CN108822015B - Method for synthesizing beta-carotene - Google Patents
Method for synthesizing beta-carotene Download PDFInfo
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- CN108822015B CN108822015B CN201810818995.0A CN201810818995A CN108822015B CN 108822015 B CN108822015 B CN 108822015B CN 201810818995 A CN201810818995 A CN 201810818995A CN 108822015 B CN108822015 B CN 108822015B
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- Prior art keywords
- reaction
- carotene
- molecular sieve
- beta
- phosphonium salt
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- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products 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=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 title claims abstract description 47
- 235000013734 beta-carotene Nutrition 0.000 title claims abstract description 47
- 239000011648 beta-carotene Substances 0.000 title claims abstract description 47
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene 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=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 title claims abstract description 47
- 229960002747 betacarotene Drugs 0.000 title claims abstract description 47
- OENHQHLEOONYIE-JLTXGRSLSA-N β-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=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 title claims description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims abstract description 43
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000007787 solid Substances 0.000 claims abstract description 32
- 150000004714 phosphonium salts Chemical class 0.000 claims abstract description 24
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000002808 molecular sieve Substances 0.000 claims abstract description 23
- 239000001301 oxygen Substances 0.000 claims abstract description 23
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 23
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 238000005691 oxidative coupling reaction Methods 0.000 claims abstract description 14
- 238000005859 coupling reaction Methods 0.000 claims abstract description 13
- 150000003682 vanadium compounds Chemical class 0.000 claims abstract description 11
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 10
- 235000019169 all-trans-retinol Nutrition 0.000 claims abstract description 7
- 239000011717 all-trans-retinol Substances 0.000 claims abstract description 7
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 230000035484 reaction time Effects 0.000 claims abstract description 5
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 4
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 17
- -1 tetrafluoroborate Chemical compound 0.000 claims description 13
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 8
- 239000002202 Polyethylene glycol Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- 229910003206 NH4VO3 Inorganic materials 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 claims description 4
- XQQZRZQVBFHBHL-UHFFFAOYSA-N 12-crown-4 Chemical compound C1COCCOCCOCCO1 XQQZRZQVBFHBHL-UHFFFAOYSA-N 0.000 claims description 3
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 claims description 3
- 150000007514 bases Chemical class 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- 229910021144 KVO3 Inorganic materials 0.000 claims description 2
- 229910019501 NaVO3 Inorganic materials 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 125000002723 alicyclic group Chemical group 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 229910000318 alkali metal phosphate Inorganic materials 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- YSSSPARMOAYJTE-UHFFFAOYSA-N dibenzo-18-crown-6 Chemical compound O1CCOCCOC2=CC=CC=C2OCCOCCOC2=CC=CC=C21 YSSSPARMOAYJTE-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 235000021317 phosphate Nutrition 0.000 claims 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 15
- 239000007800 oxidant agent Substances 0.000 abstract description 8
- 230000003647 oxidation Effects 0.000 abstract description 8
- 238000007254 oxidation reaction Methods 0.000 abstract description 8
- 230000001590 oxidative effect Effects 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 3
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- 239000004721 Polyphenylene oxide Substances 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 239000007789 gas Substances 0.000 abstract description 2
- 229910021645 metal ion Inorganic materials 0.000 abstract description 2
- 229920000570 polyether Polymers 0.000 abstract description 2
- 239000002351 wastewater Substances 0.000 abstract description 2
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 29
- 235000019155 vitamin A Nutrition 0.000 description 29
- 239000011719 vitamin A Substances 0.000 description 29
- 229940045997 vitamin a Drugs 0.000 description 29
- 238000001914 filtration Methods 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
- 238000001816 cooling Methods 0.000 description 23
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- 238000010438 heat treatment Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000006317 isomerization reaction Methods 0.000 description 12
- 238000002156 mixing Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 10
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- CDXSJGDDABYYJV-UHFFFAOYSA-N acetic acid;ethanol Chemical compound CCO.CC(O)=O CDXSJGDDABYYJV-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
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- YYGVWYKSYSKWET-UHFFFAOYSA-N C1(=CC=CC=C1)S(=O)(=O)[O-].C1(=CC=CC=C1)[PH+](C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C1(=CC=CC=C1)S(=O)(=O)[O-].C1(=CC=CC=C1)[PH+](C1=CC=CC=C1)C1=CC=CC=C1 YYGVWYKSYSKWET-UHFFFAOYSA-N 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 229960000342 retinol acetate Drugs 0.000 description 3
- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical compound CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 description 3
- 235000019173 retinyl acetate Nutrition 0.000 description 3
- 239000011770 retinyl acetate Substances 0.000 description 3
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- DXZAIXOZCUYCQT-UHFFFAOYSA-N 5-(bromomethyl)-3-hydroxy-2,2,4,4-tetramethyl-1-oxidoimidazol-1-ium Chemical compound CC1(C)N(O)C(C)(C)[N+]([O-])=C1CBr DXZAIXOZCUYCQT-UHFFFAOYSA-N 0.000 description 2
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- NCYCYZXNIZJOKI-OVSJKPMPSA-N Retinaldehyde Chemical compound O=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- BGYBTGDDOPTJSB-UHFFFAOYSA-N acetic acid;ethane-1,2-diol Chemical compound CC(O)=O.OCCO BGYBTGDDOPTJSB-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 235000020945 retinal Nutrition 0.000 description 2
- 239000011604 retinal Substances 0.000 description 2
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 2
- YGNORFLIQAXXCM-UHFFFAOYSA-N sulfuric acid;triphenylphosphane Chemical compound OS([O-])(=O)=O.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YGNORFLIQAXXCM-UHFFFAOYSA-N 0.000 description 2
- AVCVDUDESCZFHJ-UHFFFAOYSA-N triphenylphosphane;hydrochloride Chemical compound [Cl-].C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 AVCVDUDESCZFHJ-UHFFFAOYSA-N 0.000 description 2
- 229910052720 vanadium Inorganic materials 0.000 description 2
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 2
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 2
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 150000004347 all-trans-retinol derivatives Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- ZJVJZSWVDUZQPR-UHFFFAOYSA-N benzenesulfonic acid;ethane-1,2-diol Chemical compound OCCO.OS(=O)(=O)C1=CC=CC=C1 ZJVJZSWVDUZQPR-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229940006460 bromide ion Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- VTIIJXUACCWYHX-UHFFFAOYSA-L disodium;carboxylatooxy carbonate Chemical compound [Na+].[Na+].[O-]C(=O)OOC([O-])=O VTIIJXUACCWYHX-UHFFFAOYSA-L 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229940045872 sodium percarbonate Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- 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)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The synthesis process of beta-carotene includes preparing organic phosphonium salt with vitamin A alcohol or its derivative, and the intermolecular oxidative coupling reaction in oxygen atmosphere in the presence of vanadium compound catalyst and molecular sieve to obtain beta-carotene. The method adopts clean, environment-friendly, economic, easily available, convenient and safe oxygen-containing gas as the oxidant, has no harm to the environment, has low cost and is beneficial to industrial production. The vanadium compound is used as a catalyst, so that the coupling reaction time is obviously reduced; the molecular sieve is used as a cocatalyst, so that the use amount of the catalyst is reduced, the catalytic oxidation effect is improved, and the discharge of waste water containing metal ions is reduced. The polyether phase transfer catalyst is added to initiate the reaction between substrates in a heterogeneous reaction system; the solid alkaline compound and the solid alkaline compound form a complex and are dissolved in the organic phase to participate in the reaction, so that the solubility of the alkali in the organic phase is effectively controlled, the reaction is promoted, the generation of byproducts is inhibited, the yield of the seed product is increased, and the aim of improving the yield is fulfilled.
Description
Technical Field
The invention relates to beta-carotene, in particular to a synthesis method of the beta-carotene.
Background
The beta-carotene is a vitamin A source substance, can be used in the industries of medicines, foods, cosmetics, feed additives and dyes, and has good market prospect.
Many domestic researches on the synthesis of the beta-carotene are reported, and the synthesis route of the beta-carotene can be divided into condensation reactions of C19+ C2+ C19, C15+ C10+ C15 and C20+ C20 according to different reaction routes. Wherein, the organic phosphonium salt obtained by the reaction of vitamin A alcohol or the derivative thereof and triphenylphosphine is an important intermediate of beta-carotene, which can further carry out condensation reaction of C20+ C20 Wittig to prepare the beta-carotene and can also carry out self intermolecular oxidative coupling reaction in the presence of an oxidant to prepare the beta-carotene;
wittig condensation reaction route: the vitamin A alcohol or the derivative thereof reacts with triaryl phosphine to obtain organic phosphonium salt, and the organic phosphonium salt is further condensed with vitamin A aldehyde through a Wittig reaction to obtain the beta-carotene. In the process, the Wittig reaction requires no water and oxygen, the conditions are harsh, the chemical property of the vitamin A aldehyde is unstable, and the industrial preparation is difficult. The reaction formula is as follows:
the oxidative coupling reaction is to obtain the beta-carotene by oxidative coupling between two molecules of VA phosphonium salt. Because the structure of the beta-carotene is symmetrical, the process route for preparing the beta-carotene by carrying out the oxidative coupling reaction between two molecules of organic phosphonium salt is simpler.
The reaction formula is as follows:
in the prior art of preparing β -carotene by oxidative coupling reaction, Chinese patent CN101081829A discloses that β -carotene is obtained by coupling reaction of organic phosphonium salt of vitamin A alcohol or derivatives thereof in the presence of oxidant such as hypochlorite, chlorate, hydrogen peroxide, sodium percarbonate, oxygen or air, and the substances are reacted in a two-phase system consisting of water phase and organic solvent, because the organic phosphonium salt is subjected to the reaction in the reaction processThe right end of the dynamic balance is phosphine ylide which is very sensitive to protic solvents such as water and is easy to decompose when meeting water or being heated. Therefore, when the above oxidative coupling reaction is carried out in an aqueous system, the yield of the target product is not high due to the instability of the intermediate.
The oxygen is a recognized green oxidant, the reaction product is water, and the method has the advantages of economy, practicability, environmental protection and the like, and the prior art reports about the application of the oxygen in the oxidative coupling reaction of the vitamin A organic phosphonium salt, but the current research result shows that the molecular oxygen as the oxidant not only has slow reaction rate and low product yield, but also sometimes does not react in the coupling reaction.
Disclosure of Invention
In view of the above disadvantages of the prior art, the present invention aims to provide a method for preparing beta-carotene, which is simple and convenient to operate, mild in reaction conditions, low in cost, high in yield and suitable for industrial production.
The method comprises the following specific steps:
preparing organic phosphonium salt from vitamin A alcohol or its derivative, and carrying out intermolecular oxidative coupling reaction in the presence of vanadium compound catalyst and molecular sieve in oxygen atmosphere to obtain beta-carotene.
The intermolecular oxidative coupling reaction is carried out in a solid-liquid two-phase reaction system consisting of an organic solvent, a phase transfer catalyst and an alkaline compound, and the reaction route is as follows:
wherein R1, R2 and R3 are aromatic groups, aliphatic groups and alicyclic groups, and R1, R2 and R3 are phenyl, benzyl, cyclohexyl or butyl;being acid radicals of inorganic strong acids or acid radicals of organic strong acids, saidCan be selected from one of hydrogen sulfate, tetrafluoroborate, phosphate, acetate, tosylate, benzene sulfonate and the like, and preferably is chloride ion, bromide ion, iodide ion and the like.
The organic phosphonium salt reacts with an alkaline compound under the action of a phase transfer catalyst to generate phosphine ylide, and part of intermediate ylide is oxidized into corresponding VA aldehyde under the action of the catalyst; then, VA aldehyde reacts with the other part of phosphine in a ylide manner to generate a target product beta-carotene; the intermediate aldehyde and phosphine ylide are generated under the catalysis of an alkaline compound and consumption, and the generation of byproducts such as aldehyde self-condensation and the like can be effectively avoided.
Said vanadium compound may be selected from VO (acac)2、VO(OAc)2、VO(hfac)2、NH4VO3、NaVO3、KVO3、V2O5、VO(OEt)3、VO(OPr)3、VO(Oi-Pr)3Etc., preferably VO (acac)2、VO(OAc)2、NH4VO3、V2O5Etc., preferably VO (acac)2。
The molecular sieve can be selected from at least one of 3A molecular sieve, 4A molecular sieve, 5A molecular sieve and the like.
The basic compound may be at least one selected from alkali metal hydroxide, alkali metal alkoxide, alkali metal carbonate, alkali metal phosphate, alkali metal organic acid salt, etc.; preferably K2CO3、Na2CO3、Cs2CO3、Li2CO3、NaOH、KOH、LiOH、K3PO4、Na3PO4At least one of BuOK, Buona, NaOAc, KOAc, EtONa, EtOK, etc., preferably K2CO3At least one of NaOH, KOH, EtONa, BuONa, etc.
The phase transfer catalyst can be at least one selected from 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, polyethylene glycol with average molecular weight of 1000, polyethylene glycol with average molecular weight of 1500, polyethylene glycol with average molecular weight of 2000, tetraethylene glycol dimethyl ether, etc.
The organic solvent can be at least one selected from toluene, dichloromethane, chloroform, benzene, dichloroethane, n-hexane, tetrahydrofuran, petroleum ether, methyl tert-butyl ester, etc.
The molar ratio of the organic phosphonium salt to the catalyst can be 1: 0.01-1.
The ratio of the organic phosphonium salt in millimoles (mmol) to the molecular sieve in grams by mass (g) may be 1: 0.1-0.5.
The molar ratio of the organic phosphonium salt to the base can be 1: 1.5-3.
The molar ratio of the organic phosphonium salt to the phase transfer catalyst can be 1: 1.5-3.
The molar volume ratio (mol/L) of the organic phosphonium salt to the organic solvent can be 1: 10-30.
The reaction temperature of the coupling reaction can be 10-60 ℃, and preferably 25-40 ℃.
The reaction time of the coupling reaction can be 2-8 h; preferably 2-4 h.
After the intermolecular oxidative coupling reaction, the reaction liquid is cooled and layered to remove solids, the red solid obtained after the organic phase is washed with water and the solvent is concentrated and recovered is a mixture consisting of beta-carotene and a phosphine oxide compound, the mixture is washed with alcohol (such as methanol) to remove the phosphine oxide compound, and then recrystallization or heating in the solvent is carried out, and rearrangement treatment from various cis-mixtures to all-trans structures is carried out.
The invention has the following advantages:
1. the method adopts clean, environment-friendly, economic, easily available, convenient and safe oxygen-containing gas as the oxidant, has no harm to the environment, has low cost and is beneficial to industrial production.
2. The vanadium compound is used as a catalyst, so that the coupling reaction time is obviously reduced; the molecular sieve is used as a cocatalyst, so that the use amount of the catalyst is reduced, the catalytic oxidation effect is improved, and the discharge of waste water containing metal ions is reduced.
3. Carbonate can be adopted in the reaction, and organic strong alkaline compounds such as LDA, butyl lithium, sodium amide and the like are avoided.
4. The reaction is carried out in a solid-liquid two-phase reaction system consisting of an organic solvent, a phase transfer catalyst and an alkaline compound, so that the solubility of alkali in a reaction organic phase can be effectively controlled, the side reactions of VA aldehyde self-condensation and product molecule conjugated double bond damage caused by overhigh alkali concentration are avoided, and the yield of a target product is improved;
5. the reaction condition is mild, the restriction of strict anhydrous and anaerobic reaction condition is avoided, the operation is simple, and the safety factor is high; the three wastes generated by the reaction are easy to treat, and are more environment-friendly compared with other methods.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1: coupling reaction for preparing beta-carotene
90g of vitamin A acetate oil (221.3 ten thousand IU/g, 0.208mol) and 48.4g of aniline (0.52mol) are dissolved in 1100ml of ethanol to prepare a vitamin A acetate-ethanol solution. 218.2g of triphenylphosphine (0.832mol) and 2300ml of ethanol are respectively added into a three-neck flask, the temperature is reduced to be below 10 ℃, 31.0g of concentrated sulfuric acid (0.316mol) is slowly dripped into a dropping funnel, the dripping temperature is controlled to be below 10 ℃, and the stirring is continued for 2 hours after the dripping is finished. Adding vitamin A acetate-ethanol solution, and reacting at 25 ℃ for 24h to obtain vitamin A triphenyl phosphine chloride solution. Then concentrating under reduced pressure, adding 200ml acetone for dissolving, putting into a refrigerator for 24h for crystallization, filtering the crystal, washing and drying to obtain the vitamin A triphenylphosphine sulfate (the same below).
Mixing vitamin A triphenylphosphine sulfate (1.0mmol), VO (acac)2(0.1mmol), 3A molecular sieves (0.3g), 18-crown-6 (2.0mmol) and K2CO3(2.0mmol) is added into toluene (20ml), the reaction solution is stirred and reacted for 6h at 40 ℃ under the condition of introducing oxygen and keeping normal pressure, the reaction solution is cooled to room temperature, solid residues are removed by filtration, the filtrate is vacuumized and concentrated, the obtained solid is a target product β -carotene crude product, the crude product is dissolved in n-hexane under the protection of nitrogen, reflux and heating are carried out for 12h, isomerization treatment of various cis compounds to all-trans structures is carried out, then cooling, filtration and drying are carried out to obtain dark red crystals, and the analysis is carried out by adopting a GB5009.83-2016 method (the same detection method is carried out), wherein the content is 99.0 percent (HPLC) and the total yield is 84 percent.
Example 2
90g of vitamin A acetate oil (221.3 ten thousand IU/g, 0.208mol) and 48.4g of aniline (0.52mol) are dissolved in 1100ml of ethanol to prepare a vitamin A acetate-ethanol solution. 218.2g of triphenylphosphine (0.832mol) and 2300ml of ethanol are respectively added into a three-neck flask, the temperature is reduced to 10 ℃, 51.5ml of concentrated hydrochloric acid (mass concentration is 37.5 percent and 0.624mol) is slowly dripped into a dropping funnel, the dripping temperature is controlled to 10 ℃, and the stirring is continued for 2 hours after the dripping is finished. Adding vitamin A acetate-ethanol solution, and reacting at 25 ℃ for 24h to obtain vitamin A triphenyl phosphine chloride solution. Then concentrating under reduced pressure, adding 200ml acetone for dissolving, putting into a refrigerator for 24h for crystallization, filtering, washing and drying the crystals to obtain the vitamin A triphenylphosphine hydrobromide (the same below).
Mixing vitamin A triphenylphosphine hydrochloride (1.0mmol), VO (OAc)2(0.1mmol), 4A molecular sieve (0.3g), 18-crown-6 (2.0mmol) and EtONa (2.0mmol) were added to anhydrous methanol (20ml), and the reaction solutionStirring and reacting for 8h at 40 ℃ under the condition of introducing oxygen and keeping normal pressure, cooling the reaction liquid to room temperature, filtering to remove solid residues, vacuumizing and concentrating the filtrate to obtain a solid β -carotene crude product, dissolving the crude product in n-hexane under the protection of nitrogen, refluxing and heating for 12h to perform isomerization treatment of various cis-compounds to an all-trans structure, cooling, filtering, and drying to obtain a dark red crystal with the content of 99.1% (HPLC), wherein the total yield is 70%.
Example 3
90.96g vitamin A alcohol (294.97 ten thousand IU/g, 0.281mol) and 15.4ml pyridine (0.191mol) are dissolved in 500ml methanol to prepare vitamin A alcohol-methanol solution. 77.4g (0.295mol) of triphenylphosphine and 1000ml of methanol are respectively added into a three-neck flask, the temperature is reduced to 0 ℃, 45.4ml of HBr (the mass concentration is 47 percent, and the mol is 0.393mol) is slowly dripped into a dropping funnel, the dripping temperature is controlled to be 0 ℃, stirring is continuously carried out for 2h after the dripping is finished, vitamin A alcohol-methanol solution is added, and the reaction is carried out for 24h at the temperature of 10 ℃. Then concentrating under reduced pressure, adding 200ml acetone for dissolving, putting into a refrigerator for 24h for crystallization, filtering, washing and drying the crystals to obtain the vitamin A triphenylphosphine hydrobromide (the same below).
Mixing vitamin A triphenylphosphine hydrobromide (1.0mmol) and NH4VO3Adding (0.1mmol), 4A molecular sieve (0.3g), 12-crown-4 (2.0mmol) and KOH (2.0mmol) into tetrahydrofuran (20ml), stirring and reacting the reaction solution at 40 ℃ for 5h under the condition of introducing oxygen and keeping normal pressure, cooling the reaction solution to room temperature, filtering to remove solid residues, vacuumizing and concentrating the filtrate to obtain a solid β -carotene crude product, dissolving the crude product in n-hexane under the protection of nitrogen, refluxing and heating for 12h to perform isomerization treatment of various cis-compounds to an all-trans structure, cooling and filtering, and drying to obtain a dark red crystal with the content of 98.7% (HPLC), wherein the total yield is 72%.
Example 4
90g of vitamin A acetate oil (221.3 ten thousand IU/g, 0.208mol) and 22.7g of p-aminophenol (0.208mol) are dissolved in 380ml of ethylene glycol to prepare a vitamin A acetate-ethylene glycol solution. 95.5g of triphenylphosphine (0.364mol) and 880ml of ethylene glycol are respectively added into a three-neck flask, the temperature is reduced to 10 ℃, 277.4g of benzenesulfonic acid ethylene glycol solution (with the mass concentration of 19.6 percent and the mass concentration of 0.344mol) is slowly dripped into a dropping funnel, the dripping temperature is controlled to 10 ℃, and the stirring is continued for 2 hours after the dripping is finished. Adding vitamin A acetate-ethylene glycol solution, and reacting at 25 ℃ for 40h to obtain the vitamin A triphenylphosphine benzene sulfonate solution. Then concentrating under reduced pressure, adding 200ml acetone for dissolving, putting into a refrigerator for 24h for crystallization, filtering, washing and drying the crystals to obtain the vitamin A triphenylphosphine benzene sulfonate (the same below).
Mixing vitamin A triphenylphosphine benzene sulfonate (1.0mmol) and V2O5Adding (0.1mmol), 3A molecular sieve (0.3g), 18-crown ether-6 (2.0mmol) and BuONa (2.0mmol) into dichloromethane (20ml), stirring and reacting the reaction solution at 40 ℃ under the condition of introducing oxygen and keeping normal pressure for 6h, cooling the reaction solution to room temperature, filtering to remove solid residues, vacuumizing and concentrating the filtrate to obtain a solid β -carotene crude product, dissolving the crude product in n-hexane under the protection of nitrogen, refluxing and heating for 12h to perform isomerization treatment of various cis-compounds to an all-trans structure, cooling and filtering, and drying to obtain a dark red crystal with the content of 99.2% (HPLC), wherein the total yield is 68%.
Example 5
Mixing vitamin A triphenylphosphine hydrobromide (1.0mmol), VO (acac)2Adding (0.1mmol), 3A molecular sieve (0.3g), 18-crown ether-6 (2.0mmol) and KOH (2.0mmol) into toluene (20ml), stirring and reacting the reaction solution at 40 ℃ for 4h under the condition of introducing oxygen and keeping normal pressure, cooling the reaction solution to room temperature, filtering to remove solid residues, vacuumizing and concentrating the filtrate to obtain a solid β -carotene crude product, dissolving the crude product in n-hexane under the protection of nitrogen, refluxing and heating for 12h to perform isomerization treatment of various cis-compounds to an all-trans structure, cooling and filtering, and drying to obtain a dark red crystal with the content of 99.0% (HPLC), wherein the total yield is 91%.
Example 6
Mixing vitamin A triphenylphosphine hydrochloride (1.0mmol), VO (OAc)2(0.1mmol), 4A molecular sieves (0.3g), 15-crown-5 (2.0mmol) and K2CO3(2.0mmol) was added to n-hexane (20ml), and the reaction mixture was stirred at 40 ℃ under atmospheric pressure with oxygenAnd 5h, cooling the reaction liquid to room temperature, filtering to remove solid residues, vacuumizing and concentrating the filtrate to obtain a solid, namely a target product β -carotene crude product, dissolving the crude product in n-hexane under the protection of nitrogen, refluxing and heating for 12h to perform isomerization treatment of various cis-compounds to all-trans structures, cooling, filtering, and drying to obtain dark red crystals with the content of 98.5 percent (HPLC) and the total yield of 74 percent.
Example 7
Mixing vitamin A triphenylphosphine hydrobromide (1.0mmol), VO (acac)2Adding methyl tert-butyl ester (20ml), a 3A molecular sieve (0.3g), polyethylene glycol (0.01mmol) and KOH (2.5mmol), stirring the reaction solution at 40 ℃ for reaction for 7h under the condition of introducing oxygen and maintaining micro-positive pressure, cooling the reaction solution to room temperature, filtering to remove solid residues, vacuumizing and concentrating the filtrate to obtain a solid β -carotene crude product, dissolving the crude product in n-hexane under the protection of nitrogen, refluxing and heating for 12h to perform isomerization treatment of various cis-compounds to all-trans structures, cooling, filtering, and drying to obtain deep red crystals with the content of 98.9% (HPLC), wherein the total yield is 82%.
The reaction substrates used in examples 1 to 7 and the corresponding yields are shown in Table 1.
TABLE 1
Example 8
Mixing vitamin A triphenylphosphine hydrobromide (1.0mmol), VO (acac)2Adding (1.0mmol), 3A molecular sieve (0.1g), 18-crown ether-6 (1.5mmol) and KOH (1.5mmol) into toluene (30ml), stirring and reacting the reaction solution at 10 ℃ under the condition of introducing oxygen and maintaining micro-positive pressure for 6h, cooling the reaction solution to room temperature, filtering to remove solid residues, vacuumizing and concentrating the filtrate to obtain a solid β -carotene crude product, dissolving the crude product in n-hexane under the protection of nitrogen, refluxing and heating for 12h to perform isomerization treatment of various cis-compounds to an all-trans structure, cooling and filtering, and drying to obtain dark red crystals with the content of 98.8% (HPLC), wherein the total yield is 75%.
Example 9
Mixing vitamin A triphenylphosphine hydrobromide (1.0mmol), VO (acac)2Adding (0.01mmol), 3A molecular sieve (0.5g), 18-crown ether-6 (3.0mmol) and KOH (3.0mmol) into toluene (10ml), stirring and reacting the reaction solution at 60 ℃ for 2h under the condition of introducing oxygen and maintaining micro-positive pressure, cooling the reaction solution to room temperature, filtering to remove solid residues, vacuumizing and concentrating the filtrate to obtain a solid β -carotene crude product, dissolving the crude product in n-hexane under the protection of nitrogen, refluxing and heating for 12h to perform isomerization treatment of various cis-compounds to an all-trans structure, cooling and filtering, and drying to obtain a dark red crystal with the content of 99.0% (HPLC), wherein the total yield is 77%.
Example 10
Mixing vitamin A triphenylphosphine hydrobromide (1.0mmol), VO (acac)2Adding (0.05mmol), 3A molecular sieve (0.5g), 18-crown ether-6 (3.0mmol) and KOH (2.2mmol) into toluene (15ml), stirring and reacting the reaction solution at 25 ℃ for 3h under the condition of introducing oxygen and maintaining micro-positive pressure, cooling the reaction solution to room temperature, filtering to remove solid residues, vacuumizing and concentrating the filtrate to obtain a solid β -carotene crude product, dissolving the crude product in n-hexane under the protection of nitrogen, refluxing and heating for 12h to perform isomerization treatment of various cis-compounds to an all-trans structure, cooling and filtering, and drying to obtain dark red crystals with the content of 98.7 percent (HPLC), wherein the total yield is 80 percent.
Example 11
Mixing vitamin A triphenylphosphine hydrobromide (1.0mmol), VO (acac)2Adding (0.07mmol), 3A molecular sieve (0.4g), 18-crown ether-6 (2.5mmol) and KOH (2.5mmol) into toluene (25ml), stirring and reacting the reaction solution at 50 ℃ for 2h under the condition of introducing oxygen and maintaining micro-positive pressure, cooling the reaction solution to room temperature, filtering to remove solid residues, vacuumizing and concentrating the filtrate to obtain a solid β -carotene crude product, dissolving the crude product in n-hexane under the protection of nitrogen, refluxing and heating for 12h to perform isomerization treatment of various cis-compounds to an all-trans structure, cooling and filtering, and drying to obtain dark red crystals with the content of 98.5% (HPLC), wherein the total yield is 83%.
Example 12
Mixing vitamin A triphenylphosphine hydrobromide (1.0mmol), VO (acac)2Adding (1.0mmol), 3A molecular sieve (0.2g), 18-crown ether-6 (2.2mmol) and KOH (3.0mmol) into toluene (20ml), stirring and reacting the reaction solution at 30 ℃ for 3h under the condition of introducing oxygen and maintaining micro-positive pressure, cooling the reaction solution to room temperature, filtering to remove solid residues, vacuumizing and concentrating the filtrate to obtain a solid β -carotene crude product, dissolving the crude product in n-hexane under the protection of nitrogen, refluxing and heating for 12h to perform isomerization treatment of various cis-compounds to an all-trans structure, cooling and filtering, and drying to obtain dark red crystals with the purity of 99.1% (HPLC), wherein the total yield is 84%.
The reaction substrate charge ratios and the corresponding yields used in examples 9 to 12 are shown in Table 2.
TABLE 2
Examples 13 to 17
When no molecular sieve was added, examples 13 to 17 were each carried out in the same manner as in examples 8 to 12, respectively; the yields of the corresponding products are shown in table 3.
TABLE 3
As can be seen from Table 3, the yield is greatly reduced when the molecular sieve is not used; thereby demonstrating the necessity of molecular sieves for the present invention. The molecular sieve has the advantages of large surface area, uniform pore distribution, rich surface chemical properties and the like, is an ideal choice for a catalyst carrier, can reduce the usage amount of a catalyst vanadium compound by adding the molecular sieve into a reaction system, can realize the catalytic oxidation coupling reaction at normal temperature or at lower heating temperature, and can be easily separated from the reaction system for reuse.
Examples 18 to 19
When carried out in an air atmosphere, examples 18 to 19 were each carried out in the same manner as examples 11 to 12, respectively; the yields of the corresponding products are shown in table 4.
TABLE 4
As can be seen from table 4, when the reaction was carried out under an air atmosphere, the reaction did not proceed or the yield was extremely low, thereby demonstrating the necessity of an oxygen atmosphere for the present invention. The oxygen is used as the oxidant, so the cost is low, the raw materials are easy to obtain, and the method is economical and practical and is suitable for industrial production.
Examples 20 to 22
Considering the case where no catalyst vanadium compound was added during the reaction, examples 20 to 22 were each performed in the same manner as in examples 10 to 12; the yields of the corresponding products are shown in table 5.
TABLE 5
As can be seen from Table 5, when the reaction was carried out without adding the vanadium compound, the reaction proceeded very slowly and the yield of the objective product was low, thus demonstrating the importance of the vanadium compound for increasing the reaction rate and conversion. The vanadium-containing compound is a compound with high thermal stability and chemical stability, and is an excellent selective oxidation catalyst, and oxidation products can be selectively retained in aldehyde or ketone without deep oxidation. In the invention, the vanadium-containing compound is added as a catalyst for reaction, so that the time required for coupling reaction by taking oxygen as an oxidant can be greatly shortened, the reaction selectivity is improved, and deep oxidation is prevented; other impurities are not introduced in the oxidation process, and the product is easy to separate.
In the invention, a polyether phase transfer catalyst is added to initiate the reaction between substrates in a heterogeneous reaction system; the solid alkaline compound and the solid alkaline compound form a complex and are dissolved in the organic phase to participate in the reaction, so that the solubility of the alkali in the organic phase is effectively controlled, the reaction is promoted, the generation of byproducts is inhibited, the yield of the seed product is increased, and the aim of improving the yield is fulfilled.
Claims (11)
1. The synthesis method of the beta-carotene is characterized by comprising the following specific steps:
preparing organic phosphonium salt from vitamin A alcohol, and carrying out intermolecular oxidative coupling reaction in an oxygen atmosphere in the presence of a vanadium compound catalyst and a molecular sieve to obtain beta-carotene;
the intermolecular oxidative coupling reaction is carried out in a solid-liquid two-phase reaction system consisting of an organic solvent, a phase transfer catalyst and an alkaline compound, and the reaction route is as follows:
wherein R1, R2, R3 are aromatic, aliphatic, alicyclic groups; said XθOne selected from hydrogen sulfate, tetrafluoroborate, phosphate, acetate, tosylate, benzenesulfonate, chloride, bromide or iodide;
the phase transfer catalyst is selected from at least one of 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, polyethylene glycol with the average molecular weight of 1000, polyethylene glycol with the average molecular weight of 1500, polyethylene glycol with the average molecular weight of 2000, tetraethylene glycol and tetraethylene glycol dimethyl ether;
said vanadium compound is selected from VO (acac)2、VO(OAc)2、VO(hfac)2、NH4VO3、NaVO3、KVO3、V2O5、VO(OEt)3、VO(OPr)3、VO(Oi-Pr)3At least one of (1).
2. The method for synthesizing beta-carotene according to claim 1, wherein said R1, R2, R3 are phenyl, cyclohexyl or butyl.
3. The method for synthesizing beta-carotene according to claim 1, wherein said molecular sieve is at least one selected from the group consisting of 3A molecular sieve, 4A molecular sieve and 5A molecular sieve.
4. The method for synthesizing β -carotene according to claim 1, wherein said basic compound is at least one selected from the group consisting of alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal phosphates, and alkali metal organic acid salts.
5. The method of β -carotene synthesis of claim 4 wherein said basic compound is selected from the group consisting of K2CO3、Na2CO3、Cs2CO3、Li2CO3、NaOH、KOH、LiOH、K3PO4、Na3PO4BuOK, Buona, NaOAc, KOAc, EtONa, EtOK.
6. The method for synthesizing beta-carotene according to claim 1 wherein said organic solvent is at least one selected from the group consisting of toluene, methylene chloride, chloroform, benzene, dichloroethane, n-hexane, tetrahydrofuran, petroleum ether, methyl ether, and methyl tert-butyl ester.
7. The method for synthesizing beta-carotene according to claim 1, wherein the molar ratio of the organic phosphonium salt to the catalyst is 1: 0.01-1; the ratio of the organic phosphonium salt to the molecular sieve is 1: 0.1-0.5, wherein the organic phosphonium salt is calculated by millimole, and the molecular sieve is calculated by mass gram; the mol ratio of the organic phosphonium salt to the alkali is 1: 1.5-3; the molar ratio of the organic phosphonium salt to the phase transfer catalyst is 1: 1.5-3; the molar volume ratio of the organic phosphonium salt to the organic solvent is 1: 10-30, wherein the organic phosphonium salt is calculated by mol, and the organic solvent is calculated by volume liter.
8. The method for synthesizing beta-carotene according to claim 1, wherein the reaction temperature of the coupling reaction is 10-60 ℃; the reaction time of the coupling reaction is 2-8 h.
9. The method for synthesizing beta-carotene according to claim 8, wherein the reaction temperature of the coupling reaction is 25-40 ℃; the reaction time of the coupling reaction is 2-4 h.
10. The method for synthesizing β -carotene according to claim 1, wherein after the intermolecular oxidative coupling reaction, the reaction solution is cooled and layered to remove solids, the organic phase is washed with water, the solvent is concentrated and recovered to obtain a red solid which is a mixture of β -carotene and a phosphine oxide compound, the mixture is washed with an alcohol to remove the phosphine oxide compound, and then recrystallized or heated in a solvent, and then various cis mixtures are rearranged into all-trans structures.
11. The method of claim 10, wherein said alcohol is methanol.
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