CN1116292C - 用于制备苯并二氢吡喃醇衍生物的方法 - Google Patents
用于制备苯并二氢吡喃醇衍生物的方法 Download PDFInfo
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- CN1116292C CN1116292C CN99120236A CN99120236A CN1116292C CN 1116292 C CN1116292 C CN 1116292C CN 99120236 A CN99120236 A CN 99120236A CN 99120236 A CN99120236 A CN 99120236A CN 1116292 C CN1116292 C CN 1116292C
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- Prior art keywords
- acid
- oxo
- formula
- hydrogen
- alkyl
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- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 239000002253 acid Substances 0.000 claims abstract description 36
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000011701 zinc Substances 0.000 claims abstract description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 239000001257 hydrogen Substances 0.000 claims abstract description 24
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000009467 reduction Effects 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 6
- 230000032050 esterification Effects 0.000 claims abstract description 4
- 238000005886 esterification reaction Methods 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 41
- -1 alkane carboxylic acid Chemical class 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- 239000007864 aqueous solution Substances 0.000 claims description 27
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical compound C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 6
- FWGMHNMRFXRFAY-UHFFFAOYSA-N 2-hydroxy-2,3-dihydrochromen-4-one Chemical class C1=CC=C2OC(O)CC(=O)C2=C1 FWGMHNMRFXRFAY-UHFFFAOYSA-N 0.000 abstract 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- SEBPXHSZHLFWRL-UHFFFAOYSA-N 3,4-dihydro-2,2,5,7,8-pentamethyl-2h-1-benzopyran-6-ol Chemical class O1C(C)(C)CCC2=C1C(C)=C(C)C(O)=C2C SEBPXHSZHLFWRL-UHFFFAOYSA-N 0.000 abstract 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 abstract 1
- 125000002877 alkyl aryl group Chemical group 0.000 abstract 1
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 57
- 229930003799 tocopherol Natural products 0.000 description 56
- 239000011732 tocopherol Substances 0.000 description 56
- 229960001295 tocopherol Drugs 0.000 description 55
- 235000010384 tocopherol Nutrition 0.000 description 55
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 26
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 20
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- 238000006722 reduction reaction Methods 0.000 description 12
- 235000019253 formic acid Nutrition 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 10
- 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 9
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 9
- 239000004094 surface-active agent Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000013019 agitation Methods 0.000 description 7
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 7
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 7
- 150000003505 terpenes Chemical group 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 4
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 3
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 3
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 3
- 238000006317 isomerization reaction Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229940042585 tocopherol acetate Drugs 0.000 description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- 238000006214 Clemmensen reduction reaction Methods 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 2
- 241001274216 Naso Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical class CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- AQSOMAXEUJBITL-UHFFFAOYSA-N azane;dodecane Chemical compound N.CCCCCCCCCCCC AQSOMAXEUJBITL-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001733 carboxylic acid esters Chemical group 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- FTHUKEBATJXQFL-UHFFFAOYSA-N formic acid;hydrochloride Chemical compound Cl.OC=O FTHUKEBATJXQFL-UHFFFAOYSA-N 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 2
- JHPBZFOKBAGZBL-UHFFFAOYSA-N (3-hydroxy-2,2,4-trimethylpentyl) 2-methylprop-2-enoate Chemical compound CC(C)C(O)C(C)(C)COC(=O)C(C)=C JHPBZFOKBAGZBL-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- RELMFMZEBKVZJC-UHFFFAOYSA-N 1,2,3-trichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1Cl RELMFMZEBKVZJC-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- YIWUKEYIRIRTPP-UHFFFAOYSA-N 2-ethylhexan-1-ol Chemical compound CCCCC(CC)CO YIWUKEYIRIRTPP-UHFFFAOYSA-N 0.000 description 1
- GJJVAFUKOBZPCB-UHFFFAOYSA-N 2-methyl-2-(4,8,12-trimethyltrideca-3,7,11-trienyl)-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- KTFBMMKWTQVUIV-UHFFFAOYSA-N 4-[(3,4-dimethoxyphenyl)methoxymethyl]-1,2-dimethoxybenzene Chemical compound C1=C(OC)C(OC)=CC=C1COCC1=CC=C(OC)C(OC)=C1 KTFBMMKWTQVUIV-UHFFFAOYSA-N 0.000 description 1
- UQRONKZLYKUEMO-UHFFFAOYSA-N 4-methyl-1-(2,4,6-trimethylphenyl)pent-4-en-2-one Chemical group CC(=C)CC(=O)Cc1c(C)cc(C)cc1C UQRONKZLYKUEMO-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 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
- LBPACUJFGRCWDF-UHFFFAOYSA-L Cl[Mg]Cl.[Na] Chemical compound Cl[Mg]Cl.[Na] LBPACUJFGRCWDF-UHFFFAOYSA-L 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000000023 Kugelrohr distillation Methods 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101100170604 Mus musculus Dmap1 gene Proteins 0.000 description 1
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IGFHQQFPSIBGKE-UHFFFAOYSA-N Nonylphenol Natural products CCCCCCCCCC1=CC=C(O)C=C1 IGFHQQFPSIBGKE-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- HXWJFEZDFPRLBG-UHFFFAOYSA-N Timnodonic acid Natural products CCCC=CC=CCC=CCC=CCC=CCCCC(O)=O HXWJFEZDFPRLBG-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000004171 alkoxy aryl group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrane Compounds (AREA)
Abstract
通过还原式II的4-氧代苯并二氢吡喃醇衍生物制备式I的苯并二氢吡喃醇衍生物的方法,式(I)中,n是1-10,R1、R2、R3、R4分别独立地是氢或C1-C4烷基,R5是氢、C1-C4烷基、C6-C10芳基、C7-C18芳烷基、C7-C18烷芳基、C1-C22酰基或羟基保护基,该方法包括使式II的4-氧代苯并二氢吡喃醇与金属锌在酸或酸的混合物存在下反应。具有C1-C22酰基作为R5的式I化合物可通过氢原子作为R5的式II化合物的上述还原反应和同时或随后的酯化反应制备。
Description
本发明涉及通过还原相应的4-氧代苯并二氢吡喃醇衍生物制备具有烯属侧链的苯并二氢吡喃醇衍生物的方法。
具有类异戊二烯侧链的苯并二氢吡喃醇类——诸如生育酚和三烯生育酚(tocotrienol)族——表现出维生素E活性,并因此作为活性生物学成分是重要的。但是,具有烯属类异戊二烯侧链的苯并二氢吡喃醇类——诸如三烯生育酚——的制备是复杂的,因为在例如生育酚的制备中常用的酸性合成条件(Ullmann’s 5th Ed 1996,Vol.A27,Chapter 4.11.2,P484-485)导致了烯属侧链的异构化或环化(P.Karrer,H.Reutschler,Helv.Chim.Acta 27,(1944)1297;H.J.Kabbe,A.Widdig,Angew.Chem.Int.Ed.Engl.21,(1982)247-256,P.Schudel,H.Mayer,J.Metzger,R.Rüegg,O.Isler,Helv.Chim.Acta 46,(1963)2517)。
已知通过相应的4-氧代三烯生育酚的还原可以制备三烯生育酚,而4-氧代三烯生育酚可通过本身已知的方法制备(H.J.Kabbe,A.Widdig,Angew.Chem.Int.Ed.Engl.
21,(1982)247-256;H.J.Kabbe,H.Heitzer,Synthesis(1978)888)。
已知可以以多步骤方法进行还原反应,先使用硼酸钠得到4-羟基三烯生育酚,随后通过蒸馏消去水,进一步用Na/乙醇部分氢化(H.J.Kabbe,H.Heitzer,Syntheses(1978)888)。因为是多步方法,这个方法非常复杂。
还已知可以以单步骤方法进行还原反应,使用复合氢化铝(B.C.Pearce等人,J.Med.Chem.37,(1994)526-541)。以工业规模使用复合氢化物是不经济的,并且需要严格的安全预防措施。
因此,本发明的目的是弥补上述缺点,开发一种简单的单步骤还原方法来还原具有烯属类异戊二烯侧链的4-氧代苯并二氢吡喃醇类,得到相应的苯并二氢吡喃醇衍生物,而不通过异构化或环化改变双键在不饱和侧链上的构型或位置。
我们已经发现该目的可通过使相应的式II的4-氧代苯并二氢吡喃醇与金属锌在酸或酸的混合物存在下反应,还原该4-氧代苯并二氢吡喃醇,
制备式I的苯并二氢吡喃醇衍生物的方法实现,其中n是1-10,R1、R2、R3、R4分别独立地是氢或C1-C4烷基,R5是氢、C1-C4烷基、C6-C10芳基、C7-C18芳烷基、C7-C18烷芳基、C1-C22酰基或羟基保护基。
在以前认为本身已知的克莱门森还原(R.R.Read等人,Org.Synth.Collect.Vol.3,(1955)444;P.S.Bramwell,J.Chem.Soc.(1965)3882)不能实现这个目的,因为通常用于克莱门森还原的酸性反应条件不适合酸性不稳定的烯属侧链(H.J.Kabbe,H.Heitzer,Syntheses(1978)888)。已经发现,使用根据本发明的方法,可成功地还原具有不饱和侧链的4-氧代苯并二氢吡喃醇,而烯属侧链不异构化或环化。
该方法的起始原料为式II的4-氧代苯并二氢吡喃醇衍生物。烯属类异戊二烯侧链可含有1-10个类异戊二烯单元(n=1-10)。优选起始原料是有n=2-4个类异戊二烯单元的4-氧代苯并二氢吡喃醇衍生物,特别优选含有n=3个类异戊二烯单元的4-氧代苯并二氢吡喃醇衍生物。
在此,基团R1、R2、R3、R4分别独立地是氢或C1-C4烷基,诸如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,优选氢和甲基。
R5是氢、上述的C1-C4烷基、诸如苯基的C6-C10芳基、诸如苄基、苯乙基的C7-C18芳烷基、诸如甲苯基、2,4,6-三甲苯基的C7-C18烷芳基或C1-C22酰基,诸如C1-C22烷酰基,特别是甲酸酯、乙酸酯、丙酸酯、丁酸酯、戊酸酯、己酸酯、庚酸酯、2-乙基己酸酯、辛酸酯、壬酸酯、癸酸酯、十一烷酸酯、月桂酸酯、棕榈酸酯或硬脂酸酯,或诸如烯属C2-C22酰基,特别是丙烯酸酯、甲基丙烯酸酯、丁烯酸酯、山梨酸酯、9-十八烯酸酯、亚油酸酯、亚麻酸酯、二十碳五烯酸酯或二十二碳六烯酸酯。
另外,R5可以是通常的羟基保护基。为实施本发明的方法,保护基的存在并不严格限制,但也不能干扰。可作为附加的方法步骤将保护基首先引入本发明的工艺。在R5=氢的情况下,保护基可同时引入本发明的方法或作为附加步骤随后引入。原则上可使用任何保护基。优选的保护基是那些在关于羟基的文献中已知的(T.W.Greene,Protective Groups in Organic Synthesis,John Wiley & Sons NewYork,(1981),P14-71;P.J.Kocienski,Protecting Groups,Georg Thieme Verlag Stuttgart,(1994),P21-94)。保护基的例子是:酯,例如乙酸酯(Ac)、一氯到三氯乙酸酯、三氟乙酸酯、苯基乙酸酯、三苯基甲氧基乙酸酯、苯氧基乙酸酯、卤代苯氧基乙酸酯、卤代烷基苯氧基乙酸酯、甲酸酯、苯甲酰基甲酸酯、3-苯基丙酸酯、异丁酸酯、新戊酸酯(Pv)、金刚烷酸酯、丁烯酸酯、苯甲酸酯。甲硅烷基醚,例如三甲基甲硅烷基(TMS)、三乙基甲硅烷基(TES)、甲基二叔丁基甲硅烷基、叔丁基二甲基甲硅烷基(TBS或TBDMS)、叔丁基二苯基甲硅烷基(TBDPS)、三苯基甲硅烷基、三异丙基甲硅烷基(TIPS)、二乙基异丙基甲硅烷基(DEIPS)、异丙基二甲基甲硅烷基(IPDMS)、thexyl二甲基甲硅烷基(TDS)。脂族和芳族醚,例如甲基(Me)、苄基(Bn)、邻硝基苄基、对甲氧基苄基类、3,4-二甲氧基苄基醚、三苯甲基(Trt或Tr)、对甲氧基苯基二苯基甲基(MMTr)、4,4’,4”-三(苯甲酰氧基)三苯甲基(TBTr)、二(对甲氧基苯基)苯基甲基(DMTr)、叔丁基、9-苯基-9-呫吨基(pixyl),丙烯基、2-(三甲基甲硅烷基)乙基(TMSE)。缩醛(烷氧基烷基醚、芳氧基烷基醚或烷氧基芳基醚),诸如甲氧基甲基(MOM)、甲硫基甲基(MTM)、2-甲氧基乙氧基甲基(MEM)、1-甲氧基-1-甲基乙基、2-乙氧基乙基(EE)、4-甲氧基四氢吡喃-4-基(MTHP)、四氢吡喃-2-基、2-(三甲基甲硅烷基)乙氧基甲基(SEM)、3,4-二甲氧基苄基(DMB)、苄氧基甲基、对甲氧基苄基(PMB)、对甲氧基苄氧基甲基(PMBM)和甲氧基羰基和烯丙氧基羰基(Alloc),以及从这些可以是非烷基化的或烷基化的或非卤化的或卤化的基团衍生的保护基。
特别优选的起始原料是4-氧代三烯生育酚类(R5=氢,n=3),诸如4-氧代-α-三烯生育酚(R1=R2=R3=R4=甲基)、4-氧代-β-三烯生育酚(R1=R3=R4=甲基,R2=氢)、4-氧代-γ-三烯生育酚(R1=氢,R2=R3=R4=甲基)或4-氧代-δ-三烯生育酚(R1=R2=氢,R3=R4=甲基)、4-氧代-三烯生育酚(R1=R2=R3=氢,R4=甲基),4-氧代-2-脱甲基三烯生育酚(R1=R2=R3=R4=氢)和相应的在氧上保护的化合物(R5=上述保护基)或在氧上衍生的化合物(R5=C1-C4烷基、C6-C10芳基、C7-C18芳烷基、C7-C18烷芳基或C1-C22酰基)。
根据本发明,在酸或酸的混合物存在下用金属锌还原4-氧代苯并二氢吡喃醇衍生物形成相应的式I的苯并二氢吡喃醇衍生物。
酸是布恩司特酸和它们的水溶液。优选的布恩司特酸是无机酸,诸如氢卤酸、硫酸、硝酸、磷酸、硼酸或卤氧酸,特别是HCl、HBr、HI、HF、H2SO4、甲磺酸、KHSO4、HNO3、HClO4、H3PO4和H3BO3或非卤化的或卤化的C1-C22烷羧酸,即,未取代的或独立地被至多5个诸如F、Cl或Br的卤原子取代,诸如甲酸、乙酸、三氟乙酸、丙酸、丁酸、柠檬酸、草酸、己酸、辛酸、癸酸、十二烷酸(月桂酸)、十六烷酸(棕榈酸)或十八烷酸(硬脂酸)。
在水溶液的情况下,布恩司特酸在水溶液中的量当使用无机酸时,优选为5-80%重量,特别优选15-50%重量,当使用脂族或芳族C1-C22羧酸时,优选10-80%重量,特别优选35-50%重量。也可以使用上述酸的化合物。
加入的金属锌粉末的量基于4-氧代苯并二氢吡喃醇衍生物的量一般为1-25摩尔当量,特别是1-10摩尔当量。
反应温度优选0-160℃,特别是20-100℃。反应时间一般为10分钟-24小时。
在一个优选的实施方案中,将起始原料(4-氧代苯并二氢吡喃醇衍生物)、锌和酸的反应混合物与有机溶剂混合。这样可形成多相混合物。为了本发明的目的,有机溶剂是脂族或芳族烃,诸如环己烷、己烷、庚烷、辛烷、壬烷、苯、甲苯、二甲苯或乙苯,醇类,诸如辛醇、2-乙基己醇或壬基苯酚,醚类,诸如二丁基醚或叔丁基甲基醚,或C1-C22羧酸,诸如己酸、辛酸或癸酸。这些化合物的混合物也可以作为有机溶剂使用。
当加入有机溶剂时,优选用氢卤酸水溶液作为酸使用。特别优选使用HCl水溶液(盐酸溶液)。
另外,在另一个实施方案中,反应混合物可与表面活性物质或相转移活性物质混合,诸如十二烷基硫酸盐、十二烷胺或氯化十二烷铵、十三烷基胺或溴化十三烷基铵、氯化甲基三辛基铵、溴化苄基三甲基铵或溴化四苯基鏻。可加入的有益的其它物质特别是卤盐,诸如氯化锂、氯化钠、氯化镁、溴化钾、氟化铯或氯化四甲基铵。在超声下实施该方法是有利的。
在另一个优选的实施方案中,作为布恩司特酸使用的C1-C22烷基羧酸本身可作为溶剂。在这种情况下,式II的4-氧基苯并二氢吡喃醇衍生物可在如上所述的C1-C22烷基羧酸中与锌反应,无需另外加入有机溶剂。该实施方案的优选的酸是甲酸、乙酸、丙酸、丁酸、戊酸、己酸、庚酸、辛酸、癸酸、十二烷酸、棕榈酸或硬脂酸,特别优选乙酸。
如上所述,引入保护基或衍生羟基(R5)的步骤可以与根据本发明的工艺同时进行或相继进行。优选引入酯基,因为有药理学意义。
为了制备式Ia的苯并二氢吡喃醇酯,其中R1、R2、R3、R4和n具有上述意义,R6是氢,C1-C21烷基,诸如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基、二十烷基或二十一烷基,或C2-C21链烯基,诸如乙烯基、1-丙烯基、2-丙烯基、8-十七烯基、8,11-十七二烯基或8,11,14-十七三烯基,
和用常规方法与式III的C1-C22脂族羧酸衍生物反应进行酯化,
R6-COX (III),其中X是可被式Ib的苯并二氢吡喃醇的羟基替换的离去基团,
因此,酯化用本身已知的方法进行,使式Ib的苯并二氢吡喃醇与上述作为布恩司特酸的C1-C22烷羧酸(R6=C1-C21烷基,X=OH)、C2-C22烯羧酸(R6=C2-C21烯基,X=OH)——诸如丙烯酸、甲基丙烯酸、丁烯酸、山梨酸、油酸、亚油酸、亚麻酸、二十碳五烯酸或二十二碳六烯酸——反应,或与相应的脂族C1-C22羧酸衍生物(酯化剂)——即,相应的C1-C22烷羧酸衍生物或C2-C22烯羧酸衍生物反应。式III的C1-C22脂族羧酸衍生物包括羧酸酐、羧酸卤化物,诸如羧酸氯化物、氟化物或溴化物,或C1-C22烷羧酸或C2-C22烯羧酸的羧基活性酯。
羧基活性酯的例子是羧酸酯,诸如N-羟基丁二酰亚胺的羧酸酯、苯酚酯和卤代苯酚酯,诸如五氟代苯酚酯和三氯代苯酚酯。
离去基团X的例子是相应的卤化物——诸如F-、Cl-、Br-,羧酸酯——诸如乙酸酯或丙酸酯或烷氧化物,诸如丁二酰亚胺-N-羟基化物、酚盐、卤代酚盐——诸如五氟代苯酚盐、三氯代苯酚盐或苯并三唑-1-羟基化物。
优选的酯化剂是乙酰化试剂,诸如乙酸酐或乙酰氯。
在一个优选的实施方案中,为了制备苯并二氢吡喃醇的C1-C22烷羧酸酯,用本发明的方法,用C1-C22烷羧酸作为布恩司特酸或有机溶剂,用这些C1-C22烷基羧酸同时、优选就地作为酯化剂,制备R5=氢的式I的苯并二氢吡喃醇衍生物(Ib)。
本发明的方法用于通过还原相应的4-氧代苯并二氢吡喃醇衍生物简单地合成苯并二氢吡喃醇衍生物。与现有技术相比,其区别在于存在下列优点:
——可以一个步骤简单地实施该方法,
——即使在工业规模,该方法也不需要严格的安全预防措施,
——该方法使用的起始原料从工业上容易获得并且便宜。
用实施例详细说明本发明。
实施例1-6在正庚烷中使用锌和盐酸水溶液还原4-氧代-γ-三烯生育酚制备γ-三烯生育酚
用下列试验条件得到的试验结果总结于表1和2。
4-氧代-γ-三烯生育酚(1-10.3g,2.36-24mmol)用温热的正庚烷(实施例1-4)、甲苯(实施例5)或辛酸(实施例6)溶解。该溶液冷却到室温后,在搅拌下加入盐酸水溶液(20-24%重量,基于水溶液)。然后,在10分钟期间,加入锌粉(5或10摩尔当量(mol-eq.),基于4-氧代-γ-三烯生育酚),反应混合物再搅拌如表1和2所示的时间。使用Celite(Manville Corp.,USA,的商标,用于分离和提纯液体的过滤助剂。Celite由不同颗粒度的硅藻土构成)的真空过滤器过滤锌,用正庚烷洗涤(100ml)。洗涤有机相,用NaSO4干燥,浓缩,用面积积分通过GC测定纯度。
实施例1和2的粗产物的提纯使用闪蒸色谱,用甲基叔丁基醚/庚烷在硅胶上洗脱,或用Kugelrohr蒸馏。
表1
实施例1 | 实施例2 | 实施例3 | 实施例4 | |
4-氧代-γ-t.[g] | 1.0 | 5.0 | 10.3 | 10.0 |
4-氧代-γ-t.[mmol] | 2.3 | 11.8 | 24.0 | 22.7 |
Zn[mol-eq.] | 10 | 5 | 5 | 5 |
庚烷[ml] | 10 | 80 | 100 | 100 |
HCl(aq.)[ml] | 20 | 50 | 183 | 200 |
水溶液中的HCl[%重量] | 20 | 20 | 22 | 24 |
温度[℃] | RT | 60 | 40 | 40 |
时间[小时] | 1.5 | 2 | 1 | 1 |
粗产量[g] | 0.96 | 4.64 | 9.88 | 9.27 |
纯度[%] | 77 | - | 82 | 81 |
提纯前的产率[%] | 76 | - | 82 | 79 |
提纯方法 | 闪蒸色谱 | Kugelrohr蒸馏 | -(*) | - |
提纯后的产率[%] | 63 | 52 | - | - |
使用的缩写:t.=三烯生育酚
aq.=水溶液
(*)不提纯而在实施例12中继续反应
表2
实施例5 | 实施例6 | |
4-氧代-γ-t.[g] | 2.07 | 2.02 |
4-氧代-γ-t.[mmol] | 4.83 | 4.71 |
Zn[mol-eq.] | 5 | 5 |
溶剂 | 甲苯 | 辛酸 |
溶剂的量[ml] | 20 | 20 |
HCl(aq.)[ml] | 40 | 40 |
水溶液中的HCl[%重量] | 22 | 22 |
温度[℃] | 40 | 40 |
时间[小时] | 1.0 | 3.0 |
粗产量[g] | 1.83 | 1.1 |
纯度[%] | 82 | 6 2 |
提纯前的产率[%] | 76 | 38 |
使用的缩写:t.=三烯生育酚
aq.=水溶液
实施例7加入十二烷胺作为表面活性物质,在辛烷中使用锌和盐酸水溶液还原4-氧代-γ-三烯生育酚制备γ-三烯生育酚
以与实施例1-6相同的方法进行试验,加入十二烷胺作为表面活性物质,使用辛烷作为溶剂。在反应条件下,加入的十二烷胺以氯化十二烷铵形式存在。与实施例1-4相反,反应在超声下进行,不进行搅拌。表3总结了试验条件和结果。
表3
4-氧代-γ-t.[g] | 0.83 |
4-氧代-γ-t.[mmol] | 1.9 |
Zn[mol-eq.] | 10 |
辛烷[ml] | 10 |
HCl(aq.)[ml] | 30 |
水溶液中的HCl[%重量] | 20 |
表面活性物质 | 十二烷胺 |
表面活性物质的量[g] | 0.05 |
温度[℃] | 45 |
时间[分钟] | 20 |
粗产量[g] | 0.77 |
纯度[%] | 53 |
提纯前的产率[%] | 52 |
使用的缩写:t.=三烯生育酚
aq.=水溶液
实施例8加入表面活化化合物,在庚烷中使用锌和硫酸水溶液还原4-氧代-γ-三烯生育酚制备γ-三烯生育酚
以与实施例1-6相似的方法进行试验,使用硫酸水溶液(50%重量,基于水溶液)并加入表面活性物质。表4总结了试验条件和结果。
表4
4-氧代-γ-t.[g] | 2.1 |
4-氧代-γ-t.[mmol] | 4.7 |
Zn[mol-eq.] | 8.5 |
庚烷[ml] | 20 |
H2SO4(aq.)[ml] | 60 |
水溶液中的H2SO4[%重量] | 50 |
表面活性物质 | 十二烷胺 |
表面活性物质的量[g] | 0.08 |
温度[℃] | 55 |
时间[小时] | 12 |
粗产量[g] | 1.5 |
转化率[%] | 98 |
选择性[%] | 30 |
使用的缩写:t.=三烯生育酚
aq.=水溶液
实施例9在庚烷中使用锌和柠檬酸水溶液还原4-氧代-γ-三烯生育酚制备γ-三烯生育酚
4-氧代-γ-三烯生育酚(0.81g,1.9mmol)用60℃的正庚烷溶解,在搅拌下加入柠檬酸水溶液(20ml,40%重量,基于水溶液)。然后加入锌粉(1.3g,10mol-eq.,基于4-氧代-γ-三烯生育酚),反应混合物在60℃搅拌6小时,然后在75℃搅拌2小时。使用Celite真空过滤器过滤锌,分离有机相,用水洗涤,用Na2SO4干燥。用气相色谱测定转化率为24%(76%4-氧代-γ-三烯生育酚回收)。反应的选择性为86%。
实施例10在正壬烷中使用锌和柠檬酸和盐酸的水溶液混合物还原4-氧代-γ-三烯生育酚制备γ-三烯生育酚
4-氧代-γ-三烯生育酚(2.05g,4.78mmol)溶于热的(50℃)壬烷(35ml),在与柠檬酸水溶液(300ml,40%重量,基于水溶液)一起搅拌下加热到100℃。在5小时期间,在搅拌下一次一点地加入锌粉(3.1g,10mol-eq.,基于4-氧代-γ-三烯生育酚)。然后加入盐酸水溶液(30ml,24%重量,基于水溶液),再在4小时期间,在搅拌下一次一点地加入锌粉(3.1g,10mol-eq.)。冷却到室温后,分离有机相,用水洗涤,用Na2SO4干燥,浓缩。转化完全,用气相色谱测定γ-三烯生育酚产率为62%。
实施例11使用锌和冰醋酸还原4-氧代-γ-三烯生育酚制备γ-三烯生育酚
4-氧代-γ-三烯生育酚(2.07g,4.83mmol)溶于50ml冰醋酸,加热到回流(约80℃)。一次一点地加入锌粉14.2mol-eq.,在回流下搅拌混合物14小时。反应过程用薄层和气相色谱监测。当反应转化率达到62%时终止反应,滤除残留的锌粉,滤液在庚烷(100ml)和水(100ml)之间分配。用水洗涤庚烷相,用NaSO4干燥,浓缩。进行硅胶色谱,用甲基叔丁基醚/庚烷作为洗脱剂,得到0.51g(1.24mmol)γ-三烯生育酚和0.06g三烯生育酚乙酸酯。回收未反应的4-氧代-γ-三烯生育酚(0.61g)。
实施例12使用乙酸酐乙酰化γ-三烯生育酚制备γ-三烯生育酚乙酸酯
γ-三烯生育酚(粗产物,根据实施例3制备,4.8g)与10ml乙酸酐在回流下一起加热3.5小时,然后在减压下除去乙酸和乙酸酐。在硅胶上闪蒸色谱,使用乙酸乙酯/庚烷洗脱,从粗产物得到3.7gγ-三烯生育酚乙酸酯。
实施例13和14在甲苯中使用锌和盐酸水溶液或在环己烷中用锌和甲酸水溶液还原4-氧代-α-三烯生育酚制备α-三烯生育酚
4-氧代-α-三烯生育酚(0.26g,0.6mmol)在40℃溶于甲苯(实施例13)或环己烷(实施例14)中。在搅拌下加入盐酸水溶液(浓度22%)(实施例13)或甲酸水溶液(浓度80%)(实施例14)。在8.5小时期间,加入锌粉(13或15摩尔当量,基于4-氧代-α-三烯生育酚),在40℃搅拌反应混合物5小时,然后在65℃搅拌7小时。反应过程通过进行取样和薄层色谱追踪。使用Celite真空过滤器过滤锌,用正庚烷洗涤。用水洗涤有机相,用Na2SO4干燥,浓缩。表5总结了反应条件和结果。
表5
实施例15和16在甲苯中使用锌和盐酸水溶液或在环己烷中用锌和甲酸水溶液还原4-氧代-δ-三烯生育酚制备δ-三烯生育酚
实施例13 | 实施例14 | |
4-氧代-α-t.[g] | 0.26 | 0.26 |
4-氧代-α-t.[mmol] | 0.60 | 0.60 |
Zn[摩尔当量] | 13 | 15 |
溶剂 | 甲苯 | 环己烷 |
溶剂的体积[ml] | 3 | 3 |
酸(水溶液) | 盐酸 | 甲酸 |
酸的体积[ml] | 5 | 5 |
水溶液中的酸浓度[%重量] | 22%HCl | 80%HCOOH |
温度[℃] | 40和65 | 40和65 |
时间[小时] | 12 | 12 |
粗产量[g] | 0.10 | 0.10 |
转化率[%] | 91% | 88% |
选择性[%] | 93% | 93% |
在加热下将4-氧代-δ-三烯生育酚(0.20g,0.5mmol)溶于甲苯(实施例15)或环己烷(实施例16)中。在搅拌下加入盐酸水溶液(浓度22%)(实施例15)或甲酸水溶液(浓度80%)(实施例16)。在0.5小时(实施例15)或7小时(实施例16)期间,加入锌粉(6或10摩尔当量,基于4-氧代-δ-三烯生育酚),在60℃搅拌反应混合物2小时(实施例15)或9小时(实施例16)。使用Celite真空过滤器过滤锌,用正庚烷洗涤。用水洗涤有机相,用Na2SO4干燥,浓缩。表6总结了反应条件和结果。
表6
实施例17使用锌和甲酸水溶液在环己烷中还原4-氧代-γ-三烯生育酚制备γ-三烯生育酚
实施例15 | 实施例16 | |
4-氧代-δ-t.[g] | 0.20 | 0.20 |
4-氧代-δ-t.[mmol] | 0.50 | 0.50 |
Zn[摩尔当量] | 6 | 10 |
溶剂 | 甲苯 | 环己烷 |
溶剂的体积[ml] | 3 | 3 |
酸(水溶液) | 盐酸 | 甲酸 |
酸的体积[ml] | 5 | 5 |
水溶液中的酸浓度[%重量] | 22%HCl | 80%HCOOH |
温度[℃] | 60 | 60 |
时间[小时] | 2 | 9 |
粗产量[g] | 0.16 | 0.11 |
转化率[%] | 100% | 99.5% |
选择性[%] | 93% | 56% |
在65℃将4-氧代-γ-三烯生育酚(100.3g,0.24mol)溶于500ml环己烷和1升甲酸(水溶液,浓度80%)。在9.5小时期间,在搅拌下加入锌粉(160g,2.45mol),反应混合物在65℃搅拌12小时。搅拌4小时后,再加入1升甲酸(水溶液,浓度80%)。用水洗涤有机相2次,然后用甲醇/水混合物(1∶1)洗涤2次,浓缩。粗γ-三烯生育酚的产量为96.1g。91g粗产物在200℃/<0.01毫巴进行分子蒸馏,得到86gγ-三烯生育酚黄色的油。
Claims (8)
2.权利要求1的方法,其中向反应混合物中加入有机溶剂。
3.权利要求1或2的方法,其中使用氢卤酸或其水溶液作为酸。
4.权利要求1或2的方法,其中使用氢氯酸或其水溶液作为酸。
5.权利要求1的方法,其中使用C1-C22烷羧酸作为酸,并作为有机溶剂。
6.权利要求5的方法,其中使用乙酸作为C1-C22烷羧酸。
8.权利要求7的方法,其中根据权利要求5的方法制备式Ib的苯并二氢吡喃醇衍生物,和使其与存在于还原步骤的反应混合物中的C1-C22烷羧酸衍生物反应。
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EP2573063A1 (en) | 2011-09-23 | 2013-03-27 | DSM IP Assets B.V. | Process for preparing chiral quinone |
EP3016941B1 (en) | 2013-07-05 | 2017-03-22 | DSM IP Assets B.V. | Formation of chiral 4-chromanones using chiral pyrrolidines in the presence of ureas or thioureas |
JP6365949B2 (ja) | 2013-07-05 | 2018-08-01 | ディーエスエム アイピー アセッツ ビー.ブイ. | キラルピロリジン類を使用するキラル4−クロマノン類の生成 |
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ES2943653T3 (es) | 2017-07-12 | 2023-06-15 | Dsm Ip Assets Bv | Nueva síntesis de intermedios para la preparación de alfa-tocoferol |
CN111574486B (zh) * | 2020-05-22 | 2022-04-26 | 中国科学院南海海洋研究所 | 香叶基三羟基色酮及其在制备肝x受体激动剂中的应用 |
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