CN1197837C - 多烯二醛单缩醛的制备方法 - Google Patents
多烯二醛单缩醛的制备方法 Download PDFInfo
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- CN1197837C CN1197837C CNB031002145A CN03100214A CN1197837C CN 1197837 C CN1197837 C CN 1197837C CN B031002145 A CNB031002145 A CN B031002145A CN 03100214 A CN03100214 A CN 03100214A CN 1197837 C CN1197837 C CN 1197837C
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- 238000000034 method Methods 0.000 title claims description 28
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 title abstract description 8
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 title description 5
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- -1 sodium aluminum hydride compound Chemical class 0.000 claims description 22
- 239000001301 oxygen Substances 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 230000002829 reductive effect Effects 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 230000003647 oxidation Effects 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 5
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 claims description 5
- 125000005600 alkyl phosphonate group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims description 4
- 238000007171 acid catalysis Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 229910001882 dioxygen Inorganic materials 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 125000004036 acetal group Chemical group 0.000 claims 2
- 125000003118 aryl group Chemical group 0.000 claims 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 abstract 2
- 238000007239 Wittig reaction Methods 0.000 abstract 2
- 239000000543 intermediate Substances 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- 239000002585 base Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229910052783 alkali metal Inorganic materials 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 239000012266 salt solution Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 150000001340 alkali metals Chemical class 0.000 description 6
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- PANKHBYNKQNAHN-MQQNZMFNSA-N crocetin Chemical compound OC(=O)C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)C(O)=O PANKHBYNKQNAHN-MQQNZMFNSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 229960003280 cupric chloride Drugs 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229950004497 transcrocetin Drugs 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 150000004678 hydrides Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910001388 sodium aluminate Inorganic materials 0.000 description 4
- UIICPZFWHBJNIG-UHFFFAOYSA-N sodium;2-methoxyethanolate Chemical compound [Na+].COCC[O-] UIICPZFWHBJNIG-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 150000004714 phosphonium salts Chemical class 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- ANVAOWXLWRTKGA-XHGAXZNDSA-N all-trans-alpha-carotene Chemical compound CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1C(C)=CCCC1(C)C ANVAOWXLWRTKGA-XHGAXZNDSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000004176 ammonification Methods 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 235000021466 carotenoid Nutrition 0.000 description 2
- 150000001747 carotenoids Chemical class 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- REZQBEBOWJAQKS-UHFFFAOYSA-N triacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO REZQBEBOWJAQKS-UHFFFAOYSA-N 0.000 description 2
- DMASLKHVQRHNES-UPOGUZCLSA-N (3R)-beta,beta-caroten-3-ol Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C DMASLKHVQRHNES-UPOGUZCLSA-N 0.000 description 1
- VYIRVAXUEZSDNC-TXDLOWMYSA-N (3R,3'S,5'R)-3,3'-dihydroxy-beta-kappa-caroten-6'-one Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC(=O)[C@]1(C)C[C@@H](O)CC1(C)C VYIRVAXUEZSDNC-TXDLOWMYSA-N 0.000 description 1
- RBACIKXCRWGCBB-UHFFFAOYSA-N 1,2-Epoxybutane Chemical compound CCC1CO1 RBACIKXCRWGCBB-UHFFFAOYSA-N 0.000 description 1
- OQCFWECOQNPQCG-UHFFFAOYSA-N 1,3,4,8-tetrahydropyrimido[4,5-c]oxazin-7-one Chemical compound C1CONC2=C1C=NC(=O)N2 OQCFWECOQNPQCG-UHFFFAOYSA-N 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- USBJWIKCHJDWPF-UHFFFAOYSA-N 2-methylbut-2-enedial Chemical compound O=CC(C)=CC=O USBJWIKCHJDWPF-UHFFFAOYSA-N 0.000 description 1
- VYIRVAXUEZSDNC-LOFNIBRQSA-N Capsanthyn Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC(=O)C2(C)CC(O)CC2(C)C VYIRVAXUEZSDNC-LOFNIBRQSA-N 0.000 description 1
- 241001448862 Croton Species 0.000 description 1
- ITZNDVRDABSNRE-VUWSZMCHSA-N Cryptocapsin Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C(=O)[C@]1(C)C[C@@H](O)CC1(C)C ITZNDVRDABSNRE-VUWSZMCHSA-N 0.000 description 1
- ITZNDVRDABSNRE-WZLJTJAWSA-N Cryptocapsin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC(=O)C2(C)CC(O)CC2(C)C ITZNDVRDABSNRE-WZLJTJAWSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UVNZNIGDKACWAA-UHFFFAOYSA-N [Ru].C1CC=CCCC=C1 Chemical compound [Ru].C1CC=CCCC=C1 UVNZNIGDKACWAA-UHFFFAOYSA-N 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- NBZANZVJRKXVBH-ITUXNECMSA-N all-trans-alpha-cryptoxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CCCC2(C)C)C NBZANZVJRKXVBH-ITUXNECMSA-N 0.000 description 1
- 239000011795 alpha-carotene Substances 0.000 description 1
- 235000003903 alpha-carotene Nutrition 0.000 description 1
- ANVAOWXLWRTKGA-HLLMEWEMSA-N alpha-carotene Natural products C(=C\C=C\C=C(/C=C/C=C(\C=C\C=1C(C)(C)CCCC=1C)/C)\C)(\C=C\C=C(/C=C/[C@H]1C(C)=CCCC1(C)C)\C)/C ANVAOWXLWRTKGA-HLLMEWEMSA-N 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
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 235000002360 beta-cryptoxanthin Nutrition 0.000 description 1
- 239000011774 beta-cryptoxanthin Substances 0.000 description 1
- DMASLKHVQRHNES-ITUXNECMSA-N beta-cryptoxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)CCCC2(C)C DMASLKHVQRHNES-ITUXNECMSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/20—Free hydroxyl or mercaptan
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom
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- C07—ORGANIC CHEMISTRY
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- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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Abstract
描述了一种制备式I化合物的方法,该方法要求通过维悌希或维悌希-霍恩反应将式II化合物转化为式IV化合物,合适的话,通过缩醛官能团水解和维悌希或维悌希-霍恩反应将式IV化合物适当转化为式VI化合物并以两个步骤将式IV或VI化合物转化为式I化合物。基团R1、R2和R6以及k具有说明书指出的意义。同时还描述了新型中间体。
Description
本发明涉及一种制备C15或C20多烯二醛单缩醛的方法。
对于通过C15二醛结构单元与适当官能化的C15或C10结构单元或C20二醛结构单元与适当官能化的不同C10结构单元的连续反应选择合成具有不对称结构的各种C40类胡萝卜素来说,这种一端受到保护的多烯结构单元具有重大意义。具有不对称结构的C40类胡萝卜素包括例如辣椒红和克雷辣椒素(cryptocapsin)、α-胡萝卜素或β-隐黄质。
DE-A2851051描述通过2,6-二甲基辛-2,4,6-三烯-1,8-二醛与适当的C5结构单元在特定反应条件下的维悌希或维悌希-霍恩烯化制备11-(5,5-二甲基-1,3-二噁烷-2-基)-2,4,6,8,10-十二碳五烯醛的方法。但是,该方法的缺点在于所用的不对称C10二醛不是工业规模上常用的合成子。
《材料合成》(Synth.Met.)42,第1557页(1991)描述了通过藏花酸二醛二缩新戊二醇部分水解制备藏花酸二醛单缩新戊二醇。该单缩醛通过色谱法提纯。部分缩醛裂解的选择性一般是不充分的,这一点使所述方法看来不符合工业方法要求。
J.Chem.Soc.,Chem.Commun.1977,第467页和J.Chem.Soc.Perkin Trans 1(1988)第1383页描述通过醛与乙二醇的缩醛化制备11-(1,3-二氧戊环-2-基)-2,6-二甲基-2,4,6,8,10-十二碳五烯酸甲酯。
本发明的目的是提供一种制备C15和C20二醛单缩醛的方法,该方法可以以工业规模实施并且在保护基团方面具有灵活性。
我们发现该目的可以通过一种制备式I化合物的方法达到
其中
a)使式II化合物
通过与式III试剂反应
转化为式IV化合物,
b)合适的话,将式IV化合物通过缩醛官能团水解和与式V试剂反应
转化为式VI化合物
c)将式IV或VI化合物还原为式VII化合物
d)将式VII化合物氧化为式I化合物,
其中R1和R2彼此独立地为C1-C8烷基,或与和其相连接的氧原子及位于
它们之间的碳原子一起为
其中R3、R4和R5彼此独立地为氢或C1-C4烷基,
R6为C1-C8烷基,
为三芳基鏻基或膦酸二烷基酯基,和
k为0或1。
在开链缩醛的情况下,对于R1和R2可以提到的烷基为直链或支链C1-C8烷基链,例如甲基、乙基、正丙基、1-甲基乙基、正丁基、1-甲基丙基、2-甲基丙基、1,1-二甲基乙基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、2,2-二甲基丙基、1-乙基丙基、正己基、1,1-二甲基丙基、1,2-二甲基丙基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,1-二甲基丁基,1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-乙基丁基、2-乙基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、正庚基和正辛基。
对于R1和R2优选的烷基为甲基、乙基、正丙基和1-甲基乙基,特别优选甲基和乙基。
对于R3-R5可以提到的烷基为直链或支链C1-C4烷基链,例如甲基、乙基、正丙基、1-甲基乙基、正丁基、1-甲基丙基、2-甲基丙基和1,1-二甲基乙基。对于R3-R5优选的基团为氢和甲基。
式II化合物是公知的,可例如通过对甲苯磺酸催化2,7-二甲基辛-2,4,6-三烯-1,8-二醛的缩醛化获得,比较Helv.Chim.Acta 1981,64(7),第2469页。早期的专利申请DE101 12 067.2描述了一种优选的制备式II化合物的方法。在这种情况下,3-甲基-2-丁烯-1,4-二醛单缩醛与上述式III试剂反应,将所得缩醛酯还原为醇,将醇氧化为式II化合物。
优选使用式IIa化合物,
其中R3和R4相同且为氢和甲基。
在本发明方法的步骤a)中,式II化合物与式III试剂进行维悌希或维悌希-霍恩反应。
式III中的(P)可以是三芳基鏻基P(R8)3 +,其中R8是在膦和鏻盐中出现的普通基团,例如苯基、甲苯基、萘基,其中每个基团适当的话可被取代。R8优选为苯基。三芳基鏻基的正电荷由无机或有机酸,优选强无机或有机酸的等价阴离子X-抵消。
术语“强酸”包含氢卤酸(特别是盐酸和氢溴酸)、硫酸、磷酸、磺酸和其它具有相当程度解离作用的无机或有机酸。在本文中强有机酸还意味着C1-C6链烷酸,例如甲酸、乙酸、丙酸、丁酸和己酸。
盐酸、氢溴酸、硫酸、磷酸、甲酸、乙酸和/或磺酸的阴离子是特别优选的。Cl-、Br-和含有1-4个碳原子的链烷磺酸、苯磺酸、对甲苯磺酸或三氟甲烷磺酸的阴离子为非常特别优选。
作为选择,(P)为膦酸二烷基酯基PO(OR7)2,其中R7为C1-C8烷基。
在本发明方法的优选实施方案中,在步骤a)中使用式IIIa试剂
其中R6具有已经指出的意义,R7为C1-C3烷基。
式II化合物与式III试剂的反应在典型的维悌希或维悌希-霍恩反应条件下进行,参见例如Carotenoids,第二卷,“合成”,第79及以下各页,Birkhuser Verlag,1996及其中引用的文献。
II与其中(P)为三芳基鏻基的式III化合物的缩合可在例如惰性有机溶剂中进行,例如在开链或环醚如二乙醚、二异丙基醚、甲基叔丁基醚、1,4-二噁烷或四氢呋喃中,在卤代烃如二氯甲烷、氯仿中,在芳族烃如甲苯、二甲苯或苯中,或在极性溶剂如二甲基甲酰胺、二甲基亚砜或乙腈中。优选的溶剂为甲苯、四氢呋喃和二甲基亚砜或它们的混合物。
维悌希缩合常用的所有碱都可以用作碱,例如碱金属氢氧化物如氢氧化钠、氢氧化钾或氢氧化锂;碱金属的氢化物如氢化钠或氢化钾;或碱金属醇盐如甲醇钠或乙醇钠。合适的碱还有有机锂化合物,例如正丁基锂、叔丁基锂、苯基锂或碱金属氨化物,例如氨化锂、氨化钾或氨化钠,二异丙基氨化锂,此外还有碱金属的六甲基二硅氮化物。
如果X-是卤化物阴离子,使用环氧烷(oxirane)作为潜碱也可能是有利的(见Chem.Ber.1974,107,第2050页)。
该维悌希反应优选使用的碱为碱金属醇盐在相应醇或环氧烷(特别是1,2-环氧丁烷)中的溶液,没有其它溶剂或与上述溶剂中的一种或低级链烷醇混合。
碱的使用量一般为0.8-5mol/1mol所用鏻盐III,优选1-3mol/1mol所用鏻盐III。
维悌希-霍恩反应的典型条件同样用于II和其中(P)为膦酸二烷基酯的式III化合物反应。这种情况下,同样优选使用上述惰性溶剂中的一种,并且优选使用的碱为碱金属醇盐在相应链烷醇中的溶液。但是,在维悌希-霍恩反应条件下也可以使用除环氧烷以外上述用于维悌希反应的其它碱。
在本发明方法中步骤b)是可选的。在步骤b)中,C15结构单元IV转化为延伸了5个碳原子的式VI C20结构单元。为此目的,式IV化合物中的缩醛官能团首先水解为醛官能团。对此原则上适合的条件为熟练人员熟知的优选酸催化缩醛裂解的条件,例如使用稀无机酸如硫酸。已经证实特别适合用柠檬酸催化缩醛官能团水解。基于式IV化合物,柠檬酸有利地以5-50mol%,优选20-30mol%使用。水解优选在水介质中,特别是在水和水混溶性有机溶剂如乙醇等C1-C4链烷醇的混合物中,在0℃-溶剂沸点的合适温度下,优选25-55℃下进行。
然后使所得醛酯与式V试剂反应
其中R1、R2和(P)具有已经指出的意义。反应在典型的维悌希或维悌希-霍恩反应条件下进行,有关参考已在上述内容介绍。
式V化合物本身是公知的。它们可以例如由乙酸β-甲酰巴豆酯获得。它们的制备已有描述,例如Carotenoids,第2卷,“合成”,第115及以下各页,Birkhuser Verlag,1996。
优选在步骤b)中使用式Va试剂:
其中R1、R2、R8和X-具有已经指出的意义。
在本发明方法的步骤c)和d)中,式IV或VI化合物中的酯官能团以两步转化为醛官能团。
已经证实该两步转化比酯直接转化为醛更有利。在步骤c)中,酯官能团首先还原为醇。原则上该步骤可以使用本领域熟练人员公知的用于将酯还原为醇的所有试剂,优选氢化物试剂,例如碱金属的硼氢化物或碱金属的铝氢化物。
在本方法步骤c)的一个优选实施方案中,酯官能团使用氢化铝钠化合物还原,特别优选二氢化二(2-甲氧基乙氧基)铝酸钠。市售二氢化二(2-甲氧基乙氧基)铝酸钠(“Vitride”)甲苯浓溶液特别有利。该试剂不自燃,对氧不敏感(GIT Fachz.Lab.9/96,914),而且作为液体在工业规模上处理比固体氢化物配合物如氢化铝锂容易得多。
反应优选以这样的方式进行:将式IV或VI酯引入对氢化物试剂呈惰性的溶剂中,例如芳烃如甲苯、开链醚或环醚、乙二醇醚或这些溶剂的混合物,并在-20℃至30℃、优选-10℃至10℃、特别优选-5℃至0℃下计量加入还原剂。
每当量酯一般使用至少两当量氢化物,即至少0.5mol氢化铝锂/1mol酯或1.0mol Vitride/1mol酯。但是,为了达到完全转化,使用过量一定程度的还原剂是有利的。过量范围为10-50mol%,优选20-30mol%。
在本发明方法的一个优选实施方案中,式IV或VI酯用Vitride的甲苯溶液还原为式VII醇。水处理生成基本定量产率的粗产物,该粗产物可以不经提纯直接在下一步骤d)中使用。
适合在本发明方法步骤d)中将式VII化合物氧化为式I化合物的方法为本领域熟练人员熟知的用于将多烯醇转化为多烯醛的氧化方法,这些方法在例如DE-A-3705785,DE-A-4440286,DE-A-4440287和EP-A-0718283中已有描述。然而,催化方法应从该方法的经济、生态和技术角度优选。可用于此目的的催化剂尤其为钌化合物,例如过钌酸四丙基铵,氯化三(三苯基膦)钌(II)或氯化1,5-环辛二烯钌(II),在至少化学计量的4-甲基吗啉N-氧化物作为助氧化剂存在下以2-4mol%的量使用(参见J.Chem.Soc.Chem,Commun.1987,第1625页)。
但是,式VII化合物优选在N-氧基自由基和铜(I)化合物存在下用氧气氧化。N-氧基自由基一般由其中相对于氮原子的α碳原子上的取代基都不同于氢的仲胺衍生而来。适合的N-氧基自由基实例有2,2,6,6-四甲基哌啶-1-氧基和4-羟基-2,2,6,6-四甲基哌啶-1-氧基。氯化铜(I)优选作为铜(I)化合物。此外,VII催化氧化为I优选在二甲基甲酰胺作为溶剂下使用含有2,2,6,6-四甲基哌啶-1-氧基/氯化铜(I)/二甲基甲酰胺/氧气的混合物或含有4-羟基-2,2,6,6-四甲基哌啶-1-氧基/氯化铜(I)/二甲基甲酰胺/氧气的混合物进行。氧化的其它细节可见于DE-A-3705785和EP-A-0718283。
此外,本发明涉及如下式的化合物
其中R1、R2、R6和k具有已经指出的意义,并且R1和R2与和其相连的氧
原子及位于它们之间的碳原子一起为
其中如果k为0且R6为甲基,R5不是氢。
优选的化合物具有下式
其中R6是C1-C4烷基,R3和R4相同且为氢或甲基。
本发明还涉及式VII化合物
其中R1、R2和k具有已经指出的意义。
优选的化合物具有下式
其中R3和R4相同且为氢或甲基。
本发明另外涉及式I化合物
其中R1、R2和k具有已经指出的意义,并且R1和R2与和其相连的氧原子及位于它们之间的碳原子一起为
R3和R4不都是甲基。
本发明将通过下列实施例详细说明。
实施例1:11-(5,5-二甲基-1,3-二噁烷-2-基)-2,6-二甲基-2,4,6,8,10-十二碳五烯醛
a)11-(5,5-二甲基-1,3-二噁烷-2-基)-2,6-二甲基-2,4,6,8,10-十二碳五烯酸乙酯
将62.6g(0.25mol)2,7-二甲基-2,4,6-辛三烯-1,8-二醛单缩新戊二醇和79.3g(0.30mol)4-(二乙基膦酰基)-2-甲基-2-丁烯酸乙酯引入625ml的二氯甲烷中。在0℃下,在60分钟内注入112.3g 20%浓度的乙醇钠(0.33mol)乙醇溶液。所得混合物在0℃下搅拌1小时,然后在室温下搅拌24小时。之后,将100ml 10%浓度的乙酸水溶液和250ml半浓缩盐水加入混合物。分离有机相,用250ml半浓缩盐水和水各洗涤一次,在硫酸钠上干燥并在真空下于60℃浓缩。
产量:101.4g红棕色粘稠油。
为了表征,通过加热将粗产物溶于600ml异丁醇和5ml三乙胺的混合物中。冷却到0℃后,在0℃下搅拌2小时,过滤出已经形成的晶体。滤饼用冷的异丁醇洗涤并在氮气流下干燥。晶体的产率:51.5g(理论值的57.2%)。熔点为118.5-119℃。E1 1(CHCl3):2055(370nm),1818(390nm)。
滤液在真空下于50℃浓缩。得到52.8g红棕色油。
b)11-(5,5-二甲基-1,3-二噁烷-2-基)-2,6-二甲基-2,4,6,8,10-十二碳五烯醇
将27.05g(75mmol)步骤a)的晶体产物溶于300ml的THF。0℃下,在1小时内注入23.8g二氢化二(2-甲氧基乙氧基)铝酸钠在甲苯中的70%浓度溶液和300ml甲苯。在0℃用300ml己烷稀释该反应混合物。在0-5℃下,注入300ml半浓缩的盐水。分离水相并萃取两次,每次萃取使用300ml甲苯/正己烷(体积比1∶1)混合物。合并有机相用300ml半浓缩盐水洗涤一次,在硫酸钠上干燥并在旋转蒸发器中浓缩。残余物(28.8g)通过硅胶上的快速色谱法提纯(洗脱剂:环己烷/乙酸乙酯10∶1)。获得14.5g(理论值的61.4%)标题化合物。为了表征,将试样从二异丙醚中结晶。得到熔点为136-137℃的黄色晶体。E1 1(CHCl3):1096(333nm),2668(350nm),2495(339nm)。
c)11-(5,5-二甲基-1,3-二噁烷-2-基)-2,6-二甲基-2,4,6,8,10-十二碳五烯醛
将3.17g步骤b)的产物溶于12.5ml二甲基甲酰胺中。加入79.7mg(0.5mmol)2,2,6,6-四甲基-哌啶-1氧基和51.03mg(0.5mmol)氯化铜(I)。然后在20-25℃下通入氧气3小时。再加入同样量的两种催化剂,并在20-25℃下再通入氧气1小时。该反应混合物与各50ml的半浓缩盐水和乙酸乙酯混合。分离水相并用乙酸乙酯萃取三次,每次使用50ml乙酸乙酯。合并有机相用50ml半浓缩盐水洗涤,在硫酸钠上干燥并在旋转蒸发器内浓缩。残余物(3.52g)通过硅胶上的快速色谱法提纯(洗脱剂:环己烷/乙酸乙酯8∶1)。获得2.33g(理论值的73.7%)标题化合物。为了表征,将试样从二异丙醚中再结晶。熔点为139.5-140℃。E1 1(CHCl3):2052(385nm),1969(401nm)。
实施例2:15-(5,5-二甲基-1,3-二噁烷-2-基)-2,6,11-三甲基-2,4,6,8,10,12,14-十六碳七烯醛(藏花酸二醛单缩新戊二醇)
a)11-(5,5-二甲基-1,3-二噁烷-2-基)-2,6-二甲基-2,4,6,8,10-十二碳五烯酸乙酯
按照实施例1步骤a)所述制备化合物。蒸发后的残余物不经进一步提纯直接用于随后的步骤b)。
b)2,6,11-三甲基-12-氧代-2,4,6,8,10-十二碳五烯酸乙酯
将52.8g步骤a)的蒸发残余物溶于440ml乙醇中。加入6.16g(29.3mmol)柠檬酸一水合物在100ml水中的溶液,并在50℃下加热该混合物1小时。然后冷却到0℃并在0℃下搅拌24小时。吸滤出晶体,用乙醇/水混合物(体积比为8∶2)洗涤两次,每次使用50ml,然后用50ml热水洗涤一次,之后在50℃真空烘箱中干燥至恒重。产量10.1g,熔点120-121℃。
c)15-(5,5-二甲基-1,3-二噁烷-2-基)-2,6,11-三甲基-2,4,6,8,10,12,14-十六
碳七烯酸乙酯
将13.7g(50mmol)步骤b)的产物溶于125ml二氯甲烷中。加入25.7g(55mmol)氯化3-(5,5-二甲基-1,3二噁烷-2-基)丁-2-烯基三苯基鏻。0℃下,在1小时内加入20.4g 20%浓度的乙醇钠(60mmol)乙醇溶液。在0℃搅拌该混合物1小时后加入50ml半浓缩的盐水。分离有机相,用50ml半浓缩的盐水洗涤一次,在硫酸钠上干燥并在20℃下于旋转蒸发器内浓缩至20毫巴压力。残余物(38.2g)通过硅胶上的快速色谱法提纯(洗脱剂:环己烷/甲基叔丁基醚4∶1)。得到19.9g(理论值的93.4%)的标题化合物。为了表征,通过加热将产物溶于100ml乙酸乙酯中。向该热溶液中加入50ml二异丙醚,并在冷却到0℃后,搅拌混合物1小时。滤出所形成的晶体,用冷的乙酸乙酯/二异丙醚混合物(体积比为2∶1)洗涤,并在氮气流中干燥。产物:8.9g红色晶体。熔点157.5-158℃。E1 1(CHCl3):2495(423nm),2243(448nm)。
d)15-(5,5-二甲基-1,3-二噁烷-2-基)-2,6,11-三甲基-2,4,6,8,10,12,14-十六碳七烯醇
将42.3g步骤c)的产物溶于400ml四氢呋喃中。在0℃下、1小时内注入31.8g二氢化二(2-甲氧基乙氧基)铝酸钠在甲苯中的70%浓度溶液和400ml甲苯,所得混合物在0℃下搅拌1小时。然后用400ml正己烷稀释该反应混合物,并在15分钟内注入400ml半浓缩的盐水。水相用体积比1∶1的甲苯/己烷混合物洗涤两次,每次使用400ml。合并有机相在硫酸钠上干燥并在50℃下于旋转蒸发器内浓缩至压力为20毫巴。残余物通过硅胶上的快速色谱法提纯(洗脱剂:环己烷/乙酸乙酯10∶1)。得到20.12g(理论值的55.2%)标题化合物。所得产物以该形式在随后步骤e)中使用。E1 1(CHCl3):1579(383nm),2668(405nm),2919(3430nm)。
e)藏花酸二醛单缩新戊二醇
将3.09g步骤d)的产物溶于11ml二甲基甲酰胺中。加入64mg(0.4mmol)2,2,6,6-四甲基哌啶-1-氧基和41mg(0.4mmol)氯化铜(I)。然后在20-25℃下通入氧气3小时。再加入同样量的两种催化剂,并再通入氧气1小时。该混合物然后与40ml半浓缩盐水和40ml乙酸乙酯混合。分离水相并用40ml乙酸乙酯萃取。合并有机相在硫酸钠上干燥并在旋转蒸发器内浓缩。残余物通过硅胶上的快速色谱法提纯(洗脱剂:环己烷/乙酸乙酯为10∶1)。获得1.3g(理论值的43%)藏花酸二醛单缩新戊二醇。为了表征,将试样从乙酸乙酯/二异丙醚中再结晶。熔点为183.5-184℃。E1 1(CHCl3):2434(438nm)。
Claims (9)
3.如权利要求1或2所述的方法,其中在步骤a)中使用式IIIa试剂:
其中R6具有权利要求1指出的意义,R7为C1-C3烷基。
4.如权利要求1或2所述的方法,其中在步骤b)中缩醛官能团的水解用柠檬酸催化。
5.如权利要求1或2所述的方法,其中在步骤b)中使用式Va试剂:
其中R1和R2具有权利要求1指出的意义,R8为芳基和X-为无机酸或有机酸的等价阴离子。
6.如权利要求1或2所述的方法,其中氢化铝钠化合物在步骤c)中用作还原剂。
7.如权利要求1或2所述的方法,其中在步骤d)中使式VII化合物在N-氧基自由基和铜(I)化合物存在下用氧气氧化。
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