DE3909325C2 - New process for the production of optically active bicyclo [3.3.0] octane derivatives - Google Patents
New process for the production of optically active bicyclo [3.3.0] octane derivativesInfo
- Publication number
- DE3909325C2 DE3909325C2 DE3909325A DE3909325A DE3909325C2 DE 3909325 C2 DE3909325 C2 DE 3909325C2 DE 3909325 A DE3909325 A DE 3909325A DE 3909325 A DE3909325 A DE 3909325A DE 3909325 C2 DE3909325 C2 DE 3909325C2
- Authority
- DE
- Germany
- Prior art keywords
- mmol
- mixture
- nmr
- mhz
- ethyl acetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- AEBWATHAIVJLTA-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropentalene Chemical class C1CCC2CCCC21 AEBWATHAIVJLTA-UHFFFAOYSA-N 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title description 5
- -1 hydroxy, benzyloxy Chemical group 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- LQOSXLZEMUCHFD-UHFFFAOYSA-M Cl[Mg][Cu] Chemical class Cl[Mg][Cu] LQOSXLZEMUCHFD-UHFFFAOYSA-M 0.000 claims description 2
- 239000005749 Copper compound Substances 0.000 claims description 2
- FCVYBPLABCPUGU-UHFFFAOYSA-M [Cu][Zn]I Chemical compound [Cu][Zn]I FCVYBPLABCPUGU-UHFFFAOYSA-M 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- VBTCAHMANZTRMG-UHFFFAOYSA-N prop-2-ynylcyclopentane Chemical class C#CCC1CCCC1 VBTCAHMANZTRMG-UHFFFAOYSA-N 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 144
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 107
- 239000000203 mixture Substances 0.000 description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 52
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- 239000012230 colorless oil Substances 0.000 description 31
- 150000001875 compounds Chemical class 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 239000000741 silica gel Substances 0.000 description 27
- 229910002027 silica gel Inorganic materials 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000012071 phase Substances 0.000 description 21
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 20
- 235000019341 magnesium sulphate Nutrition 0.000 description 20
- 238000003756 stirring Methods 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 11
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JANVYOZZTKSZGN-WCAFQOMDSA-N 5-[(3as,5r,6r,6as)-5-hydroxy-6-[(e,3s)-3-hydroxyoct-1-enyl]-1,3a,4,5,6,6a-hexahydropentalen-2-yl]pentanoic acid Chemical class C1=C(CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 JANVYOZZTKSZGN-WCAFQOMDSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- HVAMZGADVCBITI-UHFFFAOYSA-M pent-4-enoate Chemical compound [O-]C(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-M 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 3
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- ISQVBYGGNVVVHB-UHFFFAOYSA-N cyclopentylmethanol Chemical compound OCC1CCCC1 ISQVBYGGNVVVHB-UHFFFAOYSA-N 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 2
- LLBJASAUESBJMI-MNOVXSKESA-N C(C)(=O)OC[C@@H]1CC2(C[C@@H]1CO)OCCCO2 Chemical compound C(C)(=O)OC[C@@H]1CC2(C[C@@H]1CO)OCCCO2 LLBJASAUESBJMI-MNOVXSKESA-N 0.000 description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 125000000746 allylic group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- VWWMOACCGFHMEV-UHFFFAOYSA-N dicarbide(2-) Chemical compound [C-]#[C-] VWWMOACCGFHMEV-UHFFFAOYSA-N 0.000 description 2
- UBHZUDXTHNMNLD-UHFFFAOYSA-N dimethylsilane Chemical compound C[SiH2]C UBHZUDXTHNMNLD-UHFFFAOYSA-N 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 238000003328 mesylation reaction Methods 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- QIGRQPVOWVHYBT-KABTVRTISA-N methyl 5-[(3as,5r,6r,6as)-5-hydroxy-6-[(e,3s)-3-hydroxyoct-1-enyl]-1,3a,4,5,6,6a-hexahydropentalen-2-yl]pentanoate Chemical compound C1=C(CCCCC(=O)OC)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 QIGRQPVOWVHYBT-KABTVRTISA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 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
- LQZCYXCHWNQBKX-UHFFFAOYSA-N 1-dimethoxyphosphorylheptan-2-one Chemical compound CCCCCC(=O)CP(=O)(OC)OC LQZCYXCHWNQBKX-UHFFFAOYSA-N 0.000 description 1
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 description 1
- 101710134784 Agnoprotein Proteins 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- XZFRIPGNUQRGPI-WLPVIMDJSA-N Carbacyclin Chemical compound C1\C(=C\CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 XZFRIPGNUQRGPI-WLPVIMDJSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- JGHIFJYLQAXNSR-UHFFFAOYSA-N [3-(hydroxymethyl)-6,10-dioxaspiro[4.5]decan-2-yl]methanol Chemical compound C1C(CO)C(CO)CC21OCCCO2 JGHIFJYLQAXNSR-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000004808 allyl alcohols Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VDCSGNNYCFPWFK-UHFFFAOYSA-N diphenylsilane Chemical compound C=1C=CC=CC=1[SiH2]C1=CC=CC=C1 VDCSGNNYCFPWFK-UHFFFAOYSA-N 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002373 hemiacetals Chemical class 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- WDDOQHLJFOUQMW-UHFFFAOYSA-N lithium;ethynyl(trimethyl)silane Chemical compound [Li+].C[Si](C)(C)C#[C-] WDDOQHLJFOUQMW-UHFFFAOYSA-N 0.000 description 1
- LROBJRRFCPYLIT-UHFFFAOYSA-M magnesium;ethyne;bromide Chemical compound [Mg+2].[Br-].[C-]#C LROBJRRFCPYLIT-UHFFFAOYSA-M 0.000 description 1
- RMWHUMOMMXXZFH-UHFFFAOYSA-M magnesium;methanidyloxymethylbenzene;chloride Chemical compound [Mg+2].[Cl-].[CH2-]OCC1=CC=CC=C1 RMWHUMOMMXXZFH-UHFFFAOYSA-M 0.000 description 1
- 229940057952 methanol Drugs 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000012587 nuclear overhauser effect experiment Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- DOIRQSBPFJWKBE-UHFFFAOYSA-N phthalic acid di-n-butyl ester Natural products CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
- C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
- C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von optisch aktiven Bicyclo[3.3.0]octan-Derivaten als Zwischenprodukte für die Herstellung therapeutisch wirksamer Isocarbacycline.The present invention relates to a method for producing optical active bicyclo [3.3.0] octane derivatives as intermediates for the production therapeutically effective isocarbacyclins.
Derivate des Isocarbacyclins (s. 15b im nachfolgenden Schema) sind als Thrombo zyten-Aggregations-hemmende Mittel aus Chem. Pharm. Bull. 35 (1987) 948 bekannt.Derivatives of isocarbacyclin (see 15b in the diagram below) are known as thrombo cytogenesis-inhibiting agents from Chem. Pharm. Bull. 35 (1987) 948 known.
Gegenüber den bekannten Verfahren zur Herstellung von Zwischenprodukten der
nachstehenden Formel stellt das neue Verfahren eine Verbesserung dar, weil es
sowohl enantioselektiv als auch flexibel ist.
Compared to the known processes for the production of intermediates of the formula below, the new process is an improvement because it is both enantioselective and flexible.
Die Erfindung betrifft somit ein Verfahren zur Herstellung von optisch aktiven
Bicyclo[3.3.0]octan-Derivaten der Formel I,
The invention thus relates to a process for the preparation of optically active bicyclo [3.3.0] octane derivatives of the formula I,
worin R1 Wasserstoff oder den Rest -CH2-OR3,
R2 Hydroxy, Benzyloxy oder die Reste tert.-Butyloxycarbonylmethoxy,
wherein R 1 is hydrogen or the radical -CH 2 -OR 3 ,
R 2 is hydroxy, benzyloxy or the residues of tert-butyloxycarbonylmethoxy,
X Sauerstoff oder die Reste Wasserstoff und OR3 (H, OR3) und
R3 Wasserstoff oder einen Tetrahydropyranylrest bedeuten,
das dadurch gekennzeichnet ist, daß man
3-Cyclopentyl-propin-Derivate der Formel II,
X is oxygen or the radicals hydrogen and OR 3 (H, OR 3 ) and
R 3 is hydrogen or a tetrahydropyranyl radical, which is characterized in that
3-cyclopentyl-propyne derivatives of the formula II,
worin X und R1 die oben angegebenen Bedeutungen haben, mit NaJ in Gegenwart von
Azobisisobutyronitril und mit Tributylzinnhydrid umsetzt, die Dimethyl
tert.-butylsilyl-Schutzgruppe abspaltet, in Gegenwart von DMAP acety
liert und die erhaltenen Bicyclo[3.3.0]octanderivate der Formel III,
wherein X and R 1 have the meanings given above, with NaJ in the presence of azobisisobutyronitrile and with tributyltin hydride, the dimethyl tert.-butylsilyl protective group is split off, acetylated in the presence of DMAP and the bicyclo [3.3.0] octane derivatives of the formula obtained III,
worin X und R1 die oben angegebenen Bedeutungen haben, mit Chlormagnesiumkup
fer-Verbindungen der Formel IVa oder der Jodzinkkupferverbindung IVb
wherein X and R 1 have the meanings given above, with chloromagnesium copper compounds of the formula IVa or the iodo zinc copper compound IVb
ClMgCu (R4)2 (IVa)
ClMgCu (R 4 ) 2 (IVa)
JZuCu(CN)(CH2)3 COOCH3 (IVb)
JZuCu (CN) (CH 2 ) 3 COOCH 3 (IVb)
worin R4 die Reste
wherein R 4 is the residues
bedeuten, bei tiefen Temperaturen umsetzt und gegebenenfalls anschließend die Schutzgruppe im Rest R2 abspaltet und den er haltenen Alkohol oxydiert.mean, reacted at low temperatures and, if appropriate, then subsequently splits off the protective group in the radical R 2 and oxidizes the alcohol it contains.
Durch radikalische 5-exo-dig-Cyclosierung und Substitution mit Cupraten werden
ausgehend von 1 oder 6 das Grundgerüst, die obere Seitenkette und die 2,3-Dop
pelbindung von 5 bzw. 10 aufgebaut (siehe nachfolgendes Reaktionsschema)
By radical 5-exo-dig cyclization and substitution with cuprates, the basic structure, the upper side chain and the 2,3-double bond of 5 and 10 are built up from 1 or 6 (see reaction scheme below)
X = O
X' = O; H, OH
R = THP
R' = H, SitBuMe2
R'' = H, Ac, Bz, Mes
R''' = SiMe3, H
R'''' = Bzl, H, CH2COOtBu
R''''' = CHO, CH2OH, CH2OSitBuPh2, COOCH3;
a: 1,1 Equiv.LiC = CSiMe3, THF, -78°→ -20°
b: 2 Equiv.NaJ, Azoisobutyronitril (AIBN,
Kat)
2 Equiv. n-Bu4SnH, Glyme, 50°, 96 h
c: 2 Equi. ClMgCu[(CH2)4OSitBuPh2]2 (V) oder IVb
Ether, -25°C→RT
d: 3 Equiv. ClMgCu(CH2OCH2Ph)2(VI), THF,
-20°→RT
e: 3 Equiv. BrMgC = CH, THF
f: 2 Equiv. NaJ, AIBN(Kat), 2 Equiv. n-
Bu3SnH , Glyme, 50°, 96h
g: 3 Equiv. V oder IVb, Ether -25°→RT
h: 2 Equiv. VI, THF, -25°→RT
X = O
X '= O; H, OH
R = THP
R '= H, SitBuMe 2
R '' = H, Ac, Bz, Mes
R '''= SiMe 3 , H
R '''' = Bzl, H, CH 2 COOtBu
R '''''= CHO, CH 2 OH, CH 2 OSitBuPh 2 , COOCH 3 ;
a: 1.1 Equiv.LiC = CSiMe 3 , THF, -78 ° → -20 °
b: 2 Equiv.NaJ, azoisobutyronitrile (AIBN, Kat)
2 equiv. n-Bu 4 SnH, glyme, 50 °, 96 h
c: 2 equi. ClMgCu [(CH 2 ) 4 OSitBuPh 2 ] 2 (V) or IVb ether, -25 ° C → RT
d: 3 equiv. ClMgCu (CH 2 OCH 2 Ph) 2 (VI), THF, -20 ° → RT
e: 3 equiv. BrMgC = CH, THF
f: 2 equiv. NaJ, AIBN (Kat), 2 equiv. n- Bu 3 SnH, glyme, 50 °, 96h
g: 3 equiv. V or IVb, ether -25 ° → RT
h: 2 equiv. VI, THF, -25 ° → RT
Optimierte Synthesen mit enzymkatalysierten asymmetrischen Schlüsselschritten
für die Edukte (-)-1a1) und (+)-6a2),3) sind in den nachstehenden Publikationen
beschrieben4):
Optimized syntheses with enzyme-catalyzed asymmetric key steps for the starting materials (-) - 1a 1) and (+) - 6a 2) , 3) are described in the following publications 4) :
- 1) H. Hemmerle, H.-J. Gais, Tetrahedron Lett. 28 (1987) 3471.1) H. Hemmerle, H.-J. Gais, Tetrahedron Lett. 28 (1987) 3471.
- 2) a) H.-J. Gais, K. L. Lukas, W. A. Ball, S. Braun, H. J. Lindner, Liebias Ann. Chem. 1986, 687; b) H.-J. Gais, H. J. Lindner, T. Lied, K. L. Lukas, W. A. Ball, B. Rosenstock, H. Sliwa, ibid. 1986, 1179.2) a) H.-J. Gais, K.L. Lukas, W.A. Ball, S. Braun, H.J. Lindner, Liebias Ann. Chem. 1986, 687; b) H.-J. Gais, H.J. Lindner, T. Lied, K.L. Lukas, W.A. Ball, B. Rosenstock, H. Sliva, ibid. 1986, 1179.
- 3) Carbacyclin-Synthesen mit (+)-6a: a) H.-J. Gais, W. A. Ball, J. Bund, Tetrahedron Lett. 29 (1988) 781; b) H.-J. Gais, G. Schmiedl, W. A. Ball, J. Bund, 1. Erdelmeier, ibid. 29 (1988) 1773; I. Erdelmeier, H.-J. Gais, J. Am. Chem. Soc., 111 (1989), No. 2.3) Carbacyclin syntheses with (+) - 6a: a) H.-J. Gais, W. A. Ball, J. Bund, Tetrahedron Lett. 29 (1988) 781; b) H.-J. Gais, G. Schmiedl, W. A. Ball, J. Bund, 1. Erdelmeier, ibid. 29 (1988) 1773; I. Erdelmeier, H.-J. Gais, J. Am. Chem. Soc., 111 (1989), No. 2nd
-
4) B. Riefling, W. P. Brümmer, H.-J. Gais, NATO ASI Ser. C
Vol. 178 (1986) 347.
4) B. Riefling, WP Brümmer, H.-J. Gais, NATO ASI Ser. C Vol. 178 (1986) 347.
Die Synthese des allylischen Acetats 3 (X = O, R' = Ac) beginnt mit der Oxidation
des Alkohols 1a zum Aldehyd 1 und dessen Addition an Lithium(trimethylsilyl)-
acetylid. Man erhält das Alkinol 2a (R' = H, R'' = Ac, R3 = SiMe3, X = O) als Diaster
eomerenmischung ((1'R)-2a : (1'S)-2a = 3 : 1); C-2-Epimere sind jedoch nicht vor
handen. Silylierung, selektive Abspaltung der Trimethylsilyl- sowie Acetylgrup
pe und anschließende Mesylierung ergeben das Mesylat 2d (R' = SitBuKe2, (R'' = Mes,
R''' = H). Das darauf in situ erzeugte primäre Jodid wird radikalisch in 91% Aus
beute zu 3a (R' = SitBuMe2) cyclisiert, und dieses dann in 3 überführt.
Mit den Cupraten V und VI reagiert 3 unter Substitution zu den bicyclischen
Alkenen (4 bzw. 5), die in Ausbeuten von 87%, 91% bzw. 84% isoliert werden. Die
Transformation 3→4 gelingt auch mit dem stabilen Benzyloxymethylmagnesiumchlo
rid in Gegenwart von 10 Mol% Cu(I)J. Von besonderer Bedeutung ist, daß auch die
direkte Umwandlung von 3→5 (R''''' = COOCH3) mit IVb [Z. Yoshida et al. J.Org.
Chem. 52 (1987) 4420] gelingt. Racemate von Bicyclen des Typs 4 und 5 hat
man bereits in rac-11a bzw. rac-11b (R = n-C5H11) überführt (K. Kojima et al.
Chem. Pharm. Bull. 35 (1987) 948 und K. Kojima et al. ibid. 35 (1987) 4000]:
The synthesis of allylic acetate 3 (X = O, R '= Ac) begins with the oxidation of alcohol 1a to aldehyde 1 and its addition to lithium (trimethylsilyl) acetylide. Alkinol 2a (R '= H, R''= Ac, R 3 = SiMe 3 , X = O) is obtained as a diasteromer mixture ((1'R) -2a: (1'S) -2a = 3: 1); However, C-2 epimers are not available. Silylation, selective cleavage of the trimethylsilyl and acetyl groups and subsequent mesylation give the mesylate 2d (R '= SitBuKe 2 , (R''= Mes, R''' = H). The primary iodide generated thereon becomes radical in 91 % Of the prey is cyclized to 3a (R '= SitBuMe 2 ), and this is then converted to 3. With the cuprates V and VI, 3 reacts with substitution to give the bicyclic alkenes (4 and 5), respectively, in yields of 87%, 91 % or 84% are isolated. The transformation 3 → 4 can also be achieved with the stable benzyloxymethylmagnesium chloride in the presence of 10 mol% Cu (I) J. It is particularly important that the direct conversion of 3 → 5 (R ''"" = COOCH 3 ) with IVb [Z. Yoshida et al. J.Org. Chem. 52 (1987) 4420]. Racemates of bicycles of types 4 and 5 have already been found in rac-11a and rac-11b, respectively (R = nC 5 H 11 ) (K. Kojima et al. Chem. Pharm. Bull. 35 (1987) 948 and K. Kojima et al. Ibid. 35 (1987) 4000):
Zur Synthese des C-4-funktionalisierten allylischen Acetats 8 ( R' = Ac, R = THP) wird das Lacton 6a in das Hemiacetal 6(X' = H, OH; R = THP) überführt und aus diesem mit 3 Äquivalenten Brommagnesiumacetylid die Mischung der diastereomeren Al kindiole 7a (R' = R'' = H) (1'S : 1'R = 6 : 1) hergestellt; C-4-Epimere finden sich nicht. Die Diastereomerenverhältnisse von 2a und 7a zeigen entgegengesetzte asymmetrische Induktionen für die Acetylidadditionen an 1 und an den mit depro toniertem 6 im Gegengewicht stehenden Aldehyd an. Das Mesylat 7 wird dann aus 7a mittels Schutzgruppen-Manipulationen und Mesylierung erhalten. Der radika lische Ringschluß des aus 7 in situ erzeugten primären Jodids zu 8a verläuft glatt in 82% Ausbeute.For the synthesis of the C-4-functionalized allylic acetate 8 (R '= Ac, R = THP) the lactone 6a is converted into the hemiacetal 6 (X '= H, OH; R = THP) and from there with 3 equivalents of bromomagnesium acetylide, the mixture of the diastereomeric Al kindiole 7a (R '= R' '= H) (1'S: 1'R = 6: 1) produced; C-4 epimers are found Not. The diastereomeric ratios of 2a and 7a show opposite asymmetric induction for acetylide additions to 1 and to those with depro toned 6 counterbalanced aldehyde. The mesylate 7 is then made 7a obtained by means of protective group manipulations and mesylation. The radika ring closure of the primary iodide to 8a generated from 7 in situ smooth in 82% yield.
Die Flexibilität des neuen Konzepts beim Aufbau oberer Seitenketten demonstrie ren die Reaktionen von 8 mit den Cupraten V und VI bzw. IVb zu den Alkenen 9a (R'''' = Bzl) (92%) 10 (R'''' = CH2OSitBuPh2) (95%) bzw. 13a (89%) mit der für die wirksamen Isocarbacycline richtigen Position der Doppelbindung.The flexibility of the new concept in the construction of upper side chains is demonstrated by the reactions of 8 with the cuprates V and VI and IVb to the alkenes 9a (R '''' = Bzl) (92%) 10 (R '''' = CH 2 OSitBuPh 2 ) (95%) or 13a (89%) with the correct position of the double bond for the effective isocarbacyclins.
Das aus (1'S)-2 [bzw. (1'S)-7] intermediär erzeugte Alkylradikal cyclisiert trotz größerer sterischer Hinderung überraschend ebenso gut wie sein aus (1'R)- 2 [bzw. (1'R)-7] resultierendes Epimer und auch beide C-6 epimeren Acetate 3 [8] reagieren mit den Cupraten V und VI, ohne daß dabei Regioisomere entstehen. (Die Konfiguration an C-4' von 3 und C-1 von 8 wurde durch Entkoppelungs- und NOE-Experimente bestimmt).That from (1'S) -2 [or (1'S) -7] Intermediate alkyl radical cyclized surprisingly as good as its from (1'R) - despite its greater steric hindrance - 2 [or (1'R) -7] resulting epimer and also both C-6 epimeric acetates 3 [8] react with the cuprates V and VI without the formation of regioisomers. (The configuration at C-4 'of 3 and C-1 of 8 was determined by decoupling and NOE experiments determined).
Um die Zwischenverbindung 9c (R'''' = CH2COOtBu) mit oberer Seitenkette von 11b zu erhalten, wurde der Benzylether 9a (R'''' = Bzl) auf übliche Weise zum Alkohol 9b (R'''' = H) gespalten und dieser mit tert-Butylbromoacetat verethert. Die Ver bindung 12a mit der oberen Seitenkette von 11a erhält man aus 10a (R''''' = CH2OSitBuPh2) über die Stufen des Alkohols 10b (R''''' = CH2OH) und des Aldehyds 10c (R''''' = CHO).In order to obtain the intermediate 9c (R '''' = CH 2 COOtBu) with the upper side chain of 11b, the benzyl ether 9a (R '''' = Bzl) was converted to the alcohol 9b (R '''' = H in the usual way ) split and etherified with tert-butyl bromoacetate. The compound 12a with the upper side chain of 11a is obtained from 10a (R '''' = CH 2 OSitBuPh 2 ) via the stages of the alcohol 10b (R '''''= CH 2 OH) and the aldehyde 10c ( R '''''= CHO).
Das nachfolgende Schema zeigt exemplarisch den Standardweg zur Anbindung der
unteren Seitenkette von 11a an 12a. Stereoselektive Reduktion des Hydroxy-Enons
14b, das man in 40% Ausbeute bezogen auf 12a erhält, mit dem Yamamoto-Reagenz
ergibt die epimeren allylischen Alkohole 14c ((3''S)-14c: (3''R)-14c =
9 : 1), die sich chromatographisch leicht trennen lassen und laut HPLC frei von
isomeren Carbacyclinen sind. Verseifung von (3''S)-14c liefert
(+)-Isocarbacyclin (15a), dessen 400 MHz 1H-NMR Spektrum keinen Hinweis auf ein
Isomer mit der Doppelbindung C-1 und C-2 enthält.
The following diagram shows an example of the standard route for connecting the lower side chain from 11a to 12a. Stereoselective reduction of the hydroxy enone 14b, which is obtained in 40% yield based on 12a, with the Yamamoto reagent gives the epimeric allylic alcohols 14c ((3''S) -14c: (3''R) -14c = 9 : 1), which can be easily separated by chromatography and are free of isomeric carbacyclins according to HPLC. Saponification of (3''S) -14c gives (+) - isocarbacyclin (15a), the 400 MHz 1 H-NMR spectrum of which contains no evidence of an isomer with the double bond C-1 and C-2.
a) Ag2O, NaOH, EtOH, H2O; H3O+; CH2N2; 85%. b) MeOH, PPTS (Kat); 93%. c) tBuMe2SiCl, ImH, DMF; 86%. d) Dihydropyran, PPTS (Kat); 91%. e) nBu4NF, THF; 92%. f) Me2SO, SO3 . Pyridin, NEt3, 93% (Rohausbeute). g) 3 Äquiv. (MeO)2PO-CH2-CO-(CH2)4Me, NaH, Glyme, 0°C; 65% (f+g). h) MeOH, PPTS (Kat); 92%. i) 10 Äquiv. 2,6-(tBu)2-4- Me-C6H2OAl (iBu)2, -78°C→ -10°C; 87%. j) NaOH, MeOH, H2O; H3O+, 95%.a) Ag 2 O, NaOH, EtOH, H 2 O; H 3 O + ; CH 2 N 2 ; 85%. b) MeOH, PPTS (Kat); 93%. c) t BuMe 2 SiCl, ImH, DMF; 86%. d) dihydropyran, PPTS (cat); 91%. e) n Bu 4 NF, THF; 92%. f) Me 2 SO, SO 3 . Pyridine, NEt 3 , 93% (crude yield). g) 3 equiv. (MeO) 2 PO-CH 2 -CO- (CH 2 ) 4 Me, NaH, glyme, 0 ° C; 65% (f + g). h) MeOH, PPTS (Kat); 92%. i) 10 equiv. 2,6- ( t Bu) 2 -4- Me-C 6 H 2 OAl ( i Bu) 2 , -78 ° C → -10 ° C; 87%. j) NaOH, MeOH, H 2 O; H 3 O + , 95%.
Die Erfindung betrifft außerdem die neuen Verbindungen der Formeln I, II und III und ihre Verwendung als Zwischenprodukte für die Herstellung von pharmako logisch wirksamen Isocarbacyclin-Derivaten. The invention also relates to the new compounds of the formulas I, II and III and their use as intermediates for the manufacture of pharmaco logically effective isocarbacyclin derivatives.
Die Darstellung erfolgt durch PPL-katalysierte Hydrolyse des entsprechenden Diacetats (cis-6,10-Diocaspiro[4.5]decan-2,3-dimethanoldiacetat, Tetrahedron Letters 28 (1987) 3471. Der Enantiomerenüberschuß dieser Reaktion beträgt 78%.The representation is carried out by PPL-catalyzed hydrolysis of the corresponding Diacetates (cis-6,10-diocaspiro [4.5] decane-2,3-dimethanol diacetate, tetrahedron Letters 28 (1987) 3471. The enantiomeric excess of this reaction is 78%.
Die ausgehend von (2R-cis)-6,10-Dioxaspiro[4.5]decan-2,3-dimethanolmonoacetat dargestellten Produkte und die dazu angegebenen chiroptischen Daten beziehen sich auf diese Enantioselektivität.The starting from (2R-cis) -6,10-dioxaspiro [4.5] decane-2,3-dimethanol monoacetate refer to the products shown and the chiroptical data provided focus on this enantioselectivity.
Die Darstellung eines dem Baustein (2R-cis)-6,10-Dioxaspiro[4.5]decan-2,3-di methanolmonoacetat äquivalenten Synthons mit einer Enantioselektivität <95% ist durch PPl-katalysierte Umesterung in Vinylacetat möglich. Durch Schutzgrup pen-Operation kann ein äquivalenter Baustein erhalten werden.The representation of a building block (2R-cis) -6,10-dioxaspiro [4.5] decan-2,3-di methanol monoacetate equivalent synthons with an enantioselectivity <95% is possible through PPl-catalyzed transesterification in vinyl acetate. By protection group an equivalent building block can be obtained.
500 mg (2.48 mmol) 6,10-Dioxaspiro[4.5]decan-2,3-dimethanol werden in 500 ml
Vinylacetat gelöst und 2 g PPL-Kieselgur, entsprechend Tetrahedron Letters 28
(1987) 3471, zugegeben. Man rührt 1.5 h und bricht die Reaktion durch Abfil
trieren des Enzym/Kieselgur-Niederschlags ab. Nach Einengen im Vakuum wird der
Rückstand durch Säulenchromatographie an Kieselgel (Laufmittel: Essigester/
Hexan/Methanol 3 : 1 : 0.2) aufgetrennt. Man erhält 398.6 mg (66%) der Titelverbin
dung und 210.5 mg (29%) des entsprechenden Diacetats.
ee <95%
500 mg (2.48 mmol) of 6,10-dioxaspiro [4.5] decane-2,3-dimethanol are dissolved in 500 ml of vinyl acetate and 2 g of PPL diatomaceous earth, according to Tetrahedron Letters 28 (1987) 3471, are added. The mixture is stirred for 1.5 h and the reaction is stopped by filtering off the enzyme / diatomaceous earth precipitate. After concentration in vacuo, the residue is separated by column chromatography on silica gel (mobile phase: ethyl acetate / hexane / methanol 3: 1: 0.2). 398.6 mg (66%) of the title compound and 210.5 mg (29%) of the corresponding diacetate are obtained.
ee <95%
[α]D +5.8 (c = 1.20 in Methylenchlorid).
[α] D +5.8 (c = 1.20 in methylene chloride).
1H-NMR (300 MHz, CDCl3): δ = 1.68-1.73 (m, 2H), 1.84 (dd, J = 14.0, J = 7.0 Hz, 1H),
2.05 (s. acetyl, 3H), 2.09 (dd, J = 14.0, J = 8.0 Hz, 2H), 2.32-2.39 (m, 1h), 2.45-2.52
(m, 1H), 2.79 (t, OH, 1H), 3.59-3.67 (m, 12-H, 2H), 3.85-3.91 (m, 4H),
4.05-4.25 (m, 2H).
1 H-NMR (300 MHz, CDCl 3 ): δ = 1.68-1.73 (m, 2H), 1.84 (dd, J = 14.0, J = 7.0 Hz, 1H), 2.05 (see acetyl, 3H), 2.09 ( dd, J = 14.0, J = 8.0 Hz, 2H), 2.32-2.39 (m, 1h), 2.45-2.52 (m, 1H), 2.79 (t, OH, 1H), 3.59-3.67 (m, 12-H , 2H), 3.85-3.91 (m, 4H), 4.05-4.25 (m, 2H).
13C-NMR (75 MHz, CDCl3): δ = 20.97, 25.55, 38.02, 38.87, 39.47, 61.36, 61.7,
62.8, 64.36, 108.5, 171.005.
MS (FI): m/z 244 (M⁺).
13 C-NMR (75 MHz, CDCl 3 ): δ = 20.97, 25.55, 38.02, 38.87, 39.47, 61.36, 61.7, 62.8, 64.36, 108.5, 171.005.
MS (FI): m / z 244 (M⁺).
Zu einer Lösung von 12 ml (0,132 mol) Oxalylchlorid in 200 ml abs. Methylen chlorid wird unter Rühren und N2-Atmosphäre bei -60°C eine Lösung von 20,4 ml (0,264 mol) Dimethylsulfoxid in 20 ml Methylenchlorid getropft. Man wartet danach 5 Minuten und gibt anschließend innerhalb von 5 Minuten 15,0 g (0,062 mol) des Alkohols nach Beispiel 2 in 40 ml Methylenchlorid zu. Nach 30 Minuten werden bei -50° bis -60°C 84 ml Triethylamin zugegeben. Nach beendeter Zugabe rührt man 5 Minuten bei -60°C und läßt die Lösung anschließend auf Raumtempe ratur aufwärmen. Nach Zugabe von 200 ml Wasser extrahiert man portionsweise mit 300 ml Essigester. Man trocknet mit Magnesiumsulfat und engt im Vakuum bei 20°C ein. Das ausfallende Triethylammoniumhydrochlorid wird durch Auflösen des semi kristallinen Rückstandes in 40 ml Ether und Absaugen über eine Glasfritte (G3) abgetrennt. Nach dem Einengen im Vakuum werden 13,4 g (90%) des epimerenreinen Titel-Aldehyds als gelbes Öl isoliert.To a solution of 12 ml (0.132 mol) oxalyl chloride in 200 ml abs. Methylene chloride is added dropwise with stirring and N 2 atmosphere at -60 ° C a solution of 20.4 ml (0.264 mol) of dimethyl sulfoxide in 20 ml of methylene chloride. Then wait 5 minutes and then add 15.0 g (0.062 mol) of the alcohol according to Example 2 in 40 ml of methylene chloride within 5 minutes. After 30 minutes, 84 ml of triethylamine are added at -50 ° to -60 ° C. After the addition has ended, the mixture is stirred at -60 ° C. for 5 minutes and the solution is then allowed to warm up to room temperature. After adding 200 ml of water, the mixture is extracted in portions with 300 ml of ethyl acetate. It is dried with magnesium sulfate and concentrated in vacuo at 20 ° C. The precipitated triethylammonium hydrochloride is separated off by dissolving the semi-crystalline residue in 40 ml of ether and suctioning through a glass frit (G3). After concentration in vacuo, 13.4 g (90%) of the epimer-pure title aldehyde are isolated as a yellow oil.
Eine weitere Reinigung durch Chromatographie an Kieselgel ist nicht möglich, da
teilweise Epimerisierung zum trans-Aldehyd katalysiert durch Kieselgel auf
tritt.
1H-NMR (250 MHz, CDCl3): δ = 1.51-1.72 (m, 3H). 1.92 (s.acetyl, 3H). 2.04-2.27
(m. 3H), 2.63-2.78 (m, 3-HB, 1H). 2.76-2.95 (m, 2-HB, 1H), 3.69-3.86 (m. 7-H,
9-H, 4H), 4.01-4.05 (m. 1''-H, 2H), 9.69 (d. J = 2 Hz, 1'-H. 1H).
13C-NMR (20 MHz, CDCl3): δ = 20.14, 24.95, 34.0, 37.84, 38.10, 50.50, 60.73,
61.35, 63.31, 107.02 (C-5), 169.80, 201.53.
IR (Film): 2950, 2830, 2700, 1690, 1450, 1360, 1230, 1100 cm-1.
MS(CI): m/z(%) 243 (50) M⁺+1. 183 (100).
Further purification by chromatography on silica gel is not possible, since epimerization to trans-aldehyde catalyzed by silica gel occurs in some cases.
1 H NMR (250 MHz, CDCl 3 ): δ = 1.51-1.72 (m, 3H). 1.92 (s.acetyl, 3H). 2.04-2.27 (m. 3H), 2.63-2.78 (m, 3-HB, 1H). 2.76-2.95 (m, 2-HB, 1H), 3.69-3.86 (m. 7-H, 9-H, 4H), 4.01-4.05 (m. 1 '' - H, 2H), 9.69 (i.e. = 2 Hz, 1'-H. 1H).
13 C-NMR (20 MHz, CDCl 3 ): δ = 20.14, 24.95, 34.0, 37.84, 38.10, 50.50, 60.73, 61.35, 63.31, 107.02 (C-5), 169.80, 201.53.
IR (film): 2950, 2830, 2700, 1690, 1450, 1360, 1230, 1100 cm -1 .
MS (CI): m / z (%) 243 (50) M⁺ + 1. 183 (100).
Zu einer Lösung von 4.45 g (45.41 mmol) Trimethylsilylacetylen in 80 ml abs. Tetrahydrofuran werden bei -78°C unter N2-Atmosphäre 26,5 ml einer 1.56 M n- BuLi-Lösung in Hexan getropft. Nach 30 Minuten wird eine auf -80°C vorgekühlte Lösung von 10.0 g (41.3 mmol) der Aldehyds nach Beispiel 3 in 80 ml abs. Tetra hydrofuran unter kräftigem Rühren zugegeben. Die Reaktionsmischung erwärmt sich dabei auf -55°C. - Man läßt die Lösung über 30 Minuten auf -20°C aufwärmen und versetzt mit 100 ml gesätt. Ammoniumchlorid-Lösung. Anschließend wird mit 400 ml Essigester extrahiert und im Vakuum eingeengt. Der ölige Rückstand wird durch Säulenchromatographie an Kieselgel (Laufmittel: Essigester/Hexan 2 : 1) gerei nigt. Man erhält 7.8 g (78%) des Titel-Gemisches als farbloses Öl (Sdp. (KRD): 180°C/10-3 Torr).To a solution of 4.45 g (45.41 mmol) trimethylsilylacetylene in 80 ml abs. Tetrahydrofuran are added dropwise at -78 ° C under N 2 atmosphere 26.5 ml of a 1.56 M n-BuLi solution in hexane. After 30 minutes, a pre-cooled to -80 ° C solution of 10.0 g (41.3 mmol) of the aldehyde according to Example 3 in 80 ml abs. Tetra hydrofuran added with vigorous stirring. The reaction mixture heats up to -55 ° C. - The solution is allowed to warm up to -20 ° C over 30 minutes and 100 ml of sat. Ammonium chloride solution. The mixture is then extracted with 400 ml of ethyl acetate and concentrated in vacuo. The oily residue is purified by column chromatography on silica gel (mobile phase: ethyl acetate / hexane 2: 1). 7.8 g (78%) of the title mixture are obtained as a colorless oil (bp. (KRD): 180 ° C./10 -3 Torr).
Die beiden (1'R)- und (1'S)-Epimeren können durch präperative Mitteldruckchro matographie an Kieselgel (Laufmittel: Essigester/Hexan 3 : 1) getrennt werden. Man erhält 5.81 g der (1'R)-Titelverbindung und 1.95 g der (1'S)-Titelverbin dung. The two (1'R) and (1'S) epimers can be prepared by preparative medium pressure chro matography on silica gel (eluent: ethyl acetate / hexane 3: 1) are separated. 5.81 g of the (1'R) title compound and 1.95 g of the (1'S) title compound are obtained dung.
H-NMR (250 MHz. CDCl3 H-NMR (250 MHz. CDCl 3
): δ = 0.12 (s, 9H), 1.56-1.74 (m, 2H), 1.83 (dd. J = 7.5.
J = 13.5 Hz, 1H), 1.98 (s, acetyl, 3H), 2.02-2.21 (m, 3H), 2.22-2.55 (m, 2-HB,
2H), 3.14 (d, OH, 1H), 3.76-3.95 (m, 4H), 4.06-4.27 (m, 1''-H, 2H), 4.36 (dd,
3 = 8.0, 3 = 6.0 Hz, 1'-H, 1H).
13 ): δ = 0.12 (s, 9H), 1.56-1.74 (m, 2H), 1.83 (dd. J = 7.5. J = 13.5 Hz, 1H), 1.98 (s, acetyl, 3H), 2.02-2.21 (m , 3H), 2.22-2.55 (m, 2-HB, 2H), 3.14 (d, OH, 1H), 3.76-3.95 (m, 4H), 4.06-4.27 (m, 1 '' - H, 2H), 4.36 (dd, 3 = 8.0, 3 = 6.0 Hz, 1'-H, 1H).
13
C-NMR (20 MHz, CDCl3 C-NMR (20 MHz, CDCl 3
): δ = -0.21. 20.92. 25.39. 37.70. 38.45. 39.23. 45.17.
61.42. 61.556. 63.00. 64.49. 89.58. 106.28. 108.49. 170.75.
[α]): δ = -0.21. 20.92. 25.39. 37.70. 38.45. 39.23. 45.17. 61.42. 61,556. 63.00. 64.49. 89.58. 106.28. 108.49. 170.75.
[α]
20|D 20 | D
+10.6 (c = 2.67, Methylenchlorid).+10.6 (c = 2.67, methylene chloride).
H-NMR (250 MHz. CDCl3): δ = 0.13 ppm (s 9H). 1.60-1.76 (m, 2H), 1.84-1.98 (m,
2H), 2.01 (s. acetyl, 3H), 2.06-2.14 (m, 1H), 2.17-2.28 (m, 1H), 2.35-2.57 (m,
2-Hβ, 3-Hβ, OH, 3H), 3.78-3.91 (m, 4H), 4.01-4.10 (m, 1''-H, 1H), 4.24-4.31
(m, 1''-H, 1H), 4.36 (dd, J = 5.0, J = 8.0 Hz, 1'-H, 1H).
13 H-NMR (250 MHz. CDCl3): δ = 0.13 ppm (s 9H). 1.60-1.76 (m, 2H), 1.84-1.98 (m, 2H), 2.01 (see acetyl, 3H), 2.06-2.14 (m, 1H), 2.17-2.28 (m, 1H), 2.35-2.57 (m , 2-Hβ, 3-Hβ, OH, 3H), 3.78-3.91 (m, 4H), 4.01-4.10 (m, 1 '' - H, 1H), 4.24-4.31 (m, 1 '' - H, 1H), 4.36 (dd, J = 5.0, J = 8.0 Hz, 1'-H, 1H).
13
C-NMR (20 MHz, CDCl3 C-NMR (20 MHz, CDCl 3
): δ = -0.16, 21.05, 25.60, 37.41, 37.79, 39.39, 46.00,
61.34, 61.75, 63.30, 64.66, 90.42, 105.90, 107.93, 170.88.
[α]): δ = -0.16, 21.05, 25.60, 37.41, 37.79, 39.39, 46.00, 61.34, 61.75, 63.30, 64.66, 90.42, 105.90, 107.93, 170.88.
[α]
20|D 20 | D
+12.4 (c = 1.32, Methylenchlorid).
IR (Film): 3490, 2950, 2840, 2250, 2190, 1740, 1420, 1390, 1330, 1250, 1160,
1110, 1060 cm-1 +12.4 (c = 1.32, methylene chloride).
IR (film): 3490, 2950, 2840, 2250, 2190, 1740, 1420, 1390, 1330, 1250, 1160, 1110, 1060 cm -1
.
MS(EI): m/z(%) 340 (1) M⁺, 309 (2), 280 (2), 267 (3), 213 (15), 153 (14).
.
MS (EI): m / z (%) 340 (1) M⁺, 309 (2), 280 (2), 267 (3), 213 (15), 153 (14).
Zu einer Lösung von 6.0 g (17.6 mmol) des Gemisches nach Beispiel 4 und 3.47 g (51.0 mmol) Imidazol in 30 ml abs. DMF werden unter Rühren 3.07 g (20.4 mmol) t-BuMe2SiCl bei Raumtemperatur gegeben. Nach 12 h wird mit 50 ml Wasser ver setzt und mit 300 ml Essigester extrahiert. Man engt im Vakuum ein und chroma tographiert den öligen Rückstand an Kieselgel (Laufmittel Essigester/Hexan 1 : 5). Man erhält 6.88 g (89%) des Silylether-Gemisches als farbloses Öl.To a solution of 6.0 g (17.6 mmol) of the mixture according to Example 4 and 3.47 g (51.0 mmol) of imidazole in 30 ml of abs. DMF are added with stirring 3.07 g (20.4 mmol) t-BuMe 2 SiCl at room temperature. After 12 h, it is mixed with 50 ml of water and extracted with 300 ml of ethyl acetate. The mixture is concentrated in vacuo and the oily residue is chromatographed on silica gel (mobile phase ethyl acetate / hexane 1: 5). 6.88 g (89%) of the silyl ether mixture are obtained as a colorless oil.
H-NMR(250 MHz, CDCl3 H-NMR (250 MHz, CDCl 3
): δ = 0.07 (s, 3H), 0.10 (s, 9H), 0.12 (s, 3H), 0.84 (s,
9H), 1.57-1.74 (m, 2H), 1.78-1.91 (m, 1H), 1.94-2.20 (m, 6H), 2.23-2.38 (m,
2H), 3.76-3.88 (m, 4H), 3.97 (dd. J = 10.5 Hz, 1''-H, 1H), 4.33 (d. J = 7.0 Hz,
1'-H, 1H), 4.34 (dd. J = 4.5, J = 10.5 Hz, 1''-H. 1H).
13 ): δ = 0.07 (s, 3H), 0.10 (s, 9H), 0.12 (s, 3H), 0.84 (s, 9H), 1.57-1.74 (m, 2H), 1.78-1.91 (m, 1H), 1.94-2.20 (m, 6H), 2.23-2.38 (m, 2H), 3.76-3.88 (m, 4H), 3.97 (dd. J = 10.5 Hz, 1 '' - H, 1H), 4.33 (i.e. = 7.0 Hz, 1'-H, 1H), 4.34 (dd. J = 4.5, J = 10.5 Hz, 1 '' - H. 1H).
13
C-NMR (20 MHz), CDCl3 C-NMR (20 MHz), CDCl 3
): δ = -4.88, -4.18, -0.32, 18.14, 20.98, 25.70, 25.82,
37.64, 38.83, 46.15, 61.02, 63.87, 64.53, 106.64, 107.98, 170.78.
[α]): δ = -4.88, -4.18, -0.32, 18.14, 20.98, 25.70, 25.82, 37.64, 38.83, 46.15, 61.02, 63.87, 64.53, 106.64, 107.98, 170.78.
[α]
20|D 20 | D
+13.8 (c = 0,52, Methylenchlorid).
(1'S)-Silylether: δ = 0,06 (s, 3H), 0.09 (s, 9H), 0,11 (s, 3H), 0.83 (s, 9H),
1.56-1.70 (m, 2H), 1.77-2.10 (m, 6H), 2.27-2.48 (m, 3H), 3.73-3.87 (m, 4H),
4.01-4.08 (m, 1''-H, 1H), 4.15-4.17 (m, 1-H, 1H) 4.29 (d, J = 7.0 Hz, 1'H,
1H).
13 +13.8 (c = 0.52, methylene chloride).
(1'S) silyl ether: δ = 0.06 (s, 3H), 0.09 (s, 9H), 0.11 (s, 3H), 0.83 (s, 9H), 1.56-1.70 (m, 2H), 1.77 -2.10 (m, 6H), 2.27-2.48 (m, 3H), 3.73-3.87 (m, 4H), 4.01-4.08 (m, 1 '' - H, 1H), 4.15-4.17 (m, 1-H , 1H) 4.29 (d, J = 7.0 Hz, 1'H, 1H).
13
C-NMR (20 MHz, CDCl3 C-NMR (20 MHz, CDCl 3
): δ = -4.89, -4.04, -0.25, 18.18, 21.06, 25.72, 25.85,
37.37, 39.17, 46.29, 61.18, 63.59, 64.83, 106.58, 108.11, 170.98.
MS(CI): m/z(%) 455 (3) M⁺, 395 (6). 323 (100), 263 (19), 101 (38).
): δ = -4.89, -4.04, -0.25, 18.18, 21.06, 25.72, 25.85, 37.37, 39.17, 46.29, 61.18, 63.59, 64.83, 106.58, 108.11, 170.98.
MS (CI): m / z (%) 455 (3) M⁺, 395 (6). 323 (100), 263 (19), 101 (38).
Zu einer Lösung von 1 g Kaliumhydroxid in 100 ml Methanol werden bei 0°C 5.0 g
(11.0 mmol) des Silylether-Gemisches nach Beispiel 5 in 5 ml Methanol gegeben.
Man rührt 3 h und erhält nach Säulenfiltration über Kieselgel (Laufmittel:
Essigester) 3.1 g (83%.) des Titelgemisches als farbloses Öl.
5.0 g (11.0 mmol) of the silyl ether mixture according to Example 5 in 5 ml of methanol are added to a solution of 1 g of potassium hydroxide in 100 ml of methanol at 0.degree. The mixture is stirred for 3 h and, after column filtration through silica gel (mobile phase: ethyl acetate), 3.1 g (83%.) Of the title mixture are obtained as a colorless oil.
1H-NMR(250 MHz, (D3)2SO): δ = 0.08 (s, 3H), 0.11, (s, 3H), 0.85 (s, 9H), 1.45-2.27
(m, 8H), 2.43-2.44 (d, J = 2.0 Hz, 1H), 3.25-3.56 (m, 2H), 3.65-3.84 (m,
4H), 4.30-4.50 (m-1H).
MS(CI): m/z(%) 341 (100) m⁺, 323 (10), 283 (6), 209 (56).
1 H-NMR (250 MHz, (D 3 ) 2 SO): δ = 0.08 (s, 3H), 0.11, (s, 3H), 0.85 (s, 9H), 1.45-2.27 (m, 8H), 2.43 -2.44 (d, J = 2.0 Hz, 1H), 3.25-3.56 (m, 2H), 3.65-3.84 (m, 4H), 4.30-4.50 (m-1H).
MS (CI): m / z (%) 341 (100) m⁺, 323 (10), 283 (6), 209 (56).
Zu einer Lösung von 4.5 g (13.1 mmol) des Gemisches nach Beispiel 6 in 50 ml abs.To a solution of 4.5 g (13.1 mmol) of the mixture according to Example 6 in 50 ml abs.
Methylenchlorid und 10 ml Triethylamin werden bei -20°C 100 mg Dimethylaminopyridin zugesetzt und anschließend langsam eine Lösung von 1.97 g (17.0 mmol) Methansulfonsäurechlorid in 5 ml abs. Methylenchlorid zugetropft. Nach 1 h bei -20°C werden 50 ml Wasser zugesetzt und mit 200 ml Essigester extrahiert. Nach Säulenfiltration über Kieselgel (Laufmittel: Essigester) werden 5.18 g (94%) des Mesylats-Gemisches als farbloses Öl isoliert.Methylene chloride and 10 ml triethylamine are at -20 ° C. 100 mg of dimethylaminopyridine are added and then slowly a solution of 1.97 g (17.0 mmol) Methanesulfonic acid chloride in 5 ml abs. Methylene chloride dripped. After 1 h at -20 ° C 50 ml of water added and extracted with 200 ml of ethyl acetate. After Column filtration over silica gel (eluent: ethyl acetate) 5.18 g (94%) of the mesylate mixture as a colorless oil isolated.
H-NMR (400 MHz, CDCl3 H-NMR (400 MHz, CDCl 3
): δ = 0.09 (s. 3H), 014 (s, 3H), 0.83, (s, 9H), 1.59-1.80 (m, 3H), 1.98-2.15 (m, 2H), 1.98-2.15 (m, 2H), 2.22-2.31 (m, 1H), 2.39-2.60 (m, 3H), 2.95 (s, 3H), 3.68-3.95 (m, 4H), 4.19-4.28 (m, 1H), 4.31-4.34 (m, 1H), 4.37-4.45 (m, 1H).): δ = 0.09 (see 3H), 014 (see 3H), 0.83, (s, 9H), 1.59-1.80 (m, 3H), 1.98-2.15 (m, 2H), 1.98-2.15 (m, 2H), 2.22-2.31 (m, 1H), 2.39-2.60 (m, 3H), 2.95 (s, 3H), 3.68-3.95 (m, 4H), 4.19-4.28 (m, 1H), 4.31-4.34 (m, 1H), 4.37-4.45 (m, 1H).
H-NMR (250 MHz, CDCl3 H-NMR (250 MHz, CDCl 3
): δ = 0.10 (s, 3H), 0.87 (s, 9H), 1.63-1.73 (m, 2H), 1.85-2.21 (m, 4H), 2.39-2.53 (m, 1H), 2.48 (d, J = 2.0 Hz, 1H), 2.96 (s, SO2 ): δ = 0.10 (s, 3H), 0.87 (s, 9H), 1.63-1.73 (m, 2H), 1.85-2.21 (m, 4H), 2.39-2.53 (m, 1H), 2.48 (d, J = 2.0 Hz, 1H), 2.96 (s, SO 2
Me, 3H), 3.77-3.92
(m, 4H), 4.20 (dd, J = 10.0, J = 11,5 Hz, 1''-H, 1H), 4,38
(dd, J = 6.0, J = 2.0 Hz, 1'-H), 4.59 (dd, J = 5.5, J = 11.5 Hz,
1''-H, 1H).
HMS: ber. für C19 Me, 3H), 3.77-3.92 (m, 4H), 4.20 (dd, J = 10.0, J = 11.5 Hz, 1 '' - H, 1H), 4.38 (dd, J = 6.0, J = 2.0 Hz, 1'-H), 4.59 (dd, J = 5.5, J = 11.5 Hz, 1 '' - H, 1H).
HMS: calculated for C 19
H34 H 34
O6 O 6
SSi 418.1845; gef. 418.1857. SSi 418.1845; found 418.1857.
In einer Lösung von 2.73 g (1.82 mmol) wasserfreien NaJ in 40 ml abs. Glyme werden bei Raumtemperatur 3.81 g (0.91 mmol) des vorstehenden Mesylat-Gemisches gelöst. Man erhitzt unter Rühren langsam auf 55°C und gibt 5 mg Azobisiso butyronitril zu. Anschließend tropft man über 3 h eine Lösung von 5.23 g (1.82 mmol) Tributylzinnhydrid in 10 ml abs. Glyme zu und beläßt die Reaktions mischung unter Rühren 96 h bei 55°C.In a solution of 2.73 g (1.82 mmol) anhydrous NaI in 40 ml abs. Glyme 3.81 g (0.91 mmol) of the above mesylate mixture are at room temperature solved. The mixture is slowly heated to 55 ° C. with stirring and 5 mg of azobisiso are added butyronitrile too. A solution of 5.23 g is then added dropwise over 3 h (1.82 mmol) tributyltin hydride in 10 ml abs. Glyme and leaves the reaction mix with stirring at 55 ° C for 96 h.
Anschließend engt man die Reaktionsmischung im Vakuum ein und filtriert über eine Glasfritte den festen Niederschlag ab. Das Filtrat wird durch zweimaliges Chromatographieren an Kieselgel (Laufmittel: Essigester/Hexan 1 : 10) gereinigt. Man erhält 2.09 g (91%) des Titelgemisches als farbloses Öl (Sdp. (KRD): 115°C (10-3 Torr).The reaction mixture is then concentrated in vacuo and the solid precipitate is filtered off through a glass frit. The filtrate is purified by chromatography twice on silica gel (mobile phase: ethyl acetate / hexane 1:10). 2.09 g (91%) of the title mixture are obtained as a colorless oil (bp. (KRD): 115 ° C. (10 -3 torr).
H-NMR (400 MHz, C6 H-NMR (400 MHz, C 6
D6 D 6
): δ = 0.04 (s. 3H), 0.05 (s, 3H), 0.99, (s 9H), 1.19-1.56 (m, 3H), 1.31-1.89 (m, 1H), 1.90-2.02 (m, 1H), 2.21-2.50 (m, 4H9, 2.58-2.54 (m, 1H), 5.22-5.25 (m, 1H).): δ = 0.04 (see 3H), 0.05 (see 3H), 0.99, (see 9H), 1.19-1.56 (m, 3H), 1.31-1.89 (m, 1H), 1.90-2.02 (m, 1H), 2.21-2.50 (m, 4H9, 2.58-2.54 (m, 1H), 5.22-5.25 (m, 1H).
H-NMR (250 MHz, CDCl3 H-NMR (250 MHz, CDCl 3
): δ = 0.04 (s, 3H), 0.07 (s, 3H), 0.87 (s, 9H), 1.21-1.78
(m, 4H), 1.90-2.06 (m, 1H), 2.16-2.38 (m, 3H), 2.51-2.69 (m, 2H), 3.78-3.90
(m, 4H), 4.08-4.14 (m, 1H), 4.83-4.87 (m, 1H), 4.90-4.95 (m, 1H).
[α]): δ = 0.04 (s, 3H), 0.07 (s, 3H), 0.87 (s, 9H), 1.21-1.78 (m, 4H), 1.90-2.06 (m, 1H), 2.16-2.38 (m, 3H ), 2.51-2.69 (m, 2H), 3.78-3.90 (m, 4H), 4.08-4.14 (m, 1H), 4.83-4.87 (m, 1H), 4.90-4.95 (m, 1H).
[α]
20|D 20 | D
-3.3 (c = 1.17, Methylenchlorid).
[α]-3.3 (c = 1.17, methylene chloride).
[α]
20|365 20 | 365
-17.9 (c = 1.17, Methylenchlorid).
MS(EI): m/z(%) 324 (5) M⁺, 267 (41), 209 (92), 151 (7), 139 (27), 135 (33),
133 (41), 177 (13), 105 (36), 100 (10), 91 (26), 81 (14), 79 (15), 77 (21),
75 (100), 73 (57).
[α]-17.9 (c = 1.17, methylene chloride).
MS (EI): m / z (%) 324 (5) M⁺, 267 (41), 209 (92), 151 (7), 139 (27), 135 (33), 133 (41), 177 ( 13), 105 (36), 100 (10), 91 (26), 81 (14), 79 (15), 77 (21), 75 (100), 73 (57).
[α]
20|D 20 | D
-31.3 (c = 1.15, Methylenchlorid)
-31.3 (c = 1.15, methylene chloride)
Zu einer Lösung von 2,50 g ( 7,70 mmol) des Gemisches nach Beispiel 8 in 20 ml abs. THF und 3 ml abs. Triethylamin werden unter Rühren bei Raumtemperatur 20 ml einer 1 M Tetrabutylammoniumfluorid-Lösung in Tetrahydrofuran getropft. Man rührt 24 h und destilliert anschließend im Vakuum das Lösungsmittel ab.To a solution of 2.50 g (7.70 mmol) of the mixture according to Example 8 in 20 ml Section. THF and 3 ml abs. Triethylamine are stirred at room temperature 20 ml of a 1 st Drops of tetrabutylammonium fluoride solution in tetrahydrofuran. The mixture is stirred for 24 hours and then distilled off the solvent in vacuo.
Der ölige Rückstand wird durch Säulenfiltration über Kieselgel (Laufmittel:
Essigester) gereinigt. Man eluiert 1.62 g (82%) des Alkohol-Gemisches als
farbloses Öl.
The oily residue is purified by column filtration over silica gel (eluent: ethyl acetate). 1.62 g (82%) of the alcohol mixture is eluted as a colorless oil.
1H-NMR (250 MHz, CDCl3): δ = 1.44-1.59 (m, 1H), 1.60-1.80 (m, 3H), 1.99-2.14
(m, 1H), 2.21-2.42 (m, 4H), 2.57-2.80 (m, 2H), 3.80-3.98 (m, 4H), 4.11-4.19 (m,
1H), 4.85-4.97 (m; 1H), 4.11-4.19 (m, 1H), 4.85-4.97 (m, 1H), 5.04-5.08
(m, 1H).
1 H-NMR (250 MHz, CDCl 3 ): δ = 1.44-1.59 (m, 1H), 1.60-1.80 (m, 3H), 1.99-2.14 (m, 1H), 2.21-2.42 (m, 4H), 2.57-2.80 (m, 2H), 3.80-3.98 (m, 4H), 4.11-4.19 (m, 1H), 4.85-4.97 (m; 1H), 4.11-4.19 (m, 1H), 4.85-4.97 (m , 1H), 5.04-5.08 (m, 1H).
1.71 g (8.14 mmol) des allylischen Alkohols nach Beispiel 9 werden in 20 ml abs. Methylenchlorid und 4 ml Triethylamin vorgelegt. Nach Zugabe von 100 mg Dimethylaminopyridin tropft man bei 0°C 1.25 g (12.25 mmol) Acetanhydrid zu. Nach 6 Stunden Rühren bei Raumtemperatur versetzt man die Reaktionsmischung mit 20 ml Wasser und extrahiert portionsweise mit 200 ml Essigester. Die vereinigten organischen Phasen werden mit Magnesiumsulfat getrocknet und im Va kuum eingeengt. Der Rückstand wird durch Säulenchromatographie an Kieselgel (Laufmittel: Essigester/Hexan 2 : 1) gereinigt. Man erhält 1.85 g (90%) des Allylacetat-Gemisches als farbloses Öl.1.71 g (8.14 mmol) of the allylic alcohol according to Example 9 are in 20 ml Section. Methylene chloride and 4 ml of triethylamine submitted. After adding 100 mg Dimethylaminopyridine is added dropwise at 0 ° C 1.25 g (12.25 mmol) acetic anhydride. After 6 hours of stirring at room temperature, the reaction mixture is added with 20 ml of water and extracted in portions with 200 ml of ethyl acetate. The United organic phases are dried with magnesium sulfate and in Va concentrated in a vacuum. The residue is purified by column chromatography on silica gel (Eluent: ethyl acetate / hexane 2: 1) cleaned. 1.85 g (90%) of the Allyl acetate mixture as a colorless oil.
H-NMR (400 MHz, CDCl3 H-NMR (400 MHz, CDCl 3
): δ = 1.51-1.57 (m, 1H). 1.62-1.83 (m, 3H), 2.07 (s,
acetyl, 3H). 2.07-2.15 (m, 1H), 2.22-2.28 (m, 1H), 2.34-2.39 (m, 1H), 2.45-2.53
(m, 1H), 5.03-5.06 (m, 1H), 5.11-5.14 (m, 1H), 5.18-5.20 (m, 1H).
[α]): δ = 1.51-1.57 (m, 1H). 1.62-1.83 (m, 3H), 2.07 (s, acetyl, 3H). 2.07-2.15 (m, 1H), 2.22-2.28 (m, 1H), 2.34-2.39 (m, 1H), 2.45-2.53 (m, 1H), 5.03-5.06 (m, 1H), 5.11-5.14 (m , 1H), 5.18-5.20 (m, 1H).
[α]
20|D 20 | D
-4.3 (c = 1.30, Methylenchlorid)-4.3 (c = 1.30, methylene chloride)
H-NMR (400 MHz, CDCl3 H-NMR (400 MHz, CDCl 3
): δ = 1.43-1.49 (m, 1H), 1.55-1.80 (m, 1H), 1.62-1.79
(m, 2H), 2.05-2.12 (m, 3H), 2.38-2.43 (m, 1H), 2.10 (s, acetyl, 3H), 2.47-2.60
(m, 2H), 2.83-2.92 (m, 1H), 3.82-3.94 (m, 4H), 4.98-5.01 (m, 1H).
[α]): δ = 1.43-1.49 (m, 1H), 1.55-1.80 (m, 1H), 1.62-1.79 (m, 2H), 2.05-2.12 (m, 3H), 2.38-2.43 (m, 1H), 2.10 (s, acetyl, 3H), 2.47-2.60 (m, 2H), 2.83-2.92 (m, 1H), 3.82-3.94 (m, 4H), 4.98-5.01 (m, 1H).
[α]
20|D 20 | D
-62.9 (c = 0.80, Methylenchlorid)
-62.9 (c = 0.80, methylene chloride)
Zu 271.0 mg (1.43 mmol) Cu(I)J wird unter Rühren bei -50°C unter N2-Atmosphäre
27.2 ml einer 0.21 M ClMgCH2OCH2 Ph-Lösung (nach B. Castro, Bull.Soc.Chim.
Fr. 1967, 1533) in Tetrahydrofuran zugetropft. Man rührt 30 Min. bei -50°C und
läßt die Lösung auf 20°C aufwärmen. Nach 15 Min. bei dieser Temperatur werden
120.2 mg (0.476 mmol) des Acetat-Gemisches nach Beispiel 10 in 3 ml abs. THF
langsam zugetropft. Nach 10 min. läßt man die heterogene Reaktionsmischung auf
Raumtemperatur aufwärmen. Anschließend kühlt man erneut auf -10°C ab und fügt
vorsichtig 5 ml gesätt. Natriumhydrogencarbonat-Lösung hinzu. Es wird portions
weise mit 150 ml Essigester extrahiert. Die vereinigten organischen Phasen
wurden mit Magnesiumsulfat getrocknet und im Vakuum eingeengt. Der ölige Rück
stand wird durch Säulenchromatographie an Kieselgel (Laufmittel: Essigester/Hexan
1 : 10) gereinigt. Man erhält 130.0 mg (87%) der Titelverbindung als farb
loses Öl.
To 271.0 mg (1.43 mmol) of Cu (I) J is added 27.2 ml of a 0.21 M ClMgCH 2 OCH 2 Ph solution (according to B. Castro, Bull.Soc.Chim. Fr.) With stirring at -50 ° C under an N 2 atmosphere 1967, 1533) was added dropwise in tetrahydrofuran. The mixture is stirred at -50 ° C. for 30 minutes and the solution is allowed to warm to 20 ° C. After 15 minutes at this temperature, 120.2 mg (0.476 mmol) of the acetate mixture according to Example 10 in 3 ml of abs. THF slowly added dropwise. After 10 min. the heterogeneous reaction mixture is allowed to warm up to room temperature. The mixture is then cooled again to -10 ° C. and 5 ml of sat. Add sodium bicarbonate solution. It is extracted in portions with 150 ml of ethyl acetate. The combined organic phases were dried with magnesium sulfate and concentrated in vacuo. The oily residue is purified by column chromatography on silica gel (mobile phase: ethyl acetate / hexane 1:10). 130.0 mg (87%) of the title compound are obtained as a colorless oil.
1H-NMR (400 MHz, CDCl3): δ = 1.50 (dd, J = 13.5, J = 9.0 Hz. 1H), 1.56 (dd. J = 13.5,
J = 7.0 Hz, 1H), 1.65 (m, 2H), 1.99-2.07 (m, 2H), 2.28-2.41 (m, 4H), 2.43-2.58
(m, 1H), 2.66-2.75 (m, 1H), 3.10-3.20 (m, 1H), 3.57 (t, 2H), 3.79-3.98 (m, 4H),
4,52 (s, 2H), 5.29-5.31 (m, 1H), 7.23-7.41 (m, 5H).
[α] 20|D -16.9 (c = 0.25, Methylenchlorid).
MS (CI): m/z(%) 315 (11) M⁺ + 1, 257 (100), 239 (40), 193 (10), 183 (22), 181
(10), 165 (20), 149 (9), 137 (30), 107 (18), 91 (54).
1 H-NMR (400 MHz, CDCl 3 ): δ = 1.50 (dd, J = 13.5, J = 9.0 Hz. 1H), 1.56 (dd. J = 13.5, J = 7.0 Hz, 1H), 1.65 (m, 2H), 1.99-2.07 (m, 2H), 2.28-2.41 (m, 4H), 2.43-2.58 (m, 1H), 2.66-2.75 (m, 1H), 3.10-3.20 (m, 1H), 3.57 ( t, 2H), 3.79-3.98 (m, 4H), 4.52 (s, 2H), 5.29-5.31 (m, 1H), 7.23-7.41 (m, 5H).
[α] 20 | D -16.9 (c = 0.25, methylene chloride).
MS (CI): m / z (%) 315 (11) M⁺ + 1, 257 (100), 239 (40), 193 (10), 183 (22), 181 (10), 165 (20), 149 (9), 137 (30), 107 (18), 91 (54).
Zu 170.2 mg (0.894 mmol) Cu(I)J werden unter N2-Atmosphäre bei -50°C 15.4 ml einer 0.23 M ClMg(CH2)4 OsitBuPh2-Lösung in Ether zugetropft. Man rührt 30 min bei -50°C und 15 min bei -20°C.15.4 ml of a 0.23 M ClMg (CH 2 ) 4 OsitBuPh 2 solution in ether are added dropwise to 170.2 mg (0.894 mmol) of Cu (I) J under an N 2 atmosphere at -50 ° C. The mixture is stirred at -50 ° C for 30 min and at -20 ° C for 15 min.
Anschließend tropft man langsam 75.1 mg (0.24 mmol) des Allylacetat-Gemisch
nach Beispiel 11 in 2 ml abs. Ether zu. Es wird 30 Min. bei -20°C gerührt und
auf Raumtemperatur aufgewärmt. Nach erneutem Abkühlen auf -10°C fügt man
vorsichtig 5 ml einer gesättigten Natiumhydrogencarbonat-Lösung zu. Man
extrahiert die Reaktionsmischung portionsweise mit 200 ml Essigester und engt
nach Trocknen mit Magnesiumsulfat die vereinigten organischen Phasen im Vakuum
ein. Der ölige Rückstand wird chromatographisch an Kieselgel (Laufmittel:
Essigester/Hexan 1 : 10) gereinigt. Man erhält 119.2 mg (84%) der Titelverbindung
als farbloses Öl.
Then 75.1 mg (0.24 mmol) of the allyl acetate mixture according to Example 11 are slowly added dropwise in 2 ml of abs. Ether too. The mixture is stirred at -20 ° C. for 30 minutes and warmed to room temperature. After cooling again to -10 ° C., 5 ml of a saturated sodium bicarbonate solution are carefully added. The reaction mixture is extracted in portions with 200 ml of ethyl acetate and, after drying with magnesium sulfate, the combined organic phases are concentrated in vacuo. The oily residue is purified by chromatography on silica gel (mobile phase: ethyl acetate / hexane 1:10). 119.2 mg (84%) of the title compound are obtained as a colorless oil.
[α] 20|D -28.1 (c = 0.74, Methylenchlorid).
1H-NMR (400 MHz, CDCl3): α = 1.05 (s, 9H), 1.28-1.72 (m, 13H), 1.93-2.02 (m, 3H),
2.29-2.38 (m, 2H), 2.41-2.52 (m, 1H), 2.63-2.76 (m, 1H), 3.08-3.19 (m, 1H),
3.61-3.70 (t, J = 7.0 Hz, 2H), 3.30-3.92 ( m, 4H), 5.19-5.22 (m, 1H), 7.35-7.46
(m, 6H), 7.66-7.70 (m, 4H).
MS(EI): m/z(%) 504 (0.2) M⁺, 447 (1) M+-tBu. 389 (94).
199 (100), 173 (58), 91 (83).
[α] 20 | D -28.1 (c = 0.74, methylene chloride).
1 H-NMR (400 MHz, CDCl 3 ): α = 1.05 (s, 9H), 1.28-1.72 (m, 13H), 1.93-2.02 (m, 3H), 2.29-2.38 (m, 2H), 2.41- 2.52 (m, 1H), 2.63-2.76 (m, 1H), 3.08-3.19 (m, 1H), 3.61-3.70 (t, J = 7.0 Hz, 2H), 3.30-3.92 (m, 4H), 5.19- 5.22 (m, 1H), 7.35-7.46 (m, 6H), 7.66-7.70 (m, 4H).
MS (EI): m / z (%) 504 (0.2) M⁺, 447 (1) M + -tBu. 389 (94). 199 (100), 173 (58), 91 (83).
20.0 g (116.0 mmol) [3aR-(3aα,4α,5β,6aα]-Hexahydro-4-(hydroxymethyl)-5-hydroxy- 1H-cyclopenta[c]furan-1-on und 100 mg Pyridinum-p-toluol-sulfonat werden in 250 ml abs. Tetrahydrofuran vorgelegt. Unter Rühren tropft man bei 0°C 38.98 g (464.0 mmol) Dihydropyran zu.20.0 g (116.0 mmol) [3aR- (3aα, 4α, 5β, 6aα] -hexahydro-4- (hydroxymethyl) -5-hydroxy- 1H-cyclopenta [c] furan-1-one and 100 mg pyridinum-p-toluenesulfonate are in 250 ml abs. Tetrahydrofuran submitted. 38.98 g are added dropwise at 0 ° C. with stirring (464.0 mmol) dihydropyran.
Anschließend erwärmt man langsam auf 50°C und rührt 2 h.The mixture is then slowly warmed to 50 ° C. and stirred for 2 hours.
Durch Säulenfiltration an Kieselgel (Laufmittel: Essigester) und Einengen im
Vakuum 37.47 g (95%) des Bis-THP-Ethers als farbloses Öl, der nach längerer
Zeit bei 0°C kristallisiert.
By column filtration on silica gel (mobile phase: ethyl acetate) and concentration in vacuo 37.47 g (95%) of the bis-THP ether as a colorless oil, which crystallizes after a long time at 0 ° C.
Fp.: 51°C.
[α] 20|D + 83.8 (c = 3.2, Methylenchlorid).
1H-NMR (400 MHz, C5D5CD3): δ = 1.17-1.80 (m, 13H), 1.89-2.50 (m, 4H). 2.85-3.07
(m, 1H)), 3.29-3.49 (m, 3H), 3.58-4.27 (m, 5H), 4.33-4.46 (m, 1H), 4.59-4.65
(m, 1H).
MS(EI): m/z(%) 255 (8) M⁺-THP, 239 (7), 173 (12, 172 (9), 155 (11), 101 (27),
93 (12), 86 (20), 85 (100), 79 (10), 67 (32), 57 (27), 55 (18), 43 (39), 41
(23).
Mp .: 51 ° C.
[α] 20 | D + 83.8 (c = 3.2, methylene chloride).
1 H-NMR (400 MHz, C 5 D 5 CD 3 ): δ = 1.17-1.80 (m, 13H), 1.89-2.50 (m, 4H). 2.85-3.07 (m, 1H)), 3.29-3.49 (m, 3H), 3.58-4.27 (m, 5H), 4.33-4.46 (m, 1H), 4.59-4.65 (m, 1H).
MS (EI): m / z (%) 255 (8) M⁺-THP, 239 (7), 173 (12, 172 (9), 155 (11), 101 (27), 93 (12), 86 (20), 85 (100), 79 (10), 67 (32), 57 (27), 55 (18), 43 (39), 41 (23).
Zu einer Lösung von 32.5 g (95.6 mmol) des Bis-THP-Ethers nach Beispiel 13 in abs. THF wurden unter N2-Atmosphäre bei -70°C 105.2 ml einer 1M Diisobutyl aluminiumhydrid-Lösung in n-Hexan getropft. Man rührt 2 h bei -70°C und 6 h bei -20°C. Anschließend läßt man auf 0°C aufwärmen und gibt 50 ml Wasser zu. Die Reaktionsmischung wird danach mit 70 g Magnesiumsulfat versetzt und 40 min gerührt. Der Niederschlag wird über eine Glasfritte abgesaugt und portionsweise mit 500 ml Essigester gründlich gewaschen.To a solution of 32.5 g (95.6 mmol) of the bis-THP ether according to Example 13 in abs. THF was added dropwise under an N 2 atmosphere at -70 ° C. to 105.2 ml of a 1M diisobutyl aluminum hydride solution in n-hexane. The mixture is stirred for 2 h at -70 ° C and 6 h at -20 ° C. Then allowed to warm to 0 ° C and 50 ml of water are added. The reaction mixture is then mixed with 70 g of magnesium sulfate and stirred for 40 minutes. The precipitate is filtered off with a glass frit and washed thoroughly in portions with 500 ml of ethyl acetate.
Man erhält nach dem Einengen 31.06 g (95%) des Titelgemisches als farbloses
Öl.
[α] 20|365 + 31.8 (c = 1.13, Methylenchlorid),
1H-NMR (250 MHz, C6D5CD3): δ = 1.13-2.64 (m, 17H), 2.98-4.42, (m, 10H), 4,42-4.70
(m, 2H), 5.33-5.51 (m, 1H).
MS(EI): m/z(%) 257 (7) M⁺-THP, 173 (6), 157 (7), 139 (18), 101 (12), 93 (9), 85
(100), 67 (26), 57 (22), 55 (14), 43 (24).
After concentration, 31.06 g (95%) of the title mixture are obtained as a colorless oil.
[α] 20 | 365 + 31.8 (c = 1.13, methylene chloride),
1 H-NMR (250 MHz, C 6 D 5 CD 3 ): δ = 1.13-2.64 (m, 17H), 2.98-4.42, (m, 10H), 4.42-4.70 (m, 2H), 5.33- 5.51 (m, 1H).
MS (EI): m / z (%) 257 (7) M⁺-THP, 173 (6), 157 (7), 139 (18), 101 (12), 93 (9), 85 (100), 67 (26), 57 (22), 55 (14), 43 (24).
Zu 300 ml einer 0.59 H Lösung von Ethinylmagnesiumbromid in abs. Tetrahydrofu
ran werden unter Rühren und N-Atmosphäre bei 0°C 20.3 g (59.4 mmol) des
Lactons nach Beispiel 13 gelöst in 100 ml THF getropft. Man läßt die
Reaktionsmischung auf Raumtemperatur aufwärmen und rührt 12 h.
Anschließend wird die Lösung auf 0°C abgekühlt und mit 200 ml gesättigter
Natriumhydrogencarbonat-Lösung gequenscht. Man extrahiert portionsweise mit
600 ml Essigester und trocknet die vereinigten organischen Phasen mit
Magnesiumsulfat. Nach Abziehen des Lösungsmittels im Vakuum wird der ölige
Rückstand durch Säulenchromatographie gereinigt. Man erhält 20.97 g (96%) des
Diol-Gemisches als farbloses Öl.
To 300 ml of a 0.59 H solution of ethynylmagnesium bromide in abs. Tetrahydrofuran, 20.3 g (59.4 mmol) of the lactone according to Example 13 dissolved in 100 ml of THF are added dropwise with stirring and under an N atmosphere at 0 ° C. The reaction mixture is allowed to warm to room temperature and is stirred for 12 h. The solution is then cooled to 0 ° C. and quenched with 200 ml of saturated sodium bicarbonate solution. It is extracted in portions with 600 ml of ethyl acetate and the combined organic phases are dried with magnesium sulfate. After the solvent has been stripped off in vacuo, the oily residue is purified by column chromatography. 20.97 g (96%) of the diol mixture are obtained as a colorless oil.
[α] 20|D + 4.7 (c = 1.01, Methylenchlorid).
1H-NMR (250 MHz, CDCl3): δ = 1.40-2.50 (m, 17H), 3.37-4.14 (m, 10H), 4.38-4.67
(m, 4H).
MS(EI): m/z(%) 283 (10) M⁺-THP, 230 (8), 201 (9), 199 (36), 183 (50), 181 (44),
166 (10), 165 (54), 183 (11).
[α] 20 | D + 4.7 (c = 1.01, methylene chloride).
1 H NMR (250 MHz, CDCl 3 ): δ = 1.40-2.50 (m, 17H), 3.37-4.14 (m, 10H), 4.38-4.67 (m, 4H).
MS (EI): m / z (%) 283 (10) M⁺-THP, 230 (8), 201 (9), 199 (36), 183 (50), 181 (44), 166 (10), 165 (54), 183 (11).
8.75 g (23.78 mmol) des Diolgemisches nach Beispiel 15 werden in 100 ml abs.
Pyridin gelöst und unter Rühren bei -30°C langsam mit 3.67 g (26.15 mmol)
Benzoylchlorid versetzt. Nach 12 h bei -30°C werden 100 ml Wasser zugegeben und
mit 400 ml Essigester portionsweise extrahiert. Die vereinigten organischen
Phasen werden mit Magnesiumsulfat getrocknet und im Vakuum eingeengt. Der
Rückstand wird durch Säulenchromatographie an Kieselgel (Laufmittel:
Essigester/Hexan 1 : 2) gereinigt. Man erhält 8.31 g (74%) des Benzoat-Gemisches
als farbloses Öl.
8.75 g (23.78 mmol) of the diol mixture according to Example 15 are abs. In 100 ml. Dissolved pyridine and slowly added 3.67 g (26.15 mmol) of benzoyl chloride with stirring at -30 ° C. After 12 h at -30 ° C, 100 ml of water are added and extracted in portions with 400 ml of ethyl acetate. The combined organic phases are dried with magnesium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel (mobile phase: ethyl acetate / hexane 1: 2). 8.31 g (74%) of the benzoate mixture are obtained as a colorless oil.
[α] 20|D -121.1 (c = 1.69, Methylenchlorid).
1H-NMR (250 MHz, CDCl3): δ = 1.45-2.02 (m, 14H), 2.12-2.57, (m, 5H), 2.58-2.85
(m, 1H), 3.31-3.65 (m, 3H), 3.77-3.97 (m, 3H), 4.06-4.19 (m, 1H). 4.51-4.86
(m, 4H), 7.40-7.60 (m, 3H), 8.03-8.13 (m, 2H).
[α] 20 | D -121.1 (c = 1.69, methylene chloride).
1 H-NMR (250 MHz, CDCl 3 ): δ = 1.45-2.02 (m, 14H), 2.12-2.57, (m, 5H), 2.58-2.85 (m, 1H), 3.31-3.65 (m, 3H) , 3.77-3.97 (m, 3H), 4.06-4.19 (m, 1H). 4.51-4.86 (m, 4H), 7.40-7.60 (m, 3H), 8.03-8.13 (m, 2H).
Zu einer Lösung von 7.20 g (15.25 mmol) des nach Beispiel 16 hergestellten Gemisches und 3.11 g (45.75 mmol) Imidazol werden bei Raumtemperatur unter Rühren 2.76 g (17.7 mmol) t-BuMe2SiCl gegeben. 2.76 g (17.7 mmol) of t-BuMe 2 SiCl are added at room temperature to a solution of 7.20 g (15.25 mmol) of the mixture prepared according to Example 16 and 3.11 g (45.75 mmol) of imidazole.
Nach 18 h versetzt man die Lösung mit 50 ml Wasser, extrahiert mit 200 ml
Essigester und trocknet die vereinigten organischen Phasen mit Magnesiumsulfat.
Nach dem Abziehen des Lösungsmittels im Vakuum wird der Rückstand durch Säulen
chromatographie an Kieselgel (Laufmittel: Essigester/Hexan 1 : 3) gereinigt. Man
erhält 8.67 g (97 Y.) des Titelgemisches als farbloses Öl.
After 18 h, the solution is mixed with 50 ml of water, extracted with 200 ml of ethyl acetate and the combined organic phases are dried with magnesium sulfate. After the solvent has been stripped off in vacuo, the residue is purified by column chromatography on silica gel (mobile phase: ethyl acetate / hexane 1: 3). 8.67 g (97%) of the title mixture are obtained as a colorless oil.
[α] 20|D -16.2 (c = 1.33, Methylenchlorid).
1H-NMR (250 MHz, CDCl3): δ = 0.08-0.11 (m, 6H), 0.8-0.9 (m, 9H), 1.38-1.91 (m,
14H), 2.10-2.53 (m, 5H), 3.31-3.53 (m, 3H), 3.64-4.18 (m, 4H), 3.34-4.60 (m,
4H), 7.34-7.56 (m, 3H), 7.89-8.09 (m, 2H).
MS(EI): m/z(%) 586 (0.2), 417 (2), 361 (4), 323 (12), 279 (2), 239 (11), 179
(12), 105 (20), 85 (100), 75 (5), 73 (5), 67 (5), 57 (8), 43 (7).[α] 20 | D -16.2 (c = 1.33, methylene chloride).
1 H-NMR (250 MHz, CDCl 3 ): δ = 0.08-0.11 (m, 6H), 0.8-0.9 (m, 9H), 1.38-1.91 (m, 14H), 2.10-2.53 (m, 5H), 3.31-3.53 (m, 3H), 3.64-4.18 (m, 4H), 3.34-4.60 (m, 4H), 7.34-7.56 (m, 3H), 7.89-8.09 (m, 2H).
MS (EI): m / z (%) 586 (0.2), 417 (2), 361 (4), 323 (12), 279 (2), 239 (11), 179 (12), 105 (20) , 85 (100), 75 (5), 73 (5), 67 (5), 57 (8), 43 (7).
8.1 g (13.82 mmol) des Gemisches nach Beispiel 17 werden in 10 ml Methanol
gelöst und bei 0°C zu einer Lösung von 1 g Kaliumhydroxid in 100 ml Methanol
gegeben. Nach 10 h bei 0°C wird ein großer Teil des Methanols abdestilliert und
150 ml Wasser zugesetzt. Anschließend extrahiert man portionsweise mit 400 ml
Essigester, wäscht mit gesättigter Natriumchlorid-Lösung und trocknet mit
Magnesiumsulfat. Das Lösungsmittel wird im Vakuum abgezogen und der Rückstand
durch Säulenchromatographie an Kieselgel (Laufmittel: Essigester/Hexan 1 : 1)
gereinigt. Man erhält 4.73 g (71%) des Titelgemisches als farbloses Öl.
[α] 20|D -28.8 (c = 0.5, Methylenchlorid).
1H-NMR (250 MHz, CDCl3): δ = 0.07-0.11 (m, 6H), 0.76-0.91 (m, 9H); 1.30-1.83 (m,
15H), 1.87-2.30 (m, 5H), 2.39-2.41 (m, 1H), 3.15-3.98 (m, 7H), 4.36-4.43 (m,
3H).
MS(EI): m/z(%) 482 (4) M⁺, 455 (1), 398 (2), 382 (1), 313 (6), 295 (4), 279
(6), 257 (68), 239 (16), 129 (30), 101 (33), 85 (98). 75 (100), 67 (74), 57
(90), 43 (61).
8.1 g (13.82 mmol) of the mixture according to Example 17 are dissolved in 10 ml of methanol and added at 0 ° C. to a solution of 1 g of potassium hydroxide in 100 ml of methanol. After 10 h at 0 ° C., a large part of the methanol is distilled off and 150 ml of water are added. Then extracted in portions with 400 ml of ethyl acetate, washed with saturated sodium chloride solution and dried with magnesium sulfate. The solvent is removed in vacuo and the residue is purified by column chromatography on silica gel (mobile phase: ethyl acetate / hexane 1: 1). 4.73 g (71%) of the title mixture are obtained as a colorless oil.
[α] 20 | D -28.8 (c = 0.5, methylene chloride).
1 H NMR (250 MHz, CDCl 3 ): δ = 0.07-0.11 (m, 6H), 0.76-0.91 (m, 9H); 1.30-1.83 (m, 15H), 1.87-2.30 (m, 5H), 2.39-2.41 (m, 1H), 3.15-3.98 (m, 7H), 4.36-4.43 (m, 3H).
MS (EI): m / z (%) 482 (4) M⁺, 455 (1), 398 (2), 382 (1), 313 (6), 295 (4), 279 (6), 257 ( 68), 239 (16), 129 (30), 101 (33), 85 (98). 75 (100), 67 (74), 57 (90), 43 (61).
4.22 g (8.76 mmol) des nach Beispiel 18 erhaltenen Gemisches werden in 50 ml
Methylenchlorid und 10 ml Triethylamin gelöst und bei -20°C mit 100 mg
Dimethylaminopyridin versetzt. Dazu tropft man langsam unter Rühren 1.50 g
(13.10 mmol) Methansulfonsäurechlorid in 5 ml abs. Methylenchlorid. Nach 3 h
bei -20°C werden 50 ml Wasser zugegeben und mit 300 ml Wasser portionsweise
extrahiert. Die vereinigten organischen Phasen werden mit Magnesiumsulfat
getrocknet und im Vakuum eingeengt. Säulenfiltration des Rückstandes über
Kieselgel (Laufmittel: Essigester) liefert 4.66 g (95%) des Titelgemisches als
farbloses Öl.
4.22 g (8.76 mmol) of the mixture obtained in Example 18 are dissolved in 50 ml of methylene chloride and 10 ml of triethylamine, and 100 mg of dimethylaminopyridine are added at -20 ° C. 1.50 g (13.10 mmol) of methanesulfonic acid chloride in 5 ml of abs are slowly added dropwise with stirring. Methylene chloride. After 3 h at -20 ° C 50 ml of water are added and extracted with 300 ml of water in portions. The combined organic phases are dried with magnesium sulfate and concentrated in vacuo. Column filtration of the residue over silica gel (mobile phase: ethyl acetate) gives 4.66 g (95%) of the title mixture as a colorless oil.
1H-NMR (250 MHz, CDCl3): δ = 0.15-0.2 (m, 6H), 0.75-0.96 (m, 9H), 1.41-1.88 (m,
13H), 1.98-2.53 (m, 6H). 2.90-3.00 (m, 3H), 3.63-3.88 (m, 3H), 3.92-4.18 (m,
1H), 4.20-4.47 (m, 4H), 4.53-4.67 (m, 1H).
NMS: Ber. für
C27H48O8SSi: 560.2839; gef. 560.2831 M⁺.
C22H39O7SSi: 475.2185; gef. 475.2195 M⁺-THP.
1 H NMR (250 MHz, CDCl 3 ): δ = 0.15-0.2 (m, 6H), 0.75-0.96 (m, 9H), 1.41-1.88 (m, 13H), 1.98-2.53 (m, 6H). 2.90-3.00 (m, 3H), 3.63-3.88 (m, 3H), 3.92-4.18 (m, 1H), 4.20-4.47 (m, 4H), 4.53-4.67 (m, 1H).
NMS: Calc. For
C 27 H 48 O 8 SSi: 560.2839; found 560.2831 M⁺.
C 22 H 39 O 7 SSi: 475.2185; found 475.2195 M⁺-THP.
Analog Beispiel 8 erhält man aus 2.52 g (4.46 mmol) des Gemisches aus Beispiel
19 1.7 g (92%) des Titelgemisches als farbloses Öl.
Analogously to Example 8, 2.52 g (4.46 mmol) of the mixture from Example 19 gives 1.7 g (92%) of the title mixture as a colorless oil.
[α] 20|D +10.7 (c = 0.96, Methylenchlorid).
1H-NMR (250 MHz, CDCl3): δ = 0.06-0.16 (m, 6H), 0.78-1.00 (m, 9H), 1.17-2.96 (m,
17H), 3.26-3.96 (m, 9H), 4.37-4.44 (m, 1H), 4.51-4.72 (m, 2H), 4.82-5.01 (m,
2H).
MS(CI): m/z(%) 484 (0.2) M⁺+NH3), 383 (1), 299 (58), 268 (14), 251 (12), 184
(100), 132 (38), 102 (96), 85 (14).
[α] 20 | D +10.7 (c = 0.96, methylene chloride).
1 H-NMR (250 MHz, CDCl 3 ): δ = 0.06-0.16 (m, 6H), 0.78-1.00 (m, 9H), 1.17-2.96 (m, 17H), 3.26-3.96 (m, 9H), 4.37-4.44 (m, 1H), 4.51-4.72 (m, 2H), 4.82-5.01 (m, 2H).
MS (CI): m / z (%) 484 (0.2) M⁺ + NH 3 ), 383 (1), 299 (58), 268 (14), 251 (12), 184 (100), 132 (38 ), 102 (96), 85 (14).
Analog Beispiel 9 erhält man aus 1.39 g (3.00 mmol) des Gemisches aus Beispiel
20 0.916 g (87%) des Titelgemisches als farbloses Öl.
Analogously to Example 9, 1.39 g (3.00 mmol) of the mixture from Example 20 gives 0.916 g (87%) of the title mixture as a colorless oil.
1H-NMR (250 MHz, CDCl3): δ = 1.40-2.92 (m, 19H), 3.19-4.14 (m, 8H), 4.33-4.48 (m,
1H), 4.55-4.76 (m, 2H), 4.93-5.14 (m, 2H).
[α] 20|D +3.5 (c = 0.57, Methylenchlorid).
1 H-NMR (250 MHz, CDCl 3 ): δ = 1.40-2.92 (m, 19H), 3.19-4.14 (m, 8H), 4.33-4.48 (m, 1H), 4.55-4.76 (m, 2H), 4.93-5.14 (m, 2H).
[α] 20 | D +3.5 (c = 0.57, methylene chloride).
Analog Beispiel 10 erhält man aus 0,911 g (2.59 mmol) des Gemisches aus
Beispiel 21 0,929 g (91%) des Titelgemisches als farbloses Öl.
Analogously to example 10, 0.929 g (2.59 mmol) of the mixture from example 21 gives 0.929 g (91%) of the title mixture as a colorless oil.
[α] 20|D + 12.5 (c = 0.51, Methylenchlorid).
1H-NMR (250 MHz. CDCl3): δ = 1.21-2.61 (m, 21H), 2.62-2.80 (m, 1H), 3.32-4.21 (m,
5H), 4.53-4.70 (m, 2H), 4.95-5.20 (m, 2H), 5.34-5.50 (m. 1H).[α] 20 | D + 12.5 (c = 0.51, methylene chloride).
1 H-NMR (250 MHz. CDCl 3 ): δ = 1.21-2.61 (m, 21H), 2.62-2.80 (m, 1H), 3.32-4.21 (m, 5H), 4.53-4.70 (m, 2H), 4.95-5.20 (m, 2H), 5.34-5.50 (m. 1H).
Analog Beispiel 11 erhält man aus 150.2 mg (0.381 mmol) des Gemisches aus Bei
spiel 22 159.8 g (92%) des Titelgemisches als farbloses Öl.
Analogously to Example 11, 150.2 mg (0.381 mmol) of the mixture from example 22 gives 159.8 g (92%) of the title mixture as a colorless oil.
1H-NMR (250 MHz, CDCl3): δ = 1.2-2.57 (m, 20H), 2.81-3.19 (m, 1H), 3.33-4.05 (m,
9H), 4.49-4.69 (m, 4H), 5.30-5.36 (m, 1H), 7.20-7.44 (m, 5H).
[α] 20|365 -19.6 (c = 0.5, Methylenchlorid).
HMS: ber. für (C18H24O3, M⁺): 288.3902; gef. 288.1734.
1 H-NMR (250 MHz, CDCl 3 ): δ = 1.2-2.57 (m, 20H), 2.81-3.19 (m, 1H), 3.33-4.05 (m, 9H), 4.49-4.69 (m, 4H), 5.30-5.36 (m, 1H), 7.20-7.44 (m, 5H).
[α] 20 | 365 -19.6 (c = 0.5, methylene chloride).
HMS: calc. For (C 18 H 24 O 3 , M⁺): 288.3902; found 288.1734.
Zu einer Lösung von 131.2 mg (0.288 mmol) der Verbindung aus Beispiel 23 in 40 ml Ammoniak und 15 ml Tetrahydrofuran werden bei -78°C 132.2 mg (5,76 mmol) Na zugegeben. Nach 1 h bei -78°C wird mit 5 ml Ammoniumchlorid-Lösung vorsich tig gequentscht. Anschließend läßt man bei Raumtemperatur den Ammoniak abdampfen. Den Rückstand extrahiert man mit 250 ml Ether. Nach Trocknen der vereinigten organischen Phasen mit Magnesiumsulfat wird im Vakuum eingeengt und der Rückstand durch Säulenchromatographie (Laufmittel: Essigester/Hexan 2 : 1) gereinigt. Man erhält 86.4 mg (821.) der Titelverbindung als farbloses Öl.To a solution of 131.2 mg (0.288 mmol) of the compound from Example 23 in 40 ml ammonia and 15 ml tetrahydrofuran are 132.2 mg (5.76 mmol) at -78 ° C Well admitted. After 1 h at -78 ° C with 5 ml of ammonium chloride solution squeezed. The ammonia is then left at room temperature evaporate. The residue is extracted with 250 ml of ether. After drying the combined organic phases with magnesium sulfate is concentrated in vacuo and the residue by column chromatography (mobile phase: ethyl acetate / hexane 2: 1) cleaned. 86.4 mg (821.) of the title compound are obtained as a colorless oil.
Zu einer Mischung von 84,4 mg (0.24 mmol) der Verbindung aus Beispiel 24 und
924.0 mg (4.72 mmol) Bromessigsäure-t-butylester in 0.6 ml abs. Methylenchlorid
werden unter Rühren 81.4 mg (0,24 mmol) Tetrabutylammonium-hydrogensulfat und
1.2 ml 50% NaOH gegeben. Man rührt 2 d und extrahiert anschließend die Reak
tionsmischung mit 150 ml Ether. Die vereinigten organischen Phasen werden
werden mit Magnesiumsulfat getrocknet und im Vakuum eingeengt. Der Rückstand
wird durch Säulenchromatographie gereinigt und man erhält 82.9 mg (74%) der
Titelverbindung.
To a mixture of 84.4 mg (0.24 mmol) of the compound from Example 24 and 924.0 mg (4.72 mmol) of t-butyl bromoacetate in 0.6 ml of abs. Methylene chloride 81.4 mg (0.24 mmol) of tetrabutylammonium hydrogen sulfate and 1.2 ml of 50% NaOH are added with stirring. The mixture is stirred for 2 d and then extracted with 150 ml of ether. The combined organic phases are dried with magnesium sulfate and concentrated in vacuo. The residue is purified by column chromatography and 82.9 mg (74%) of the title compound are obtained.
1H-NMR (400 MHz, CDCl3): δ 1.20-1.91 (m, 23H), 2.06-2.72 (m, 7H). 2.92-3.03
(m, 1H), 3.32-4.05 (m, 10H), 4.56-4,68 (m, 2H), 5.33-5.39 (m, 1H).
MS(CI): m/z(%) 498 (100) M⁺+NH3), 414 (18), 397 (4), 330 (58), 313 (42), 274
(28), 257 (6), 211 (5), 118 (8), 102 (18), 85 (25).
1 H NMR (400 MHz, CDCl 3 ): δ 1.20-1.91 (m, 23H), 2.06-2.72 (m, 7H). 2.92-3.03 (m, 1H), 3.32-4.05 (m, 10H), 4.56-4.68 (m, 2H), 5.33-5.39 (m, 1H).
MS (CI): m / z (%) 498 (100) M⁺ + NH 3 ), 414 (18), 397 (4), 330 (58), 313 (42), 274 (28), 257 (6 ), 211 (5), 118 (8), 102 (18), 85 (25).
H-NMR (400 MHz. CDCl3 H-NMR (400 MHz. CDCl 3
): δ = 1.31-1.61 (m, 11H), 1.63-1.72 (m, 1H), 1.92-2.40 (m,
6H), 2.95-3.08 (m, 3a-Hα), 3.58-3.66 (m, 1H) 3.61 (t. J = 7 Hz). 3.83-3.99 (m,
2H9, 3.95 (s. 2H). 5.39-5.41 (m, 1H).
13 ): δ = 1.31-1.61 (m, 11H), 1.63-1.72 (m, 1H), 1.92-2.40 (m, 6H), 2.95-3.08 (m, 3a-Hα), 3.58-3.66 (m, 1H) 3.61 (t. J = 7 Hz). 3.83-3.99 (m, 2H9, 3.95 (see 2H). 5.39-5.41 (m, 1H).
13
C-NMR (100 MHz, CDCl3 C-NMR (100 MHz, CDCl 3
): δ = 28.24, 31.27, 40.42, 40.87, 41.25, 46.69, 55.75,
66.44, 68.87, 70.12, 78.27, 81.64, 129.88, 138.63, 169.8.
[α]): δ = 28.24, 31.27, 40.42, 40.87, 41.25, 46.69, 55.75, 66.44, 68.87, 70.12, 78.27, 81.64, 129.88, 138.63, 169.8.
[α]
20|D 20 | D
+ 3.8 (c = 0.51, Methylenchlorid).
MS(CI): m/z(%) 330 (4), M⁺+NH3 + 3.8 (c = 0.51, methylene chloride).
MS (CI): m / z (%) 330 (4), M⁺ + NH 3
, 313 (12) M⁺, 274 (100).
MS(EI): 256 (4) M⁺-Isobuten. 181 (15), 162 (14), 144 (14), 131 (27), 129 (12),
117 (15), 105 (28), 91 (43), 79 (24), 77 (21), 57 (100).
HMS ber. für (C13 , 313 (12) M⁺, 274 (100).
MS (EI): 256 (4) M⁺ isobutene. 181 (15), 162 (14), 144 (14), 131 (27), 129 (12), 117 (15), 105 (28), 91 (43), 79 (24), 77 (21), 57 (100).
HMS calc. For (C 13
H20 H 20
Os O s
, M⁺-Isobuten): 256.3014; gef. 256.1315., M⁺-isobutene): 256.3014; found 256.1315.
Analog Beispiel 7 erhält man aus 810.2 mg (2.056 mmol) des Gemisches aus Bei
spiel 22 1.327 g (95%) des Titelgemisches als farbloses Öl.
Analogously to Example 7, 810.2 mg (2,056 mmol) of the mixture from example 22 gives 1,327 g (95%) of the title mixture as a colorless oil.
1H-NMR (400 MHz), C6D6): δ = 0.8-1.90 (m, 18H), 1.95-2.71 (m, 7H), 2.94-3,98 (m,
1H), 3.36-4.32 (m, 10H), 4.61-4.81 (m, 2H), 5.28-5.39 (m, 1H), 7.20-7.39 (m,
6M), 7.72-7.90 (m, 4H).
MS(EI): m/z(%) 646 (1) M⁺, 589 (2), 562 (1), 505 (9), 469 (1), 403 (12), 343
(10), 283 (10), 199 (48), 187 (74), 145 (24), 131 (30), 105127), 91 (40), 85
(100), 67 (64), 57 (60), 43 (54).
1 H-NMR (400 MHz), C 6 D 6 ): δ = 0.8-1.90 (m, 18H), 1.95-2.71 (m, 7H), 2.94-3.98 (m, 1H), 3.36-4.32 ( m, 10H), 4.61-4.81 (m, 2H), 5.28-5.39 (m, 1H), 7.20-7.39 (m, 6M), 7.72-7.90 (m, 4H).
MS (EI): m / z (%) 646 (1) M⁺, 589 (2), 562 (1), 505 (9), 469 (1), 403 (12), 343 (10), 283 ( 10), 199 (48), 187 (74), 145 (24), 131 (30), 105127), 91 (40), 85 (100), 67 (64), 57 (60), 43 (54) .
1.25 g (1.93 mmol) der Verbindung aus Beispiel 26 werden in 10 ml abs. THF und
1 ml Tetrahydrofuran gelöst. In diese Lösung werden unter Rühren 4 ml einer 1 M
Tetrabutylammoniumfluorid-Lösung in Tetrahydrofuran zugetropft. Nach 6 h wird
das Lösungsmittel im Vakuum abdestilliert und der Rückstand durch Säulenchroma
tographie an Kieselgel (Laufmittel: Essigester/Hexan/Methanol 1 : 1 : 0.05) gerei
nigt. Man erhält 724.4 mg der Titelverbindung als farbloses Öl.
1.25 g (1.93 mmol) of the compound from Example 26 are abs in 10 ml. THF and 1 ml of tetrahydrofuran dissolved. 4 ml of a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran are added dropwise to this solution with stirring. After 6 h, the solvent is distilled off in vacuo and the residue is purified by column chromatography on silica gel (mobile phase: ethyl acetate / hexane / methanol 1: 1: 0.05). 724.4 mg of the title compound are obtained as a colorless oil.
1H-NMR (400 MHz, CDCl3): δ = 1.18-1.92 (m, 20H). 1.99-2.58 (m, 8H), 2.90-3.04 (m,
3a-Hα, 1H), 3.38-4.07 (m, 6H) 3.68 (t, J = 7 Hz, 2H) 4.57-4.72 (m, 2H). 5.24-5.29
(m, 1H).
[α] 20|D -24.5 (c = 1.78. Methylenchlorid). 1 H NMR (400 MHz, CDCl 3 ): δ = 1.18-1.92 (m, 20H). 1.99-2.58 (m, 8H), 2.90-3.04 (m, 3a-Hα, 1H), 3.38-4.07 (m, 6H) 3.68 (t, J = 7 Hz, 2H) 4.57-4.72 (m, 2H). 5.24-5.29 (m, 1H).
[α] 20 | D -24.5 (c = 1.78. methylene chloride).
Zu einer gerührten Lösung von 710.3 mg (1.74 mmol) des vorstehenden Pentanols in 5 ml Dimethylsulfoxid werden 1.44 ml (10.45 mmol) Triethylamin und 1.67 g (10.45 mmol) SO3. Pyridin in 5 ml Dimethyl-sulfoxid bei Raumtemperatur zugetropft. Nach 50 Minuten gibt man 5 ml Eiswasser zu und extrahiert mit 150 ml Essigester. Man trocknet die organische Phase mit Magnesiumsulfat und engt im Vakuum ein. Der Rückstand wird durch Chromatographie an Kieselgel (Laufmittel Essigester) gereinigt. Man eluiert 671.4 mg (95%) des Aldehyds als farbloses Öl. 1.44 ml (10.45 mmol) of triethylamine and 1.67 g (10.45 mmol) of SO 3 are added to a stirred solution of 710.3 mg (1.74 mmol) of the above pentanol in 5 ml of dimethyl sulfoxide. Pyridine in 5 ml of dimethyl sulfoxide was added dropwise at room temperature. After 50 minutes, 5 ml of ice water are added and the mixture is extracted with 150 ml of ethyl acetate. The organic phase is dried with magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel (mobile phase ethyl acetate). 671.4 mg (95%) of the aldehyde is eluted as a colorless oil.
671.4 mg (1.65 mmol) der Verbindung aus Beispiel 28 und 1.1 g (6.6 mmol) AgNO3
werden in 10 ml Ethanol und 2 ml Wasser gelöst. Zu dieser gerührten Lösung
tropft man bei Raumtemperatur 0,7 ml einer 50%igen Natronlauge über 30 Minuten
zu. Nach 4 h filtriert man den Silberniederschlag ab und neutralisiert
anschließend mit 0.01 M Salzsäure. Danach destilliert man im Vakuum das Ethanol
ab und gibt zum Rückstand unter kräftigem Rühren 50 ml einer 0.54 M Diazome
thanlösung in Ether zu. Nach 2 h Rühren der heterogenen Mischung wird mit 300 ml
Essigester extrahiert. Man trocknet die vereinigten organischen Phasen mit Mag
nesiumsulfat und engt im Vakuum ein. Den Rückstand reinigt man durch Chromato
graphie an Kieselgel (Laufmittel: Essigester/Hexan 1 : 3). Man erhält 612.3 mg
(85%) der Titelverbindung.
671.4 mg (1.65 mmol) of the compound from Example 28 and 1.1 g (6.6 mmol) of AgNO 3 are dissolved in 10 ml of ethanol and 2 ml of water. 0.7 ml of a 50% sodium hydroxide solution is added dropwise to this stirred solution at room temperature over 30 minutes. After 4 h, the silver precipitate is filtered off and then neutralized with 0.01 M hydrochloric acid. The ethanol is then distilled off in vacuo and 50 ml of a 0.54 M diazomethane solution in ether are added to the residue with vigorous stirring. After the heterogeneous mixture has been stirred for 2 hours, it is extracted with 300 ml of ethyl acetate. The combined organic phases are dried with magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent: ethyl acetate / hexane 1: 3). 612.3 mg (85%) of the title compound are obtained.
[α] 20|D -28.2 (c = 1.4. Methylenchlorid).
1H-NMR (400 MHz, CDCl3): δ = 1.19-1.50 (m, 1H). 1.51-2.29 (m, 20H), 2.0-2.58 (m,
7H), 2,90-3,02 (m, 1H), 3.36-3.361 (m, 3H), 3.69 (s, OCH3, 3H), 3.75-4.07 (m,
4H), 4.57-4.70 (m, 1H), 5.26-5.33 (m, 1H).
MS(EI): m/z(%) 352 (0.2) M⁺, 334 (0.2), 268 (3), 117 (6), 105 (6), 85 (100), 67
(28), 57 (25), 43 (35).
[α] 20 | D -28.2 (c = 1.4. methylene chloride).
1 H NMR (400 MHz, CDCl 3 ): δ = 1.19-1.50 (m, 1H). 1.51-2.29 (m, 20H), 2.0-2.58 (m, 7H), 2.90-3.02 (m, 1H), 3.36-3.361 (m, 3H), 3.69 (s, OCH 3 , 3H), 3.75-4.07 (m, 4H), 4.57-4.70 (m, 1H), 5.26-5.33 (m, 1H).
MS (EI): m / z (%) 352 (0.2) M⁺, 334 (0.2), 268 (3), 117 (6), 105 (6), 85 (100), 67 (28), 57 ( 25), 43 (35).
580.4 mg (1.33 mmol) der Verbindung aus Beispiel 29 werden in 50 ml abs. Metha
nol gelöst und 20 mg Pyridinium-p-toluolsulfonat bei Raumtemperatur zugegeben.
Man erwärmt anschließend 4 h auf 40°C und filtriert die Reaktionslösung danach
über Kieselgel (Laufmittel: Essigester). Man isoliert 331.3 mg (93%) der Titel
verbindung als farblose Kristalle. Fp.: 51.0°C (Essigester/Hexan).
580.4 mg (1.33 mmol) of the compound from Example 29 in 50 ml of abs. Dissolved methanol and added 20 mg of pyridinium p-toluenesulfonate at room temperature. The mixture is then heated to 40 ° C. for 4 h and the reaction solution is then filtered through silica gel (mobile phase: ethyl acetate). 331.3 mg (93%) of the title compound are isolated as colorless crystals. Mp .: 51.0 ° C (ethyl acetate / hexane).
[α] 20|365 -11.5 (c = 0.21, Methylenchlorid).
1H-NMR (400 MHz, CDCl3): δ = 1.29-1.38 (m, 1H), 1.40-1.51 (m, 2H), 1.58-1.73 (m,
3H), 2.02-2.09 (m, 3H), 2.10-2.21 (m, 1H), 2.22-2.39 (m, 3H), 2.41-2.59 (m,
2H), 2.68-2.80 (m, OH, 1H), 2.97-3.05 (m, 1H), 3.63-3.73 (m, 4H), 3.85-4.0 (m,
2H), 5.28-5.33 (m, 1H).
13C-NMR (100 MHz, CDCl3): δ = 24.69, 27.22, 30.56, 33.96, 40.47, 40.65, 40.78,
46.30, 51.78, 55.40, 66.21, 78.13, 128.35, 141.57, 174.32.
[α] 20 | 365 -11.5 (c = 0.21, methylene chloride).
1 H-NMR (400 MHz, CDCl 3 ): δ = 1.29-1.38 (m, 1H), 1.40-1.51 (m, 2H), 1.58-1.73 (m, 3H), 2.02-2.09 (m, 3H), 2.10-2.21 (m, 1H), 2.22-2.39 (m, 3H), 2.41-2.59 (m, 2H), 2.68-2.80 (m, OH, 1H), 2.97-3.05 (m, 1H), 3.63-3.73 (m, 4H), 3.85-4.0 (m, 2H), 5.28-5.33 (m, 1H).
13 C-NMR (100 MHz, CDCl 3 ): δ = 24.69, 27.22, 30.56, 33.96, 40.47, 40.65, 40.78, 46.30, 51.78, 55.40, 66.21, 78.13, 128.35, 141.57, 174.32.
Zu einer Lösung von 255,2 mg (0,95 mmol) der Verbindung aus Beispiel 30 in 5 ml abs. Dimethylformamid gibt man bei 0°C 193,8 mg (2,85 mmol) Imidazol und 157,3 mg (1,05 mmol) t-BuMe2 SiCl und rührt 4 Stunden bei 0°C. Anschließend gibt man 10 ml Wasser zu und extrahiert mit 150 ml Essigester. Nach Trocknen mit Magnesiumsulfat engt man im Vakuum ein. Den öligen Rückstand reinigt man durch Säulenchromatographie (Laufmittel: Essigester/Hexan 1 : 3) Man eluiert 312,1 mg (86%) der Titelverbindung als farbloses Öl.To a solution of 255.2 mg (0.95 mmol) of the compound from Example 30 in 5 ml of abs. Dimethylformamide is added at 0 ° C 193.8 mg (2.85 mmol) imidazole and 157.3 mg (1.05 mmol) t-BuMe 2 SiCl and stirred for 4 hours at 0 ° C. Then 10 ml of water are added and the mixture is extracted with 150 ml of ethyl acetate. After drying with magnesium sulfate, the mixture is concentrated in vacuo. The oily residue is purified by column chromatography (mobile phase: ethyl acetate / hexane 1: 3). 312.1 mg (86%) of the title compound is eluted as a colorless oil.
303,4 mg (0,79 mmol) der Verbindung aus Beispiel 31 werden in 4 ml abs. Methy lenchlorid gelöst und 5 mg Pyridinium-p-toluolsulfonat zugesetzt. Anschließend gibt man 86,3 mg (2,37 mmol) Dihydropyran zu und rührt 3 Stunden. Danach wird die Reaktionsmischung über Kieselgel filtriert (Laufmittel: Essigester) und im Vakuum eingeengt. Man erhält 335,0 mg (91%) der Titelverbindung als farbloses Öl.303.4 mg (0.79 mmol) of the compound from Example 31 in 4 ml of abs. Methy Lenchlorid dissolved and 5 mg of pyridinium p-toluenesulfonate added. Subsequently 86.3 mg (2.37 mmol) of dihydropyran are added and the mixture is stirred for 3 hours. After that the reaction mixture is filtered through silica gel (mobile phase: ethyl acetate) and in Vacuum concentrated. 335.0 mg (91%) of the title compound are obtained as colorless Oil.
335,0 mg (0,72 mmol) der Verbindung aus Beispiel 32 werden in 3 ml Tetrahydro
furan gelöst und 0,2 ml Triethylamin zugegeben. Man tropft anschließend 1 ml 1M
Tetrabutylammoniumfluorid-Lösung in THF zu. Nach 6 Stunden wird die Reaktions
mischung über Kieselgel (Laufmittel: Essigester) filtriert. Man eluiert 233.1
mg (921.) der Titelverbindung als farbloses Öl.
335.0 mg (0.72 mmol) of the compound from Example 32 are dissolved in 3 ml of tetrahydrofuran and 0.2 ml of triethylamine is added. 1 ml of 1M tetrabutylammonium fluoride solution in THF is then added dropwise. After 6 hours, the reaction mixture is filtered through silica gel (mobile phase: ethyl acetate). 233.1 mg (921.) of the title compound is eluted as a colorless oil.
1H-NMR (250 MHz. CDCl3): δ = 1.14-1.83 (m, 17H), 1,95-2,58 (m, 11H). 2,77-3,01 (m, 1H), 3,10-3,41 (m, 1H), 3,43-3,96 (m, 8H), 4,53-4,68 (m, 1H), 5,26-5,32 (m, 1H). 1 H NMR (250 MHz. CDCl 3 ): δ = 1.14-1.83 (m, 17H), 1.95-2.58 (m, 11H). 2.77-3.01 (m, 1H), 3.10-3.41 (m, 1H), 3.43-3.96 (m, 8H), 4.53-4.68 (m, 1H) ), 5.26-5.32 (m, 1H).
Zu einer gerührten Lösung von 215,4 mg (0,61 mmol) der Verbindung aus Beispiel 27 in 5 ml Dimethylsulfoxid werden 0,72 ml (5,22 mmol) Triethylamin und 0,84 g (5,23 mmol) SO3-Pyridin in 5 ml Dimethyl-sulfoxid bei Raumtemperatur zugetropft Nach 50 Minuten gibt man 5 ml Eiswasser zu und extrahiert mit 150 ml Essige ster. Man trocknet die organische Phase mit Magnesiumsulfat und engt im Vakuum ein. Der ölige Rückstand (Rohausbeute 93%) wird wegen seiner Labilität ohne weitere Reinigung zur Olefinierung eingesetzt. Hierzu werden 43,9 mg (1,83 mmol) Natriumhydrid in 4 ml Glyme vorgelegt und 411,1 mg (1,85 mmol) Dimethyl- (2-oxoheptyl)-phosphonat in 2 ml Glyme zugetropft. Zu dieser gelartigen Lösung gibt man bei 0°C den Aldehyd gelöst in 2 ml Glyme langsam zu.0.72 ml (5.22 mmol) of triethylamine and 0.84 g (5.23 mmol) of SO 3 - are added to a stirred solution of 215.4 mg (0.61 mmol) of the compound from Example 27 in 5 ml of dimethyl sulfoxide. Pyridine in 5 ml of dimethyl sulfoxide added dropwise at room temperature. After 50 minutes, 5 ml of ice water are added and the mixture is extracted with 150 ml of ethyl acetate. The organic phase is dried with magnesium sulfate and concentrated in vacuo. Because of its lability, the oily residue (crude yield 93%) is used for olefining without further purification. For this purpose, 43.9 mg (1.83 mmol) of sodium hydride in 4 ml of glyme are introduced and 411.1 mg (1.85 mmol) of dimethyl (2-oxoheptyl) phosphonate in 2 ml of glyme are added dropwise. The aldehyde dissolved in 2 ml of glyme is slowly added to this gel-like solution at 0 ° C.
Nach 4 Stunden bei 0°C wird mit 10 ml Wasser versetzt und mit 200 ml Essigester
extrahiert. Man trocknet mit Magnesiumsulfat und engt im Vakuum ein. Den öligen
Rückstand reinigt man durch Säulenchromatographie (Laufmittel: Essigester/Hexan
1 : 5). Man erhält 176,8 mg (65%) der Titelverbindung als farbloses Öl.
After 4 hours at 0 ° C., 10 ml of water are added and the mixture is extracted with 200 ml of ethyl acetate. It is dried with magnesium sulfate and concentrated in vacuo. The oily residue is purified by column chromatography (mobile phase: ethyl acetate / hexane 1: 5). 176.8 mg (65%) of the title compound are obtained as a colorless oil.
1H-NMR (400 MHz, CDCl3): δ = 0,82-0,93 (m, 3H), 1,22-1,83 (m, 17M), 1,91-2,08
(m, 8H), 2,98-3,10 (m, 1H), 3,41-3,51 (m, 1H), 3,69 (s, OCH3, 3H), 3,73-4,20
(m, 2H), 4,55-5,70 (m, 1H), 5,28-5,32 (m, 1H), 6,15-6,22 (m, 1H), 6,74-6,88 (m,
1H).
13C-NMR (100 MHz, CDCl3): δ = 13.94, 18.95, 19.65, 22.45, 24.08, 24.69, 25.41,
27.20, 30.53, 30.68, 30.78, 31.50, 31,53, 33.91, 36.67, 39.01, 39,65, 39.79,
40.07, 40.44, 43.61, 43.64, 45.79, 45.85, 51.48, 55.17, 55.97, 61.61, 62.61,
79.19, 82,82, 96,21, 99.51, 128.06, 128.17, 130.61, 130.80, 141.14, 141.29,
148.12, 148.39, 174.12, 200.73, 200.94.
1 H-NMR (400 MHz, CDCl 3 ): δ = 0.82-0.93 (m, 3H), 1.22-1.83 (m, 17M), 1.91-2.08 (m, 8H), 2.98-3.10 (m, 1H), 3.41-3.51 (m, 1H), 3.69 (s, OCH 3 , 3H), 3.73-4.20 (m , 2H), 4.55-5.70 (m, 1H), 5.28-5.32 (m, 1H), 6.15-6.22 (m, 1H), 6.74-6.88 (m, 1H).
13 C-NMR (100 MHz, CDCl 3 ): δ = 13.94, 18.95, 19.65, 22.45, 24.08, 24.69, 25.41, 27.20, 30.53, 30.68, 30.78, 31.50, 31.53, 33.91, 36.67, 39.01, 39, 65, 39.79, 40.07, 40.44, 43.61, 43.64, 45.79, 45.85, 51.48, 55.17, 55.97, 61.61, 62.61, 79.19, 82.82, 96.21, 99.51, 128.06, 128.17, 130.61, 130.80, 141.14, 141.29, 148.12, 148.39, 174.12, 200.73, 200.94.
165,4 mg (0,37 mmol) der Verbindung aus Beispiel 34 werden in 5 ml Methanol
gelöst und 5 mg Pyridinium-p-toluolsulfonat zugesetzt. Nach 2 Stunden bei 40°C
gibt man 10 ml gesättigte Natriumhydrogencarbonat-Lösung zu und extrahiert mit
200 ml Essigester. Die organische Phase wird mit Magnesiumsulfat getrocknet und
im Vakuum eingeengt. Den Rückstand reinigt man durch Chromatographie an Kiesel
gel (Laufmittel: Essigester/Hexan/Methanol 1 : 2 : 0,1). Man erhält 123,2 mg (0,34
mmol) der Titelverbindung als farbloses Öl, das bei längerem Stehen kristal
lisiert.
165.4 mg (0.37 mmol) of the compound from Example 34 are dissolved in 5 ml of methanol and 5 mg of pyridinium p-toluenesulfonate are added. After 2 hours at 40 ° C., 10 ml of saturated sodium bicarbonate solution are added and the mixture is extracted with 200 ml of ethyl acetate. The organic phase is dried with magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel (mobile phase: ethyl acetate / hexane / methanol 1: 2: 0.1). 123.2 mg (0.34 mmol) of the title compound are obtained as a colorless oil which crystallizes on standing for a long time.
1H-NMR (400 MHz, CDCl3): δ = 0,89 (t, J = 7,0 Hz, CH3, 3H), 1,20-1,70 (m, 13H),
1,80-1,90 (m, OH, 1H), 1,93-2,23 (m, 4H), 2,29-2,59 (m, 7H), 3,0-3,14 (m, 1H),
3,67 (s, OCH3, 3H), 3,86-4,02 (m, 1H), 5,28-5,35 (m, 1H), 6,17-6,30 (m, 1H),
6,70-6,84 (m, 1H).
[α] 20|D +21,7 (c = 0,89 Methanol).
1 H-NMR (400 MHz, CDCl 3 ): δ = 0.89 (t, J = 7.0 Hz, CH 3 , 3H), 1.20-1.70 (m, 13H), 1.80- 1.90 (m, OH, 1H), 1.93-2.23 (m, 4H), 2.29-2.59 (m, 7H), 3.0-3.14 (m, 1H), 3.67 (s, OCH 3 , 3H), 3.86-4.02 (m, 1H), 5.28-5.35 (m, 1H), 6.17-6.30 (m, 1H) , 6.70-6.84 (m, 1H).
[α] 20 | D +21.7 (c = 0.89 methanol).
Zu einer Lösung von 378,4 mg (1,72 mmol) 2,6-Di-t-butyl-4-methylphenol in 15 ml abs. Toluol werden bei 4°C unter N2-Atmosphäre 0,86 ml einer 1 M Diisobutylalu miniumhydridlösung in Hexan über 20 Minuten getropft. Man läßt danach die Lö sung 1 Stunde bei 4°C rühren. Anschließend kühlt man die Reaktionslösung auf -78°C ab und tropft langsam 31,1 mg (0,086 mmol) der Verbindung aus Beispiel 35 gelöst in 2 ml abs. Toluol zu. Die Reaktionslösung färbt sich dabei orange. Bei gleicher Temperatur rührt man 2 Stunden und läßt anschließend auf -40°C aufwär men und rührt weitere 4 Stunden. Zuletzt läßt man die Lösung innerhalb einer Stunde auf -10°C aufwärmen und fügt 5 ml gesättigte Ammoniumchlorid-Lösung hin zu. Nach Extraktion mit 200 ml Essigester und Trocknen mit Magnesiumsulfat engt man im Vakuum ein. Die anschließende Chromatographie des Rückstandes an Kiesel gel (Laufmittel: Essigester) liefert 27,2 mg (87%) der Titelverbindung als farbloses Öl. Die beiden Epimeren lassen sich problemlos durch Mitteldruckchro matographie an Kieselgel (Laufmittel: Essigester) trennen. Man erhält 22,0 mg (35*)-Epimeres.To a solution of 378.4 mg (1.72 mmol) of 2,6-di-t-butyl-4-methylphenol in 15 ml of abs. Toluene is added dropwise at 4 ° C under N 2 atmosphere 0.86 ml of a 1 M diisobutylaluminum hydride solution in hexane over 20 minutes. The solution is then allowed to stir at 4 ° C. for 1 hour. The reaction solution is then cooled to -78 ° C. and 31.1 mg (0.086 mmol) of the compound from Example 35 dissolved in 2 ml of abs are slowly added dropwise. Toluene too. The reaction solution turns orange. At the same temperature, the mixture is stirred for 2 hours and then allowed to warm up to -40 ° C. and stirring is continued for 4 hours. Finally, the solution is allowed to warm to -10 ° C. within an hour and 5 ml of saturated ammonium chloride solution are added. After extraction with 200 ml of ethyl acetate and drying with magnesium sulfate, the mixture is concentrated in vacuo. The subsequent chromatography of the residue on silica gel (eluent: ethyl acetate) yields 27.2 mg (87%) of the title compound as a colorless oil. The two epimers can be easily separated by medium pressure chromatography on silica gel (eluent: ethyl acetate). 22.0 mg (35 *) epimer are obtained.
H-NMR (400 MHz, CDCl3 H-NMR (400 MHz, CDCl 3
): δ = 0,89 (t, J = 7.0 Hz, CH3 ): δ = 0.89 (t, J = 7.0 Hz, CH 3
, 3H), 1.20-1.81 (m, 15H), 1.82-2.1 (m, 4H), 2.3-2.4 (m, 2H), 2.31 (t, J = 7.0 Hz, 2H), 2.41 (dd, J = 16.0, J = 9.0 Hz, 1H), 2.95-3.05 (m, 1H), 3.67 (s, OCH3 , 3H), 1.20-1.81 (m, 15H), 1.82-2.1 (m, 4H), 2.3-2.4 (m, 2H), 2.31 (t, J = 7.0 Hz, 2H), 2.41 (dd, J = 16.0 , J = 9.0 Hz, 1H), 2.95-3.05 (m, 1H), 3.67 (s, OCH 3
, 3H), 3.73-3.81 (m, 1M), 4.07-4.13
(m, 1H), 5.29-5.31 (m, 1H), 5.50-5.61 (m, 2H).
13 , 3H), 3.73-3.81 (m, 1M), 4.07-4.13 (m, 1H), 5.29-5.31 (m, 1H), 5.50-5.61 (m, 2H).
13
C-NMR (100 MHz, CDCl3 C-NMR (100 MHz, CDCl 3
): δ = 14.09, 22.69, 24.75, 25.27, 27.25, 30.62, 31.81,
33.99, 37.36, 39.71, 39.77, 44.42, 45.72, 51.55, 58.23, 73,20, 77.30, 128.42,
133.07, 135.53, 141.46, 174.27.
[α]): δ = 14.09, 22.69, 24.75, 25.27, 27.25, 30.62, 31.81, 33.99, 37.36, 39.71, 39.77, 44.42, 45.72, 51.55, 58.23, 73.20, 77.30, 128.42, 133.07, 135.53, 141.46, 174.27.
[α]
20|D 20 | D
+9,7 (c = 0,35, Methanol). +9.7 (c = 0.35, methanol).
Zu 17,5 mg (0,048 mmol) Isocarbacyclinmethylester werden bei Raumtemperatur
eine Lösung von 20 mg Kaliumhydroxid in 5 ml Methanol gegeben. Nach 50 Minuten
wird mit 0,1 M Salzsäure angesäuert und mit Methylenchlorid kontinuierlich
extrahiert. Anschließend trocknet man mit Magnesiumsulfat und engt im Vakuum
ein. Man erhält 15,9 mg (95%) als farbloses Öl, das aus Acetonitril kristalli
siert.
Fp.: 76-78°C.
A solution of 20 mg of potassium hydroxide in 5 ml of methanol is added to 17.5 mg (0.048 mmol) of isocarbacyclin methyl ester at room temperature. After 50 minutes it is acidified with 0.1 M hydrochloric acid and extracted continuously with methylene chloride. Then it is dried with magnesium sulfate and concentrated in vacuo. 15.9 mg (95%) are obtained as a colorless oil which crystallizes from acetonitrile.
Mp .: 76-78 ° C.
1H-NMR, 13C-NMR und chiroptische Daten: siehe Publikation. MS(CI): m/z(%) 368 (100) M⁺+NH3, 350 (70) M+, 333 (64), 315 (42). 1 H-NMR, 13 C-NMR and chiroptical data: see publication. MS (CI): m / z (%) 368 (100) M + NH 3 , 350 (70) M +, 333 (64), 315 (42).
Claims (1)
worin R1 Wasserstoff oder den Rest -CH2-OR3
R2 Hydroxy, Benzyloxy oder die Reste tert.-Butyloxycarbonylmethoxy,
X Sauerstoff oder die Reste Wasserstoff und OR3 (H, OR3) und
R3 Wasserstoff oder einen Tetrahydropyranylrest bedeuten,
das dadurch gekennzeichnet ist, daß man 3-Cyclopentyl-propin-Derivate der Formel II,
worin X und R1 die oben angegebenen Bedeutungen haben, mit NaJ in Gegenwart von Azobisisobutyronitril und mit Tributylzinnhydrid umsetzt, die Dimethyl- tert.-butylsilyl-Schutzgruppe abspaltet, in Gegenwart von DMAP acety liert und die erhaltenen Bicyclo[3.3.0]octanderivate der Formel III,
worin X und R1 die oben angegebenen Bedeutungen haben, mit Chlormagnesiumkup fer-Verbindungen der Formel IVa oder der Jodzinkkupferverbindung IVb
ClMgCu (R4)2 (IVa)
JZuCu(CN)(CH2)3COOCH3 (IVb),
worin R4 die Reste
bedeuten, bei tiefen Temperaturen umsetzt und gegebenenfalls anschließend die Schutzgruppe im Rest R2 abspaltet und den er haltenen Alkohol oxydiert.Process for the preparation of optically active bicyclo [3.3.0] octane derivatives of the formula I,
wherein R 1 is hydrogen or the radical -CH 2 -OR 3
R 2 is hydroxy, benzyloxy or the residues of tert-butyloxycarbonylmethoxy,
X is oxygen or the radicals hydrogen and OR 3 (H, OR 3 ) and
R 3 is hydrogen or a tetrahydropyranyl radical,
which is characterized in that 3-cyclopentyl-propyne derivatives of the formula II,
wherein X and R 1 have the meanings given above, with NaJ in the presence of azobisisobutyronitrile and with tributyltin hydride, the dimethyl tert-butylsilyl protective group is split off, acetylated in the presence of DMAP and the bicyclo [3.3.0] octane derivatives obtained Formula III,
wherein X and R 1 have the meanings given above, with chloromagnesium copper compounds of the formula IVa or the iodo zinc copper compound IVb
ClMgCu (R 4 ) 2 (IVa)
JZuCu (CN) (CH 2 ) 3 COOCH 3 (IVb),
wherein R 4 is the residues
mean, reacted at low temperatures and, if appropriate, then subsequently splits off the protective group in the radical R 2 and oxidizes the alcohol it contains.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3909325A DE3909325C2 (en) | 1989-03-17 | 1989-03-17 | New process for the production of optically active bicyclo [3.3.0] octane derivatives |
| PCT/DE1990/000219 WO1990011276A1 (en) | 1989-03-17 | 1990-03-19 | Novel process for producing optically active bicyclo [3.3.0] -octane derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3909325A DE3909325C2 (en) | 1989-03-17 | 1989-03-17 | New process for the production of optically active bicyclo [3.3.0] octane derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE3909325A1 DE3909325A1 (en) | 1990-09-20 |
| DE3909325C2 true DE3909325C2 (en) | 1998-08-27 |
Family
ID=6376894
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE3909325A Expired - Lifetime DE3909325C2 (en) | 1989-03-17 | 1989-03-17 | New process for the production of optically active bicyclo [3.3.0] octane derivatives |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE3909325C2 (en) |
| WO (1) | WO1990011276A1 (en) |
-
1989
- 1989-03-17 DE DE3909325A patent/DE3909325C2/en not_active Expired - Lifetime
-
1990
- 1990-03-19 WO PCT/DE1990/000219 patent/WO1990011276A1/en active Application Filing
Non-Patent Citations (2)
| Title |
|---|
| Gais, Hans-Joachim et. al. In: Liebigs Ann. Chem. (1986), S.1179-1212 * |
| Gais, Hans-Joachim et. al. In: Tetrahedron Letters, Vol.29, No.7, S.7819-784 (1988) * |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3909325A1 (en) | 1990-09-20 |
| WO1990011276A1 (en) | 1990-10-04 |
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