CN1093110C - 多烯醇衍生物及其制备方法 - Google Patents
多烯醇衍生物及其制备方法 Download PDFInfo
- Publication number
- CN1093110C CN1093110C CN98115404A CN98115404A CN1093110C CN 1093110 C CN1093110 C CN 1093110C CN 98115404 A CN98115404 A CN 98115404A CN 98115404 A CN98115404 A CN 98115404A CN 1093110 C CN1093110 C CN 1093110C
- Authority
- CN
- China
- Prior art keywords
- formula
- sulphones
- reaction
- compound
- iii
- 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 - Fee Related
Links
- -1 Polyene alcohol derivative Chemical class 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 20
- 125000001174 sulfone group Chemical group 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 4
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 4
- 150000004703 alkoxides Chemical class 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 7
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Natural products OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 7
- 239000011701 zinc Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229910052725 zinc Inorganic materials 0.000 description 6
- 229910000765 intermetallic Inorganic materials 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000011592 zinc chloride Substances 0.000 description 4
- 235000005074 zinc chloride Nutrition 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 235000019169 all-trans-retinol Nutrition 0.000 description 3
- 239000011717 all-trans-retinol Substances 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 3
- 125000001207 fluorophenyl group Chemical group 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 125000006303 iodophenyl group Chemical group 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 2
- WQKHERPPDYPMNX-UHFFFAOYSA-N 6-chloro-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=CC(Cl)=CC=C21 WQKHERPPDYPMNX-UHFFFAOYSA-N 0.000 description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 2
- FSNCEEGOMTYXKY-JTQLQIEISA-N Lycoperodine 1 Natural products N1C2=CC=CC=C2C2=C1CN[C@H](C(=O)O)C2 FSNCEEGOMTYXKY-JTQLQIEISA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000004791 alkyl magnesium halides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000004799 bromophenyl group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- ZFSLODLOARCGLH-UHFFFAOYSA-N isocyanuric acid Chemical compound OC1=NC(O)=NC(O)=N1 ZFSLODLOARCGLH-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 229950009390 symclosene Drugs 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 235000019155 vitamin A Nutrition 0.000 description 2
- 239000011719 vitamin A Substances 0.000 description 2
- 229940045997 vitamin a Drugs 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 2
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 description 2
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 1
- HYZQBNDRDQEWAN-LNTINUHCSA-N (z)-4-hydroxypent-3-en-2-one;manganese(3+) Chemical compound [Mn+3].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O HYZQBNDRDQEWAN-LNTINUHCSA-N 0.000 description 1
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 1
- PLAWCFOMHQCJBK-UHFFFAOYSA-N 1-(2,2-dimethylpropylperoxy)pentane Chemical compound CCCCCOOCC(C)(C)C PLAWCFOMHQCJBK-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- YMHOBZXQZVXHBM-UHFFFAOYSA-N 2,5-dimethoxy-4-bromophenethylamine Chemical compound COC1=CC(CCN)=C(OC)C=C1Br YMHOBZXQZVXHBM-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 description 1
- 239000005750 Copper hydroxide Substances 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 241000545067 Venus Species 0.000 description 1
- FMRLDPWIRHBCCC-UHFFFAOYSA-L Zinc carbonate Chemical compound [Zn+2].[O-]C([O-])=O FMRLDPWIRHBCCC-UHFFFAOYSA-L 0.000 description 1
- 239000005083 Zinc sulfide Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 1
- 229940116318 copper carbonate Drugs 0.000 description 1
- 150000001880 copper compounds Chemical class 0.000 description 1
- 229910001956 copper hydroxide Inorganic materials 0.000 description 1
- BWFPGXWASODCHM-UHFFFAOYSA-N copper monosulfide Chemical compound [Cu]=S BWFPGXWASODCHM-UHFFFAOYSA-N 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- YRNNKGFMTBWUGL-UHFFFAOYSA-L copper(ii) perchlorate Chemical compound [Cu+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O YRNNKGFMTBWUGL-UHFFFAOYSA-L 0.000 description 1
- GQDHEYWVLBJKBA-UHFFFAOYSA-H copper(ii) phosphate Chemical compound [Cu+2].[Cu+2].[Cu+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GQDHEYWVLBJKBA-UHFFFAOYSA-H 0.000 description 1
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 description 1
- PWGQHOJABIQOOS-UHFFFAOYSA-N copper;dioxido(dioxo)chromium Chemical compound [Cu+2].[O-][Cr]([O-])(=O)=O PWGQHOJABIQOOS-UHFFFAOYSA-N 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- QNZRVYCYEMYQMD-UHFFFAOYSA-N copper;pentane-2,4-dione Chemical compound [Cu].CC(=O)CC(C)=O QNZRVYCYEMYQMD-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 229960004643 cupric oxide Drugs 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- YSXPITOLXCZGFY-UHFFFAOYSA-N cyano thiocyanate zinc Chemical compound S(C#N)C#N.[Zn] YSXPITOLXCZGFY-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- HIGQPQRQIQDZMP-UHFFFAOYSA-N geranil acetate Natural products CC(C)=CCCC(C)=CCOC(C)=O HIGQPQRQIQDZMP-UHFFFAOYSA-N 0.000 description 1
- HIGQPQRQIQDZMP-DHZHZOJOSA-N geranyl acetate Chemical compound CC(C)=CCC\C(C)=C\COC(C)=O HIGQPQRQIQDZMP-DHZHZOJOSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 description 1
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- CNFDGXZLMLFIJV-UHFFFAOYSA-L manganese(II) chloride tetrahydrate Chemical compound O.O.O.O.[Cl-].[Cl-].[Mn+2] CNFDGXZLMLFIJV-UHFFFAOYSA-L 0.000 description 1
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 description 1
- XMWCXZJXESXBBY-UHFFFAOYSA-L manganese(ii) carbonate Chemical compound [Mn+2].[O-]C([O-])=O XMWCXZJXESXBBY-UHFFFAOYSA-L 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 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
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- LRXTYHSAJDENHV-UHFFFAOYSA-H zinc phosphate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O LRXTYHSAJDENHV-UHFFFAOYSA-H 0.000 description 1
- 229910000165 zinc phosphate Inorganic materials 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- NDKWCCLKSWNDBG-UHFFFAOYSA-N zinc;dioxido(dioxo)chromium Chemical compound [Zn+2].[O-][Cr]([O-])(=O)=O NDKWCCLKSWNDBG-UHFFFAOYSA-N 0.000 description 1
- RXBXBWBHKPGHIB-UHFFFAOYSA-L zinc;diperchlorate Chemical compound [Zn+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O RXBXBWBHKPGHIB-UHFFFAOYSA-L 0.000 description 1
- NHXVNEDMKGDNPR-UHFFFAOYSA-N zinc;pentane-2,4-dione Chemical compound [Zn+2].CC(=O)[CH-]C(C)=O.CC(=O)[CH-]C(C)=O NHXVNEDMKGDNPR-UHFFFAOYSA-N 0.000 description 1
- DRDVZXDWVBGGMH-UHFFFAOYSA-N zinc;sulfide Chemical compound [S-2].[Zn+2] DRDVZXDWVBGGMH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/02—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms
- C07C317/08—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/02—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms
- C07C317/10—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/02—Acyclic alcohols with carbon-to-carbon double bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/05—Alcohols containing rings other than six-membered aromatic rings
- C07C33/14—Alcohols containing rings other than six-membered aromatic rings containing six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
-
- 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)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了新的式[I]多烯醇衍生物及其制备方法，式中，R代表氢原子或羟基的保护基并且Y代表下式基团(A或B)，式中，R1、R2和R3可以相同或不同并且代表氢原子或具有1-3个碳原子的烷基。
Description
本发明涉及可用作药物中间体，例如，视黄醇(维他命A)中间体的新的多烯醇衍生物及其制备方法。
本发明提供了以下四个方面：
1.式P[I]的多烯醇衍生物，其中，R代表氢原子或羟基的保护基并且
Y代表下示基团：
其中，R1、R2和R3可以相同或不同并且代表氢原子或具有1-3个碳原子的烷基；
2.制备式[I]的多烯醇衍生物的方法，包括使式[II]的砜化合物与碱反应，
其中，R和Y与权利要求1中的定义相同，Ar代表可被取代的芳基；
3.如上文所定义的式[II]的砜化合物；和
4.制备如上文所定义的式[II]的砜化合物的方法，包括在碱性化合物存在下，使式[III]的化合物，Y-CH2-SO2Ar [III]其中，Ar和Y定义如上，与式[IV]的卤化物反应，
其中，R定义如上，X代表卤原子。
首先对涉及式[I]的多烯醇衍生物的本发明的第一个方面进行说明。
在式[I]中，对于羟基的保护基，见“有机合成中的保护基团”，Greene andWuts，第二版，(1992)，John Wiley & Sons，Inc.，其中公开的保护基在本发明中被引作参考。
羟基的保护基的实例包括：酰基，例如乙酰基、三甲基乙酰基、苯甲酰基或对硝基苯甲酰基，甲硅烷基，例如三甲基甲硅烷基、叔丁基二甲基甲硅烷基或叔丁基二苯基甲硅烷基，烷氧基甲基，例如四氢吡喃基、甲氧基甲基、甲氧基乙氧基甲基或1-乙氧基乙基，叔丁基，三苯甲游基，苄基，对甲氧苄基，三氯乙氧羰基，烯丙氧基羰基等等。
在式[I]中，R1、R2和R3可以相同或不同并且代表氢原子或具有1-3个碳原子的烷基，其实例包括甲基、乙基、正丙基和异丙基。
Y代表下式基团：
通过使如上所定义的式[II]的砜化合物与碱反应能得到本发明的式[I]的多烯醇衍生物。
在上述式[II]中，Ar代表可被取代的芳基，其实例包括苯基、萘基，并且苯基或萘基可被C1-C5的低级烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、新戊基、叔戊基)、C1-C5的低级烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、新戊氧基、叔戊氧基)、卤原子(例如氯、溴、碘、氟)、硝基等取代。
Ar的具体实例包括：苯基、萘基、邻甲苯基、间甲苯基、对甲苯基、邻甲氧苯基、间甲氧苯基、对甲氧苯基、邻氯苯基、间氯苯基、对氯苯基、邻溴苯基、间溴苯基、对溴苯基、邻碘苯基、间碘苯基、对碘苯基、邻氟苯基、间氟苯基、对氟苯基、邻硝基苯基、间硝基苯基、对硝基苯基。
在该方法中所用碱的实例包括碱金属氢化物、碱土金属氢化物、碱金属醇盐、碱土金属醇盐、碱金属氢氧化物、碱土金属氢氧化物和碱金属氨化物。
其具体的实例包括碱金属氢化物如氢化钠、氢化钾等，碱土金属氢化物如氢化钙，碱金属醇盐如甲醇钠、甲醇钾、叔丁醇钾等，碱金属氢氧化物如氢氧化钠等，碱土金属氢氧化物等等。
碱的量一般为大约2-20摩尔/1摩尔砜化合物[II]。
在上述反应中，通常使用溶剂。反应中所用溶剂及其用量未被具体限制并包括，例如，烃类溶剂如脂族烃(例如正己烷、环己烷、正戊烷)和芳香烃(例如甲苯和二甲苯)，醚溶剂如乙醚、四氢呋喃和苯甲醚，卤代烃溶剂如氯仿、二氯甲烷、二氯乙烷和一氯代苯，极性非质子传递溶剂如DMF、DMSO、N，N-二甲基乙酰胺、六甲基磷酰三胺等。
反应温度一般在大约-78℃至反应中所用溶剂的沸点的范围内。
完成反应后，必要时可用普通的后处理方法，例如，萃取、蒸馏和色谱法，分离和/或提纯式[I]的多烯醇衍生物。
按照如在“有机合成中的保护基团”Greene and Wuts，第2版，(1992)，JohnWiley & Sons，Inc.中所描述的常用方法，通过选择合适的条件能实现所得化合物的保护基的解封。同时通过适当地选择反应结束后的后处理条件也可以实现保护基的解封。
本发明的多烯醇衍生物[I]或砜化合物[II]可以任取E或Z几何异构体、旋光体和外消旋体或其混合物。
用下述方法能获得砜化合物[II]，该方法包括在碱性化合物存在下，使如上文所定义的式[III]化合物与如上文所定义的式[IV]卤化物反应。
在式[III]化合物中Ar的实例也包括在式[II]中描述的Ar的实例。
式[IV]卤化物中的R的实例包括上述式[II]砜化合物中的R的实例。
卤原子X的实例包括氯原子、溴原子、碘原子等。
在该方法中可使用任何能产生化合物[III]的阴离子的碱性化合物。在该反应使用的碱性化合物中，优选使用格利雅试剂如卤化烷基镁和烷基锂。
所述碱的用量一般为大约1-3摩尔/1摩尔化合物[III]。
碱性化合物包括烷基锂、格利雅试剂、碱金属氢氧化物、碱土金属氢氧化物、碱金属氢化物、碱土金属氢化物、碱金属醇盐和碱土金属醇盐。
碱性化合物的具体实例包括正丁基锂、仲丁基锂、叔丁基锂、溴化乙基镁、氯化乙基镁、氢氧化钠、氢氧化钾、氢化钠、氢化钾、甲醇钠、甲醇钾和叔丁醇钾。
该反应中优选使用格利雅试剂如卤化烷基镁和烷基锂。
碱性化合物的用量一般为1-3摩尔/1摩尔化合物[III]。
反应中常使用有机溶剂。有机溶剂的实例是醚溶剂如乙醚、四氢呋喃和苯甲醚，烃类溶剂如正己烷、环己烷、正戊烷、甲苯和二甲苯，卤代烃溶剂如氯仿、二氯甲烷、二氯乙烷、一氯代苯和邻二氯苯，和极性非质子传递溶剂如N，N-二甲基甲酰胺、二甲基亚砜、N，N-二甲基乙酰胺和六甲基磷酰三胺。
碱性化合物与化合物[III]一般在大约-78℃-50℃范围内接触。当使用烷基锂时，温度一般为大约-78℃-0℃，当使用其它试剂时，温度一般为大约-30℃-50℃。
在碱性化合物与化合物[III]接触后，可向所得反应混合物中加入锌化合物以增强反应性。锌化合物通常在-78℃-20℃，优选在-20℃-0℃的温度下与所得混合物接触。
锌化合物的实例包括卤化锌、氧化锌、硫化锌、氢氧化锌、羧酸锌、硝酸锌、硫酸锌、碳酸锌、磺酸锌、磷酸锌、硫氰酸锌、铬酸锌、高氯酸锌、烃氧基锌、氰化锌和乙酰丙酮锌。优选使用卤化锌，例如，氯化锌(ZnCl2)、溴化锌(ZnBr2)或碘化锌(ZnI2)。锌化合物的用量一般为0.1-2摩尔/1摩尔碱性化合物。
在该反应中，还可加入金属催化剂。金属催化剂的实例包括铜、锰、铁、镍、钴、银、铬和锌的金属化合物。
金属化合物的实例包括卤化物、氧化物、硫化物、氢氧化物、羧酸盐、硝酸盐、硫酸盐、碳酸盐、磺酸盐、磷酸盐、硫氰酸盐、铬酸盐、高氯酸盐、醇盐、氰化物、乙酰丙酮化物和所述金属的配合物，例如，具有磷配位体或二甲硫醚的配合物，如三芳基膦基配合物或卤化亚铜二甲硫醚配合物。
金属化合物的具体实例包括氯化亚铜、氯化铜、溴化亚铜、溴化铜、碘化亚铜、氧化亚铜、氧化铜、硫化铜、乙酸铜、硝酸铜、硫酸铜、碳酸铜、氢氧化铜、氰化铜、乙酰丙酮铜、磷酸铜、硫氰酸铜、铬酸铜、高氯酸铜、甲氧基铜、氯化锰、乙酸锰、碳酸锰、硝酸锰、硫酸锰、乙酰丙酮锰、氯化钴、氯化镍、氯化亚铁、氯化铁、铁的氧化物和氧化银。优选使用铜化合物。
金属化合物的用量一般为0.01-1摩尔/1摩尔化合物[III]，优选0.05-0.2摩尔/1摩尔化合物[III]。一般在-78℃-20℃，优选在-20℃-0℃的温度下，将金属化合物加入反应混合物。
然后，通常在-10℃-70℃的温度下，使卤化物[IV]与所得反应混合物反应。
反应结束后，通过普通的后处理法分离和/或提纯式[II]的砜化合物，必要时可用硅胶色谱法进一步提纯。
在本发明中，用已知的方法(Yukagaku，44(4)，316-21，1995，Yukagaku，39(2)，83-9，1990，Tetrahedron Letters，41(24)，5741-6，1986)能容易地合成式[III]的化合物和式[IV]的卤化物。
在该反应中可以使用式[IV]的卤化物，其羟基可被保护也可未被保护。使用如在“有机合成中的保护基团”Greene and Wuts，第2版，(1992)，John Wiley& Sons，Inc.中所描述的常用方法能引入保护基。
例如，在室温或更低温度下，在氯化锌存在下或在乙酸酐中回流，通过与乙酸酐反应能引入乙酰基。
本发明的多烯醇衍生物[I]可用作药物，例如，用作维他命A的中间体。
实施例
下述实施例进一步详细说明了本发明，但是不能认为其限制了本发明的范围。乙酸6-氯-3，7-二甲基辛-2，7-二烯-1-酯的制备方法
将40g(0.204mol)醋酸香叶酯溶解于己烷中，向该溶液中逐渐加入17.1g(0.071mol)三氯异氰脲酸，将混合物保持在-10-0℃。反应后，通过过滤从反应混合物中除去过量的三氯异氰脲酸和副产物异氰脲酸。用碳酸氢钠和水顺序洗涤滤液，用无水硫酸镁进行脱水，然后，通过蒸发溶剂得到粗产物。
所得粗产物用硅胶柱色谱法提纯，以85.5％的收率得到所需卤化物乙酸6-氯-3，7-二甲基辛-2，7-二烯-1-酯。
实施例1
将5.85g(20mmol)β-环香叶基-对-甲苯基砜[即1-甲基-4-(2，6，6-三甲基-环己-1-烯基甲磺酰基)苯]溶解在60ml的THF中，溶液冷却至-60℃或更低，然后在氮气气氛下通过注射管将12.5ml(20mmol)的正丁基锂缓慢滴加到该溶液中。滴加完毕后，使溶液处于室温并维持在0℃，然后在相同温度下搅拌3小时。
随后，将溶液冷却至-15℃，迅速加入2.05g(15mmol)氯化锌并搅拌2小时。然后加入0.4g(2mmol)溴化亚铜二甲硫醚配合物(Me2S·CuBr)并搅拌混合物1小时。
在-10℃-0℃向该混合物中滴加上文得到的3.46g(15mmol)乙酸6-氯-3，7-二甲基辛-2，7-二烯-1-酯，在相同温度下搅拌该混合物2小时，然后在60℃搅拌混合物6小时。用TLC检测原料的消失，用常规的方法进行后处理，得到粗产物。所得粗产物用硅胶柱色谱法提纯，以85％的收率得到浅黄油状的所需化合物[1-乙酰氧基-3，7-二甲基-9-(对-甲苯磺酰基)-9-(2，6，6-三甲基-环己-1-烯基)-2，6-壬二烯]。
1H-NMRδ(CDCl3)
0.85(3H，s)，1.08(3H，s)，1.20(3H，s)，-1.22-1.62(4H，m)，
1.68(3H，s)，1.97(2H，s，2.02(2H，s)； 2.06(3H，s)，2.43(3H，s)，
2.55-2.98(2H，m)，3.89(1H，t，J＝9Hz)，4.59(2H，d，J＝9Hz)，
5.12(1H，Br)，5.31(1H，t，J＝9Hz)，7.29(2H，d，J＝8Hz)，
7.75(2H，d，J＝8Hz)
13C-NMRδ(CDCl3)
15.4，16.3，18.9，20.9，21.4，22.8，26.0，28.1，29.0，34.4，
35.4，39.0，39.6，40.9，61.1，65.5，118.3，127.9，129.2，
130.1，130.8，137.3，138.7，141.6，143.8，170.9实施例2
将5.85g(20mmol)香叶基-对-甲苯基砜[即1-(3，7-二甲基辛-2，6-二烯-1-磺酰基)-4-甲基苯]溶解在60mlTHF中，溶液冷却至-60℃或更低，然后在氮气气氛下通过注射管将12.5ml(20mmol)的正丁基锂缓慢滴加到该溶液中。滴加完毕后，使溶液处于室温并维持在0℃，然后在相同温度下搅拌1小时。
随后，将溶液冷却至-15℃，迅速加入2.05g(15mmol)氯化锌并搅拌2小时。然后加入0.4g(2mmol)溴化亚铜二甲硫醚配合物(Me2S·CuBr)并搅拌混合物1小时。
在-10-0℃向该混合物中滴加上文得到的3.46g(15mmol)乙酸6-氯-3，7-二甲基辛-2，7-二烯-1-酯，在相同温度下搅拌该混合物2小时，然后在60℃搅拌混合物6小时。用TLC检测原料的消失，用常规的方法进行后处理，得到粗产物。所得粗产物用硅胶色谱法提纯，以71％的收率得到浅黄油状的所需化合物[1-乙酰氧基-3，7，11，15-四甲基-9-(对-甲苯磺酰基)十六碳-2，6，10，14-四烯]。
1H-NMRδ(CDCl3)
1.14(3H，s)，1.52(3H，s)，1.56(3H，s)，1.62(3H，s)，1.64(3H，s)，
1.95(4H，s)，2.03(4H，5)，2.43(3H，s)，2.17-2.89(2H，m)，
3.87(1H，d t，J＝4，10Hz)，4.56(2H，d，J＝9Hz)，4.89(1H，d，
J＝9Hz)，5.02(1H，s)，5.12(1H，d，J＝9Hz)，5.30(1H，d，J＝9Hz)，
7.29(2H，d，J＝8Hz)，7.75(2H，d，J＝8Hz)
13C-NMRδ(CDCl3)
15.8，16.1，17.5，20.9，21.5，22.8，25.5，26.0，37.4，
39.5，39.6，61.1，63.3，117.3，118.3，123.4，127.9，
129.5，130.3，131.7，134.8，141.5，144.1，144.8，170.9
实施例3
将16.54g(34mmol)在实施例1中得到的砜化合物溶解在100mlDMF中并加热该溶液至80℃。向其中滴加32.8ml(170mmol)28％的甲醇钠，在相同温度下搅拌该溶液8小时。用TLC检测原料的消失，用常规的方法进行后处理，以得到粗产物。所得粗产物用硅胶色谱法提纯，以76％的收率得到浅黄油状的11，12-二氢视黄醇[即1-羟基-3，7-二甲基-9-(2，6，6-三甲基-环己烯基)壬-2，7，9-三烯]。
1H-NMRδ(CDCl3)
1.02(6H，s)，1.41-1.48(2H，m)，1.52-1.59(2H，m)，1.60(3H，s)，
1.75(3H，s)，2.03(2H，t，J＝9Hz)，2.11(2H，t，J＝9Hz)，
2.21-2.29(2H，m)，4.12(2H，d，J＝9Hz)，5.31-5.45(4H，m)，
5.97(2H，s)
13C-NMRδ(CDCl3)
12.3，16.2，19.2，21.6，22.8，26.4，32.7，34.1，39.5，
39.6，58.9，123.4，124.2，128.2，129.6，134.0，137.6，139.0
实施例4
将16.54g(34mmol)在实施例1中得到的化合物溶解在100ml环己烷中并加热该溶液至40℃。向其中滴加11.92g(170mmol)甲醇钾，在相同温度下搅拌该溶液6小时。用TLC检测原料的消失，用常规的方法进行后处理，以得到粗产物。所得粗产物用硅胶色谱法提纯，以90％的收率得到浅黄油状的11，12-二氢视黄醇[1-羟基-3，7-二甲基-9-(2，6，6-三甲基-环己烯基)壬-2，7，9-三烯]。
Claims (8)
1.式[I]的多烯醇衍生物，
其中，R代表氢原子或羟基的保护基并且
Y代表如下基团：
其中，R1、R2和R3可以相同或不同并且代表氢原子或具有1-3个碳原子的烷基。
2.制备如权利要求1中定义的式[I]的多烯醇衍生物的方法，包括使式[II]的砜化合物与碱反应，
其中，R和Y与权利要求1中的定义相同，Ar代表可被取代的芳基。
3.权利要求2的方法，其中碱选自碱金属氢氧化物、碱土金属氢氧化物、碱金属氢化物、碱土金属氢化物、碱金属醇盐和碱土金属醇盐。
4.如权利要求2中所定义的式[II]的砜化合物。
5.制备如权利要求2中所定义的式[II]的砜化合物的方法，包括在碱性化合物存在下，使式[III]的化合物，Y-CH2-SO2Ar [III]其中，Ar和Y与权利要求2中的定义相同，与式[IV]的卤化物反应，
其中，R与权利要求2中的定义相同，X代表卤原子。
6.权利要求5的方法，其中式[III]的化合物与式[IV]的卤化物之间的反应是在金属催化剂的共存下进行。
7.权利要求6的方法，其中金属催化剂是铜催化剂。
8.权利要求2的方法，其中使用了通过权利要求5的方法制得的式[II]的砜化合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP140006/97 | 1997-05-29 | ||
| JP14000697 | 1997-05-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1201775A CN1201775A (zh) | 1998-12-16 |
| CN1093110C true CN1093110C (zh) | 2002-10-23 |
Family
ID=15258748
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98115404A Expired - Fee Related CN1093110C (zh) | 1997-05-29 | 1998-05-29 | 多烯醇衍生物及其制备方法 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US6087541A (zh) |
| EP (1) | EP0881204B1 (zh) |
| CN (1) | CN1093110C (zh) |
| DE (1) | DE69802465T2 (zh) |
| RU (1) | RU2196133C2 (zh) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1595056A (en) * | 1976-10-12 | 1981-08-05 | Wellcome Found | Pharmaceutical combination |
| WO1997030038A1 (fr) * | 1996-02-15 | 1997-08-21 | Mitsubishi Chemical Corporation | Derives du diarylsultame |
| US5902738A (en) * | 1996-04-18 | 1999-05-11 | Roche Vitamins Inc. | Enzymatic acylation |
-
1998
- 1998-05-28 DE DE69802465T patent/DE69802465T2/de not_active Expired - Fee Related
- 1998-05-28 EP EP98109798A patent/EP0881204B1/en not_active Expired - Lifetime
- 1998-05-29 RU RU98110786/04A patent/RU2196133C2/ru not_active IP Right Cessation
- 1998-05-29 CN CN98115404A patent/CN1093110C/zh not_active Expired - Fee Related
- 1998-05-29 US US09/086,542 patent/US6087541A/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| CHEMISTRY LETTERS P1009-1012 1977.1.1 T.Kato,et al:"Cyclisation of polyenes XXVII,Synthesis of oxocrinol,d1-caul * |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2196133C2 (ru) | 2003-01-10 |
| EP0881204A1 (en) | 1998-12-02 |
| US6087541A (en) | 2000-07-11 |
| EP0881204B1 (en) | 2001-11-14 |
| CN1201775A (zh) | 1998-12-16 |
| DE69802465T2 (de) | 2002-06-27 |
| DE69802465D1 (de) | 2001-12-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Vedejs et al. | An internally activated tin hydride with enhanced reducing ability | |
| EP0187259B2 (en) | Process for producing vitamin A or its carboxylic acid esters, and intermediate compounds useful for the process | |
| CN1163452C (zh) | 硝基联苯的制备方法 | |
| JP2016504303A5 (zh) | ||
| KR100880787B1 (ko) | 3,3',5,5',6,6'-헥사알킬-2,2'-비페놀,3,3',4,4',5,5'-헥사알킬-2,2'-비페놀 및3,3',4,4',5,5',6,6'-옥타알킬-2,2'-비페놀의 제조 방법 | |
| US6326519B1 (en) | Diallylic sulfides and processes for preparing the same | |
| CN1093110C (zh) | 多烯醇衍生物及其制备方法 | |
| EP1414833B1 (de) | Neue übergangsmetall-komplexe und deren einsatz in übergangsmetall-katalysierten reaktionen | |
| Oshiki et al. | The reactions of optically pure menthyloxymethylphenylphosphine-borane with organolithium reagents. | |
| CN111848675A (zh) | 四氢喹啉骨架手性膦-氮配体及其制备方法和应用 | |
| Okuma et al. | One-pot synthesis of enantiomerically pure (methylenecyclopropyl) carbinol: a key intermediate to the synthesis of the causative agent of Jamaican vomiting sickness | |
| CN1286247A (zh) | 制备番茄红素及其中间体的方法 | |
| JPH1143454A (ja) | ポリエンアルコール誘導体、スルホン誘導体およびそれらの製造法 | |
| Clayden et al. | Additions of lithiated β-hydroxy alkyldiphenylphosphine oxides to aldehydes, and palladium (II)-catalysed allylic transpositions of bis-acetoxy alkyldiphenylphosphine oxides: synthesis of O-protected (E, E)-and (E, Z) hepta-2, 4-dien-1-ol and of alkyldiphenylphosphine oxides bearing remotely related chiral centres | |
| CN1309120A (zh) | 维生素a醛的制备方法及其中间体 | |
| WO2006051595A1 (ja) | 大環状ケトン類の製造方法およびその中間体 | |
| CN114478211B (zh) | 一种依他佐辛中间体的制备方法 | |
| CN1356317A (zh) | 生产视黄醇的方法和用于生产视黄醇的中间体化合物 | |
| JP5134883B2 (ja) | フッ素置換基を持つ不斉触媒と光学活性化合物の製造方法 | |
| Van der Vecht et al. | The chemistry of small ring compounds. Part 32: Synthesis of some 1‐arylcyclopropanols and 1‐arylcyclopropyl chlorides | |
| JPH10101614A (ja) | α，α−ジフルオロ−β−ヒドロキシエステルの製造方法 | |
| EP1085008A1 (en) | Process for the preparation of vitamin a, intermediates, and process for the preparation of the intermediates | |
| Mortlock et al. | Aspects of the chemistry of 4-tributylstannyl-, 4-trimethylsilyl-and 2-phenylsulfinylallylstannanes | |
| US20040034257A1 (en) | Novel sulfone derivatives and process for producing these | |
| CN1308044A (zh) | 二卤代化合物和制备维生素a衍生物的方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |