1, 1979 , 1379-1383)
（２）３，４−Ｏ−イソプロピリデン−Ｄ−マンニトールの合成
（文献：C.Morpain, M, M.Tisserand, J.C.S.Perkin1, 1979, 1379-1383）
(2) Synthesis of 3,4-O-isopropylidene-D-mannitol
(Reference: C. Morpain, M, M. Tisserand, JCSPerkin1, 1979 , 1379-1383)
（３）１，６−ビス−ｐ−トルエンスルホキシ−３，４−Ｏ−イソプロピリデン−Ｄ−マンニトールの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．２６（６Ｈ，ｓ，(ＣＨ ３)２Ｃ），２．４０（６Ｈ，ｓ，Ｐｈ−Ｏ−ＣＨ ３），３．７５（６Ｈ，ｍ，−ＯＨ，−ＣＨ ２（ＯＴｓ）−ＣＨ（ＯＨ）−ＣＨ（Ｏ−）），４．０７（２Ｈ，ｄｄ，Ｊ＝５．６，１０．８，−ＣＨ ２（ＯＴｓ）−ＣＨ（ＯＨ）−ＣＨ（Ｏ−）），４．２８（２Ｈ，ｄ，Ｊ＝９．６Ｈｚ，−ＣＨ２（ＯＴｓ）−ＣＨ（ＯＨ）−ＣＨ（Ｏ−），７．３３（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ），７．７８（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ）。
（文献：Y. Le. Merrer, A. Dureault, C.Gravier, D. Languin et J. C. Depezay, Tetrahedron Lett. 1985, 26, 319-322）
(3) Synthesis of 1,6-bis-p-toluenesulfoxy-3,4-O-isopropylidene-D-mannitol
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.26 (6H, s, (C H 3 ) 2 C), 2.40 (6H, s, Ph—O—C H 3 ), 3.75 ( 6H, m, -O H, -C H 2 (OTs) -C H (OH) -CH (O -)), 4.07 (2H, dd, J = 5.6,10.8, -C H 2 (OTs) -CH (OH) -CH (O -)), 4.28 (2H, d, J = 9.6Hz, -CH 2 (OTs) -CH (OH) -C H (O-), 7.33 (2H, d, J = 8.4 Hz, Ph ), 7.78 (2H, d, J = 8.4 Hz, Ph ).
(Reference: Y. Le. Merrer, A. Dureault, C. Gravier, D. Languin et JC Depezay, Tetrahedron Lett. 1985, 26 , 319-322)
（４）１，２；５，６−ジアンヒドロ−３，４−Ｏ−イソプロピリデン−Ｄ−マンニトールの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４３（６Ｈ，ｓ，(ＣＨ ３)２Ｃ），２．７１（２Ｈ，ｄｄ，Ｊ＝２．８，４．８Ｈｚ，ＣＨ ２−ＣＨ−ＣＨ），２．８３（２Ｈ，ｄｄ，Ｊ＝３．６，４．８Ｈｚ，ＣＨ ２−ＣＨ−ＣＨ），３．１１（２Ｈ，ｍ，ＣＨ２−ＣＨ−ＣＨ），３．８３（２Ｈ，ｄｄ，Ｊ＝３．２，１．２Ｈｚ，ＣＨ２−ＣＨ−ＣＨ）。
１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ：１１０．１，７８．１，５１．３，４５．０，２６．６。
ＩＲ（ＫＢｒ，ｎｅａｔ）１２５６，１２１４，１０６０ｃｍ−１
（文献：Y. Le. Merrer, A. Dureault, C.Gravier, D. Languin et J. C. Depezay, Tetrahedron Lett. 1985, 26, 319-322）
(4) Synthesis of 1,2; 5,6-dianhydro-3,4-O-isopropylidene-D-mannitol
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.43 (6H, s, (C H 3 ) 2 C), 2.71 (2H, dd, J = 2.8, 4.8 Hz, C H 2 -CH-CH), 2.83 (2H , dd, J = 3.6,4.8Hz, C H 2 -CH-CH), 3.11 (2H, m, CH 2 -C H -CH), 3.83 (2H, dd, J = 3.2,1.2Hz, CH 2 -CH-C H).
13 C-NMR (100 MHz, CDCl 3 ) δ: 110.1, 78.1, 51.3, 45.0, 26.6.
IR (KBr, neat) 1256, 1214, 1060 cm −1
(Reference: Y. Le. Merrer, A. Dureault, C. Gravier, D. Languin et JC Depezay, Tetrahedron Lett. 1985, 26 , 319-322)
（２Ｚ，４Ｒ，６Ｚ，８Ｅ）−メチル−１０−ブロモ−４−メトキシ−３−メチル−デカ−２，６，８−トリエノエート（ボンクレキン酸のＣ １１ 〜Ｃ ２２ セグメント）の合成
（１）（５Ｒ，６Ｒ，７Ｒ，８Ｒ）−１，１２−（４−メトキシフェニルメチルオキシ）−５，８−ヒドロキシ−６，７−（２，２−ジメチル−［１，３］ジオキソラン）−ドデカサ−２，１０−ジインの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．３５（６Ｈ，ｓ，(ＣＨ ３)２Ｃ），２．５２（２Ｈ，ｍ，−ＣＨ ２−ＣＨ（ＯＨ）−），２．７４（２Ｈ，ｍ，−ＣＨ ２−ＣＨ（ＯＨ）−），３．４６（２Ｈ，ｂｒ．ｓ，−ＯＨ），３．７９−３．８６（１０Ｈ，Ｐｈ−Ｏ（ＣＨ３），−ＣＨ２−ＣＨ（ＯＨ）−ＣＨ（Ｏ−）），４．１４（４Ｈ，ｍ，−Ｏ−ＣＨ ２−Ｃ≡Ｃ−），４．５１（４Ｈ，ｓ，Ｐｈ−ＣＨ ２−Ｏ），６．８３（４Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ），７．２６（４Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ）。
１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ：１５９．２（ｓ），１２９．６（ｄ），１１３．７（ｄ），１０９．４（ｓ），８２．５（ｓ），８１．５（ｄ），７８．７（ｓ），７１．２（ｄ），７１．１（ｔ），５７．３（ｔ），５５．２（ｑ），２６．９（ｑ），２４．９（ｔ）。
ＩＲ（ＫＢｒ，ｎｅａｔ）３３８９，２２８４，１６１２，１５１３，１２４９ｃｍ−１。
(2Z, 4R, 6Z, 8E ) - methyl-10-bromo-4-methoxy-3-methyl - Synthesis of deca-2,6,8-trienoate (C 11 -C 22 segments of bongkrekic acid) (1) ( 5R, 6R, 7R, 8R) -1,12- (4-methoxyphenylmethyloxy) -5,8-hydroxy-6,7- (2,2-dimethyl- [1,3] dioxolane) -dodecasa-2 , 10-Diyne synthesis
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.35 (6H, s, (C H 3 ) 2 C), 2.52 (2H, m, —C H 2 —CH (OH) —), 2 .74 (2H, m, -C H 2 -CH (OH) -), 3.46 (2H, br.s, -O H), 3.79-3.86 (10H, Ph-O (CH 3 ), - CH 2 -C H ( OH) -C H (O -)), 4.14 (4H, m, -O-C H 2 -C≡C -), 4.51 (4H, s, Ph -C H 2 -O), 6.83 ( 4H, d, J = 8.4Hz, Ph), 7.26 (4H, d, J = 8.4Hz, Ph).
13 C-NMR (100 MHz, CDCl 3 ) δ: 159.2 (s), 129.6 (d), 113.7 (d), 109.4 (s), 82.5 (s), 81.5 (D), 78.7 (s), 71.2 (d), 71.1 (t), 57.3 (t), 55.2 (q), 26.9 (q), 24.9 ( t).
IR (KBr, neat) 3389, 2284, 1612, 1513, 1249 cm −1 .
（２）（４Ｒ，５Ｒ）−４，５−ビス［（Ｒ）−１−メトキシ−５−（４−メトキシフェニルメチルオキシ）−３−ペンチニル］−２，２−ジメチル−［１，３］ジオキソランの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４０（６Ｈ，ｓ，(ＣＨ ３)２Ｃ），２．５５（２Ｈ，ｍ，Ｃ≡Ｃ−ＣＨ２−ＣＨ），２．６５（２Ｈ，ｍ，Ｃ≡Ｃ−ＣＨ２−ＣＨ），３．４２−３．５２（８Ｈ，ｍ，ＣＨ２−ＣＨ（ＯＣＨ３）−，ＣＨ２−ＣＨ（ＯＣＨ ３）−），３．８２（６Ｈ，ｓ，Ｐｈ−ＯＣＨ ３），４．１４（６Ｈ，ｍ，Ｏ−ＣＨ ２−Ｃ≡Ｃ，ＣＨ２−ＣＨ−ＣＨ），４．５０（４Ｈ，ｓ，Ｐｈ−ＣＨ ２−Ｏ−），６．８７（４Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ），７．２７（４Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ）。
１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ：１５９．２（ｓ），１２９．６（ｄ），１１３．７（ｄ），１０９．９（ｓ），８３．５（ｓ），８０．８（ｄ），７９．２（ｄ），７７．９（ｓ），７０．９（ｓ），５８．３（ｑ），５７．３（ｔ），５５．２（ｑ），２７．４（ｑ），２０．５（ｔ）。
ＩＲ（ＫＢｒ，ｎｅａｔ）１６１２，１５１３，１２４９ｃｍ−１。
(2) (4R, 5R) -4,5-bis [(R) -1-methoxy-5- (4-methoxyphenylmethyloxy) -3-pentynyl] -2,2-dimethyl- [1,3] Synthesis of dioxolane
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.40 (6H, s, (C H 3 ) 2 C), 2.55 (2H, m, C≡C—CH 2 —CH), 2.65 (2H, m, C≡C-CH 2 -CH), 3.42-3.52 (8H, m, CH 2 -C H (OCH 3) -, CH 2 -CH (OC H 3) -), 3.82 (6H, s, Ph—OC H 3 ), 4.14 (6H, m, O—C H 2 —C≡C, CH 2 —CH—C H ), 4.50 (4H, s, Ph-C H 2 -O -) , 6.87 (4H, d, J = 8.4Hz, Ph), 7.27 (4H, d, J = 8.4Hz, Ph).
13 C-NMR (100 MHz, CDCl 3 ) δ: 159.2 (s), 129.6 (d), 113.7 (d), 109.9 (s), 83.5 (s), 80.8 (D), 79.2 (d), 77.9 (s), 70.9 (s), 58.3 (q), 57.3 (t), 55.2 (q), 27.4 ( q), 20.5 (t).
IR (KBr, neat) 1612, 1513, 1249 cm −1 .
（３）（５Ｒ，６Ｒ，７Ｒ，８Ｒ）−１，１２−（４−メトキシフェニルメチルオキシ）−５，８−メトキシ−６，７−（２，２−ジメチル−［１，３］ジオキソラン）−ドデカサ−２Ｚ，１０Ｚ−ジエンの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．５２（６Ｈ，ｓ，(ＣＨ ３)２Ｃ），２．３６（４Ｈ，ｍ，−ＣＨ ２ＣＨ（ＯＣＨ ３）−），３．２８（２Ｈ，ｍ，−ＣＨ２ＣＨ（ＯＣＨ３）−ＣＨ（Ｏ−）），３．３６（６Ｈ，ｓ，−ＣＨ（ＯＣＨ ３）−），３．７８（６Ｈ，ｓ，Ｐｈ−Ｏ−ＣＨ ３），３．９０（２Ｈ，ｍ，−ＣＨ２ＣＨ（ＯＣＨ ３）−），４．０８（４Ｈ，ｍ，−Ｏ−ＣＨ２−Ｃ≡Ｃ−），４．４２（４Ｈ，ｓ，Ｐｈ−ＣＨ２−Ｏ−），５．６８（４Ｈ，ｍ，−ＣＨ＝ＣＨ−），６．８７（４Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ），７．２５（４Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ）。
(3) (5R, 6R, 7R, 8R) -1,12- (4-methoxyphenylmethyloxy) -5,8-methoxy-6,7- (2,2-dimethyl- [1,3] dioxolane) Synthesis of dodecasa-2Z, 10Z-diene
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.52 (6H, s, (C H 3 ) 2 C), 2.36 (4H, m, —C H 2 CH (OC H 3 ) —), 3.28 (2H, m, -CH 2 CH (OCH 3) -C H (O -)), 3.36 (6H, s, -CH (OC H 3) -), 3.78 (6H, s , Ph-OC H 3), 3.90 (2H, m, -CH 2 C H (OC H 3) -), 4.08 (4H, m, -O-CH 2 -C≡C-) , 4.42 (4H, s, Ph -CH 2 -O -), 5.68 (4H, m, -C H = C H -), 6.87 (4H, d, J = 8.4Hz, Ph ), 7.25 (4H, d, J = 8.4 Hz, Ph ).
（４）（２Ｚ，５Ｒ，６Ｒ，７Ｒ，８Ｒ，１０Ｚ）−１，１２−ビス（４−メトキシフェニルメチルオキシ）−５，８−ジメトキシ−ドデカサ−２，１０−ジエン−６，７−ジオールの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．３８（２Ｈ，−ＣＨ ２−ＣＨ（ＯＣＨ ３）−），３．１５（２Ｈ，ｂｒ．ｓ，−ＯＨ），３．３１−３．４５（８Ｈ，ｍ，−ＣＨ（ＯＣＨ ３）−，ＣＨ２−ＣＨ（ＯＣＨ３）−ＣＨ（Ｏ−），３．６１（２Ｈ，ｔ，−ＣＨ（ＯＣＨ３）−），３．６７（６Ｈ，ｓ，Ｐｈ−ＣＨ２−Ｏ−），４．０２（４Ｈ，ｍ，−Ｏ−ＣＨ２−ＣＨ＝ＣＨ−），４．４３（４Ｈ，ｓ，Ｐｈ−ＣＨ ２−Ｏ−），５．７２（４Ｈ，ｍ，−Ｏ−ＣＨ ２−ＣＨ＝ＣＨ−），６．８４（４Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ），７．２６（４Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ）。
１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ：１５９．１（ｓ），１２９．３（ｄ），１２９．１（ｄ），１２８．１（ｄ），１１３．７（ｄ），８２．１（ｄ），７２．０（ｔ），７０．０（ｄ），６５．４（ｔ），５８．２（ｑ），５５．２（ｑ），２８．１（ｔ）。
ＩＲ（ＫＢｒ，ｎｅａｔ）３４５５，１６１２，１５１２，１２４７，１０９７ｃｍ−１。
(4) (2Z, 5R, 6R, 7R, 8R, 10Z) -1,12-bis (4-methoxyphenylmethyloxy) -5,8-dimethoxy-dodecasa-2,10-diene-6,7-diol Synthesis of
1 H-NMR (400MHz, CDCl 3) δ: 2.38 (2H, -C H 2 -CH (OC H 3) -), 3.15 (2H, br.s, -O H), 3.31 -3.45 (8H, m, -CH ( OC H 3) -, CH 2 -CH (OCH 3) -C H (O -), 3.61 (2H, t, -C H (OCH 3) - ), 3.67 (6H, s, Ph—CH 2 —O—), 4.02 (4H, m, —O—CH 2 —CH═CH—), 4.43 (4H, s, Ph—C) H 2 -O -), 5.72 ( 4H, m, -O-C H 2 -CH = C H -), 6.84 (4H, d, J = 8.4Hz, Ph), 7.26 ( 4H, d, J = 8.4 Hz, Ph ).
13 C-NMR (100 MHz, CDCl 3 ) δ: 159.1 (s), 129.3 (d), 129.1 (d), 128.1 (d), 113.7 (d), 82.1 (D), 72.0 (t), 70.0 (d), 65.4 (t), 58.2 (q), 55.2 (q), 28.1 (t).
IR (KBr, neat) 3455, 1612, 1512, 1247, 1097 cm −1 .
（５）（２Ｒ，４Ｚ）−２−メトキシ−６−（４−メトキシフェニルメチルオキシ）−４−ヘキセナールの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．４６（２Ｈ，ｍ，ＣＨ＝ＣＨ−ＣＨ ２−ＣＨ），３．４８（３Ｈ，ｓ，−ＯＣＨ ３），３．５８（１Ｈ，ｔ，−ＣＨ（ＯＣＨ３），３．８０（５Ｈ，ｍ，−Ｐｈ−ＯＣＨ ３，−Ｏ−ＣＨ ２−ＣＨ＝ＣＨ−），４．３３（２Ｈ，ｓ，Ｐｈ−ＣＨ ２−Ｏ−），５．５７（１Ｈ，ｍ，−ＣＨ＝ＣＨ−），５．６２（１Ｈ，ｍ，−ＣＨ＝ＣＨ−），６．８６（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ），７．２６（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ），９．６４（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ，ＣＨＯ）。
(5) Synthesis of (2R, 4Z) -2-methoxy-6- (4-methoxyphenylmethyloxy) -4-hexenal
1 H-NMR (400MHz, CDCl 3) δ: 2.46 (2H, m, CH = CH-C H 2 -CH), 3.48 (3H, s, -OC H 3), 3.58 (1H , T, —CH (OCH 3 ), 3.80 (5H, m, —Ph—OC H 3 , —O—C H 2 —CH═CH—), 4.33 (2H, s, Ph—C H 2 -O -), 5.57 (1H , m, -C H = CH -), 5.62 (1H, m, -C H = CH -), 6.86 (2H, d, J = 8. 4Hz, Ph), 7.26 (2H , d, J = 8.4Hz, Ph), 9.64 (1H, d, J = 1.6Hz, C H O).
（６）（３Ｒ，５Ｚ）−１−（４−メトキシフェニルメチルオキシ）−３−メトキシ−１，１−ジブロモ−ヘプタ−２，６−ジエンの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．３５（２Ｈ，ｍ，ＣＨ＝ＣＨ−ＣＨ ２−ＣＨ−），３．３１（３Ｈ，ｓ，−ＣＨ（ＯＣＨ ３）），３．８０（３Ｈ，ｓ，−Ｐｈ−Ｏ−ＣＨ ３），３．９１（１Ｈ，ｍ，−ＣＨ（ＯＣＨ３）），４．０３（２Ｈ，ｄ，Ｊ＝６．０Ｈｚ，−Ｏ−ＣＨ ２−ＣＨ＝ＣＨ−），４．４４（２Ｈ，ｓ，Ｐｈ−ＣＨ ２−Ｏ），５．６０（１Ｈ，ｍ，−ＣＨ＝ＣＨ−），５．７２（１Ｈ，ｍ，−ＣＨ＝ＣＨ−），６．３２（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ），６．８８（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ）。
(6) Synthesis of (3R, 5Z) -1- (4-methoxyphenylmethyloxy) -3-methoxy-1,1-dibromo-hepta-2,6-diene
1 H-NMR (400MHz, CDCl 3) δ: 2.35 (2H, m, CH = CH-C H 2 -CH -), 3.31 (3H, s, -CH (OC H 3)), 3 .80 (3H, s, -Ph- O-C H 3), 3.91 (1H, m, -C H (OCH 3)), 4.03 (2H, d, J = 6.0Hz, -O -C H 2 -CH = CH -) , 4.44 (2H, s, Ph-C H 2 -O), 5.60 (1H, m, -C H = CH -), 5.72 (1H, m, -C H = CH-), 6.32 (2H, d, J = 8.4 Hz, Ph ), 6.88 (2H, d, J = 8.4 Hz, Ph ).
（７）（４Ｒ，６Ｚ）−メチル ４−メトキシ−８−（４−メトキシフェニルメチルオキシ）−６−オクテン−２−イノエートの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．５３（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ，−ＣＨ＝ＣＨ−ＣＨ ２−ＣＨ−），３．４１（３Ｈ，ｓ，−ＣＨ（ＯＣＨ ３）），３．７６（３Ｈ，ｓ，−ＣＯＯＣＨ ３），３．８０（３Ｈ，ｓ，−Ｐｈ−ＯＣＨ３），４．０７（３Ｈ，ｍ，−ＣＨ＝ＣＨ−ＣＨ２−ＣＨ−，−Ｏ−ＣＨ ２−ＣＨ＝ＣＨ−），４．４２（２Ｈ，ｓ，Ｐｈ−ＣＨ ２−Ｏ），５．６４（１Ｈ，ｍ，−ＣＨ＝ＣＨ−），５．７８（１Ｈ，ｍ，−ＣＨ＝ＣＨ−），６．８７（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ），７．２６（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ）。
(7) Synthesis of (4R, 6Z) -methyl 4-methoxy-8- (4-methoxyphenylmethyloxy) -6-octen-2-inoate
1 H-NMR (400MHz, CDCl 3) δ: 2.53 (2H, t, J = 6.4Hz, -CH = CH-C H 2 -CH -), 3.41 (3H, s, -CH ( OC H 3)), 3.76 ( 3H, s, -COOC H 3), 3.80 (3H, s, -Ph-OCH 3), 4.07 (3H, m, -CH = CH-CH 2 -C H -, - O-C H 2 -CH = CH -), 4.42 (2H, s, Ph-C H 2 -O), 5.64 (1H, m, -C H = CH-) , 5.78 (1H, m, -C H = CH -), 6.87 (2H, d, J = 8.4Hz, Ph), 7.26 (2H, d, J = 8.4Hz, Ph) .
（８）（２Ｚ，４Ｒ，５Ｚ）−メチル ４−メトキシ−８−（４−メトキシフェニルメチルオキシ）−３−メチル−オクタ−２，６−ジエノエートの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．８４（３Ｈ，ｓ，−（ＣＨ ３）Ｃ＝ＣＨ−），２．２７（１Ｈ，ｔｄ，Ｊ＝６．４，１４．０Ｈｚ，−ＣＨ＝ＣＨ−ＣＨ ２−ＣＨ−），２．４０（１Ｈ，ｔｄ，Ｊ＝６．４，１４．０Ｈｚ，−ＣＨ＝ＣＨ−ＣＨ ２−ＣＨ−），３．２２（３Ｈ，ｓ，−ＣＨ（ＯＣＨ ３）），３．６８（３Ｈ，ｓ，−ＣＯＯＣＨ ３），３．８０（３Ｈ，ｓ，−Ｐｈ−Ｏ−ＣＨ ３），４．０９（２Ｈ，ｄ，Ｊ＝５．２Ｈｚ，−Ｏ−ＣＨ ２−ＣＨ＝ＣＨ−），４．６５（２Ｈ，ｓ，Ｐｈ−ＣＨ ２−Ｏ），５．１１（１Ｈ，ｄｄ，Ｊ＝６．４，８．０Ｈｚ，−ＣＨ２−ＣＨ（ＯＣＨ ３）−），５．６１−５．７０（２Ｈ，ｍ，−ＣＨ＝ＣＨ−），５．８２（１Ｈ，ｓ，(ＣＨ３)Ｃ＝ＣＨ（ＣＯＯ−）， ６．８５（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ），７．２６（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ，Ｐｈ）。
(8) Synthesis of (2Z, 4R, 5Z) -methyl 4-methoxy-8- (4-methoxyphenylmethyloxy) -3-methyl-octa-2,6-dienoate
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.84 (3H, s, — (C H 3 ) C═CH—), 2.27 (1H, td, J = 6.4, 14.0 Hz, -CH = CH-C H 2 -CH -), 2.40 (1H, td, J = 6.4,14.0Hz, -CH = CH-C H 2 -CH -), 3.22 (3H, s, —CH (OC H 3 )), 3.68 (3H, s, —COOC H 3 ), 3.80 (3H, s, —Ph—O—C H 3 ), 4.09 (2H, d , J = 5.2Hz, -O-C H 2 -CH = CH -), 4.65 (2H, s, Ph-C H 2 -O), 5.11 (1H, dd, J = 6.4 , 8.0Hz, -CH 2 -CH (OC H 3) -), 5.61-5.70 (2H, m, -C H = C H -), 5.82 (1H, s, (CH 3 ) C = C H COO-), 6.85 (2H, d , J = 8.4Hz, Ph), 7.26 (2H, d, J = 8.4Hz, Ph).
（９）（２Ｚ，４Ｒ，６Ｚ）−メチル ８−ヒドロキシ−４−メトキシ−３−メチルオクタ−２，６−ジエノエートの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．８７（３Ｈ，ｓ，(ＣＨ ３)Ｃ＝ＣＨ（ＣＯＯ）），２．２２（１Ｈ，ｍ，−ＣＨ＝ＣＨ−ＣＨ ２−ＣＨ−），２．５１（１Ｈ，ｍ，−ＣＨ＝ＣＨ−ＣＨ ２−ＣＨ−），３．２２（３Ｈ，ｓ，−ＣＨ（ＯＣＨ ３）），３．７３（３Ｈ，ｓ，−ＣＯＯＣＨ ３），４．０４−４．１９（２Ｈ，ｍ，−ＣＨ ２ＯＨ），５．０３（１Ｈ，ｄｄ，Ｊ＝４．４，８．８Ｈｚ，−ＣＨ２−ＣＨ（ＯＣＨ３）），５．７２（１Ｈ，ｍ，−ＣＨ＝ＣＨ−），５．８５（２Ｈ，ｍ，−ＣＨ＝ＣＨ−，−（ＣＨ３）Ｃ＝ＣＨ（ＣＯＯ−））。
(9) Synthesis of (2Z, 4R, 6Z) -methyl 8-hydroxy-4-methoxy-3-methylocta-2,6-dienoate
1 H-NMR (400MHz, CDCl 3) δ: 1.87 (3H, s, (C H 3) C = CH (COO)), 2.22 (1H, m, -CH = CH-C H 2 - CH -), 2.51 (1H, m, -CH = CH-C H 2 -CH -), 3.22 (3H, s, -CH (OC H 3)), 3.73 (3H, s, -COOC H 3), 4.04-4.19 (2H , m, -C H 2 OH), 5.03 (1H, dd, J = 4.4,8.8Hz, -CH 2 -C H ( OCH 3)), 5.72 (1H , m, -C H = CH -), 5.85 (2H, m, -C H = CH -, - (CH 3) C = C H (COO-)) .
（１０）（２Ｅ，４Ｚ，７Ｒ，８Ｚ，）−ｔｅｒｔ−ブチル ７−メトキシ−１０−メトキシカルボニル−８−メチル−デカ−２，４，８−トリエノエートの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．５１（９Ｈ，(ＣＨ ３)３Ｃ−ＯＯＣ−），１．８６（３Ｈ，(ＣＨ ３)Ｃ＝ＣＨ（ＣＯＯ−）），２．５０（１Ｈ，ｍ，−ＣＨ＝ＣＨ−ＣＨ ２−ＣＨ−），２．６３（１Ｈ，ｍ，−ＣＨ＝ＣＨ−ＣＨ ２−ＣＨ−），３．２４（３Ｈ，ＣＨ（ＯＣＨ ３）），３．７８（３Ｈ，ｓ，−ＣＯＯＣＨ ３），５．１６（１Ｈ，ｄｄ，ＣＨ（ＯＣＨ ３）），５．７２−５．９０（３Ｈ，ｍ，−（ＣＨ ３）Ｃ＝ＣＨ（ＣＯＯ−），−ＣＨ＝ＣＨ（ＣＯＯｔ−Ｂｕ），ＣＨ＝ＣＨ−ＣＨ２−），６．１９（１Ｈ，ｔ，Ｊ＝１１．２Ｈｚ，ＣＨ＝ＣＨ−ＣＨ２），７．４８（１Ｈ，ｄｄ，Ｊ＝１２．０，１５．２Ｈｚ，−ＣＨ＝ＣＨ（ＣＯＯｔ−Ｂｕ）。
(10) Synthesis of (2E, 4Z, 7R, 8Z,)-tert-butyl 7-methoxy-10-methoxycarbonyl-8-methyl-deca-2,4,8-trienoate
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51 (9H, (C H 3 ) 3 C—OOC—), 1.86 (3H, (C H 3 ) C═CH (COO—)), 2.50 (1H, m, -CH = CH-C H 2 -CH -), 2.63 (1H, m, -CH = CH-C H 2 -CH -), 3.24 (3H, CH ( OC H 3)), 3.78 ( 3H, s, -COOC H 3), 5.16 (1H, dd, CH (OC H 3)), 5.72-5.90 (3H, m, - ( C H 3) C = C H (COO -), - CH = C H (COOt-Bu), C H = CH-CH 2 -), 6.19 (1H, t, J = 11.2Hz, CH = C H -CH 2 ), 7.48 (1H, dd, J = 12.0, 15.2 Hz, -C H = CH (COOt-Bu).
（１１）（２Ｅ，４Ｚ，７Ｒ，８Ｚ）−７−メトキシ−１０−メトキシカルボニル−８−メチル−デカ−２，４，８−トリエン酸の合成
これを更に精製することなく次の反応に用いた。
(11) Synthesis of (2E, 4Z, 7R, 8Z) -7-methoxy-10-methoxycarbonyl-8-methyl-deca-2,4,8-trienoic acid
This was used in the next reaction without further purification.
（１２）（２Ｚ，４Ｒ，６Ｚ，８Ｅ）−メチル １０−ヒドロキシ−４−メトキシ−３−メチル−デカ−２，６，８−トリエノエートの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．８６（３Ｈ，(ＣＨ ３)Ｃ＝ＣＨ（ＣＯＯ−），２．３８−２．５２（２Ｈ，ｍ，ＣＨ＝ＣＨ−ＣＨ ２−ＣＨ−），３．２３（３Ｈ，ｓ，−ＣＨ（ＯＣＨ ３）），３．７２（３Ｈ，−ＣＯＯＣＨ ３），４．２２（２Ｈ，ｄ，Ｊ＝５．６Ｈｚ，ＣＨ＝ＣＨ−ＣＨ２−ＯＨ），５．１２（１Ｈ，ｄｄ，Ｊ＝１０．８，１１．２Ｈｚ，−ＣＨ（ＯＣＨ ３）），５．８４（２Ｈ，ｍ，−(ＣＨ ３)Ｃ＝ＣＨ（ＣＯＯ−），６．１０（１Ｈ，ｔ，Ｊ＝１０．８Ｈｚ，−ＣＨ＝ＣＨ−ＣＨ２ＯＨ），６．６３（１Ｈ，ｄｄ，Ｊ＝１６．４，１１．２Ｈｚ，−ＣＨ＝ＣＨ−ＣＨ２ＯＨ）。
(12) Synthesis of (2Z, 4R, 6Z, 8E) -methyl 10-hydroxy-4-methoxy-3-methyl-deca-2,6,8-trienoate
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.86 (3H, (C H 3 ) C═CH (COO—), 2.38-2.52 (2H, m, CH═CH—C H 2 -CH -), 3.23 (3H, s, -CH (OC H 3)), 3.72 (3H, -COOC H 3), 4.22 (2H, d, J = 5.6Hz, CH = C H —CH 2 —OH), 5.12 (1H, dd, J = 10.8, 11.2 Hz, —C H (OC H 3 )), 5.84 (2H, m, — (C H 3 ) C = C H (COO - ), 6.10 (1H, t, J = 10.8Hz, -C H = CH-CH 2 OH), 6.63 (1H, dd, J = 16.4,11 .2Hz, -CH = C H -CH 2 OH).
（１３）（２Ｚ，４Ｒ，６Ｚ，８Ｅ）−メチル １０−ブロモ−４−メトキシ−３−メチル−デカ−２，６，８−トリエノエート（ボンクレキン酸のＣ１１〜Ｃ２２セグメント）の合成
ボンクレキン酸の合成
（１）（２Ｚ，４Ｒ，６Ｚ，８Ｅ，１２Ｅ，１６Ｅ，１８Ｚ，１５Ｓ）−メチル １１−ベンゼンスルフォニル−２０−ｔｅｒｔ−ブチルジメチルシリロキシ−１８−［２−（ｔｅｒｔ−ブチルジメチルシリロキシ）エチル］−４−メトキシ−３，１５−ジメチルエイコサ−２，６，８，１２，１６，１８−ヘキサエノエートの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．０３（６Ｈ，ｓ，−Ｓｉ(ＣＨ ３)２ｔ−Ｂｕ），０．０６（６Ｈ，ｓ，−Ｓｉ(ＣＨ ３)２ｔ−Ｂｕ），０．８８（９Ｈ，ｓ，−Ｓｉ(ＣＨ３)２ ｔ−Ｂｕ），０．９０（９Ｈ，ｓ，−Ｓｉ(ＣＨ３)２ ｔ−Ｂｕ），１．０１（３Ｈ，ｄ，−ＣＨ(ＣＨ ３)），１．８５（３Ｈ，ｓ，−(ＣＨ ３)Ｃ＝ＣＨ（ＣＯＯ−）），１．９１−２．１７（６Ｈ，ｍ，ＣＨ(ＣＨ３)−ＣＨ ２−，ＣＨ（ＳＯ２ｐＨ）−ＣＨ ２−，ＣＨ（ＯＣＨ３）−ＣＨ ２−），２．３６−２．４６（４Ｈ，ｍ，ＣＨ（ＣＨ３）−ＣＨ２−， ＣＨ（ＳＯ２ｐＨ）−ＣＨ２−， −ＣＨ２−ＣＨ２−Ｏ−Ｓｉ−），３．２２（３Ｈ，ｓ，−ＣＨ（ＯＣＨ ３）），３．６２−３．７４（５Ｈ，ｍ，−ＣＯＯＣＨ ３，−ＣＨ２−ＣＨ ２−Ｏ−Ｓｉ−），４．３０（２Ｈ，ｍ，＝ＣＨ−ＣＨ ２−Ｏ−Ｓｉ−），５．１０（１Ｈ，ｄｄ，−ＣＨ（ＯＣＨ ３）），５．２６−５．５４（５Ｈ，ｍ，），５．６４（１Ｈ，ｓ，（ＣＨ３）Ｃ＝ＣＨ（ＣＯＯ−）），５．９５（１Ｈ，ｔ，），６．０８（２Ｈ，ｍ，），６．４５（１Ｈ，ｔ，），７．５３（２Ｈ，ｍ，Ｐｈ），７．６３（１Ｈ，ｍ，Ｐｈ），７，８３（２Ｈ，ｍ，Ｐｈ）。
Synthesis of Bonglequinic Acid (1) (2Z, 4R, 6Z, 8E, 12E, 16E, 18Z, 15S) -Methyl 11-Benzenesulfonyl-20-tert-butyldimethylsilyloxy-18- [2- (tert-butyldimethyl) Synthesis of (silyloxy) ethyl] -4-methoxy-3,15-dimethyleicosa-2,6,8,12,16,18-hexaenoate
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.03 (6H, s, —Si (C H 3 ) 2 t-Bu), 0.06 (6H, s, —Si (C H 3 ) 2 t -Bu), 0.88 (9H, s , -Si (CH 3) 2 t-Bu), 0.90 (9H, s, -Si (CH 3) 2 t-Bu), 1.01 (3H, d, —CH (C H 3 )), 1.85 (3H, s, — (C H 3 ) C═CH (COO—)), 1.91-2.17 (6H, m, CH (CH 3 ) -C H 2 -, CH ( SO 2 pH) -C H 2 -, CH (OCH 3) -C H 2 -), 2.36-2.46 (4H, m, C H (CH 3) - CH 2 -, C H (SO 2 pH) -CH 2 -, -CH 2 -CH 2 -O-Si -), 3.22 (3H, s, -CH (OC H 3)), 3.62- 3.74 (5H, , -COOC H 3, -CH 2 -C H 2 -O-Si -), 4.30 (2H, m, = CH-C H 2 -O-Si -), 5.10 (1H, dd, - C H (OC H 3 )), 5.26-5.54 (5H, m,), 5.64 (1H, s, (CH 3 ) C = C H (COO-)), 5.95 (1H , T,), 6.08 (2H, m,), 6.45 (1H, t,), 7.53 (2H, m, Ph ), 7.63 (1H, m, Ph ), 7, 83 (2H, m, Ph ).
（２）（２Ｚ，４Ｒ，６Ｚ，８Ｅ，１２Ｅ，１５Ｓ，１６Ｅ，１８Ｚ）−１１−ベンゼンスルフォニル−２０−ｔｅｒｔ−ブチルジメチルシリロキシ−１８−［２−（ｔｅｒｔ−ブチルジメチルシリロキシ）エチル］−４−メトキシ−３，１５−ジメチルエイコサ−２，６，８，１２，１６，１８−ヘキサエン−１−オールの合成
（３）（２Ｚ，４Ｒ，６Ｚ，８Ｅ，１２Ｅ，１５Ｓ，１６Ｅ，１８Ｚ）−２０−ｔｅｒｔ−ブチルジメチルシリロキシ−１８−［２−（ｔｅｒｔ−ブチルジメチルシリロキシ）エチル］−４−メトキシ−３，１５−ジメチルエイコサ−２，６，８，１２，１６，１８−ヘキサエン−１−オールの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．０２（６Ｈ，ｓ，−Ｓｉ(ＣＨ ３)２ｔ−Ｂｕ），０．０４（６Ｈ，ｓ，−Ｓｉ(ＣＨ ３)２ｔ−Ｂｕ），０．８８（９Ｈ，ｓ，−Ｓｉ(ＣＨ３)２ｔ−Ｂｕ），０．９０（９Ｈ，ｓ，−Ｓｉ(ＣＨ３)２ｔ−Ｂｕ），１．０１（３Ｈ，ｄ，−ＣＨ(ＣＨ ３)ＣＨ２−），１．８４（３Ｈ，ｓ，−(ＣＨ ３)Ｃ＝ＣＨ（ＣＨ２ＯＨ）），１．９７−２．４１（１１Ｈ，ｍ，−ＣＨ(ＣＨ３)ＣＨ ２−，ＣＨ ２ＣＨ２−Ｏ−Ｓｉ−，ＣＨ(ＣＨ３)−ＣＨ ２−，＝ＣＨ−ＣＨ ２−ＣＨ ２−ＣＨ＝），３．２３（３Ｈ，ｓ，−ＣＨ（ＯＣＨ ３）），３．６７（２Ｈ，ｔ，−ＣＨ２ＣＨ ２−Ｏ−Ｓｉ−），４．０４（１Ｈ，ｔ，−ＣＨ（ＯＣＨ３）），４．３１（２Ｈ，ｄ，ＣＨ ２−Ｏ−Ｓｉ），４．５４（２Ｈ，ｍ，−(ＣＨ３)Ｃ＝ＣＨ（ＣＨ ２ＯＨ）），５．２３（１Ｈ，ｍ，−ＣＨ＝ＣＨ−ＣＨ２−ＣＨ（ＯＣＨ３）−），５．３０−５．４０（３Ｈ，ｍ，−ＣＨ（ＣＨ３）−ＣＨ２−ＣＨ＝ＣＨ−，Ｓｉ−Ｏ−ＣＨ２−ＣＨ＝Ｃ−），５．５８（２Ｈ，ｍ，−ＣＨ＝ＣＨ−ＣＨ（ＣＨ３）−，−（ＣＨ ３）Ｃ＝ＣＨ（ＣＨ２ＯＨ）），５．６４（１Ｈ，ｔｄ，−ＣＨ２−ＣＨ２−ＣＨ＝ＣＨ−ＣＨ＝），６．００（１Ｈ，ｔ，−ＣＨ＝ＣＨ−ＣＨ２−ＣＨ（ＯＣＨ３）−），６．１２（１Ｈ，ｄ，Ｊ＝１６Ｈｚ，−ＣＨ＝ＣＨ−ＣＨ（ＣＨ３）−），６．２７（１Ｈ，ｄｄ，−ＣＨ２−ＣＨ２−ＣＨ＝ＣＨ−ＣＨ＝）。
(3) (2Z, 4R, 6Z, 8E, 12E, 15S, 16E, 18Z) -20-tert-butyldimethylsilyloxy-18- [2- (tert-butyldimethylsilyloxy) ethyl] -4-methoxy- Synthesis of 3,15-dimethyleicosa-2,6,8,12,16,18-hexaen-1-ol
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.02 (6H, s, —Si (C H 3 ) 2 t-Bu), 0.04 (6H, s, —Si (C H 3 ) 2 t -Bu), 0.88 (9H, s , -Si (CH 3) 2 t- Bu), 0.90 (9H, s, -Si (CH 3) 2 t- Bu), 1.01 (3H, d, -CH (C H 3) CH 2 -), 1.84 (3H, s, - (C H 3) C = CH (CH 2 OH)), 1.97-2.41 (11H, m, -C H (CH 3) C H 2 -, C H 2 CH 2 -O-Si-, C H (CH 3) -C H 2 -, = = CH-C H 2 -C H 2 -CH), 3.23 (3H, s, -CH ( OC H 3)), 3.67 (2H, t, -CH 2 C H 2 -O-Si -), 4.04 (1H, t, -C H ( OCH 3)), 4.31 (2 , D, C H 2 -O- Si), 4.54 (2H, m, - (CH 3) C = CH (C H 2 OH)), 5.23 (1H, m, -C H = CH- CH 2 -CH (OCH 3) - ), 5.30-5.40 (3H, m, -CH (CH 3) -CH 2 -C H = C H -, Si-OCH 2 -C H = C -), 5.58 (2H, m, -CH = C H -CH (CH 3) -, - (C H 3) C = C H (CH 2 OH)), 5.64 (1H, td, -CH 2 -CH 2 -C H = CH -CH =), 6.00 (1H, t, -C H = CH-CH 2 -CH (OCH 3) -), 6.12 (1H, d, J = 16Hz, -C H = CH- CH (CH 3) -), 6.27 (1H, dd, -CH 2 -CH 2 -CH = C H -CH =).
（４）（２Ｅ，４Ｚ，６Ｒ ８Ｚ，１０Ｅ，１４Ｅ，１７Ｓ，１８Ｅ，２０Ｚ）−エチル ２２−ｔｅｒｔ−ブチルジメチルシリロキシ−２０−［２−（ｔｅｒｔ−ブチルジメチルシリロキシ）エチル］−６−メトキシ−２，５，１７−トリメチルドコサ−２，４，８，１０，１４，１８，２０−ヘプタエノエートの合成
（５）（２Ｅ，４Ｚ，６Ｒ，８Ｚ，１０Ｅ，１４Ｅ，１７Ｓ，１８Ｅ，２０Ｚ）−エチル ２２−ヒドロキシ−２０−（２−ヒドロキシエチル）−６−メトキシ−２，５，１７−トリメチルドコサ−２，４，８，１０，１４，１８，２０−ヘプタエノエートの合成
（６）（２Ｅ，４Ｚ，６Ｒ，８Ｚ，１０Ｅ，１４Ｅ，１７Ｓ，１８Ｅ，２０Ｚ−）−２２−ヒドロキシ−２０−（２−ヒドロキシエチル）−６−メトキシ−２，５，１７−トリメチルドコサ−２，４，８，１０，１４，１８，２０−ヘプタエン酸の合成
（７）（２Ｅ，４Ｚ，６Ｒ，８Ｚ，１０Ｅ，１４Ｅ，１７Ｓ，１８Ｅ，２０Ｚ）−２０−（２−ヒドロキシエチル）−６−メトキシ−２，５，１７−トリメチル−２２−オキソ−ドコサ−２，４，８，１０，１４，１８，２０−ヘプタエン酸の合成
（８）（２Ｅ，４Ｚ，６Ｒ，８Ｚ，１０Ｅ，１４Ｅ，１７Ｓ，１８Ｅ，２０Ｚ−）−２０−（２−ヒドロキシエチル）−６−メトキシ−２，５，１７−トリメチルドコサ−２，４，８，１０，１４，１８，２０−ヘプタエン二酸の合成
（９）（２Ｅ，４Ｚ，６Ｒ，８Ｚ，１０Ｅ，１４Ｅ，１７Ｓ，１８Ｅ，２０Ｚ）−２０−ホルミルメチル−６−メトキシ−２，５，１７−トリメチルドコサ−２，４，８，１０，１４，１８，２０−ヘプタエン二酸の合成
（１０）ボンクレキン酸の合成
得られたボンクレキン酸の構造を確認するため上記ボンクレキン酸の粗生成物をそのまま精製することなくトリメチルエステル化反応に付した。
以下の参考例２に、上記ボンクレキン酸の粗生成物をトリメチルエステル化した実験結果と、得られたトリメチルエステル体の分析結果を示す。
(10) Synthesis of boncrekinic acid
In order to confirm the structure of the obtained boncrekinic acid, the crude product of boncrekinic acid was subjected to a trimethyl esterification reaction without purification.
The following Reference Example 2 shows the experimental results of trimethylesterification of the above boncrekinic crude product and the analysis results of the resulting trimethylester.
参考例２ ボンクレキン酸トリメチルエステルの合成
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．０２（３Ｈ，ｄ，Ｊ＝６．４Ｈｚ，−ＣＨ(ＣＨ ３)−ＣＨ２−），１．８４（３Ｈ，ｓ，−(ＣＨ ３)Ｃ＝ＣＨ−），１．９４（３Ｈ，ｓ，−ＣＨ＝Ｃ(ＣＨ ３)ＣＯＯ−），１．９６−２．１８（６Ｈ，ｍ，），２．２８−２．４１（３Ｈ，ｍ，），２．５８（１Ｈ，ｔｄ，Ｊ＝７．２，１５．７Ｈｚ），３．２２（３Ｈ，ｓ，−ＣＨ（ＯＣＨ ３）），３．３２（２Ｈ，ｓ，−ＣＨ＝Ｃ（ＣＨ ２ＣＯＯ−），３．６８（３Ｈ，−ＣＯＯＣＨ ３），３．７０（３Ｈ，−ＣＯＯＣＨ ３），３．７５（３Ｈ，−ＣＯＯＣＨ ３），４．３４（１Ｈ，ｔ，Ｊ＝７．６Ｈｚ，−ＣＨ（ＯＣＨ３）），５．２０（１Ｈ，ｄｔ，Ｊ＝７．６，１０．４Ｈｚ，ＣＨ＝ＣＨ−ＣＨ２ＣＨ（ＯＣＨ３）−），５．３８（２Ｈ，ｍ，ＣＨ（ＣＨ３）−ＣＨ２−ＣＨ＝ＣＨ−），５．６６−５．７１（２Ｈ，ｍ，（ＣＯＯＣＨ３）ＨＣ＝Ｃ−，ＣＨ２−ＣＨ２−ＣＨ＝ＣＨ−ＣＨ＝），６．０２（１Ｈ，ｔ，Ｊ＝１１．２Ｈｚ，−ＣＨ＝ＣＨ−ＣＨ２−ＣＨ（ＯＣＨ３）−），６．０４（１Ｈ，ｄｄ，Ｊ＝７．６，１４．８Ｈｚ，−ＣＨ＝ＣＨ−ＣＨ(ＣＨ３)−），６．２６（１Ｈ，ｄｄ，Ｊ＝１３．２，１４．８Ｈｚ，ＣＨ２−ＣＨ２−ＣＨ＝ＣＨ−ＣＨ＝），６．３５（１Ｈ，ｄ，Ｊ＝１２Ｈｚ，−(ＣＨ３)Ｃ＝ＣＨ−），７．５１（２Ｈ，ｍ，−ＣＨ＝ＣＨ−ＣＨ（ＣＨ３）−，＝ＣＨ−ＣＨ＝Ｃ（ＣＨ３）ＣＯＯ−）。
１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ：１７０．５（ｓ），１６８．９（ｓ），１６６．１（ｓ），１４７．０（ｓ），１４５．３（ｓ），１４４．７（ｄ），１３４．８（ｄ），１３２．０（ｄ），１３１．３（ｄ），１３０．４（ｄ），１２８．０（ｄ），１２６．２（ｓ），１２５．４（ｄ），１２４．８（ｄ），１２４．５（ｄ），１２４．１（ｄ），１１８．１（ｄ），７８．２（ｄ），５６．３（ｑ），５２．１（ｑ），５１．７（ｑ），５１．１（ｑ），４０．３（ｔ），３９．６（ｔ），３７．５（ｄ），３２．８（ｔ），３２．３（ｔ），３２．０（ｔ），１９．２（ｑ），１８．６（ｑ），１２．３（ｑ）。
（文献：J.De Bruun, D.J.Frost, D.H. Nugteren Tetrahedron 1973, 29, 1541-1547）
Reference Example 2 Synthesis of trimethyl ester boncrekinic
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.02 (3H, d, J = 6.4 Hz, —CH (C H 3 ) —CH 2 —), 1.84 (3H, s, — (C H 3) C = CH -) , 1.94 (3H, s, -CH = C (C H 3) COO -), 1.96-2.18 (6H, m,), 2.28-2. 41 (3H, m,), 2.58 (1H, td, J = 7.2,15.7Hz), 3.22 (3H, s, -CH (OC H 3)), 3.32 (2H, s, -CH = C (C H 2 COO -), 3.68 (3H, -COOC H 3), 3.70 (3H, -COOC H 3), 3.75 (3H, -COOC H 3), 4.34 (1H, t, J = 7.6Hz, -C H (OCH 3)), 5.20 (1H, dt, J = 7.6,10.4Hz, CH = C H -CH 2 CH ( CH 3) -), 5.38 ( 2H, m, CH (CH 3) -CH 2 -C H = C H -), 5.66-5.71 (2H, m, (COOCH 3) H C = C-, CH 2 -CH 2 -C H = CH-CH =), 6.02 (1H, t, J = 11.2Hz, -C H = CH-CH 2 -CH (OCH 3) -), 6 .04 (1H, dd, J = 7.6,14.8Hz, -CH = C H -CH (CH 3) -), 6.26 (1H, dd, J = 13.2,14.8Hz, CH 2 -CH 2 -CH = C H -CH =), 6.35 (1H, d, J = 12Hz, - (CH 3) C = C H -), 7.51 (2H, m, -C H = CH-CH (CH 3) - , = CH-C H = C (CH 3) COO-).
13 C-NMR (100 MHz, CDCl 3 ) δ: 170.5 (s), 168.9 (s), 166.1 (s), 147.0 (s), 145.3 (s), 144.7 (D), 134.8 (d), 132.0 (d), 131.3 (d), 130.4 (d), 128.0 (d), 126.2 (s), 125.4 ( d), 124.8 (d), 124.5 (d), 124.1 (d), 118.1 (d), 78.2 (d), 56.3 (q), 52.1 (q) ), 51.7 (q), 51.1 (q), 40.3 (t), 39.6 (t), 37.5 (d), 32.8 (t), 32.3 (t) 32.0 (t), 19.2 (q), 18.6 (q), 12.3 (q).
(Reference: J. De Bruun, DJFrost, DH Nugteren Tetrahedron 1973, 29, 1541-1547)
本発明の製造法によれば、近時、医学分野で重要なアポトーシスの研究や関連医薬品の開発に必須なボンクレキン酸を、安価に、且つ必要量供給することが出来るので、実用化が可能なボンクレキン酸の化学的合成法として大いに期待されるものである。 According to the production method of the present invention, it is possible to supply the necessary amount of boncrekinic acid, which is essential for the research of apoptosis and the development of related drugs, which are important in the medical field, at a low cost. This is highly expected as a chemical synthesis method of boncrekinic acid.
Claims (84)
（１）一般式［１］
で示される化合物を一般式［２］
で示される化合物と反応させて、一般式［３］
で示される化合物とする工程。
（２）上記（１）で得られた一般式［３］で示される化合物をメチル化剤と反応させて、一般式［４］
で示される化合物とする工程。
（３）上記（２）で得られた一般式［４］で示される化合物の三重結合を部分水素化して一般式［５］
で示される化合物とする工程。
（４）上記（３）で得られた一般式［５］で示される化合物を酸で加水分解処理して、一般式［６］
で示される化合物とする工程。
（５）上記（４）で得られた一般式［６］で示される化合物を酸化して、一般式［７］
で示される化合物とする工程。
（６）上記（５）で得られた一般式［７］で示される化合物をジブロモメチリデン化して、一般式［８］
で示される化合物とする工程。
（７）上記（６）で得られた一般式［８］で示される化合物を一般式［９］
ＣｌＣＯ２Ｒ４ ［９］
（式中、Ｒ４はアルキル基、アリール基、アラルキル基又はトリ置換シリル基を表す。）
で示される化合物と反応させて、一般式［１０］
で示される化合物とする工程。
（８）上記（７）で得られた一般式［１０］で示される化合物の三重結合に有機銅を１，４−付加させた後プロトン化して、一般式［１１］
で示される化合物とする工程。
（９）上記（８）で得られた一般式［１１］で示される化合物の８位の水酸基の保護基Ｒ３を脱保護剤で処理することにより脱保護して、一般式［１２］
で示される化合物とする工程。
（１０）上記（９）で得られた一般式［１２］で示される化合物を酸化剤で処理した後、一般式［１３］
Ｐｈ３Ｐ＝ＣＨＣＯ２Ｒ５
（式中、Ｒ５は、ｔｅｒｔ−ブチル基又はトリ置換シリル基を表す。）
で示される化合物と反応させて、一般式［１４］
で示される化合物とする工程。
（１１）上記（１０）で得られた一般式［１４］で示される化合物の１位のカルボキシル基の保護基Ｒ５を、脱保護剤で処理することにより脱保護して、一般式［１５］
で示される化合物とする工程。
（１２）上記（１１）で得られた一般式［１５］で示される化合物の１位のカルボキシル基を還元して、一般式［１６］
で示されるヒドロキシ体とする工程。
（１３）上記（１２）で得られた一般式［１６］で示されるヒドロキシ体の１０位の水酸基をスルホン酸エステル化又はハロゲン置換して、一般式［１７］
で示される化合物とする工程。 Following (1) ~ C 11 ~C 22 preparation segment of bongkrekic acid comprising the step of (13).
(1) General formula [1]
The compound represented by general formula [2]
Is reacted with a compound represented by the general formula [3]
The process made into the compound shown by these.
(2) The compound represented by the general formula [3] obtained in the above (1) is reacted with a methylating agent to give a general formula [4].
The process made into the compound shown by these.
(3) Partial hydrogenation of the triple bond of the compound represented by the general formula [4] obtained in the above (2) to give a general formula [5]
The process made into the compound shown by these.
(4) The compound represented by the general formula [5] obtained in the above (3) is hydrolyzed with an acid to give a general formula [6].
The process made into the compound shown by these.
(5) The compound represented by the general formula [6] obtained in the above (4) is oxidized to give a general formula [7].
The process made into the compound shown by these.
(6) The compound represented by the general formula [7] obtained in the above (5) is converted to a dibromomethylidene to give a general formula [8]
The process made into the compound shown by these.
(7) The compound represented by the general formula [8] obtained in the above (6) is converted to the general formula [9].
ClCO 2 R 4 [9]
(In the formula, R 4 represents an alkyl group, an aryl group, an aralkyl group or a tri-substituted silyl group.)
Is reacted with a compound represented by the general formula [10]
The process made into the compound shown by these.
(8) 1,4-addition of organic copper to the triple bond of the compound represented by the general formula [10] obtained in the above (7), followed by protonation, followed by the general formula [11]
The process made into the compound shown by these.
(9) The protecting group R 3 of the hydroxyl group at the 8-position of the compound represented by the general formula [11] obtained in the above (8) is deprotected by treatment with a deprotecting agent, and the general formula [12]
The process made into the compound shown by these.
(10) After treating the compound represented by the general formula [12] obtained in the above (9) with an oxidizing agent, the general formula [13]
Ph 3 P = CHCO 2 R 5
(In the formula, R 5 represents a tert-butyl group or a tri-substituted silyl group.)
And a compound represented by the general formula [14]
The process made into the compound shown by these.
(11) The protecting group R 5 of the carboxyl group at the 1-position of the compound represented by the general formula [14] obtained in the above (10) is deprotected by treatment with a deprotecting agent, and the general formula [15 ]
The process made into the compound shown by these.
(12) The carboxyl group at the 1-position of the compound represented by the general formula [15] obtained in the above (11) is reduced to give the general formula [16]
The process made into the hydroxy body shown by these.
(13) The hydroxy group at the 10-position of the hydroxy compound represented by the general formula [16] obtained in the above (12) is sulfonated or substituted with a halogen to give a general formula [17]
The process made into the compound shown by these.
で示される化合物を一般式［２］
で示される化合物と反応させることを特徴とする、一般式［３］
で示される化合物の製造法。 General formula [1]
The compound represented by general formula [2]
Wherein the compound is reacted with a compound represented by the general formula [3]
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [3]
A compound represented by
で示される化合物をメチル化剤と反応させることを特徴とする、一般式［４］
で示される化合物の製造法。 General formula [3]
Wherein the compound represented by the general formula [4] is reacted with a methylating agent
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [4]
A compound represented by
で示される化合物の三重結合を部分水素化することを特徴とする、一般式［５］
で示される化合物の製造法。 General formula [4]
Wherein the triple bond of the compound represented by general formula [5] is partially hydrogenated
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [5]
A compound represented by
で示される化合物を酸で加水分解処理することを特徴とする、一般式［６］
で示される化合物の製造法。 General formula [5]
The compound represented by general formula [6], wherein the compound is hydrolyzed with an acid:
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [6]
A compound represented by
で示される化合物を酸化することを特徴とする、一般式［７］
で示される化合物の製造法。 General formula [6]
A compound represented by the general formula [7],
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [7]
A compound represented by
で示される化合物をジブロモメチリデン化することを特徴とする、一般式［８］
で示される化合物の製造法。 General formula [7]
A compound represented by the general formula [8],
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [8]
A compound represented by
で示される化合物を一般式［９］
ＣｌＣＯ２Ｒ４ ［９］
（式中、Ｒ４はアルキル基、アリール基、アラルキル基又はトリ置換シリル基を表す。）
で示される化合物と反応させることを特徴とする、一般式［１０］
で示される化合物の製造法。 General formula [8]
A compound represented by the general formula [9]
ClCO 2 R 4 [9]
(In the formula, R 4 represents an alkyl group, an aryl group, an aralkyl group or a tri-substituted silyl group.)
Wherein the compound is reacted with a compound represented by the general formula [10]
The manufacturing method of the compound shown by these.
で示される化合物。 Formula [10]
A compound represented by
で示される化合物の三重結合に有機銅を１，４−付加させた後プロトン化することを特徴とする、一般式［１１］
で示される化合物の製造法。 Formula [10]
A compound represented by the general formula [11], wherein 1,4-addition of organocopper to the triple bond of the compound represented by formula (1) is followed by protonation.
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [11]
A compound represented by
で示される化合物の８位の水酸基の保護基Ｒ３を脱保護剤で処理することにより脱保護することを特徴とする、一般式［１２］
で示される化合物の製造法。 General formula [11]
Wherein the protecting group R 3 of the hydroxyl group at the 8-position of the compound represented by the formula is deprotected by treating with a deprotecting agent [12]
The manufacturing method of the compound shown by these.
で示される化合物。 Formula [12]
A compound represented by
で示される化合物を酸化剤で処理した後、一般式［１３］
Ｐｈ３Ｐ＝ＣＨＣＯ２Ｒ５
（式中、Ｒ５はｔｅｒｔ−ブチル基又はトリ置換シリル基を表す。）
で示される化合物と反応させることを特徴とする、一般式［１４］
で示される化合物の製造法。 Formula [12]
The compound represented by formula (13) is treated with an oxidizing agent,
Ph 3 P = CHCO 2 R 5
(In the formula, R 5 represents a tert-butyl group or a tri-substituted silyl group.)
Wherein the compound is reacted with a compound represented by the general formula [14]
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [14]
A compound represented by
で示される化合物の１位のカルボキシル基の保護基Ｒ５を、脱保護剤で処理することにより脱保護することを特徴とする、一般式［１５］
で示される化合物の製造法。 General formula [14]
The protective group R 5 of the carboxyl group at the 1-position of the compound represented by the formula [15] is deprotected by treatment with a deprotecting agent.
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [15]
A compound represented by
で示される化合物の１位のカルボキシル基を還元することを特徴とする、一般式［１６］
で示されるヒドロキシ体の製造法。 General formula [15]
A carboxyl group at the 1-position of the compound represented by the general formula [16]
The manufacturing method of the hydroxy body shown by this.
で示される化合物。 Formula [16]
A compound represented by
で示される化合物の１０位の水酸基をスルホン酸エステル化又はハロゲン置換することを特徴とする、一般式［１７］
で示される化合物の製造法。 Formula [16]
Wherein the hydroxyl group at the 10-position of the compound represented by the formula is sulfonated or halogen-substituted, represented by the general formula [17]
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [17]
A compound represented by
（１４）一般式［１８］
で示される化合物と一般式［１７］
で示される化合物とを反応させて、一般式［１９］
で示される化合物とする工程。
（１５）上記（１４）で得られた一般式［１９］で示される化合物を還元して、一般式［２０］
で示されるヒドロキシ体とする工程。
（１６）上記（１５）で得られた一般式［２０］で示される化合物の１１位の−ＳＯ２Ａｒ基を脱離させて、一般式［２１］
で示される化合物とする工程。
（１７）上記（１６）で得られた一般式［２１］で示される化合物を酸化剤で処理した後、一般式［２２］
Ｐｈ３Ｐ＝Ｃ（ＣＨ３）ＣＯ２Ｒ９ ［２２］
（式中、Ｒ９はアルキル基、アリール基、アラルキル基又はトリ置換シリル基を表す。）
で示される化合物と反応させて、一般式［２３］
で示される化合物とする工程。
（１８）上記（１７）で得られた一般式［２３］で示される化合物の水酸基の保護基Ｒ７，Ｒ８を酸で処理することにより脱離させて、一般式［２４］
で示されるジヒドロキシ体とする工程。
（１９）上記（１８）で得られた一般式［２４］で示される化合物をアルカリで加水分解して、式［２５］
（２０）上記（１９）で得られた式［２５］で示される化合物の−ＣＨ２ＯＨ基の一つを酸化して、式［２６］
（２１）上記（２０）で得られた式［２６］で示されるアルデヒド体のアルデヒド基を更に酸化して、式［２７］
（２２）上記（２１）で得られた式［２７］で示されるヒドロキシジカルボン酸のヒドロキシ基を酸化して、式［２８］
（２３）上記（２２）で得られた式［２８］で示されるアルデヒド体のアルデヒド基を更に酸化して、下式
(14) General formula [18]
And a compound of the general formula [17]
And a compound represented by the general formula [19]
The process made into the compound shown by these.
(15) The compound represented by the general formula [19] obtained in the above (14) is reduced to obtain the general formula [20].
The process made into the hydroxy body shown by these.
(16) The —SO 2 Ar group at the 11-position of the compound represented by the general formula [20] obtained in the above (15) is eliminated, and the general formula [21]
The process made into the compound shown by these.
(17) After treating the compound represented by the general formula [21] obtained in the above (16) with an oxidizing agent, the general formula [22]
Ph 3 P═C (CH 3 ) CO 2 R 9 [22]
(Wherein R 9 represents an alkyl group, an aryl group, an aralkyl group or a tri-substituted silyl group.)
Is reacted with a compound represented by the general formula [23]
The process made into the compound shown by these.
(18) The hydroxyl-protecting groups R 7 and R 8 of the compound represented by the general formula [23] obtained in the above (17) are eliminated by treatment with an acid, and the general formula [24]
The process made into the dihydroxy body shown by these.
(19) The compound represented by the general formula [24] obtained in the above (18) is hydrolyzed with an alkali to obtain the formula [25].
(20) One of the —CH 2 OH groups of the compound represented by the formula [25] obtained in the above (19) is oxidized to obtain the formula [26]
(21) The aldehyde group of the aldehyde compound represented by the formula [26] obtained in the above (20) is further oxidized to obtain the formula [27]
(22) The hydroxy group of the hydroxydicarboxylic acid represented by the formula [27] obtained in the above (21) is oxidized to obtain the formula [28]
(23) The aldehyde group represented by the formula [28] obtained in the above (22) is further oxidized to give the following formula:
で示される化合物と一般式［１７］
で示される化合物とを反応させることを特徴とする、一般式［１９］
で示される化合物の製造法。 General formula [18]
And a compound of the general formula [17]
And a compound represented by the general formula [19]
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [19]
A compound represented by
で示される化合物を還元することを特徴とする、一般式［２０］
で示されるヒドロキシ体の製造法。 General formula [19]
A compound represented by the general formula [20]:
The manufacturing method of the hydroxy body shown by this.
で示される化合物。 General formula [20]
A compound represented by
で示される化合物の１１位の−ＳＯ２Ａｒ基を脱離させることを特徴とする、一般式［２１］で示される化合物の製造法。 General formula [20]
A method for producing a compound represented by the general formula [21], wherein the 11-position —SO 2 Ar group of the compound represented by the formula is eliminated.
で示される化合物。 Formula [21]
A compound represented by
で示される化合物を酸化剤で処理した後、一般式［２２］
Ｐｈ３Ｐ＝Ｃ（ＣＨ３）ＣＯ２Ｒ９ ［２２］
（式中、Ｒ９はアルキル基、アリール基、アラルキル基又はトリ置換シリル基を表す。）
で示される化合物と反応させることを特徴とする、一般式［２３］
で示される化合物の製造法。 Formula [21]
The compound represented by formula (22) is treated with an oxidizing agent, and then the general formula [22]
Ph 3 P═C (CH 3 ) CO 2 R 9 [22]
(Wherein R 9 represents an alkyl group, an aryl group, an aralkyl group or a tri-substituted silyl group.)
Wherein the compound is reacted with a compound represented by the general formula [23]
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [23]
A compound represented by
で示される化合物の水酸基の保護基Ｒ７，Ｒ８を酸で処理することにより脱離させることを特徴とする、一般式［２４］
で示される化合物の製造法。 General formula [23]
Wherein the protecting groups R 7 and R 8 of the hydroxyl group of the compound represented by formula (1) are eliminated by treatment with an acid.
The manufacturing method of the compound shown by these.
で示される化合物。 General formula [24]
A compound represented by
で示される化合物をアルカリで加水分解することを特徴とする、式［２５］
Wherein the compound represented by formula [25] is hydrolyzed with an alkali.
84. The production method according to claim 83, wherein the aldehyde group is oxidized by allowing sodium chlorite and sodium dihydrogen phosphate to act on the compound represented by the formula [28].
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| JP2003299382A JP2005068064A (en) | 2003-08-22 | 2003-08-22 | Method for producing bongkrekic acid and precursor compound thereof |
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| Application Number | Priority Date | Filing Date | Title |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104515823A (en) * | 2014-12-16 | 2015-04-15 | 云南省疾病预防控制中心 | Method for rapid determination of Flavobacterium farinofermentans toxin A in food poisoning sample |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104515823A (en) * | 2014-12-16 | 2015-04-15 | 云南省疾病预防控制中心 | Method for rapid determination of Flavobacterium farinofermentans toxin A in food poisoning sample |
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