EP3191448A1 - Procédé de préparation d'esters astaxanthine - Google Patents
Procédé de préparation d'esters astaxanthineInfo
- Publication number
- EP3191448A1 EP3191448A1 EP15750406.9A EP15750406A EP3191448A1 EP 3191448 A1 EP3191448 A1 EP 3191448A1 EP 15750406 A EP15750406 A EP 15750406A EP 3191448 A1 EP3191448 A1 EP 3191448A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- general formula
- astaxanthin
- formula
- group
- acid chloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 150000001514 astaxanthins Chemical class 0.000 title abstract description 4
- 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 claims abstract description 171
- 235000013793 astaxanthin Nutrition 0.000 claims abstract description 171
- 239000001168 astaxanthin Substances 0.000 claims abstract description 171
- 229940022405 astaxanthin Drugs 0.000 claims abstract description 171
- 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 abstract description 166
- -1 fatty acid chlorides Chemical class 0.000 claims abstract description 69
- 238000000034 method Methods 0.000 claims abstract description 62
- 239000003960 organic solvent Substances 0.000 claims abstract description 50
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 45
- 150000005690 diesters Chemical class 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 4
- 239000004615 ingredient Substances 0.000 claims abstract description 4
- 229940079593 drug Drugs 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 81
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 64
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000011541 reaction mixture Substances 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 33
- 150000001298 alcohols Chemical class 0.000 claims description 22
- 150000001412 amines Chemical class 0.000 claims description 22
- 230000008569 process Effects 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 239000007795 chemical reaction product Substances 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 229960001701 chloroform Drugs 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 235000019728 animal nutrition Nutrition 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- 150000003222 pyridines Chemical class 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-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
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 230000006735 deficit Effects 0.000 claims description 2
- 229950005499 carbon tetrachloride Drugs 0.000 claims 1
- 235000014113 dietary fatty acids Nutrition 0.000 abstract description 10
- 229930195729 fatty acid Natural products 0.000 abstract description 10
- 239000000194 fatty acid Substances 0.000 abstract description 10
- 241001465754 Metazoa Species 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 52
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 47
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 150000003254 radicals Chemical class 0.000 description 32
- RASZIXQTZOARSV-BDPUVYQTSA-N astacin Chemical compound CC=1C(=O)C(=O)CC(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(=O)CC1(C)C RASZIXQTZOARSV-BDPUVYQTSA-N 0.000 description 29
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 25
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 23
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 18
- 239000012071 phase Substances 0.000 description 16
- 102000034498 Astacin Human genes 0.000 description 15
- 108090000658 Astacin Proteins 0.000 description 15
- FMKGDHLSXFDSOU-BDPUVYQTSA-N Dienon-Astacin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)C(=O)C(=CC1(C)C)O)C=CC=C(/C)C=CC2=C(C)C(=O)C(=CC2(C)C)O FMKGDHLSXFDSOU-BDPUVYQTSA-N 0.000 description 15
- 235000003676 astacin Nutrition 0.000 description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 235000021314 Palmitic acid Nutrition 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 14
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- 238000005886 esterification reaction Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- AURDEEIHMPRBLI-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1.CC1=CC=CN=C1 AURDEEIHMPRBLI-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 9
- 150000008064 anhydrides Chemical class 0.000 description 9
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 9
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- 230000032050 esterification Effects 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- MQZIGYBFDRPAKN-UWFIBFSHSA-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=C\C=C(/C)\C=C\C1=C(C)C(=O)[C@@H](O)CC1(C)C MQZIGYBFDRPAKN-UWFIBFSHSA-N 0.000 description 7
- ITQTTZVARXURQS-UHFFFAOYSA-N beta-methylpyridine Natural products CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 7
- 238000010626 work up procedure Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 150000001805 chlorine compounds Chemical class 0.000 description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 5
- NTSLROIKFLNUIJ-UHFFFAOYSA-N 5-Ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1 NTSLROIKFLNUIJ-UHFFFAOYSA-N 0.000 description 5
- KNCHDRLWPAKSII-UHFFFAOYSA-N 5-ethyl-2-methylpyridine Natural products CCC1=CC=NC(C)=C1 KNCHDRLWPAKSII-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- UJRIYYLGNDXVTA-UHFFFAOYSA-N ethenyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OC=C UJRIYYLGNDXVTA-UHFFFAOYSA-N 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 4
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 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 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 3
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical class CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 3
- 108010084311 Novozyme 435 Proteins 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- JKQXZKUSFCKOGQ-LQFQNGICSA-N Z-zeaxanthin Natural products C([C@H](O)CC=1C)C(C)(C)C=1C=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-LQFQNGICSA-N 0.000 description 3
- 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 3
- JKQXZKUSFCKOGQ-LOFNIBRQSA-N all-trans-Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C JKQXZKUSFCKOGQ-LOFNIBRQSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 3
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000014759 maintenance of location Effects 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
- 230000009257 reactivity Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 235000010930 zeaxanthin Nutrition 0.000 description 3
- 239000001775 zeaxanthin Substances 0.000 description 3
- 229940043269 zeaxanthin Drugs 0.000 description 3
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 2
- HOBAELRKJCKHQD-UHFFFAOYSA-N (8Z,11Z,14Z)-8,11,14-eicosatrienoic acid Natural products CCCCCC=CCC=CCC=CCCCCCCC(O)=O HOBAELRKJCKHQD-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 235000021298 Dihomo-γ-linolenic acid Nutrition 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- 239000004367 Lipase Substances 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 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 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- HOBAELRKJCKHQD-QNEBEIHSSA-N dihomo-γ-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCCCC(O)=O HOBAELRKJCKHQD-QNEBEIHSSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229960002715 nicotine Drugs 0.000 description 2
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 2
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229950011008 tetrachloroethylene Drugs 0.000 description 2
- ZYECOAILUNWEAL-NUDFZHEQSA-N (4z)-4-[[2-methoxy-5-(phenylcarbamoyl)phenyl]hydrazinylidene]-n-(3-nitrophenyl)-3-oxonaphthalene-2-carboxamide Chemical compound COC1=CC=C(C(=O)NC=2C=CC=CC=2)C=C1N\N=C(C1=CC=CC=C1C=1)/C(=O)C=1C(=O)NC1=CC=CC([N+]([O-])=O)=C1 ZYECOAILUNWEAL-NUDFZHEQSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- RMGHERXMTMUMMV-UHFFFAOYSA-N 2-methoxypropane Chemical compound COC(C)C RMGHERXMTMUMMV-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- CAOMCZAIALVUPA-UHFFFAOYSA-N 3-(methylthio)propionic acid Chemical compound CSCCC(O)=O CAOMCZAIALVUPA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- DKMROQRQHGEIOW-UHFFFAOYSA-N Diethyl succinate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 description 1
- IJMWOMHMDSDKGK-UHFFFAOYSA-N Isopropyl propionate Chemical compound CCC(=O)OC(C)C IJMWOMHMDSDKGK-UHFFFAOYSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- 241001661345 Moesziomyces antarcticus Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KFNNIILCVOLYIR-UHFFFAOYSA-N Propyl formate Chemical compound CCCOC=O KFNNIILCVOLYIR-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- NHSUWMKUPCDXGS-CHSCTOIBSA-N [4-[(1e,3e,5e,7e,9e,11e,13e,15e,17e)-18-(4-hexadecanoyloxy-2,6,6-trimethyl-3-oxocyclohexa-1,4-dien-1-yl)-3,7,12,16-tetramethyloctadeca-1,3,5,7,9,11,13,15,17-nonaenyl]-3,3,5-trimethyl-6-oxocyclohexa-1,4-dien-1-yl] hexadecanoate Chemical compound O=C1C(OC(=O)CCCCCCCCCCCCCCC)=CC(C)(C)C(\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C=2C(C=C(OC(=O)CCCCCCCCCCCCCCC)C(=O)C=2C)(C)C)=C1C NHSUWMKUPCDXGS-CHSCTOIBSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
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- 230000003213 activating effect Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 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 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000001539 azetidines Chemical class 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- 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 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- BTMVHUNTONAYDX-UHFFFAOYSA-N butyl propionate Chemical compound CCCCOC(=O)CC BTMVHUNTONAYDX-UHFFFAOYSA-N 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 235000021466 carotenoid Nutrition 0.000 description 1
- 150000001747 carotenoids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- BOTLEXFFFSMRLQ-UHFFFAOYSA-N cyclopentyloxycyclopentane Chemical compound C1CCCC1OC1CCCC1 BOTLEXFFFSMRLQ-UHFFFAOYSA-N 0.000 description 1
- IPIVAXLHTVNRBS-UHFFFAOYSA-N decanoyl chloride Chemical compound CCCCCCCCCC(Cl)=O IPIVAXLHTVNRBS-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Substances CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 235000020664 gamma-linolenic acid Nutrition 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 125000005644 linolenyl group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QWKBGGMEZIVBJH-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine;5-ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1.CN(C)C1=CC=NC=C1 QWKBGGMEZIVBJH-UHFFFAOYSA-N 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
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- WTBAHSZERDXKKZ-UHFFFAOYSA-N octadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCC(Cl)=O WTBAHSZERDXKKZ-UHFFFAOYSA-N 0.000 description 1
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 150000004905 tetrazines Chemical class 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003403 water pollutant Substances 0.000 description 1
- 150000003735 xanthophylls Chemical class 0.000 description 1
- 235000008210 xanthophylls Nutrition 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 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 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- 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
Definitions
- the present invention relates to a process for producing an astaxanthin diester and its use.
- diesters of astaxanthin have also been described so far. As a rule, these are diesters which carry further O, S and N-containing functional groups in the acid radical. Examples which may be mentioned are astaxanthin diethyl succinate, astaxanthin di (3-methylthio propionate) and astaxanthin dinicotinate (WO 2003/066 583 A1, WO 201 1/095 571).
- astaxanthin is reacted with the acids, the acid chlorides or acid anhydrides in the presence of coupling reagents, such as ethyl chloroformate or N, N-dicyclohexylcarbodiimide, or bases, such as triethylamine or pyridine, and catalysts, such as DMAP.
- coupling reagents such as ethyl chloroformate or N, N-dicyclohexylcarbodiimide
- bases such as triethylamine or pyridine
- catalysts such as DMAP.
- a fatty acid ester of astaxanthin which is obtained by esterifying zeaxanthin according to the teaching of Spanish patent ES 2223270 and then oxidizing this ester with pyridinium chlorochromate. Specifically, starting from zeaxanthin, the dipalmitate is produced and the resulting astaxanthin dipalmitate is obtained by oxidation.
- Astacin of formula A differs structurally from astaxanthin of formula 2 below
- asymmetric center in position 3 and 3 ' is configured racemically, or in each case (S) - or (R) -, and R stands for a radical which is selected from the group consisting of C9-C19-alkyl-, C9-C19- Alkenyl, C9-C19-alcadienyl, C9-C19-alkylsyl, according to an inventive manufacturing method, in which astaxanthin of the formula 2
- R 1 , R 2 and R 3 are independently selected from the group consisting of a saturated C1 - C6-chain, an unsaturated C1 - C6 chain, an aromatic C6 ring, a C1 - C6 chain, which is formed from two of the three radicals R 1, R 2 and R 3, these two radicals are linked to one another form together with the nitrogen atom of the base 4 is an alkylated or non-alkylated heterocycle or an alkylated or non-alkylated heteroaromatic cycle or, a C1 - C6 chain, consisting of two of the three radicals R 1, R 2 is formed, and R 3, wherein these two radicals are linked together via another nitrogen atom and, together with the nitrogen atom of the base 4, an alkylated or non-alkylated heterocycle or an alkyl
- astaxanthin of formula 2 and astacin of formula A are completely different in their reactivity. Therefore, for the person skilled in the art, the esterification of astaxanthin of the formula 2 and of astacin of the formula A are two fundamentally different things, which are to be found essentially in the steric conditions of the six-membered system.
- Example 8 of the Widmer article in Pyridin This compound is thus concentrated, that is, used simultaneously as a solvent and nitrogen-containing base.
- the expert would have exchanged astacin for astaxanthin following Widmer, but otherwise chose the reaction conditions exactly the same, in the hope of achieving a conversion to the corresponding diester at all. Ergo, he would have worked in concentrated pyridine to achieve near-acceptable esterification of this molecule, based on Widmer, knowing the poor reactivity of astaxanthin.
- the inventive method thus differs by two essential features: 1. Instead of astacin of the formula A, astaxanthin of the formula 2 is used for the reaction in a corresponding diester. 2. An organic solvent instead of pyridine is used as the solvent. That astaxanthin despite the discouraging results in the comparative experiments with an acid chloride in good yields and after a short reaction time to the corresponding diester react and that this is possible even in an organic solvent and not exclusively in pure pyridine, is quite surprising and was for the applicant amazing.
- racemic as used in claim 1 means that the stereochemistry at position 3 or 3 'is arbitrary.
- (S) -configuration means such an arrangement of the individual substituents at positions 3 and 3', respectively. in that the counting is carried out from the heaviest substituent to the lightest substituent in the counterclockwise direction, that is to the left, while the term “(R) -configuring” is to be carried out clockwise, that is to the right, based on both counting methods, that the lightest substituent R comprises the radicals C9 C19 alkyl, C9 C19 alkenyl, C9 C19 alkadienyl, C9 C19 alkoxyls.
- C9-C19-alkyl are meant all those radicals which contain at least 9 and at most 19 saturated carbon atoms.
- C 9 -C 19 -alkyl is accordingly selected from the group consisting of n-nonyl or n-pelargonyl, n-decyl or n-capryl, n-undecyl, dodecyl or n-lauryl, n-tridecyl, n-tetradecyl or n-myristyl , n-pentadecyl, n-hexadecyl or n-palmityl, n-heptadecyl, n-octadecyl or n-stearyl, n-nonadecyl.
- C9-C19 alkenyl is meant all those radicals containing at least 9 and at most 19 carbon atoms, two of which are linked together via an E or Z-double bond.
- C9-C19 alkenyl is preferably understood to mean all those radicals which contain at least 9 and at most 19 linearly interconnected carbon atoms, two of which are linked to one another via an E or Z-double bond.
- C 9 -C 19 alkenyl is accordingly selected from the group consisting of n-nonenyl, n-decenyl, n-undecenyl, n-dodecenyl, n-tridecenyl, n-tetradecenyl, n-pentadecenyl, n-hexadecenyl, for example, (9Z) n hexadec-9-enyl or palmitoleinyl, n-heptadecenyl, n-octadecenyl, for example, (9Z) n-octadec-9-enyl or oleyl, (9E) n-octadec-9-enyl or elaidinyl, n-nonadecenyl.
- C9-C19-alkadienyl are meant all those radicals which contain at least 9 and at most 19 carbon atoms, these radicals having two E and / or Z-containing double bonds.
- C9-C19-alkadienyl is accordingly selected from the group consisting of n-nonadienyl, n-decadienyl, n-undecadienyl, n-dodecadienyl, n-tridecadienyl, n-tetradecadienyl, n-pentadecadienyl, n- hexadecadienyl, n-heptadecadienyl, n-octadecadienyl, for example, [(9Z, 12Z) octadeca-9,12-dienyl or linolyl, n-nonadecadienyl.
- C9-C19-alkyls are all those radicals which contain at least 9 and at most 19 carbon atoms, these radicals having three E and / or Z-containing double bonds.
- Under C9 - C19- Alktrienyl are preferably all those radicals which contain at least 9 and at most 19 linearly interconnected carbon atoms, these radicals having three E and / or Z-containing double bonds.
- C 9 -C 19 -alkylene is accordingly selected from the group consisting of n-nonatrienyl, n-decatrienyl, n-undecatrienyl, n-dodecatrienyl, n-tridecatrienyl, n-tetradecatrienyl, n-pentadecatrienyl, n-hexadecatrienyl, n-heptadecatrienyl, n octadecatrienyl for example (9Z, 12Z, 15Z) -octadeca-9,12,15-trienyl or linolenyl, (6Z, 9Z, 12Z) -octadeca-6,9,12-trienyl or gamma-linolenyl, (9Z, 11 £, 13E) - octadeca-9,1 1, 13-trienyl or elaeostearinyl, (5Z, 9Z,
- C9-C19-alkylsyl comprises the alkyl radical of arachidonic acid, ie a radical having 19 C atoms and four double bonds (formally a C19-alktetraenyl radical, which for the sake of readability is also included under the name "C9-C19-alkylrylsyl”) ,
- Suitable solvents for the inventive method are all organic solvents in which astaxanthin and the corresponding reactants are sufficiently soluble.
- the organic solvent therefore comprises at least one compound selected from the group consisting of dichloromethane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, ethylene carbonate, propylene carbonate, dimethylformamide, dimethylsulfoxide, ethyl acetate, n-propyl acetate, toluene, xylene, heptane, hexane , Pentane, N-methyl-2-pyrrolidone, dioxane, 2-methyl-tetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, diethyl ether, di-n-butyl ether, acetonitrile, trichloromethane, chlorobenzene and preferably from the group consisting of dichloromethane,
- nitrogen-containing base of the general formula 4" are meant all bases which contain at least one nitrogen atom, furthermore the radicals R 1 , R 2 , R 3 and with hydrogen chloride (HCl) form a hydrochloride Amides are not included in the term “Nitrogenous base”.
- a "saturated C 1 -C 6 chain” according to the invention is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl , n-hexyl, cyclopentyl, cyclohexyl.
- a "C1-C6 unsaturated chain” according to the invention is selected from the group consisting of vinyl, allyl, prenyl, isoprenyl, homoallyl, cyclopentadienyl, cyclohexenyl.
- a continuation of the inventive method provides that the astaxanthin of the formula 2 in the organic solvent with a relative to astaxanthin 2 greater than twice the molar excess of the acid chloride of the general formula 3 in the presence at least
- technical acid chloride is never completely free of the corresponding free carboxylic acids, especially if it is more widely used - zen or im continuous operation is being worked on.
- a further more specific embodiment of the inventive method provides to convert the astaxanthin of formula 2 in the organic solvent with a based on astaxanthin 2, Ifachen to 9 times the molar excess of the acid chloride of the general formula 3 in the presence of at least one nitrogen-containing base of the general formula 4, preferably at a molar excess of 2.3 to 7 times molar excess, more preferably 2.5 to 5 molar excess, and most preferably 2.7 to 3 molar molar excess.
- the amount of acid chloride used of the general formula 3 should be at least as large according to the above statements that by hydrolysis and caused by anhydride losses are compensated and per mole of astaxanthin of formula 2 at least 2 moles of reactive acid chloride of the general formula 3 are available.
- a further aspect of the invention envisages reacting astaxanthin of the formula 2 in a chlorine-containing organic solvent with the acid chloride of the general formula 3 in the presence of at least one nitrogen-containing base of the general formula 4, preferably in a chlorine-containing organic solvent is selected from the group consisting of dichloromethane, trichloromethane, carbon tetrachloride, 1, 1-dichloroethane, 1, 2-dichloroethane, trichlorethylene, tetrachlorethylene, perchlorethylene, chlorobenzene or a mixture of at least two of these solvents.
- chlorine-containing solvents such as dichloromethane, trichloromethane or chlorobenzene, or a mixture of these solvents.
- Typical of xanthophylls and also of beta-carotene itself is that they dissolve only moderately to not in solvents. This is also confirmed by Widmer on p. 678 in the last paragraph of the publication Helv. Chim. Acta.
- this aspect of the method also has inventive significance.
- the inventive method should be compared to the prior art, inter alia, energy-saving and cost.
- This goal is achieved when the astaxanthin of formula 2 in a temperature range from -20 to + 100 ° C, in particular in a temperature range from 0 ° C to 60 ° C, in the organic solvent with the acid chloride of general formula 3 in the presence of at least one Nitrogen-containing base of general formula 4 is reacted. That is, one carries out the inventive reaction in a temperature range of -20 to + 100 ° C, in particular in a temperature range of 0 ° C to 60 ° C, by.
- an inventive redirection determines astaxanthin of formula 2 in the organic solvent with the acid chloride of general formula 3 in the presence of at least one nitrogen-containing Base of the general formula 4, wherein the base 4 is selected from the group consisting of monocyclic nitrogen-containing bases, preferably pyridines or imidazoles and bicyclic nitrogen-containing bases, such as DBU.
- the base used is preferably monocyclic nitrogen-containing bases, such as pyridines, in particular pyridine, 4-dimethylaminopyridine, 3-methylpyridine and 5-ethyl-2-methylpyridine or imidazoles, such as N-methylimidazole or bicyclic nitrogen-containing bases, such as DBU.
- pyridines such as pyridines, in particular pyridine, 4-dimethylaminopyridine, 3-methylpyridine and 5-ethyl-2-methylpyridine or imidazoles, such as N-methylimidazole or bicyclic nitrogen-containing bases, such as DBU.
- Monocyclic nitrogenous bases are selected from the group comprising aziridines, azetidines, pyrroles, pyrrolidines, pyrrazoles, imidazoles, triazoles, tetrazoles, pyridines, pyridazines, pyrimidines, pyrazines, triazines, tetrazines.
- Bicyclic nitrogen-containing bases are selected from the groups comprising indoles, quinoline, isoquinolines, purines, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non- 5-ene, 1,4-diazabicyclo [2.2.2] octane, 4- (N-pyrrolidinyl) -pyridine.
- the nitrogenous base of general formula 4 is particularly preferably selected from the group consisting of N-methylimidazole, 2-methylimidazole, 4-methylimidazole, pyridine, 3-methylpyridine, 2-methylpyridine, 4-methylpyridine, 4-dimethylaminopyridine, 5-ethyl 2-methylpyridine, nicotine, because complete conversions of the acid chloride of the general formula 3 with astaxanthin of the formula 2 to the corresponding astaxanthin diester of the general formula 1 can be achieved with these nitrogenous bases.
- an important embodiment of the inventive method provides that astaxamines of formula 2 is reacted in the organic solvent with the acid chloride of the general formula 3 in the presence of at least one nitrogen-containing base of the general formula 4, wherein the base 4 is selected from A group consisting of N-methylimidazole, 2-methylimidazole, 4-methylimidazole, pyridine, 3-methylpyridine, 2-methylpyridine, 4-methylpyridine, 4-dimethylaminopyridine, 4- (N-pyrrolidinyl) -pyridine, 5-ethyl-2-methylpyridine , Nicotine.
- the diester 1 is achieved when the astaxanthin of formula 2 is reacted in the organic solvent with the acid chloride of the general formula 3 in the presence of at least one nitrogen-containing base of the general formula 4, wherein the Base 4 is selected from the group consisting of N-methylimidazole, pyridine, 3-methylpyridine, 4-dimethylaminopyridine, 5-ethyl-2-methylpyridine.
- the compound 1, 1'-carbonyldiimidazole (CDI) is not to be counted among the cyclic nitrogenous bases since it is an activating reagent for a carboxylic acid (see comparative examples below).
- the nitrogen-containing bases of the general formula 3 are generally water-soluble, but partly dissolve also in the organic solvent or precipitate out as the hydrochloride. Thus, a complete separation from the reaction mixture is particularly costly if said bases are used in amounts that exceed those required for the reaction control far.
- a further aspect of the invention is to convert the astaxamines of the formula 2 in the organic solvent with the acid chloride of the general formula 3 in the presence of at least one nitrogen-containing base of the general formula 4, wherein the base based on the Acid chloride of the general formula 3 is used in 1 to 3 times the molar ratio, preferably in 1, 1 to 2 times the molar ratio and most preferably in 1, 1 to 1, 5 times the molar ratio.
- the radicals R 5 and R 6 are selected from the group consisting of H, C 1 -C 6 -alkyl.
- the radical R 4 contains all those groupings which can be summarized by the term C 1 -C 6 -alkyl.
- the term C 1 -C 6 -alkyl includes all those groupings which are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl , n-hexyl, cyclopentyl, cyclohexyl.
- the resulting reaction mixture ie the reaction mixture after the esterification reaction, treated with at least one compound selected from alcohols of the general formula 5 and amines of the general formula 6, formed from excess acid chloride of the general formula 3 as well as from the formed Anhydrides, the corresponding ester and / or the corresponding amide.
- Both amides and esters of the acid chloride of the general formula 3 can be more easily separated from the reaction mixture in contrast to the previously mentioned anhydride. By this measure, it is possible to isolate diester of formula 1 in a simple manner as a solid.
- the subject of a particularly preferred variant of the inventive method is therefore, the astaxanthin of formula 2 in dichloromethane, trichloromethane, chlorobenzene or a mixture of at least two of these organic solvents with the acid chloride of general formula 3 in the presence of at least one nitrogen-containing base, which is selected from the group consisting of N-methylimidazole, pyridine, 3-methylpyridine, 4-dimethylaminopyridine, 5-ethyl-2-methylpyridine react; and the resulting reaction mixture with at least one compound selected from the group consisting of alcohols of the general formula 5: R 4 OH with R 4 is C 1 -C 6 -alkyl and amines of the general formula 6: R 5 R 6 NH with R 5 and R 6 are independently H or C 1 -C 6 -alkyl wherein R 5 and R 6 are each either an independent group or linked together.
- at least one nitrogen-containing base which is selected from the group consisting of N-methylimidazole, pyridine,
- salts may form. These salts must be separated from the reaction product.
- certain alcohols such as methanol, tend to partition in a two-phase mixture in both the polar phase and the hydrophobic or organic phase.
- Compound fertilize for example, are well soluble in methanol, then will also be distributed to both phases and there is no complete, therefore undesirable separation of these compounds in one phase.
- a process has been found to be particularly practicable, is reacted in the astaxanthin of formula 2 in the organic solvent with the acid chloride of the general formula 3 in the presence of at least one nitrogen-containing base of the general formula 4; and the reaction mixture obtained with the 0.1 to 0.9 times the molar amount based on the amount of acid chloride 3 at least one compound which is selected from the group consisting of alcohols of the general formula 5 and amines of the general formula 6 is added, preferably with 0.2 to 0.7 times the molar amount, more preferably 0.3 to 0.6 times the molar amount, and most preferably 0.34 to 0.5 times the molar amount.
- the inventive process also provides that astaxanthin of the formula 2 is reacted in the organic solvent with the acid chloride of the general formula 3 in the presence of at least one nitrogen-containing base of the general formula 4; and that the reaction mixture obtained is admixed with at least one alcohol of the general formula 5 which is selected from the group consisting of methanol, ethanol, n-propanol. These primary alcohols are reasonably available and cause the diester 1 to be obtained as a solid due to the described separation of by-products.
- inventive method determines that astaxanthin of formula 2 is reacted in the organic solvent with the acid chloride of the general formula 3 in the presence of at least one nitrogen-containing base of the general formula 4; and in that the resulting reaction mixture is reacted with at least one amine selected from the group consisting of methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, tert-butylamine, isobutylamine, n-pentylamine, aniline, benzylamine , is offset. Also, these amines can be purchased inexpensively and cause the diester 1 is obtained as a result of the described separation of by-products.
- a further elaborated variant of the inventive method provides to convert astaxanthin of the formula 2 in the organic solvent with the acid chloride of the general formula 3 in the presence of at least one nitrogen-containing base of the general formula 4; and the reaction mixture obtained with at least one compound selected from the group consisting of alcohols of the general formula 5 and amines of the general formula 6 for a period of 10 minutes to 3 hours, preferably for a period of 20 minutes to 2 hours, and most preferably from 30 minutes to 1 hour.
- Formula 2 is reacted in the organic solvent with the acid chloride of the general formula 3 in the presence of at least one nitrogen-containing base of the general formula 4; that the resulting reaction mixture is admixed with at least one compound selected from the group consisting of alcohols of the general formula 5 and amines of the general formula 6; and that the reaction product of the general formula 1 is crystallized from a further solvent or a mixture of a plurality of solvents.
- Another solvent to be considered is any solvent from which the diester 1 can be crystallized.
- the further solvent is alcohols with short alkyl chains, for example methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-
- a mixture of several solvents is generally understood as meaning a mixture of one of the organic solvents with another solvent. More precisely, the solvent in the heat is added to the organic solvent so much more solvent that the diester of formula 1 is barely dissolved.
- a further optimized good yield yielding embodiment of the inventive method determines that astaxanthin of formula 2 in dichloromethane with the acid chloride of general formula 3 in the presence of at least one selected from the group consisting of N-methylimidazole, pyridine, 3-methylpyridine, 4-dimethylaminopyridine 5-ethyl-2-methylpyridine is reacted with selected nitrogen-containing base; the reaction mixture obtained is treated with at least one compound selected from the group consisting of methanol, ethanol and n-propanol; and that the reaction product of the general formula 1 is crystallized from an alcohol / ether mixture or from an alcohol / ester mixture.
- An alcohol ether mixture consists of at least one alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol and the various pentanols, and also cyclopentanol and cyclohexanol; and at least one ether selected from the group consisting of diethyl ether, dipropyl ether, diisopropyl ether, methyl isopropyl ether, t-butyl methyl ether, di-butyl ether, dicyclopentyl ether, cyclopentyl methyl ether.
- An alcohol / ester mixture consists of at least one alcohol which is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol and the various pentanols further Cyclopentanol and cyclohexanol; and at least one ester selected from the group consisting of methyl formate, ethyl formate, n-propyl formate, iso-propyl formate, n-butyl formate, methyl acetate, ethyl acetate, n-propyl acetate, iso-propyl acetate, n-butyl acetate, methyl propionate, ethyl propionate, n-propylpropionate, iso-propylpropionate, n-butylpropionate.
- the reaction mixture is due to the various added bases more or less strongly alkaline. Under basic conditions, esters as well as the diester of formula 1 are only moderately stable over time. Remedy here brings another embodiment of the inventive method in which the astaxanthin of formula 2 is reacted in the organic solvent with the acid chloride of the general formula 3 in the presence of at least one nitrogen-containing base of the general formula 4; the reaction mixture obtained with at least one compound which is selected from the group consisting of alcohols of the general formula 5 and amines of the general formula 6 is added; it is subjected to an acidic work-up; and the reaction product of general formula 1 is crystallized from a further solvent or a mixture of a plurality of solvents.
- acidic work-up is meant any kind of action on the reaction mixture which brings it to a neutral or slightly acidic pH, usually this action means adding a Br ⁇ nsted acid, for example sulfuric acid, hydrochloric acid , Phosphoric acid, citric acid, formic acid or acetic acid.
- a Br ⁇ nsted acid for example sulfuric acid, hydrochloric acid , Phosphoric acid, citric acid, formic acid or acetic acid.
- the following inventive embodiment is advantageous. It describes a process in which the astaxanthin of formula 2 is reacted in the organic solvent with the acid chloride of the general formula 3 in the presence of at least one nitrogen-containing base of the general formula 4; the resulting reaction mixture is admixed with at least one compound selected from the group consisting of alcohols of general formula 5 and amines of general formula 6; water is subsequently added to it, subjected to an acidic work-up; and that the reaction product of the general formula 1 is crystallized from a further solvent or a mixture of a plurality of solvents.
- a further aspect of the invention relates to the non-therapeutic use of the diester 1 in which R is a radical selected from the group consisting of C 13 -C 19 -alkyl, C 13 -C 19 -alkenyl, C 13 -C 19 -alkadienyl, C13 - C19-alkylthienyl prepared by the inventive process, in human or animal nutrition and in a preparation of human or animal nutrition; preferably, a diester in which R is a radical selected from the group consisting of C 15 -C 19 -alkyl, C 15 -C 19 -alkenyl, C 15 -C 19 -alkadienyl, C 15 -C 19 -alkyls; more preferably selected from the group consisting of C 16 -C 19 alkyl, C 16 -C 19 alkenyl, C 16 -C 19 alkadienyl, C 16 -C 19 alkylsyl; and most preferably, diester 1 wherein R is
- the invention comprises the diester 1 prepared by the method according to the invention for therapeutic use as a medicament and as an ingredient for a medicinal preparation; preferred the diester 1 prepared by the inventive process, wherein R is a radical selected from the group consisting of C 13 -C 19 alkyl, C 13 -C 19 alkenyl, C 13 -C 19 alkadienyl, C 13 -C 19 -Alktrienyl; more preferably selected from the group consisting of C15-C19-alkyl, C15-C19-alkenyl, C15-C19-alkadienyl, C15-C19-alkylsyl; even more preferably produced by the process according to the invention.
- R is a radical selected from the group consisting of C 13 -C 19 alkyl, C 13 -C 19 alkenyl, C 13 -C 19 alkadienyl, C 13 -C 19 -Alktrienyl; more preferably selected from the group consisting of C15-
- R is a radical selected from the group consisting of C 16 -C 19 -alkyl, C 16 -C 19 -alkenyl, C 16 -C 19 -alkadienyl, C 16 -C 19 -alkyls; and most preferably the diester 1 prepared by the process of the invention wherein R is a radical selected from the group consisting of C 16 -C 18 alkyl, C 16 -C 18 alkenyl, C 16 -C 18 alkadienyl, C 16 C18-alkylidenyl.
- TLC Thin layer chromatogram of the reaction astaxanthin 2, palmitic acid, N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDC), N, N-dimethylaminopyridine (DMAP).
- TLC Thin layer chromatogram of the reaction astaxanthin 2, palmitic acid, N, N-diisopropylpodiimide (DIC), ⁇ , ⁇ -dimethylaminopyridine (DMAP).
- TLC Thin-layer chromatogram of the reaction astaxanthin 2, palmitic acid, propylphosphonic anhydride, ⁇ , ⁇ -diisopropylethylamine (DIPEA).
- TLC Thin-layer chromatogram of the reaction astaxanthin 2, palmitic acid, 1, 1 - carbonyldiimidazole (CDI), acetic acid.
- TLC Thin-layer chromatogram of the reaction astaxanthin 2, palmitic acid chloride, ⁇ , ⁇ -dimethylaminopyridine (DMAP), alkylamine base.
- TLC Thin-layer chromatogram of the reaction astaxanthin 2, palmitic acid chloride, pyridine or diisopropylethylamine (DIPEA) or triethylamine (TEA).
- DIPEA diisopropylethylamine
- TAA triethylamine
- Fig. 1 shows that after 3 hours and even after 7 hours in no way a reaction can be detected. Even the formation of astaxanthin monopalmitate, ie the corresponding monoester of astaxanthin 2, does not occur.
- retinoic acid or dihomo-gamma-linolenic acid (DGLA) or gamma-linolenic acid (GLA) instead of palmitic acid under otherwise identical conditions.
- DGLA dihomo-gamma-linolenic acid
- GLA gamma-linolenic acid
- FIG. 4 shows that no astaxanthine dipalmitate is formed after 6 hours. At most, traces of astaxanthin monopalmitate are detectable. Even after 20 hours, there are still large amounts of unreacted astaxanthin 2 and some astaxanthin monopalmitate. The desired astaxanthin dipalmitate can only be detected in very small amounts.
- Example 2 Reaction of astaxanthin 2 with palmitic chloride in the presence of N, N-dimethylaminopyridine (DMAP) and an alkylamine base. 0.85 g (0.42 mmol) of astaxanthin 2 were dissolved in 2.09 ml (2.79 g, 30 mmol). Dichloromethane each presented in Example 2a and Example 2b.
- DMAP N, N-dimethylaminopyridine
- Example 2a and Example 2b in one portion 140 mg (192.66 ⁇ , 1, 38 mmol) of triethylamine (TEA) and 5.12 mg (0.04 mmol) of ⁇ , ⁇ -dimethylaminopyridine (DMAP) were added in Example 2a and in Example 2b also in one portion of 180 mg (240.77 ⁇ M, 1.38 mmol) of N, N-diisopropylethylamine (DIPEA) and 5.12 mg (0.04 mmol) of ⁇ , ⁇ -dimethylaminopyridine (DMAP). Then, in Example 2a and Example 2b, in each case 380 ⁇ l (350 mg, 1, 26 mmol) of palmitic acid chloride were added and the mixture was stirred overnight.
- TAA triethylamine
- DIPEA N, N-diisopropylethylamine
- DMAP ⁇ , ⁇ -dimethylaminopyridine
- Example 4 Reaction of astaxanthin 2 with palmitic acid chloride in the presence of pyridine or diisopropylethylamine (DIPEA) or triethylamine (TEA)
- Example 4A 0.85 g (0.42 mmol) of astaxanthin 2 was used for each of Examples 4A, 4B, 4D in 2.09 ml (2.79 g, 30 mmol) of dichloromethane and for Example 4E in 4.19 ml (5.57 g, 70 mmol) of dichloromethane.
- 10 mg (11.1, 34 ⁇ , 1.38 mmol) of pyridine were added in Example 4A, 180 mg (240.77 ⁇ , 1.38 mmol) of ⁇ , ⁇ -diisopropylamine in Example 4B (DIPEA) and in Examples 4D and 4E each 140 mg (192.66 ⁇ , 1, 38 mmol) of triethylamine (TEA).
- the second plot in FIG. 9 shows a sample from example 4A taken after 4 hours. It can be seen that astaxanthin 2 has already completely converted into the corresponding astaxanthin dipalmitate after this time.
- DIPEA diisopropylethylamine
- TAA triethylamine
- Example 5a 550 mg (609.99 ⁇ M, 2.01 mmol) of palmitic acid chloride were added, in Example 5b with 520 mg (569.32 ⁇ M, 1.89 mmol) of palmitic acid chloride, in Example 5c with 480 mg (528, 66 ⁇ , 1.75 mmol) of palmitic acid chloride and in Example 5d with 440 mg (487.99 ⁇ , 1.60 mmol) of palmitic acid chloride. It was allowed to react for 5 hours and a sample of each example by HPLC under the following conditions
- UV detector ⁇ 470 nm
- BW 50 nm
- astaxanthin 2 elutes after a retention time of 3.2 minutes, astaxanthin monopalmitate after a retention time of 5.3 minutes and astaxanthin dipalmitate after a retention time of 6.5 minutes.
- Example 5a gives the best result. It will be according to the integrated peaks were 92.48% astaxanthin dipalmitate and 0.63% astaxanthin monopalmitate. The starting compound astaxanthin 2 is no longer available. Thus, a particularly good yield of astaxanthin dipalmitate is obtained when the molar ratio between palmitic chloride and astaxanthin 2 is 3.
- the organic phase is rotated at 50 ° C., the residue is taken up in about 250 ml of t-butyl methyl ether and concentrated again completely.
- the residue is dissolved in 67 ml of t-butyl methyl ether and 201 ml of ethanol at 53.degree. It is cooled to 45 ° C, seeded and then cooled within 17 h to 0 ° C from.
- the precipitated crystalline solid is filtered off, washed twice with 200 ml of ethanol and dried at 40 ° C in a vacuum oven. 15.1 g (80% yield) of astaxanthin dioctadecanoate (mp 70.5 ° C.) are obtained.
- inventive method is not limited to one of the prescribed embodiments but can be modified in a variety of ways
- This disclosure discloses an environmentally friendly, resource-saving and inexpensive process for the preparation of astaxanthin diesters of the formula 1, in which astaxanthin of the formula 2 is esterified twice with fatty acid chlorides of the general formula 3. Compounds 2 and 3 are reacted for this purpose in an organic solvent in the presence of a nitrogen-containing base of the general formula 4.
- R is a radical selected from the group consisting of C 13 -C 19 -alkyl, C 13 -C 19 -alkenyl, C 13 -C 19 -alkadienyl, C13 - C19-Alktrienyl, in human or animal nutrition and the diester 1 prepared according to the method for therapeutic use as a medicament and as an ingredient for a medicinal preparation.
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Abstract
L'invention concerne un procédé bon marché, économe en ressources et respectueux de l'environnement pour la préparation de diesters d'astaxanthine de la formule 1, dans lequel l'astaxanthine de la formule 2 est estérifiée à deux reprises avec des chlorures d'acides gras de la formule générale 3. Pour cela, on fait réagir les composés 2 et 3 dans un solvant organique en présence d'une base azotée de la formule générale 4. L'invention concerne en outre l'utilisation non thérapeutique du diester 1 dans lequel R est un radical qui est choisi dans le groupe constitué par un alkyle en C13 à C19, un alcényle en C13 à C19, un alkyldiényl- en C13 à C19, un alkyltriényl en C13 à C19, dans l'alimentation humaine ou animale et le diester 1 préparé selon le procédé pour une utilisation thérapeutique comme médicament et comme principe actif d'une préparation médicinale.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14184483 | 2014-09-11 | ||
PCT/EP2015/068445 WO2016037785A1 (fr) | 2014-09-11 | 2015-08-11 | Procédé de préparation d'esters astaxanthine |
Publications (1)
Publication Number | Publication Date |
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EP3191448A1 true EP3191448A1 (fr) | 2017-07-19 |
Family
ID=51542186
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP15750406.9A Withdrawn EP3191448A1 (fr) | 2014-09-11 | 2015-08-11 | Procédé de préparation d'esters astaxanthine |
Country Status (11)
Country | Link |
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US (1) | US20170305849A1 (fr) |
EP (1) | EP3191448A1 (fr) |
JP (1) | JP2017526712A (fr) |
KR (1) | KR20170052630A (fr) |
CN (1) | CN106687443A (fr) |
AU (1) | AU2015314580A1 (fr) |
BR (1) | BR112017004761A2 (fr) |
CA (1) | CA2958386A1 (fr) |
MX (1) | MX2017003237A (fr) |
RU (1) | RU2017112051A (fr) |
WO (1) | WO2016037785A1 (fr) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
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MX363918B (es) | 2014-05-20 | 2019-04-05 | Asta Pharmaceuticals Co Ltd | Derivado de carotenoides, sal farmaceuticamente aceptable del mismo, o ester o amida farmaceuticamente aceptables del mismo. |
EP3274465B1 (fr) | 2015-03-26 | 2022-08-03 | Basf Se | Production bio-catalytique de fucose l |
ES2856454T3 (es) | 2015-05-08 | 2021-09-27 | Basf Agro Bv | Procedimiento para la preparación de epóxido de terpinoleno. |
CN107848922A (zh) | 2015-05-08 | 2018-03-27 | 巴斯夫农业公司 | 柠檬烯‑4‑醇的制备方法 |
WO2017009205A1 (fr) | 2015-07-10 | 2017-01-19 | Basf Se | Procédé pour l'hydroformylation de butadiènes 2-substitués et la fabrication de produits réactionnels à partir de ceux-ci, notamment d'ambrox |
MX2018010024A (es) | 2016-02-19 | 2018-11-09 | Basf Se | Ciclacion enzimatica de acido homofarnesilico. |
WO2017215929A1 (fr) | 2016-06-15 | 2017-12-21 | BASF Agro B.V. | Procédé d'époxydation d'un alcène tétrasubstitué |
BR112018076043B1 (pt) | 2016-06-15 | 2023-09-26 | Basf Agro B.V | Processo de epoxidação de alqueno tetrassubstituído e uso de agente oxidante |
CN108250119A (zh) * | 2018-03-07 | 2018-07-06 | 广州立达尔生物科技股份有限公司 | 从侧金盏花油树脂中提纯制备高含量天然虾青素酯的方法 |
KR20240034947A (ko) | 2022-09-07 | 2024-03-15 | 전북대학교산학협력단 | 크립토캅신과 루테인을 주성분으로 하는 복합 추출물 및 그의 제조방법 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
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JPH07300421A (ja) * | 1994-04-28 | 1995-11-14 | Itano Reitou Kk | 抗炎症剤 |
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 |
CA2474208C (fr) * | 2002-02-06 | 2011-03-29 | Dsm Ip Assets B.V. | Esters d'astaxanthine |
ES2223270B1 (es) | 2003-04-10 | 2006-04-16 | Carotenoid Technologies, S.A. | Procedimiento para la sintesis de astaxantina. |
CN101386879A (zh) * | 2008-10-30 | 2009-03-18 | 广州立达尔生物科技有限公司 | 一种制备虾青素酯的方法 |
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 |
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2015
- 2015-08-11 EP EP15750406.9A patent/EP3191448A1/fr not_active Withdrawn
- 2015-08-11 US US15/509,905 patent/US20170305849A1/en not_active Abandoned
- 2015-08-11 RU RU2017112051A patent/RU2017112051A/ru not_active Application Discontinuation
- 2015-08-11 KR KR1020177009259A patent/KR20170052630A/ko unknown
- 2015-08-11 WO PCT/EP2015/068445 patent/WO2016037785A1/fr active Application Filing
- 2015-08-11 AU AU2015314580A patent/AU2015314580A1/en not_active Abandoned
- 2015-08-11 BR BR112017004761A patent/BR112017004761A2/pt not_active IP Right Cessation
- 2015-08-11 CN CN201580048767.4A patent/CN106687443A/zh active Pending
- 2015-08-11 CA CA2958386A patent/CA2958386A1/fr not_active Abandoned
- 2015-08-11 MX MX2017003237A patent/MX2017003237A/es unknown
- 2015-08-11 JP JP2017513547A patent/JP2017526712A/ja not_active Withdrawn
Non-Patent Citations (3)
Title |
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PATRICIA HUBBARD ET AL: "Mechanism of Amine-Catalyzed Ester Formation from an Acid Chloride and Alcohol", JOURNAL OF ORGANIC CHEMISTRY, vol. 63, no. 3, 1 February 1998 (1998-02-01), pages 677 - 683, XP055520848, ISSN: 0022-3263, DOI: 10.1021/jo9716643 * |
See also references of WO2016037785A1 * |
ZHIHUI LIU ET AL: "4-( N,N -Dimethylamino)pyridine Hydrochloride as a Recyclable Catalyst for Acylation of Inert Alcohols: Substrate Scope and Reaction Mechanism", ORGANIC LETTERS, vol. 16, no. 1, 16 December 2013 (2013-12-16), US, pages 236 - 239, XP055520837, ISSN: 1523-7060, DOI: 10.1021/ol4030875 * |
Also Published As
Publication number | Publication date |
---|---|
MX2017003237A (es) | 2017-06-29 |
BR112017004761A2 (pt) | 2017-12-05 |
KR20170052630A (ko) | 2017-05-12 |
AU2015314580A1 (en) | 2017-04-06 |
CN106687443A (zh) | 2017-05-17 |
CA2958386A1 (fr) | 2016-03-17 |
US20170305849A1 (en) | 2017-10-26 |
RU2017112051A (ru) | 2018-10-11 |
JP2017526712A (ja) | 2017-09-14 |
WO2016037785A1 (fr) | 2016-03-17 |
RU2017112051A3 (fr) | 2019-03-06 |
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