CN100349865C - 类胡萝卜素的制备方法 - Google Patents
类胡萝卜素的制备方法 Download PDFInfo
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- CN100349865C CN100349865C CNB2003801035099A CN200380103509A CN100349865C CN 100349865 C CN100349865 C CN 100349865C CN B2003801035099 A CNB2003801035099 A CN B2003801035099A CN 200380103509 A CN200380103509 A CN 200380103509A CN 100349865 C CN100349865 C CN 100349865C
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- 235000021466 carotenoid Nutrition 0.000 title claims abstract description 16
- 150000001747 carotenoids Chemical class 0.000 title claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 17
- 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 abstract description 11
- 238000009833 condensation Methods 0.000 claims abstract description 10
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- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
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- 125000001424 substituent group Chemical group 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 16
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 235000013793 astaxanthin Nutrition 0.000 claims description 8
- 239000001168 astaxanthin Substances 0.000 claims description 8
- 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 claims description 8
- 229940022405 astaxanthin Drugs 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- 150000004703 alkoxides Chemical class 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 229910052728 basic metal Inorganic materials 0.000 claims description 3
- 150000003818 basic metals Chemical class 0.000 claims description 3
- 235000012682 canthaxanthin Nutrition 0.000 claims description 3
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
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- JKQXZKUSFCKOGQ-JLGXGRJMSA-N (3R,3'R)-beta,beta-carotene-3,3'-diol 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)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-JLGXGRJMSA-N 0.000 description 4
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- QOPRSMDTRDMBNK-RNUUUQFGSA-N Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCC(O)C1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C QOPRSMDTRDMBNK-RNUUUQFGSA-N 0.000 description 4
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein 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(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 4
- 235000010930 zeaxanthin Nutrition 0.000 description 4
- 239000001775 zeaxanthin Substances 0.000 description 4
- 229940043269 zeaxanthin Drugs 0.000 description 4
- 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
- 238000007239 Wittig reaction Methods 0.000 description 3
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- 238000002425 crystallisation Methods 0.000 description 3
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- 238000010992 reflux Methods 0.000 description 3
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- 238000005406 washing Methods 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
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- 239000006184 cosolvent Substances 0.000 description 2
- 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 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
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- 239000012074 organic phase Substances 0.000 description 2
- 150000003008 phosphonic acid esters Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- REZQBEBOWJAQKS-UHFFFAOYSA-N triacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO REZQBEBOWJAQKS-UHFFFAOYSA-N 0.000 description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 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 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
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 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
- 241000370738 Chlorion Species 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 244000124209 Crocus sativus Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
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- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001746 carotenes Chemical class 0.000 description 1
- 235000005473 carotenes Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
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- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
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- 239000002178 crystalline material Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
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- 238000005516 engineering process Methods 0.000 description 1
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- 238000003818 flash chromatography Methods 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 235000016709 nutrition Nutrition 0.000 description 1
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- 239000003960 organic solvent Substances 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
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- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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Classifications
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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
- C07C403/24—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
- C07C1/34—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen reacting phosphines with aldehydes or ketones, e.g. Wittig reaction
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
- C07C43/15—Unsaturated ethers containing only non-aromatic carbon-to-carbon double bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
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Abstract
本发明涉及一种制备类胡萝卜素的方法。所述方法的特征在于将通式I的二烷氧基二醛(其中R1＝C1-C6-烷基)在双Wittig缩合中与式II的鏻盐反应，或在双Wittig-Horner缩合中与式III的膦酸酯反应，其中式II和III中的取代基各自独立地具有以下含义：R2＝IV；R3是芳基；R4-R6是C1-C6-烷基，和X-是无机酸或有机酸的阴离子等同物。
Description
本发明涉及一种有需要作为营养剂、食品着色剂和食品添加剂的类胡萝卜素例如β-胡萝卜素、玉米黄质、斑蝥黄、虾青素、番茄红素和藏花酸的制备方法。
已知类胡萝卜素尤其是通过C15鏻盐(C15-P)与对称C10二醛的双Wittig缩合而制备的(Cartenoids(类胡萝卜素)，第2卷，89页起，Birkhuser Verlag，1996)。
根据欲制备的类胡萝卜素的结构，例如可以在上述Wittig反应中，将以下C15鏻盐(P1-P5)反应，其中Ph是苯基，而X-是无机或有机酸的阴离子等同物：
为了合成藏花酸二酯(藏红花色素藏花酸的前体)，将C5酯鏻盐(C5-P)或C5酯膦酸酯(C5-EP)与C10二醛进行相应的Wittig或Wittig-Horner缩合(Angew.Chem.
72，911(1960)；Chem.Ber.93，1349(1960))。
这些合成方法所需的C10二醛是一种结晶物质，仅微溶于许多溶剂。因此，使用C10二醛进行的类胡萝卜素合成往往必须在作为溶剂或共溶剂的氯代烃诸如二氯甲烷或三氯甲烷或者环氧烷中进行(类胡萝卜素，第2卷，92页起；Birkhuser-Verlag，1996)。从毒性角度而言，将这些溶剂用于制备食品添加剂是不适宜的。
这就是为什么有许多方法，尤其是EP-A-0 733 619和EP-A-0 908 449，致力于在毒性上更适宜的溶剂诸如低级醇中进行这些工业方法。但是，所有这些方法仍然都需要制备和分离，以及处理和计量结晶C10二醛。但处理固体将使得基本投资较高，生产成本因此较高。
在EP-A-0 509 273中公开了一种避免上述缺点的可能性。
其中描述的方法使用式(1)的2，5-二氢呋喃作为C10二醛的合成替代品，所述2，5-二氢呋喃是油状的，并且通过2，5-二烷氧基-2，5-二氢呋喃(2)与烷基丙烯基醚(3)反应制备。
但是，该方法的缺点如下。(1)的收率只有理论值的38-56％，对于工业过程而言是不足的。其它出版物证实，类似方法一般只给出了二烷基化产物(1)的较低收率(J.Gen.Chem.USSR，
32，4，1082 f.(1962)；Tetrahedron Lett.
42，10，2003 f.(2001))。只有一个通过(1)的反应合成类胡萝卜素的实施例以52％的总收率得到β-胡萝卜素。该方法在工业化和经济上没有吸引力，因为(1)不易获得且收率低。
因此，本发明的目的是提供一种克服上述现有技术缺点的制备类胡萝卜素的方法。
该目的是通过一种制备类胡萝卜素的方法实现的，包括将通式I的二烷氧基二醛
其中R1＝C1-C6-烷基，
在双Wittig缩合中与式II的鏻盐反应，或者在双Wittig-Horner缩合中与式III的膦酸酯反应，
其中取代基各自独立地具有以下含义：
R2是：
R3是芳基；
R4-R6是C1-C6-烷基，和
X-是无机或有机酸的阴离子等同物。
上述R1和R4-R6中的烷基是支链或直链的C1-C6-烷基链，诸如甲基、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。优选的烷基是C1-C4-烷基，特别优选甲基、乙基、正丙基和1-甲基乙基，非常优选甲基和乙基。
R3的术语烷基是指膦和鏻盐中出现的常规芳基，诸如分别任选取代的苯基、甲苯基、萘基，优选苯基。
基团X-是无机或有机酸的、优选强无机酸或有机酸的阴离子等同物。
术语“强酸”包括氢卤酸(尤其是氢氯酸和氢溴酸)、硫酸、磷酸、磺酸和具有相当离解度的其它无机或有机酸。在本文中，强有机酸也指C1-C6-链烷酸。
优选提及的阴离子是选自氢卤酸、硫酸、磷酸、甲酸、乙酸和磺酸中的酸的阴离子。特别优选提及的阴离子是选自盐酸、氢溴酸、硫酸、膦酸、甲酸、乙酸和磺酸的那些酸的阴离子。特别优选Cl-、Br-、CnH2n+1-SO3 -(n＝1-4)、Ph-SO3 -、p-Tol-SO3 -或CF3-SO3 -。
本发明方法的优选实施方案涉及制备选自虾青素、番茄红素和斑蝥黄的类胡萝卜素，包括将式Ia的二烷氧基二醛
与式IIa的鏻盐反应，
其中取代基各自独立地具有以下含义：
R2是：
Ph是苯基；
Hal是卤素，优选Cl-或Br-。
Wittig或Wittig-Horner反应是在已经描述用于这些反应的条件下进行(类胡萝卜素，第2卷，79页起，Birkhuser-Verlag，1996，及其中引用的参考文献；和EP-A-0 733 619)。该反应可以在例如由惰性有机溶剂诸如卤代烃或者环状醚或开链醚以及碱金属或碱土金属醇盐组成的体系中进行，优选在相应链烷醇中的溶液。此时，也可以使用环氧烷，优选1，2-环氧丁烷，按照本身已知的方式，作为潜在碱(latent base)和共溶剂与低级链烷醇结合。
常规用于Wittig缩合的所有碱均可用作碱，例如碱金属氢氧化物，诸如氢氧化钠、氢氧化钾或氢氧化锂；碱金属氢化物，诸如氢化钠或氢化钾。
但优选使用的溶剂是所需终产物微溶于该溶剂中，而作为Wittig反应副产物得到的氧化三苯膦易溶于该溶剂中。
适用于该目的的尤其是低级醇，优选C1-C6醇，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇或叔丁醇，特别优选甲醇。此时优选使用的碱是碱金属或碱土金属醇盐，优选甲醇钠。可以通过用水稀释混合物除去氧化三苯基膦和无机盐。
缩合反应一般在-30℃至+50℃，优选-20至+30℃，特别优选-10℃至+25℃，非常优选0℃至+20℃的温度下进行。
在本文中，可以将两种原料化合物(鏻盐和醛)一起引入溶剂中并向其中加入碱，也可以向鏻盐的溶液中加入碱，随后才加入醛的溶液。
碱的用量一般是按每摩尔使用的鏻盐II或膦酸酯III计的0.8-5摩尔，优选1-3摩尔。
在Wittig或Wittig-Horner反应之后，可以按照已知方式，通过在70-120℃的温度范围、优选于所用溶剂的沸点下加热数小时，将产物热异构化为全部(E)形式，并且通过过滤以高收率和高纯度分离。
用于本发明的二烷氧基二醛I或Ia
是在用六烷氧基衍生物V作为原料、随后进行缩醛裂解和消去反应的C10二醛工业合成中以中间体形式出现的，但通常无需分离(类胡萝卜素，第2卷，117/118页和301/302页，Birkhuser Verlag，1996；CH专利.321 106).通过反应条件的适当选择，可以在I的中间阶段中止操作。可以通过蒸馏分离和纯化I(J.Gen.Chem.USSR，
34，1，64 f.(1964))。
式I的二烷氧基二醛是易溶的稳定物质，并且是液体或油状的，因此省去了C10二醛固体的加工处理。使用I的其它优点在于通过一步合成和一步除去固体而缩短了制备C10单元的工艺。
已经令人惊奇地发现，式I的中间体，优选Ia，特别适用于上述所有Wittig和Wittig-Horner缩合。此时出现的中间体是通式IV的烷氧基衍生物。
如果需要，这些中间体阶段可以分离出来。但是，优选在反应条件下能消去所需的多烯，优选通过提高反应温度来进行。
本发明还涉及式IV的化合物，
其中取代基各自独立地具有以下含义：
R1是C1-C6-烷基；
R2是：
R6是C1-C6-烷基。
优选的化合物是式IV的那些，
其中
R1是甲基或乙基，特别优选甲基；和
R2是：
以下实施例用于更详细地解释本发明的方法。
实施例1
制备虾青素
将71.9g(0.125mol)虾青素C15鏻盐P5(X-＝溴离子)引入150ml甲醇中。于0℃下加入11.4g C10二醛Ia(纯度95％；相当于0.0475mol)。随后于0℃下经1小时滴加24.8g浓度30％的甲醇钠的甲醇溶液(＝0.137molNaOMe)，混合物于0℃下再搅拌1小时，并随后达到室温。滴加1.5g(25mmol)乙酸于115ml水中的溶液，混合物加热至回流(约75℃)并接着在回流下搅拌20小时。使其达到室温，滤出结晶。用60∶40(v/v)甲醇/水混合物洗涤滤饼二次，每次100ml，用热水(100ml)洗涤一次，用甲醇(100ml；25℃)洗涤一次，并在+50℃下于真空干燥箱中干燥。
最终重量：23.5g虾青素＝收率83.0％(基于使用的Ia)；HPLC纯度：99.17％
实施例2
虾青素中间体阶段IVe的分离
将71.9g(0.125mol)虾青素C15鏻盐P5(X-＝溴离子)溶于250ml二氯甲烷中。在0℃下加入11.4g C10二醛Ia(纯度95％；相当于0.0475mol)。随后于0℃下经1小时滴加46.8g浓度20％的乙醇钠的乙醇溶液(0.137molNaOEt)。混合物于0℃下搅拌1小时。然后滴加1.5g乙酸于250ml水中的溶液。分离有机相。水相用40ml二氯甲烷反萃取二次。用水洗涤合并的有机相两次，每次125ml，经硫酸钠干燥并在旋转蒸发器中浓缩。通过在硅胶上闪蒸色谱法纯化亮红色糊状残余物(洗脱液：环己烷/甲基叔丁基醚＝4∶1-1∶1)。
得到27.05g(理论值的86.3％)粘稠的红色油状物，根据H-NMR、C-NMR和IR分析，获得了含有立体异构体混合物形式的IVe。E1 1(CHCl3)：335(260nm)；468(351nm)。
实施例3
制备玉米黄质
将14.9g(0.0288mol)玉米黄质C15鏻盐P3(X-＝氯离子)溶于63ml乙醇。加入2.85g C10二醛Ia(纯度95％；相当于0.012mol)和16.6g环氧丁烷(1，2-环氧丁烷)。随后将混合物在回流下加热20小时。得到的悬浮液冷却至0℃，并于该温度下搅拌1小时。抽滤出结晶。使用乙醇洗涤滤饼三次，每次50ml，并于真空干燥箱中干燥。
最终重量：5.52g玉米黄质＝理论值的81％(基于使用的Ia)。
Claims (7)
1.一种制备类胡萝卜素的方法，包括将通式I的二烷氧基二醛
其中R1＝C1-C6-烷基，
在双Wittig缩合中与式II的鏻盐反应，或在双Wittig-Horner缩合中与式III的膦酸酯反应
其中取代基各自独立地具有以下含义：
R2是：
R3是芳基；
R4-R6是C1-C6-烷基，和
X-是无机酸或有机酸的阴离子。
2.权利要求1的方法，其中X-是选自氢卤酸、硫酸、磷酸、甲酸、乙酸和磺酸中的酸的阴离子。
3.权利要求2的方法，其中X-选自Cl-、Br-、CnH2n+1-SO3 -，其中n＝1-4，苯磺酸根、对甲苯磺酸根或CF3-SO3 -。
4.权利要求1的方法，用于制备选自虾青素、番茄红素和斑蝥黄的类胡萝卜素，其中包括将式Ia的二烷氧基二醛
与式IIa的鏻盐反应，
其中取代基各自独立地具有以下含义：
R2是：
Ph是苯基；
Hal是卤素。
5.权利要求1-4任一项的方法，其中该反应是使用碱金属或碱土金属醇盐作为碱在C1-C6醇中进行。
6.权利要求1-5任一项的方法，其中将反应产物热异构化为所有(E)形式，并通过过滤分离。
7.式IV的化合物，
其中取代基R1和R2各自独立地具有权利要求1所述的含义。
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| US7759506B2 (en) | 2002-02-25 | 2010-07-20 | Diffusion Pharmaceuticals Llc | Bipolar trans carotenoid salts and their uses |
| US7235688B1 (en) | 2004-11-04 | 2007-06-26 | University Of Notre Dame Du Lac | Process for preparing histone deacetylase inhibitors and intermediates thereof |
| CN101180257A (zh) | 2005-02-24 | 2008-05-14 | 扩散药品有限公司 | 反式类胡萝卜素、其合成、制剂和用途 |
| WO2007128574A1 (en) * | 2006-05-10 | 2007-11-15 | Dsm Ip Assets B.V. | Process for the preparation of astaxanthin |
| FR2915200B1 (fr) * | 2007-04-20 | 2009-07-03 | Centre Nat Rech Scient | Procede de preparation de ligands de type phosphines butadieniques,leurs complexes avec le cuivre,et leurs applications en catalyse |
| JP2011502125A (ja) | 2007-10-31 | 2011-01-20 | ディフュージョン・ファーマシューティカルズ・エルエルシー | 小分子拡散を促進する新しい種類の治療法 |
| JP5787884B2 (ja) | 2009-06-22 | 2015-09-30 | ディフュージョン・ファーマシューティカルズ・エルエルシー | 拡散増強化合物、及びその単独使用又は血栓溶解剤との併用 |
| TWI501946B (zh) * | 2010-02-08 | 2015-10-01 | Basf Se | 蝦紅素二琥珀酸二甲酯之製造方法 |
| CN105287473A (zh) | 2010-06-02 | 2016-02-03 | 扩散药品有限公司 | 包含双极性反式类胡萝卜素的组合物及其应用 |
| WO2013010820A1 (en) * | 2011-07-15 | 2013-01-24 | Dsm Ip Assets B.V. | Process for the maintaining of a ratio of isomers of carotenoid compounds |
| WO2015097717A2 (en) * | 2013-12-23 | 2015-07-02 | Laurus Labs Private Limited | AN IMPROVED PROCESS FOR THE PREPARATION OF β-CAROTENE |
| DK2957565T3 (en) | 2014-06-18 | 2018-05-22 | Allied Biotech Corp | Methods for Preparing Lycopene from C-15-Wittig Salts and Methods for Purifying C15-Wittig Salts with High All-E Content and High 6Z Content |
| US10480274B2 (en) * | 2014-12-15 | 2019-11-19 | Enpro Subsea Limited | Apparatus, systems and method for oil and gas operations |
| KR20230014850A (ko) | 2016-03-24 | 2023-01-30 | 디퓨젼 파마슈티컬즈 엘엘씨 | 암을 치료하기 위한, 화학 요법 및 방사선 요법과의 양극성 트랜스 카로티노이드의 용도 |
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| DE19509955A1 (de) * | 1995-03-18 | 1996-09-19 | Basf Ag | Verfahren zur Herstellung von Astaxanthin |
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- 2003-11-17 EP EP03767554A patent/EP1565434A1/de not_active Withdrawn
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- 2003-11-17 AU AU2003292029A patent/AU2003292029A1/en not_active Abandoned
- 2003-11-17 JP JP2004554359A patent/JP2006507332A/ja not_active Withdrawn
- 2003-11-17 WO PCT/EP2003/012804 patent/WO2004048323A1/de active Application Filing
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0908449A1 (de) * | 1997-10-03 | 1999-04-14 | F. Hoffmann-La Roche Ag | Herstellung von Carotinoiden |
Also Published As
| Publication number | Publication date |
|---|---|
| US20060106257A1 (en) | 2006-05-18 |
| DE10254809A1 (de) | 2004-06-03 |
| JP2006507332A (ja) | 2006-03-02 |
| EP1565434A1 (de) | 2005-08-24 |
| CN1711240A (zh) | 2005-12-21 |
| US7378558B2 (en) | 2008-05-27 |
| WO2004048323A1 (de) | 2004-06-10 |
| AU2003292029A8 (en) | 2004-06-18 |
| AU2003292029A1 (en) | 2004-06-18 |
| WO2004048323A8 (de) | 2005-07-21 |
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