CN1098101A - 虾青素的制备、制备它的新中间体以及其制备 - Google Patents
虾青素的制备、制备它的新中间体以及其制备 Download PDFInfo
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- JEBFVOLFMLUKLF-IFPLVEIFSA-N Astaxanthin Natural products CC(=C/C=C/C(=C/C=C/C1=C(C)C(=O)C(O)CC1(C)C)/C)C=CC=C(/C)C=CC=C(/C)C=CC2=C(C)C(=O)C(O)CC2(C)C JEBFVOLFMLUKLF-IFPLVEIFSA-N 0.000 title claims abstract description 22
- MQZIGYBFDRPAKN-ZWAPEEGVSA-N astaxanthin Chemical compound C([C@H](O)C(=O)C=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)C(=O)[C@@H](O)CC1(C)C MQZIGYBFDRPAKN-ZWAPEEGVSA-N 0.000 title claims abstract description 22
- 235000013793 astaxanthin Nutrition 0.000 title claims abstract description 22
- 239000001168 astaxanthin Substances 0.000 title claims abstract description 22
- 229940022405 astaxanthin Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- -1 alkene alkynes Chemical class 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 230000000903 blocking effect Effects 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims abstract description 12
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 239000012442 inert solvent Substances 0.000 claims abstract description 9
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims abstract 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 21
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 13
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 12
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 6
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 238000007239 Wittig reaction Methods 0.000 claims description 2
- 150000003509 tertiary alcohols Chemical class 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- 229910052725 zinc Inorganic materials 0.000 description 6
- 239000007818 Grignard reagent Substances 0.000 description 5
- 150000004795 grignard reagents Chemical class 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 150000001241 acetals Chemical class 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 2
- FDSDTBUPSURDBL-LOFNIBRQSA-N canthaxanthin Chemical compound CC=1C(=O)CCC(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)C(=O)CCC1(C)C FDSDTBUPSURDBL-LOFNIBRQSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000005595 deprotonation Effects 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000004246 zinc acetate Substances 0.000 description 2
- RBACIKXCRWGCBB-UHFFFAOYSA-N 1,2-Epoxybutane Chemical group CCC1CO1 RBACIKXCRWGCBB-UHFFFAOYSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- PXSBSBDNZRLRLK-UHFFFAOYSA-N 2-(2h-pyran-2-yloxy)-2h-pyran Chemical group O1C=CC=CC1OC1OC=CC=C1 PXSBSBDNZRLRLK-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- WITIHNSHWSGZLH-UHFFFAOYSA-N CC1=CC([O])OCC1 Chemical compound CC1=CC([O])OCC1 WITIHNSHWSGZLH-UHFFFAOYSA-N 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910003849 O-Si Inorganic materials 0.000 description 1
- 229910003872 O—Si Inorganic materials 0.000 description 1
- OOUTWVMJGMVRQF-DOYZGLONSA-N Phoenicoxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)C(=O)C(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)C(=O)CCC2(C)C OOUTWVMJGMVRQF-DOYZGLONSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 125000004036 acetal group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000005011 alkyl ether group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- AXEPYENIMXTQSM-UHFFFAOYSA-N benzene;phosphane Chemical compound P.C1=CC=CC=C1 AXEPYENIMXTQSM-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000012682 canthaxanthin Nutrition 0.000 description 1
- 239000001659 canthaxanthin Substances 0.000 description 1
- 229940008033 canthaxanthin Drugs 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical class O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 235000021463 dry cake Nutrition 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000010653 organometallic reaction Methods 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000003822 preparative gas chromatography Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/24—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by six-membered non-aromatic rings, e.g. beta-carotene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/04—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
- C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
- C07C403/10—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by etherified hydroxy groups
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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
- C07D317/44—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 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—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 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5435—Cycloaliphatic phosphonium compounds
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
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- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- 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
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明描述了式Ⅰ化合物,其中R1为氢或
C1-C4-烷基,R2为C1-C4-烷基及R3为可被水解反
应转化为羟基的醚、甲硅烷基醚或醛缩醇保护基团,
特别是-CH(CH3)-O-CH2-CH3或
中的一个基团;这些化合物的制备方法(即在惰性溶剂中
在氨基化锂的存在下使式Ⅱ的链烯炔烃与式Ⅲ的环
己烯酮反应);以及式Ⅰ化合物在制备虾青素方面的应用。
Description
本发明涉及式(Ⅰ)化合物、其制备以及其在制备虾青素和其它必需的虾青素前体方面的应用,
其中
R1为H或C1-C4-烷基;R2为C1-C4-烷基;及R3为可通过水解反应转化为羟基的醚、甲硅烷基醚或醛缩醇保护基团,优选为下列基团之一:
式Ⅴ的C40-类胡萝卜素虾青素是鱼色素形成作用中所需要的染料,
从天然资源(例如藻或酵母类)中分离虾青素的可能性是有限的。因此人们一直试图通过合成的方法来制备虾青素。
一种工业上可行的虾青素的合成方法被描述于EP5748和Helv.Chim.Acta 64(1981)2436中以及下列等等。其合成路线如下:
在每一情况中所用的C9单元是2,2,4,6,6-五甲基-7,7α-二氢-2H,6H-1,3-苯并间二氧杂环戊烯-5-酮,它可由3,4-二羟基-2,6,6-三甲基-2-环己烯-1-酮与丙酮或2,2-二甲氧基丙烷反应来制备:
在所述参考文献中提及的C6单元为具有被保护的OH基的下式3-甲基戊烯炔-1-醇:
所提及的保护基除三烷基甲硅烷基外,还有叔丁基和-C(CH3)2-O-CH3基团。此外,EP5748还提及作为C6单元的下式3-甲基戊烯炔-3-醇的三烷基甲硅烷基醚:
没有给出该3-甲基戊烯炔-3-醇醚与C9单元的反应的实验实例。该合成中的关键步骤是借助于有机金属反应将C9单元键合到C5单元上。或者用格利雅试剂[在四氢呋喃(THF)中]或者用丁基锂溶液将乙炔去质子化。格利雅试剂变体和丁基锂变体在Helv.Chim.Acta 64(1981)2439中进行了系统地比较,明确优选的是丁基锂变体。在此情况中偶联产物的产率为理论值的85.6%。
经在无机酸介质中处理可以从该偶联产物中除掉所有保护基团,形成6-羟基-3-(3-甲基-5-羟基-3-戊烯-1-基炔基)-2,4,4-三甲基-2-环己烯酮。可以这样制备:用锌粉和乙酸在CH2Cl2中还原三键,随后使其与HBr反应,然后再与三苯膦反应,所得C15-三苯基鏻盐可与2,7-二甲基-2,4,6-辛三烯二醛反应制得虾青素。
所述方法本来是非常好的,只是具有必须使用丁基锂的缺点,丁基锂是非常昂贵的,易燃并且不易进行工业处理。此外,丁基锂一般以在己烷中的溶液的形式存在,所以在反应后必须处理有机溶剂的混合物。
使用格利雅试剂在工业上也不是非常有利的,这是因为处理低沸点烷基卤化物存在一定困难并且在制备格利雅试剂(在反应的开始阶段)中可能遇到某些技术问题。
本发明的一个目的是改进已知的虾青素的合成方法,以避免先有技术在将C9单元键合到C6单元上时的缺点。
我们已发现,这个目的可如下达到:当C6单元是式Ⅱ的3-甲基戊烯炔-3-醇的衍生物时,
其中R3为可经水解反应转化的羟基的醚、甲硅烷基醚或醛缩醇保护基团,特别是下列基团之一:
在工业上简单得多的条件下,即在有机溶剂中在替代丁基锂或格利雅试剂的氨基化锂的存在下,将C9单元键合到适宜的C6单元上。该反应导致形成式Ⅰ化合物,该化合物在文献中未见描述过。
该反应的平稳性是特别惊人的,因为当具有1位的醚基团的下式C6单元用作起始原料时,
在甲基叔丁基醚中它与C9单元的反应是察觉不到的。
因此本发明还涉及制备式Ⅰ化合物的方法,
其中
R1为H或C1-C4-烷基;R2为C1-C4-烷基;及R3为可通过水解反应转化为羟基的醚、甲硅烷基醚或醛缩醇保护基团;该方法包含使式Ⅱ的链烯炔烃与式Ⅲ的环己烯酮在惰性溶剂中在氨基化锂的存在下发生反应,
其中R1和R2具有上述意义。
优选的C9单元为其中R1为H或甲基且R2为甲基的式Ⅲ环己烯酮类化合物。其中R1=H且R2=甲基的式Ⅲ环己烯酮在文献中未见描述过。该化合物可通过使3,4-二羟基-2,6,6-三甲基-2-环己烯-1-酮与乙烯基乙基醚反应来制备。该C9单元与其中R3为-O-CH(CH3)-O-CH2-CH3的式Ⅱ的链烯炔烃的反应在工业上和经济上是特别优越的,因为这二个单元是用相同来源的保护基团即用乙烯基乙基醚来制备的。该链烯炔烃公开于J.Org.Chem.47(1982)2130-2134中。按照上述引用文献,在鸡油菌黄质的合成中,用丁基锂使其被金属取代,然后键合到2,6,6-三甲基-2-环己烯酮上。
适于式Ⅱ的链烯炔烃类的保护基团是那些可通过水解反应相对容易地转化为羟基的保护基团。可以提及的实例为醚基团,例如
、甲硅烷基醚基团例如-O-Si(CH3)3或醛缩醇基团例如下列各式的α-烷氧基烷基醚基团:
-O-CH2-O-CH3,
和适宜的吡喃基醚基团,例如四氢吡喃基氧基和4-甲基-5,6-二氢-2H-吡喃基氧基。
特别优越地是使用其中R3为下式四氢吡喃基氧基的式Ⅱ的链烯炔烃类,
或使用其中R3为下式的α-乙氧基乙氧基的式Ⅱ的链烯炔烃类。
式Ⅱ的链烯炔烃类的使用量基于式Ⅲ的C9单元一般过量0至100mol%,优选50至75mol%。
适宜于本发明方法的惰性溶剂一般为对氨基化锂呈惰性的溶剂。有利的是使用含醚的溶剂,例如二烷基醚类、四氢呋喃或二噁烷,特别是与水不混溶的甲基叔丁基醚。
氨基化锂的用量基于式Ⅱ的链烯炔烃一般为1.0至1.05,优选约1.02当量。
所述方法一般按下述方式进行实施:将固体氨基化锂悬浮于惰性溶剂中,并向该悬浮液中慢慢加入式Ⅱ的链烯炔烃,后者被氨基化锂去质子化;将式Ⅲ的C9单元加入到所得链烯炔锂的悬浮液中;在反应继续进行数小时后,加入水以进行水解反应,如果用甲基叔丁基醚作为溶剂,则所需式Ⅰ产物存在于上层有机相中,这极大地简化了该方法的工业实施;通过蒸馏除去溶剂和任何过量C6单元可以约95%的产率分离出式Ⅰ产物;所蒸馏出的C6单元可以容易地返送回该合成过程中。
令人惊奇的是,可以在惰性有机溶剂中有利地进行式Ⅲ的环己烯酮与式Ⅱ的链烯炔烃的反应,因为在先有技术中,例如当使用氨基化锂时,必须在-40℃并在液氨中使下式的6-氧代异佛尔酮与链烯炔烃反应(参见Helv.Chim.Acta 65(1982)No.89,958-967,尤其是960),这在工业上是非常复杂和昂贵的。
所述键合反应的温度一般为室温至所述溶剂的沸点。
在含水的酸性介质中从本发明式Ⅰ化合物中消除保护基团可以实际上定量的产率得到式Ⅵ的6-羟基-3-(3-羟基-3-甲基-4-戊烯-1-基炔基)-4,4,6-三甲基-2-环己烯-1-酮。
式Ⅵ的炔二醇在Helv.Chim.Acta 65(1982)671以及下列等等中所公开的方法中是已知的,其中尽管键合时使用了丁基锂,但其产率只有56.2%,式Ⅵ的炔二醇可用锌粉和乙酸在氯代烃(例如二氯甲烷)中或在其它惰性有机溶剂例如甲基叔丁基醚或甲苯中或者在冰醋酸中还原为式Ⅳ的C15-二醇。
用锌/乙酸还原式Ⅵ的炔二醇在文献中未见描述过。
优选使用大约20%浓度的式Ⅵ的炔二醇在二氯甲烷/冰醋酸中的溶液,所用二氯甲烷/冰醋酸的比例为约1∶2至1∶2.5。每摩尔起始原料适宜使用的锌量为约1-3克原子,优选约1.3至1.5克原子。该氢化反应的温度为-20℃至室温,优选约0℃。
以这种方法获得的式Ⅳ的C15-二醇可随后被转化为虾青素,有利地是按Helv.Chim.Acta 64(1981)2419-2446中所描述的方法进行。我们还发现由式Ⅵ的炔二醇出发合成虾青素还无需中间分离式Ⅳ的C15-二醇和由其制得的式Ⅶ的C15-溴化物,或由其制备的式Ⅷ的C15-三苯基鏻盐,即实际上以“一罐煮”的反应方式进行。与先有技术合成虾青素的方法相比,这进一步提供了更大的优点。
因此本发明还涉及一种非常优越的制备式Ⅴ的虾青素的总方法,该方法包含:
A.在惰性溶剂中在氨基化锂存在下使式Ⅱ的链烯炔烃与式Ⅲ的环己烯酮反应,
其中
R3为可通过水解反应转化为羟基的醚、甲硅烷基醚或醛缩醇保护基团,
其中R1为H或C1-C4-烷基,R2为C1-C4-烷基;
B.在含水的酸性介质中除掉所得式Ⅰ化合物中的保护基团;
C.在二氯甲烷/乙酸中用锌粉还原所得的式Ⅵ的炔二醇;
D.使所得式Ⅳ的C15-二醇与盐酸或氢溴酸反应;
E.使所得式Ⅶ的C15-卤化物与三苯膦反应;
其中X为Cl或Br,和
F.使所得式Ⅷ的三苯基鏻盐与2,7-二甲基-2,4,6-辛三烯二醛进行Wittig反应,得到虾青素。
其中X为Cl或Br。
实施例1
a.C9单元的制备
将170g(1.0mol)晶状的3,4-二羟基-2,6,6-三甲基-2-环己烯-1-酮悬浮于500ml二氯甲烷中。首先向该悬浮液中加入500mg(2.9mmol)对甲苯磺酸,然后在室温(RT)下在2小时(h)的时间内加入144g(2.0mol)乙烯基乙基醚。然后将混合物在室温下搅拌4h,然后加入100ml 5%浓度的氢氧化钠溶液。分出下面的有机相,水相用100ml二氯甲烷萃取一次,合并有机相,用200ml水洗涤,并在旋转蒸发仪上浓缩。残余物在极大地减压(油泵)的条件下干燥,得到2,4,6,6-四甲基-7,7a-二氢-6H-苯并[1,3]间二氧杂环戊烯-5-酮,为黄色油状物,用薄层色谱法(TLC)检测其为纯的,用气相色谱法(GC)检测其几乎为纯的。
粗产物通过蒸馏法(在90℃/0.1毫巴)纯化。
产量为185g,相应于理论值的94.4%。
b.式Ⅰ的C15单元的制备
将118g(5.13mol)固体氨基化锂加入到2.0升甲基叔丁基醚(MTB)中,并将该无色悬浮液在+50℃搅拌30分钟(min)。然后在30分钟时间内加入840g(5.0mol)3-(1-乙氧基乙氧基)-3-甲基-1-戊烯-4-炔,并将混合物在+50℃搅拌2小时。将其冷却至+25至30℃,然后在15分钟时间内加入558g(2.85mol)实施例1a的C9单元。将反应混合物在室温下搅拌1.5小时,然后在15分钟内将其加入到另一含有1.5升水的容器中。将各相搅拌10分钟。分出水相(下层)。有机相用水洗涤三次,每次用500ml,并在+50℃浴中在减压至150毫巴的条件下于旋转蒸发仪中浓缩。
蒸发后残余物重1435g。
通过Sambay蒸馏法(夹套温度为110℃,2-3毫巴,沸点为40-45℃)除去过量的3-(1-乙氧基乙氧基)-3-甲基-1-戊烯-4-炔。
Sambay排出物:1023g 5-[3-(1-乙氧基乙氧基)-3-甲基戊-4-烯-1-基炔基]-2,4,6,6-四甲基-5,6,7,7a-四氢苯并[1.3]间二氧杂环戊烯-5-醇,纯度为95%。
c.6-羟基-3-(3-羟基-3-甲基-4-戊烯-1-基炔基)-2,4,4-三甲基-2-环己烯-1-酮(Ⅵ)的制备
将603g(1.65mol)在1b中得到的式Ⅰ的叔醇(Sambay排出物)溶于1400ml CH2Cl2中,向其中加入500ml水,然后加入250ml 30%浓度的H2SO4,并将混合物在室温搅拌过夜。分出有机相(下层)并用500ml 5%浓度的NaHCO3溶液和500ml水各洗涤一次。
在旋转蒸发仪中浓缩有机相,在极大减压的条件下干燥油状残余物。
重量:408g 6-羟基-3-(3-羟基-3-甲基-4-戊烯-1-基炔基)-2,4,4-三甲基-2-环己烯-1-酮,相应于定量的粗产率。
d.式Ⅷ的三苯基鏻盐的制备
将248g(1mol)在实施例1c中制备的式Ⅵ的炔二醇粗品溶于1000ml二氯甲烷中。冷却至0℃后,加入180g(3.0mol)乙酸。然后在0℃以15分钟间隔分批加入11g锌粉(总共加入88g锌,相当于1.35克原子)。在最后一批锌加入之后,将混合物在0℃搅拌45分钟。滤出所得乙酸锌,滤饼用二氯甲烷洗涤二次,每次用250ml。在0℃在15分钟时间内向滤液中加入258g 47%浓度的HBr(1.50 mol HBr)的水溶液,并然后将混合物在0℃搅拌20分钟,然后加入900ml水,分出有机相(下层)。水相用150ml二氯甲烷洗涤一次。合并有机相,并与900ml水混合。加入47g固体NaHCO3,然后将各相搅拌几分钟。分出下层的那一相,用900ml水洗涤,并加入8ml 1,2-环氧丁烷。在冷却至≤+10℃的同时,在约15分钟时间内,分批加入262g(1.0mol)固体三苯膦,并在约30分钟时间内使混合物达到室温,再加入8ml 1,2-环氧丁烷。
然后,在大气压力下,蒸掉二氯甲烷,同时加入MTB直至沸点达到+55℃为止。
将三苯基鏻盐悬浮液冷却至室温,在室温下搅拌30分钟后抽滤。滤饼用MTB洗涤二次,每次用800ml,在N2气流下干燥过夜。
重量:419g(理论值的73%)。
实施例2
由式Ⅵ的炔二醇出发不分离式Ⅷ的三苯基鏻盐进行虾青素的制备
将100g式Ⅵ的炔二醇粗品(GC检测其纯度为约86%)溶于400ml二氯甲烷中。冷却至0℃后,加入72g乙酸。在0℃下,以15分钟时间间隔分批加入4.4g锌粉(总共加入35.2g锌)。在加完最后一批锌后,将混合物在0℃搅拌45分钟。滤掉所得乙酸锌,滤饼用二氯甲烷洗涤两次,每次用70ml。滤液用水洗涤两次,每次用300ml,在0℃下在30分钟时间内逐滴加入到104g 47%浓度的HBr水溶液中。将混合物在0℃搅拌30分钟,加入360ml水,分出有机相。水相用50ml二氯甲烷萃取一次。合并有机相,并与360ml水混合。加入47g固体NaHCO3,然后将各相在一起短暂地搅拌。分出下层的那相,用360ml水洗涤,加入3ml 1,2-环氧丁烷。在冷却至≤+10℃的同时,加入105g三苯鏻,并将混合物在室温下搅拌18小时。然后加入22.8g(0.139mol)C10-二醛2,7-二甲基-2,4,6-辛三烯二醛,将混合物冷却至0℃,并在0℃下加入57.5g 30%浓度的甲醇钠的甲醇溶液。将混合物在0℃搅拌3小时,然后加入500ml水。分出有机相,水相用二氯甲烷萃取两次,每次用100ml。合并有机相,用400ml水洗涤一次。在大气压力下,蒸出二氯甲烷,同时加入甲醇直至沸点为+65℃。将悬浮液回流15小时,然后冷却至0℃。滤出所得晶体,用甲醇和庚烷洗涤,然后溶于500ml二氯甲烷中。按如上所述用甲醇再次置换溶剂。干燥滤饼得到63g(理论值的76.0%)虾青素,HPLC测定纯度为98.2%。
Claims (10)
4、权利要求3中要求保护的方法,其中所述反应在作为惰性溶剂的甲基叔丁基醚中进行。
5、权利要求3中要求保护的方法,其中式Ⅱ链烯炔烃的用量基于式Ⅲ的环己烯酮过量0至100mol%。
6、权利要求3中要求保护的方法,其中所述反应在室温至所述溶剂的沸点进行。
10、制备权利要求9中要求保护的式Ⅴ虾青素的方法,其中步骤C、D、E和F实施时,无需分离式Ⅳ、Ⅶ和Ⅷ的中间体。
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DE10049271A1 (de) * | 2000-09-28 | 2002-04-11 | Basf Ag | Verfahren zur katalytischen Reduktion von Alkinverbindungen |
DE10140180A1 (de) | 2001-08-22 | 2003-03-06 | Basf Ag | Verfahren zur selektiven Reduktion von Alkinverbindungen |
CA2458696A1 (en) * | 2001-08-29 | 2003-03-13 | Basf Aktiengesellschaft | Method for producing oxocyclohexyl derivatives or oxocyclohexylene derivatives |
US6372946B1 (en) * | 2001-09-13 | 2002-04-16 | Prodemex, S.A. De C.V. | Preparation of 4,4′-diketo-β-carotene derivatives |
US7253297B2 (en) * | 2002-02-06 | 2007-08-07 | Dsm Ip Assetts B.V. | Astaxanthin esters |
US7763649B2 (en) * | 2002-07-29 | 2010-07-27 | Cardax Pharmaceuticals, Inc. | Carotenoid analogs or derivatives for controlling connexin 43 expression |
MXPA05001202A (es) * | 2002-07-29 | 2005-11-23 | Hawaii Biotech Inc | Analogos carotenoides estructurales para la inhibicion y mejora de la enfermedad. |
US7345091B2 (en) * | 2002-07-29 | 2008-03-18 | Cardax Pharmaceuticals, Inc. | Carotenoid ether analogs or derivatives for the inhibition and amelioration of disease |
US20050009788A1 (en) * | 2002-07-29 | 2005-01-13 | Lockwood Samuel Fournier | Carotenoid ester analogs or derivatives for controlling connexin 43 expression |
US7723327B2 (en) * | 2002-07-29 | 2010-05-25 | Cardax Pharmaceuticals, Inc. | Carotenoid ester analogs or derivatives for the inhibition and amelioration of liver disease |
US20050059635A1 (en) * | 2002-07-29 | 2005-03-17 | Lockwood Samuel Fournier | Carotenoid ester analogs or derivatives for controlling C-reactive protein levels |
US20050059659A1 (en) * | 2002-07-29 | 2005-03-17 | Lockwood Samuel Fournier | Carotenoid analogs or derivatives for controlling C-reactive protein levels |
US20050004235A1 (en) * | 2002-07-29 | 2005-01-06 | Lockwood Samuel Fournier | Carotenoid analogs or derivatives for the inhibition and amelioration of liver disease |
US20050143475A1 (en) * | 2002-07-29 | 2005-06-30 | Lockwood Samuel F. | Carotenoid analogs or derivatives for the inhibition and amelioration of ischemic reperfusion injury |
US20050148517A1 (en) * | 2002-07-29 | 2005-07-07 | Lockwood Samuel F. | Carotenoid ether analogs or derivatives for controlling connexin 43 expression |
US20050026874A1 (en) * | 2002-07-29 | 2005-02-03 | Lockwood Samuel Fournier | Carotenoid ether analogs or derivatives for the inhibition and amelioration of liver disease |
US7320997B2 (en) * | 2002-07-29 | 2008-01-22 | Cardax Pharmaceuticals, Inc. | Pharmaceutical compositions including carotenoid ester analogs or derivatives for the inhibition and amelioration of disease |
US20050049248A1 (en) * | 2002-07-29 | 2005-03-03 | Lockwood Samuel Fournier | Carotenoid ether analogs or derivatives for controlling C-reactive protein levels |
US7375133B2 (en) | 2002-07-29 | 2008-05-20 | Cardax Pharmaceuticals, Inc. | Pharmaceutical compositions including carotenoid ether analogs or derivatives for the inhibition and amelioration of disease |
US7521584B2 (en) * | 2002-07-29 | 2009-04-21 | Cardax Pharmaceuticals, Inc. | Carotenoid analogs or derivatives for the inhibition and amelioration of disease |
DE10254809A1 (de) * | 2002-11-22 | 2004-06-03 | Basf Ag | Verfahren zur Herstellung von Carotinoiden |
DE10358003A1 (de) * | 2003-12-11 | 2005-07-14 | Basf Ag | Verfahren zur Herstellung von Astaxanthin- und Canthaxanthin-Vorprodukten |
EP1750723A1 (en) * | 2004-04-14 | 2007-02-14 | Hawaii Biotech, Inc. | Carotenoid analogs or derivatives for the inhibition and amelioration of inflammation |
US20060058269A1 (en) * | 2004-04-14 | 2006-03-16 | Lockwood Samuel F | Carotenoid analogs or derivatives for the inhibition and amelioration of inflammation |
US20060167319A1 (en) * | 2004-10-01 | 2006-07-27 | Lockwood Samuel F | Methods for the synthesis of unsaturated ketone intermediates useful for the synthesis of carotenoids |
US20060078889A1 (en) * | 2004-10-08 | 2006-04-13 | Arindam Bhattacharjee | Array-based methods for producing ribonucleic acids |
US20070099195A1 (en) * | 2005-11-02 | 2007-05-03 | Huang Xiaohua C | Methods and compositions for separating nucleic acids from a solid support |
CL2008001699A1 (es) | 2008-06-09 | 2010-02-05 | Univ Chile | Secuencia de adn que codifica enzima con actividad citocromo p450 reductasa de x. dendrorhous; secuencia de polipeptido codificada; vector o plasmido; celula hesped; proceso de produccion de polipeptido; proceso de produccion de astaxantina desde beta-caroteno; composiciones, productos y/o formulaciones. |
CN109965279A (zh) * | 2013-11-07 | 2019-07-05 | 帝斯曼知识产权资产管理有限公司 | 包含合成的食品级虾青素的粉状制剂、油质悬浮物和膳食补充剂 |
WO2015067707A1 (en) * | 2013-11-07 | 2015-05-14 | Dsm Ip Assets B.V. | Process for the purification of astaxanthin |
WO2015067709A1 (en) * | 2013-11-07 | 2015-05-14 | Dsm Ip Assets B.V. | Process for the purification of astaxanthin |
WO2016023732A1 (de) | 2014-08-12 | 2016-02-18 | Basf Se | Verfahren zur herstellung von astaxanthin aus astacin |
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DE2964401D1 (en) * | 1978-06-02 | 1983-02-03 | Hoffmann La Roche | Process for the preparation of cyclohexenyl derivatives, and intermediates produced in the synthesis |
EP0005749B1 (de) * | 1978-06-02 | 1983-03-30 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Cyclohexenderivate, Verfahren zu deren Herstellung, sowie deren Verwendung |
DE3377127D1 (en) * | 1982-08-20 | 1988-07-28 | Hoffmann La Roche | Process for the preparation of astaxanthine and intermediates in the astaxanthine synthesis |
DE4014203A1 (de) * | 1990-05-03 | 1991-11-07 | Basf Ag | Verfahren zur herstellung von canthaxanthin und astaxanthin |
-
1993
- 1993-07-05 DE DE4322277A patent/DE4322277A1/de not_active Withdrawn
-
1994
- 1994-06-27 US US08/265,741 patent/US5455362A/en not_active Expired - Lifetime
- 1994-06-27 DE DE59408898T patent/DE59408898D1/de not_active Expired - Lifetime
- 1994-06-27 EP EP94109921A patent/EP0633258B1/de not_active Expired - Lifetime
- 1994-06-29 CA CA002127047A patent/CA2127047C/en not_active Expired - Fee Related
- 1994-07-04 NO NO942523A patent/NO307828B1/no not_active IP Right Cessation
- 1994-07-04 JP JP15244394A patent/JP3679430B2/ja not_active Expired - Fee Related
- 1994-07-05 CN CN94108274A patent/CN1052001C/zh not_active Expired - Lifetime
-
1995
- 1995-05-23 US US08/471,314 patent/US5625099A/en not_active Expired - Lifetime
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2004
- 2004-07-08 JP JP2004202237A patent/JP2004292461A/ja not_active Withdrawn
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Also Published As
Publication number | Publication date |
---|---|
JP2004292461A (ja) | 2004-10-21 |
CN1052001C (zh) | 2000-05-03 |
EP0633258A1 (de) | 1995-01-11 |
CA2127047A1 (en) | 1995-01-06 |
NO942523D0 (no) | 1994-07-04 |
EP0633258B1 (de) | 1999-11-10 |
US5455362A (en) | 1995-10-03 |
DE4322277A1 (de) | 1995-01-12 |
NO942523L (no) | 1995-01-06 |
US5625099A (en) | 1997-04-29 |
NO307828B1 (no) | 2000-06-05 |
JP3679430B2 (ja) | 2005-08-03 |
CA2127047C (en) | 2005-09-20 |
JPH0753508A (ja) | 1995-02-28 |
DE59408898D1 (de) | 1999-12-16 |
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