CN111995512B - Full racemization plant alcohol composition and preparation method and application thereof - Google Patents
Full racemization plant alcohol composition and preparation method and application thereof Download PDFInfo
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- CN111995512B CN111995512B CN202010386025.5A CN202010386025A CN111995512B CN 111995512 B CN111995512 B CN 111995512B CN 202010386025 A CN202010386025 A CN 202010386025A CN 111995512 B CN111995512 B CN 111995512B
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- sodium
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- 239000000203 mixture Substances 0.000 title claims abstract description 127
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 100
- 230000006340 racemization Effects 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- KEVYVLWNCKMXJX-ZCNNSNEGSA-N Isophytol Natural products CC(C)CCC[C@H](C)CCC[C@@H](C)CCC[C@@](C)(O)C=C KEVYVLWNCKMXJX-ZCNNSNEGSA-N 0.000 claims abstract description 16
- 239000001707 (E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-ol Substances 0.000 claims abstract description 13
- BLUHKGOSFDHHGX-UHFFFAOYSA-N Phytol Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)C=CO BLUHKGOSFDHHGX-UHFFFAOYSA-N 0.000 claims abstract description 13
- HNZBNQYXWOLKBA-UHFFFAOYSA-N Tetrahydrofarnesol Natural products CC(C)CCCC(C)CCCC(C)=CCO HNZBNQYXWOLKBA-UHFFFAOYSA-N 0.000 claims abstract description 13
- BOTWFXYSPFMFNR-OALUTQOASA-N all-rac-phytol Natural products CC(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)=CCO BOTWFXYSPFMFNR-OALUTQOASA-N 0.000 claims abstract description 13
- BOTWFXYSPFMFNR-PYDDKJGSSA-N phytol Chemical compound CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC\C(C)=C\CO BOTWFXYSPFMFNR-PYDDKJGSSA-N 0.000 claims abstract description 13
- 238000005886 esterification reaction Methods 0.000 claims abstract description 11
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 5
- 230000032050 esterification Effects 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical group ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000006136 alcoholysis reaction Methods 0.000 claims description 6
- 230000002140 halogenating effect Effects 0.000 claims description 6
- 235000011056 potassium acetate Nutrition 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 5
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 claims description 5
- 239000004280 Sodium formate Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical group [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 4
- 235000019254 sodium formate Nutrition 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Chemical group 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 239000011630 iodine Chemical group 0.000 claims description 3
- 229910052740 iodine Chemical group 0.000 claims description 3
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 claims description 3
- 239000011654 magnesium acetate Substances 0.000 claims description 3
- 235000011285 magnesium acetate Nutrition 0.000 claims description 3
- 229940069446 magnesium acetate Drugs 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- 239000004300 potassium benzoate Substances 0.000 claims description 3
- 235000010235 potassium benzoate Nutrition 0.000 claims description 3
- 229940103091 potassium benzoate Drugs 0.000 claims description 3
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 3
- 239000004299 sodium benzoate Substances 0.000 claims description 3
- 235000010234 sodium benzoate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 claims description 2
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 229940088594 vitamin Drugs 0.000 claims description 2
- 229930003231 vitamin Natural products 0.000 claims description 2
- 235000013343 vitamin Nutrition 0.000 claims description 2
- 239000011782 vitamin Substances 0.000 claims description 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims 2
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims 1
- 239000011772 phylloquinone Substances 0.000 abstract description 21
- MBWXNTAXLNYFJB-LKUDQCMESA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCCC(C)CCCC(C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-LKUDQCMESA-N 0.000 abstract description 20
- 239000002994 raw material Substances 0.000 abstract description 13
- 230000026030 halogenation Effects 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 49
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 30
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 27
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 21
- 229930003448 Vitamin K Natural products 0.000 description 20
- 239000011712 vitamin K Substances 0.000 description 20
- 235000019168 vitamin K Nutrition 0.000 description 20
- 150000003721 vitamin K derivatives Chemical class 0.000 description 20
- 229940046010 vitamin k Drugs 0.000 description 20
- 238000012544 monitoring process Methods 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012141 concentrate Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000004817 gas chromatography Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 150000001298 alcohols Chemical class 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- HECLRDQVFMWTQS-RGOKHQFPSA-N 1755-01-7 Chemical compound C1[C@H]2[C@@H]3CC=C[C@@H]3[C@@H]1C=C2 HECLRDQVFMWTQS-RGOKHQFPSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XJWSAJYUBXQQDR-UHFFFAOYSA-M dodecyltrimethylammonium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)C XJWSAJYUBXQQDR-UHFFFAOYSA-M 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 2
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 description 2
- BGQMOFGZRJUORO-UHFFFAOYSA-M tetrapropylammonium bromide Chemical compound [Br-].CCC[N+](CCC)(CCC)CCC BGQMOFGZRJUORO-UHFFFAOYSA-M 0.000 description 2
- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-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
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000008599 Biliary fistula Diseases 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 208000002881 Colic Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010017999 Gastrointestinal pain Diseases 0.000 description 1
- 208000034767 Hypoproteinaemia Diseases 0.000 description 1
- 206010023129 Jaundice cholestatic Diseases 0.000 description 1
- ABSPRNADVQNDOU-UHFFFAOYSA-N Menaquinone 1 Natural products C1=CC=C2C(=O)C(CC=C(C)C)=C(C)C(=O)C2=C1 ABSPRNADVQNDOU-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 201000005267 Obstructive Jaundice Diseases 0.000 description 1
- 238000006742 Retro-Diels-Alder reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 208000019902 chronic diarrheal disease Diseases 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- -1 hydrocarbyl carboxylic acids Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 235000019175 phylloquinone Nutrition 0.000 description 1
- MBWXNTAXLNYFJB-NKFFZRIASA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-NKFFZRIASA-N 0.000 description 1
- 229960001898 phytomenadione Drugs 0.000 description 1
- 125000001189 phytyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])([H])[C@@](C([H])([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])[C@@](C([H])([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- CUNPJFGIODEJLQ-UHFFFAOYSA-M potassium;2,2,2-trifluoroacetate Chemical compound [K+].[O-]C(=O)C(F)(F)F CUNPJFGIODEJLQ-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- UYCAUPASBSROMS-AWQJXPNKSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-][13C](=O)[13C](F)(F)F UYCAUPASBSROMS-AWQJXPNKSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C50/00—Quinones
- C07C50/10—Quinones the quinoid structure being part of a condensed ring system containing two rings
- C07C50/14—Quinones the quinoid structure being part of a condensed ring system containing two rings with unsaturation outside the ring system, e.g. vitamin K1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C21/00—Acyclic unsaturated compounds containing halogen atoms
- C07C21/02—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds
- C07C21/04—Chloro-alkenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C21/00—Acyclic unsaturated compounds containing halogen atoms
- C07C21/02—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds
- C07C21/14—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds containing bromine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/095—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of organic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/02—Acyclic alcohols with carbon-to-carbon double bonds
- C07C33/025—Acyclic alcohols with carbon-to-carbon double bonds with only one double bond
- C07C33/03—Acyclic alcohols with carbon-to-carbon double bonds with only one double bond in beta-position, e.g. allyl alcohol, methallyl alcohol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C50/00—Quinones
- C07C50/16—Quinones the quinoid structure being part of a condensed ring system containing three rings
- C07C50/20—Quinones the quinoid structure being part of a condensed ring system containing three rings with unsaturation outside the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
- C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/86—Ring systems containing bridged rings containing four rings
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- Chemical & Material Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a full racemization plant alcohol composition with high E type configuration content, a preparation method thereof and application thereof in preparing vitamin K 1 The composition comprises all-racemized plant alcohol with Z-type and E-type configurations, wherein Z/(Z+E) is less than or equal to 15%; the preparation method takes isophytol as a raw material, and the whole racemization phytol composition with high E-type configuration content is obtained through the steps of halogenation, esterification, de-esterification and the like.
Description
Technical Field
The invention provides a composition, a preparation method and application thereof, and in particular relates to a full racemization plant alcohol composition, a preparation method thereof and application thereof in preparing vitamin K 1 Belongs to the fields of organic chemistry and pharmacy.
Background
Vitamin K 1 Naturally occurring in a variety of plants, its naturally occurring form has the chemical name 2-methyl-3- [ (2E, 7R, 11R) -3,7,11, 15-tetramethylhexadec-2-en-1-yl]-1, 4-naphthoquinone with chemical structural formula as shown in formula I-1.
Vitamin K 1 Is a fat-soluble vitamin medicine, and has important functions in blood coagulation, energy metabolism and body tissue movement of human body. Vitamin K 1 Can be used for treating vitamin K 1 Bleeding caused by deficiency, such as bleeding caused by obstructive jaundice, biliary fistula, chronic diarrhea, etc., hypoproteinemia caused by coumarin, sodium salicylate, etc., neonatal hemorrhage, and vitamin K in vivo caused by long-term application of broad-spectrum antibiotics 1 Lack of. Vitamin K 1 It also has analgesic and bronchospasm relieving effects, and can be used for treating visceral smooth muscle angina, biliary tract spasm, and colic caused by intestinal spasm. Thus, vitamin K 1 The importance in the medical and health care fields is increasingly highlighted.
Vitamin K 1 The side chain structure has a double bond at the 2 position and two chiral centers at the 7 and 11 positions. Studies have shown that cis-trans (Z/E) isomerism of the side chain 2-position double bond affects vitamin K 1 Is of the E-type structureA shape; chiral configuration of side chain 7 and 11 positions for vitamin K 1 Has no influence on the activity of (2E, 7R, 11R), (2E, 7S, 11S), (2E, 7R, 11S) and (2E, 7S, 11R) of vitamin K 1 Is equivalent in activity. Thus, in the multinational formulary, only vitamin K is treated 1 The content of Z-type isomer in the preparation is controlled, such as vitamin K only in Chinese pharmacopoeia (2015 edition), united states pharmacopoeia (USP 41 edition), european pharmacopoeia (EP 9.0 edition), etc 1 The Z-type isomer content in the extract is not more than 21.0%, namely the vitamin K which accords with the medicinal standard in the early stage 1 May be present in the form of a composition as shown in formula I:
vitamin K 1 The 7 and 11 positions of the side chain contain two chiral centers, and are brought in by the side chain raw material. Early preparation of vitamin K 1 The side chain raw material of (2) is natural plant alcohol extracted from plants, and the 7 position and the 11 position of the side chain raw material are both R configuration. With the development of organic synthesis chemistry and the enhancement of environmental awareness, the side chain raw materials synthesized artificially replace the side chain raw materials extracted naturally. For example, in the latest United states pharmacopoeia of 2019 (USP 42) and European pharmacopoeia (EP 9.6), in which vitamin K is published 1 The structure of (C) is changed into vitamin K with side chain of formula II' being racemized 1 Namely, the full racemization vitamin K shown in the formula II 1 Comprising 4 forms with side chains in the (2E, 7R, 11R), (2E, 7S, 11S), (2E, 7R, 11S) and (2E, 7S, 11R) configurations.
In addition, to further promote the full racemization of vitamin K 1 In EP9.6, the Z isomer content is also reduced from the original "no more than 21.0%" to "no more than 15.0%"; and the specific rotation is controlled to be-0.05 degrees to minus 0.05 degrees. I.e. the upgraded version of the pharmaceutical vitamin K1 may be present in the form of a composition as shown in formula II:
thus, the side chain of industrialized development is artificially synthesized, full racemization and contains vitamin K with high E configuration content 1 (i.e., vitamin K represented by formula II) 1 Composition) will be a necessary trend.
Development of all-racemic vitamin K 1 The key to (a) is the choice of side chain starting materials. At present, the full racemization vitamin K is prepared 1 The side chain raw material of (a) is generally selected from artificially synthesized isophytol (CAS number: 505-32-8, chemical structural formula is shown as formula III), and the total racemization vitamin K is prepared by rearrangement of isophytol double bond and condensation with main ring 1 . For example, the following synthetic routes are disclosed in the literature, "organic communications.2003,33 (5): 763-772," et al:
however, according to the prior art, Z-isomer content is difficult to control when the isophytol double bond is rearranged to be lower than 15.0%, and the prior art does not provide further reduction of subsequent intermediates or products of vitamin K 1 A method for preparing the Z-type isomer content. Therefore, developing an artificially synthesized side chain raw material meeting specific requirements can effectively promote the full racemization of vitamin K 1 Is an industrial development of (a).
In order to overcome the defects in the prior art, the invention aims at the full racemization vitamin K 1 The side bond raw material and the preparation method thereof are researched, and on the basis of a large number of experimental researches, a novel full-racemization plant alcohol composition with high E-type configuration content is surprisingly developed, and the full-racemization plant alcohol composition not only can be directly used for preparing full-racemization vitamin K with high E-type configuration content 1 In addition, the preparation method of the full racemization plant alcohol composition is simple and convenient, the operation is easy to realize, the raw materials are easy to obtain, and the full racemization plant alcohol composition is suitable for industrial application.
Disclosure of Invention
One of the objects of the present invention is to provide a high E configurationThe full racemization plant alcohol composition with the content can be directly used for preparing full racemization vitamin K with high E configuration content 1 In addition, the preparation method of the full racemization plant alcohol is simple and convenient, the operation is easy to realize, the raw materials are easy to obtain, and the full racemization plant alcohol is suitable for industrial application.
The invention also aims to provide a preparation method of the full racemization plant alcohol with high E-type configuration content.
It is still another object of the present invention to provide a process for preparing full racemic vitamin K with high E-type configuration content using the full racemic plant alcohol with high E-type configuration content as described above 1 Is a method of (2).
In order to achieve the above purpose, the present invention adopts the following technical scheme:
in one aspect, the present invention provides a full racemic plant alcohol composition of formula VII having a high E-configuration content, the composition comprising a full racemic plant alcohol of formula VII-1 and a full racemic plant alcohol of formula VII-2, wherein the content of the full racemic plant alcohol of formula Z is not more than 15% relative to the total content of the full racemic plant alcohols of formula Z and E.
In the structural formula VII, a wave bond connected with a double bond represents that the bond can form an E-type configuration of the double bond or a Z-type configuration of the double bond; the expression "Z/(Z+E). Ltoreq.15%" means that the content of Z-type full racemic plant alcohol (represented by formula VII-2) in the composition is not more than 15% relative to the total content of Z-type (represented by formula VII-2) and E-type full racemic plant alcohol (represented by formula VII-1).
In one embodiment, the present invention provides a full racemic phytol composition with high E-configuration content selected from the group consisting of:
a full racemic plant alcohol composition comprising an E full racemic plant alcohol represented by formula VII-1 and a Z full racemic plant alcohol represented by formula VII-2, wherein the content of Z full racemic plant alcohol is not more than 12% relative to the total content of Z and E full racemic plant alcohols; or alternatively, the first and second heat exchangers may be,
a full racemic plant alcohol composition comprising an E full racemic plant alcohol represented by formula VII-1 and a Z full racemic plant alcohol represented by formula VII-2, wherein the content of Z full racemic plant alcohol is not more than 10% relative to the total content of Z full racemic plant alcohol and E full racemic plant alcohol; or alternatively, the first and second heat exchangers may be,
a full racemic plant alcohol composition comprising an E full racemic plant alcohol represented by formula VII-1 and a Z full racemic plant alcohol represented by formula VII-2, wherein the content of Z full racemic plant alcohol is not more than 8% relative to the total content of Z full racemic plant alcohol and E full racemic plant alcohol; or alternatively, the first and second heat exchangers may be,
a full racemic plant alcohol composition comprising an E full racemic plant alcohol represented by formula VII-1 and a Z full racemic plant alcohol represented by formula VII-2, wherein the content of Z full racemic plant alcohol is not more than 5% relative to the total content of Z full racemic plant alcohol and E full racemic plant alcohol.
The term "all-racemic plant alcohol" refers to an equal mixture of plant alcohols having R-type or S-type configuration in which the configurations of the two chiral centers at positions 7 and 11 are independent, respectively, that is, equal mixtures of four plant alcohols of (7R, 11R), (7S, 11S), (7R, 11S) and (7S, 11R). The three-dimensional configuration can be judged according to the synthetic raw materials and the synthetic method of the full racemization plant alcohol; one of the characteristics is that the specific rotation is-0.1 degree to-0.1 degree, preferably-0.05 degree to-0.05 degree, more preferably 0 degree, and the specific rotation test conditions and methods can be carried out according to the conventional methods in the art.
The 'E-type full racemization plant alcohol' refers to full racemization plant alcohol with 2-position double bond as E-type, and is shown as a formula VII-1.
The Z-type full racemization plant alcohol refers to full racemization plant alcohol with a Z-type double bond at a 2-position, and is shown as a formula VII-2.
The "all-racemic plant alcohol composition" may contain other impurities in addition to the E-type all-racemic plant alcohol and the Z-type all-racemic plant alcohol. The "impurities" refer to organic impurities, inorganic impurities, residual solvents, etc. associated with the full racemic plant alcohol composition or the preparation process thereof.
The expression "the content of Z-type full-racemized plant alcohol relative to the total content of Z-type and E-type full-racemized plant alcohols" means that Z-type full-racemized plants are contained in the compositionThe percentage of alcohol in total of Z-type and E-type full racemization plant alcohol can be rounded, and the obtained calculation result can be processed by rounding, and the characterization can be carried out in a conventional manner in the field. In one embodiment, the relative content is calculated by dividing the area of the Z-type full racemic plant alcohol peak by the sum of the areas of the Z-type and E-type full racemic plant alcohol peaks as measured by Gas Chromatography (GC) or Liquid Chromatography (LC), and then performing percent conversion and rounding; the selection of GC or LC chromatographic conditions can be made according to conventional techniques in the art. In another embodiment, nuclear magnetic resonance hydrogen spectrum is used 1 H NMR) dividing the characteristic hydrogen peak area of the Z-type full racemic plant alcohol by the sum of the characteristic hydrogen peak areas of the Z-type full racemic plant alcohol and the E-type full racemic plant alcohol, and performing percentage conversion and rounding treatment to calculate the relative content.
The characterization methods of the wave bond, Z/(Z+E) and the relative content in the structural formula can be correspondingly understood by referring to the above description unless otherwise specified.
In another aspect, according to the object of the present invention, there is provided a process for preparing the above all-racemic phytol composition, comprising: the isophytol is subjected to halogenation, esterification and de-esterification. The method specifically comprises the following steps:
(1) Carrying out halogenation reaction on isophytol shown in a formula III and a halogenating reagent to convert the isophytol into a composition shown in a formula V,
(2) Esterifying the composition shown in formula V with an esterifying reagent to obtain a composition shown in formula VIII,
(3) The composition shown in the formula VIII is subjected to hydrolysis or alcoholysis de-esterification reaction in the presence of alkali, and is separated to obtain the full racemization plant alcohol composition shown in the formula VII,
in the composition represented by the formula V, X is a halogen atom selected from fluorine, chlorine, bromine and iodine.
In the composition shown in the formula VIII, R is hydrogen, alkyl or substituted alkyl. The alkyl is selected from alkyl, alkenyl, alkyne, aryl and the like; the substituent of the substituted hydrocarbon group is selected from halogen, cyano, nitro, aryl, alkoxy, acyloxy, alkylthio, alkylamino, acyl and the like. Wherein R is preferably hydrogen or an alkanyl radical such as methyl, ethyl, propyl, phenyl, etc.
In the above process step (1), the isophytol is commercially available or prepared according to the prior art.
In the above method step (1), the halogenating reagent comprises phosphorus trichloride, phosphorus tribromide, hydrochloric acid, hydrobromic acid, hydroiodic acid, thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus tribromide and the like, wherein phosphorus tribromide and phosphorus trichloride are preferred.
In the above method step (1), the solvent may be omitted or a suitable solvent may be added. Suitable solvents may be selected from ethers (such as diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tetrahydrofuran, etc.), halogenated hydrocarbons (such as methylene chloride, chloroform, 1, 2-dichloroethane, etc.), alkanes (such as n-hexane, n-heptane, isooctane, etc.), aromatic hydrocarbons (such as toluene, benzene, xylene, etc.), etc. Among them, ethers such as diisopropyl ether, methyl tert-butyl ether, methyl tetrahydrofuran are preferable.
In the above method step (1), a phase transfer catalyst selected from tetrabutylammonium bromide (chloride, iodide), tetramethylammonium bromide (chloride, iodide), tetrapropylammonium bromide (chloride, iodide), tetraethylammonium bromide (chloride, iodide), dodecyltrimethylammonium bromide (chloride, iodide) and the like may be added.
In the above method step (1), the reaction monitoring and the post-treatment may be carried out in a manner conventional in the art.
In the above method step (2), the esterifying reagent is selected from the group consisting of salts of alkali metals or alkaline earth metals corresponding to formic acid, hydrocarbyl or substituted hydrocarbyl carboxylic acids, such as sodium formate, potassium formate, sodium acetate, potassium acetate, magnesium acetate, sodium benzoate, potassium benzoate, sodium trifluoroacetate, potassium trifluoroacetate, and the like.
In the above method step (2), the reaction solvent is preferably an aprotic polar solvent such as N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, acetonitrile or the like.
In the above method step (2), a phase transfer catalyst selected from tetrabutylammonium bromide (chloride, iodide), tetramethylammonium bromide (chloride, iodide), tetrapropylammonium bromide (chloride, iodide), tetraethylammonium bromide (chloride, iodide), dodecyltrimethylammonium bromide (chloride, iodide) and the like may be added.
In the above method step (2), the reaction monitoring and post-treatment may be performed in a conventional manner in the art, or may be directly used for the next reaction after the reaction is completed.
In the above method step (3), the base comprises an organic base or an inorganic base, and may be selected from triethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and the like.
In the above method step (3), the alcohol used for the alcoholysis may be selected from methanol, ethanol, n-propanol, isopropanol, etc.
In the above method step (3), the reaction monitoring and the post-treatment may be performed in a conventional manner in the art.
In the above method step (3), the separation may include further purification, and the purification method includes column chromatography, distillation, and the like. In one embodiment, further purification is performed by column chromatography, the packing is silica gel, and the eluent is n-hexane or a mixed solvent of n-heptane and ethyl acetate or methyl tert-butyl ether.
In still another aspect, the present invention provides a method for preparing a full racemic vitamin K with high E-type configuration content shown in formula II from the full racemic plant alcohol composition with high E-type configuration content shown in formula VII 1 The method comprises the following steps:
(i) Converting the full racemic phytol composition of formula VII into a composition of formula IX in the presence of a chlorinating or brominating agent,
(ii) Reacting the composition of formula IX with a compound of formula IV in the presence of a base to produce a composition of formula VI,
(iii) Decyclopentadiene of the composition of formula VI is removed to obtain the composition of formula II.
In the above method step (i), the chlorinating agent is selected from phosphorus trichloride, hydrochloric acid, thionyl chloride, phosphorus oxychloride and the like, wherein phosphorus trichloride and hydrochloric acid are preferable; the brominating reagent is selected from phosphorus tribromide, hydrobromic acid, dibromosulfoxide, phosphorus tribromide and the like, wherein phosphorus tribromide and hydrobromic acid are preferred.
In the above method step (i), the reaction solvent may be selected from ethers (such as diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tetrahydrofuran, etc.), halogenated hydrocarbons (such as methylene chloride, chloroform, 1, 2-dichloroethane, etc.), alkanes (such as n-hexane, n-heptane, isooctane, etc.), aromatic hydrocarbons (such as toluene, benzene, xylene, etc.), etc.
In the above process step (i), the reaction monitoring and the post-treatment may be carried out in a manner conventional in the art.
In the above method step (ii), the compound of formula IV is commercially available or prepared as described in literature, "organic.communications.2003,33 (5): 763-772 et al.
In the above method step (ii), the base is selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, potassium isopropoxide, sodium amide and the like.
In the above method step (ii), the reaction solvent may be selected from ethers (e.g., tetrahydrofuran, methyltetrahydrofuran, diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether, etc.), alkanes (e.g., n-hexane, n-heptane, isooctane, etc.), aromatics (e.g., toluene, benzene, xylene, etc.), alcohols (e.g., methanol, ethanol, propanol, isopropanol, tert-butanol, etc.), etc.
In the above process step (ii), the reaction monitoring and the working-up can be carried out in a manner customary in the art.
In the above method step (iii), the said dicyclopentadiene removal is a retro Diels-Alder reaction, and the method is generally heating, the heating temperature is generally higher than 50 ℃, preferably higher than 70 ℃.
In the above process step (iii), the dicyclopentadiene may be removed in the absence of solvent, in the composition shown in directly heated VI; or in a solvent selected from n-heptane, isooctane, acetic acid, acetonitrile, chloroform, tetrachloromethane, toluene, benzene, xylene, ethanol, etc.
In the above process step (iii), the reaction monitoring and the post-treatment may be carried out in a manner conventional in the art.
In the above method step (iii), the resulting composition of formula II may be further purified by methods conventional in the art, such as column chromatography, distillation, and the like.
In one embodiment, the present invention provides a process for preparing full racemic vitamin K with high E-type configurational content 1 (composition of formula II) the following intermediate composition:
compared with the prior art, the full racemization plant alcohol composition with high E type configuration content prepared by the specific synthesis method has the following advantages:
(1) Provides a full racemization plant alcohol composition which is not provided by the prior art, and can efficiently prepare vitamin K with higher quality 1 。
(2) The preparation method of the full racemization plant alcohol composition is simple and convenient, the operation is easy to realize, the raw materials are easy to obtain, and the full racemization plant alcohol composition is suitable for industrial application.
Drawings
FIG. 1 is a hydrogen spectrum of a full racemic phytol composition of formula VII according to example 1 of the present invention;
FIG. 2 shows the preparation of example 5 of the invention of full-racemic vitamin K of formula II with a high E-type conformational content 1 Hydrogen profile of the composition;
FIG. 3 is a gas chromatogram of the full racemic phytol composition of formula VII of example 4 of the present invention.
Detailed Description
The invention will be further described in connection with test examples and examples which will enable those skilled in the art to more fully understand the invention, but without limiting the invention in any way.
EXAMPLE 1 preparation of full racemic phytol composition with high E-type configuration content (formula VII)
(1) Preparation of the composition of formula V-a
Dissolving isophytol (formula III) 5kg in methyl tertiary butyl ether 18kg, stirring and cooling to below-10deg.C, and dropwise adding solution prepared from phosphorus tribromide 2.28kg and methyl tertiary butyl ether 2kg at below 0deg.C; after the dripping is finished, continuously controlling the temperature to be below 0 ℃ for reaction; after TLC monitoring reaction is finished, dropwise adding 1kg of water at the temperature below 0 ℃; after the dripping, standing and separating, washing the obtained organic phase with water until the pH value is=5-6, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a composition shown as a formula V-a, and directly using the composition for the next reaction.
(2) Preparation of the composition of formula VIII-a
Adding the composition shown in the formula V-a obtained above, 268g of tetrabutylammonium bromide and 1.80kg of potassium acetate into 6kg of N, N-dimethylformamide, and stirring and reacting at 50-60 ℃; TLC monitors the end of the reaction to obtain a mixed solution of the composition shown in VIII-a, which is directly used for the next reaction.
(3) Preparation of full racemic plant alcohol composition represented by formula VII
Adding 14kg of methanol and 5kg of anhydrous potassium carbonate into the mixed solution of the composition shown in the formula VIII-a, heating, refluxing and stirring for reaction; after TLC monitoring reaction is finished, filtering a reaction solution, and concentrating filtrate under reduced pressure to obtain a concentrate; adding methyl tertiary butyl ether and water into the concentrate for extraction, and collecting an organic phase; washing the organic phase with saturated sodium chloride aqueous solution, and concentrating under reduced pressure; subjecting the concentrate to silica gel column chromatography, eluting with n-heptane/ethyl acetate (10/1, v/v); collecting target fraction, and concentrating under reduced pressure to obtain full racemization plant alcohol composition shown in formula VII.
1 H NMR(400MHz，CDCl 3 ) δ:5.410 (t, 1H), 4.160-4.142 (d, 2H), 1.990 (t, 2H), 1.736-1.734 (s, 0.4H) and 1.669 (s, 2.6H), 1.541-1.508 (m, 1H), 1.410-1.352 (m, 4H), 1.297-1.251 (m, 8H), 1.232-1.049 (m, 6H), 0.875-0.836 (m, 12H). The method comprises 1 In the H NMR results, the signal peaks at chemical shifts 1.736-1.734 (s, 0.40H) and 1.669 (s, 2.68H) were assigned to 3H's on the double bond-linked methyl groups (labeled "position" in the above structure) in the Z-and E-type full racemic plant alcohols, respectively, and from the integrated areas of the two signal peaks, Z/(z+e) was calculated to be 13% in the sample.
Specific rotation: 0 deg..
EXAMPLE 2 preparation of full racemic phytol composition with high E-type configuration content (formula VII)
(1) Preparation of the composition of formula V-b
Mixing 0.5kg of isophytol (formula III), 3.5kg of concentrated hydrochloric acid and 20g of tetramethyl ammonium chloride, and stirring at a temperature of between 10 and 20 ℃ for reaction; after TLC monitoring reaction is finished, n-heptane is added for extraction; the organic phase was washed with water to ph=5-6, dried over anhydrous sodium sulfate, filtered, and concentrated to give a composition of formula V-b, which was directly used in the next reaction.
(2) Preparation of the composition of formula VIII-b
Adding the composition shown in the formula V-b, 30g of tetramethyl ammonium chloride and 344g of sodium formate into 5kg of acetonitrile, and stirring and reacting at 50-60 ℃; TLC monitoring reaction is finished, and filtering is carried out; the obtained filtrate is concentrated under reduced pressure to obtain the composition shown in VIII-b, which is directly used for the next reaction.
(3) Preparation of full racemic plant alcohol composition represented by formula VII
Mixing the composition shown in the formula VIII-b with 4kg of water and 135g of sodium hydroxide, and stirring and reacting at the temperature of 40-50 ℃; after TLC monitoring reaction is finished, filtering a reaction solution, and concentrating filtrate under reduced pressure; subjecting the concentrate to silica gel column chromatography, eluting with n-hexane/methyl tert-butyl ether (15/1, v/v); collecting target fraction, and concentrating under reduced pressure to obtain full racemization plant alcohol composition shown in formula VII.
GC：Z/(Z+E)＝15％；
Specific rotation: 0 deg..
EXAMPLE 3 preparation of full racemic phytol composition with high E-type configuration content (formula VII)
(1) Preparation of the composition of formula V-a
Dissolving isophytol (formula III) 5kg in methyl tertiary butyl ether 18kg, stirring and cooling to below-10deg.C, and dropwise adding solution prepared from phosphorus tribromide 2.28kg and methyl tertiary butyl ether 2kg at below 0deg.C; after the dripping is finished, continuously controlling the temperature to be below 0 ℃ for reaction; after TLC monitoring reaction is finished, dropwise adding 1kg of water at the temperature below 0 ℃; after the dripping, standing and separating, washing the obtained organic phase by saturated sodium bicarbonate aqueous solution until the pH of the obtained aqueous phase is=5-6, drying the obtained organic phase by anhydrous sodium sulfate, filtering and concentrating to obtain the composition shown in the formula V-a, and directly using the composition in the next reaction.
(2) Preparation of the composition of formula VIII-a
Adding the composition shown in the formula V-a obtained above, 268g of tetrabutylammonium bromide and 1.80kg of potassium acetate into 6kg of N, N-dimethylformamide, and stirring and reacting at 20-30 ℃; TLC monitors the end of the reaction to obtain a mixed solution of the composition shown in VIII-a, which is directly used for the next reaction.
(3) Preparation of full racemic plant alcohol composition represented by formula VII
Adding 14kg of methanol and 5kg of anhydrous potassium carbonate into the mixed solution of the composition shown in the formula VIII-a, heating, refluxing and stirring for reaction; after TLC monitoring reaction is finished, filtering a reaction solution, and concentrating filtrate under reduced pressure to obtain a concentrate; adding methyl tertiary butyl ether and water into the concentrate for extraction, and collecting an organic phase; washing the organic phase with saturated sodium chloride aqueous solution, and concentrating under reduced pressure; the resulting concentrate was split in two parts:
subjecting the first concentrate to silica gel column chromatography, eluting with n-heptane/ethyl acetate (20/1, v/v); collecting target fraction, and concentrating under reduced pressure to obtain full racemization plant alcohol composition shown in formula VII. GC: z/(z+e) =8.7%, specific rotation: 0 deg..
Subjecting the second concentrate to silica gel column chromatography, eluting with n-heptane/ethyl acetate (20/1, 10:1, v/v); collecting target fraction, and concentrating under reduced pressure to obtain full racemization plant alcohol composition shown in formula VII.
GC：Z/(Z+E)＝6.9％；
Specific rotation: 0 deg..
EXAMPLE 4 preparation of full racemic phytol composition with high E-type configuration content (formula VII)
(1) Preparation of the composition of formula V-a
2.5kg of isophytol (formula III) is dissolved in 9kg of methyl tertiary butyl ether, stirred and cooled to below-10 ℃, and solution prepared from 1.14kg of phosphorus tribromide and 1kg of methyl tertiary butyl ether is dropwise added at the temperature below 0 ℃; after the dripping is finished, continuously controlling the temperature to be below 0 ℃ for reaction; after TLC monitoring reaction, dropwise adding 0.5kg of water at the temperature below 0 ℃; after the dropping, standing and separating, washing the obtained organic phase with water until the pH of the water phase is=6-7, drying the obtained organic phase with anhydrous sodium sulfate, filtering and concentrating to obtain the composition shown in the formula V-a, and directly using the composition for the next reaction.
(2) Preparation of the composition of formula VIII-a
Adding the composition shown in the formula V-a obtained above, 134g of tetrabutylammonium bromide and 0.90kg of potassium acetate into 3kg of N, N-dimethylformamide, and stirring and reacting at 30-40 ℃; TLC monitors the end of the reaction to obtain a mixed solution of the composition shown in VIII-a, which is directly used for the next reaction.
(3) Preparation of full racemic plant alcohol composition represented by formula VII
Adding 7kg of methanol and 2.5kg of anhydrous potassium carbonate into the mixed solution of the composition shown in the formula VIII-a, heating, refluxing and stirring for reaction; after TLC monitoring reaction is finished, filtering a reaction solution, and concentrating filtrate under reduced pressure to obtain a concentrate; adding methyl tertiary butyl ether and water into the concentrate for extraction, and collecting an organic phase; washing the organic phase with saturated sodium chloride aqueous solution, and concentrating under reduced pressure; subjecting the concentrate to silica gel column chromatography, eluting with n-heptane/ethyl acetate (20/1, 10:1,5:1, v/v); collecting target fraction, and concentrating under reduced pressure to obtain full racemization plant alcohol composition shown in formula VII.
GC: z/(z+e) =1.1%, and the GC detection pattern is shown in fig. 3.
The results of the GC test are shown in the following table:
| peak number | Retention time (min) | Peak width (min) | Peak area | Peak height | Percent peak area (%) |
| 1 | 18.852 | 0.0779 | 39.99957 | 7.00097 | 1.05757 |
| 2 | 19.460 | 0.1070 | 3721.21802 | 579.52155 | 98.38721 |
| 3 | 21.244 | 0.0589 | 20.99978 | 5.31842 | 0.55522 |
In the table, peak 1 is Z-configuration full-racemized plant alcohol, peak 2 is E-configuration full-racemized plant alcohol, and Z/(Z+E) =1.1% can be calculated from the peak area percentages of the two.
EXAMPLE 5 high E-configuration content full racemic vitamin K 1 (composition of formula II)
(1) Preparation of the composition of formula IX-a
1.24kg of the full racemic plant alcohol composition (formula VII, prepared according to example 1) was dissolved in 8.0kg of methyl tert-butyl ether, and the mixture was stirred and cooled to below-10℃and a solution of 0.57kg of phosphorus tribromide and 0.4kg of methyl tert-butyl ether was added dropwise at a temperature below 0 ℃. After the dripping is finished, continuously controlling the temperature to be below 0 ℃ for reaction; after TLC monitoring reaction, dropwise adding 0.4kg of water at the temperature below 0 ℃; after the dripping, standing and separating, washing the obtained organic phase with water until the pH value is=5-6, drying with anhydrous sodium sulfate, filtering and concentrating to obtain the composition shown in the formula IX-a, and directly using the composition in the next reaction.
(2) Preparation of the composition of formula VI
Under the protection of nitrogen, 8.0kg of tetrahydrofuran and 0.47kg of potassium tert-butoxide are mixed, stirred and cooled to below-3 ℃, and 1.0kg of a compound of formula IV dissolved in 3.0kg of tetrahydrofuran is added dropwise; after the dripping, stirring continuously for about 0.5 hour, and then dripping the composition shown in the formula IX-a obtained in the last step below the temperature of minus 3 ℃ into 2.0kg of solution of tetrahydrofuran; after the dripping, the temperature is controlled to be between 5 ℃ below zero and 5 ℃ for continuous reaction. After TLC monitoring reaction, controlling the temperature below 10 ℃ and adjusting the pH value to be between 5 and 6 by using 2mol/L hydrochloric acid; concentrating under reduced pressure, extracting the concentrated solution with methyl tert-butyl ether 15.0kg, and separating; the obtained organic phase is washed by saturated sodium chloride aqueous solution, dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the composition shown in the formula VI, and the composition is directly used for the next reaction.
(3) Full racemization vitamin K shown in formula II 1 Is prepared from
Under the protection of nitrogen, the composition shown in the formula VI obtained in the previous step is dissolved in 5.0kg of acetic acid, stirred and heated to 90-100 ℃ for reaction in the absence of light; after TLC monitoring reaction, concentrating under reduced pressure to obtain full racemization vitamin K shown in formula II 1 。
HPLC：Z/(Z+E)＝12％；
1 H NMR(400MHz，CDCl 3 ) δ:8.084-8.055 (m, 2H), 7.684-7.662 (m, 2H), 5.011-5.008 (t, 1H), 3.377-3.359 (d, 2H), 2.188 (s, 3H), 1.945-1.926 (t, 2H), 1.778-1.679 (s, 3H), 1.515-1.498 (m, 1H), 1.375-1.285 (m, 5H), 1.264-1.183 (m, 7H), 1.151-1.111 (m, 2H), 1.065-1.009 (m, 4H), 0.887-0.806 (m, 12H). Specific rotation: 0 deg..
Claims (2)
1. A process for preparing a full racemic phytol composition of formula VII comprising:
(1) Carrying out halogenation reaction on isophytol shown in a formula III and a halogenating reagent to convert the isophytol into a composition shown in a formula V,
(2) The composition shown in the formula V is subjected to esterification reaction with an esterification reagent to be converted into a composition shown in the formula VIII,
(3) The composition shown in the formula VIII is subjected to hydrolysis or alcoholysis de-esterification reaction in the presence of alkali, and is separated to obtain the full racemization plant alcohol composition shown in the formula VII,
the formula VII comprises a Z-type configuration and an E-type configuration, wherein Z/(Z+E) is less than or equal to 15%; the E-type and Z-type configurations are respectively shown as formulas VII-1 and VII-2:
x in the composition shown in the formula V is selected from fluorine, chlorine, bromine and iodine; r in the composition shown in the formula VIII is selected from methyl, ethyl, propyl or phenyl; in the step (1), the halogenating reagent is selected from phosphorus trichloride, phosphorus tribromide, hydrochloric acid, hydrobromic acid, hydroiodic acid, thionyl chloride, dibromosulfoxide, phosphorus oxychloride or phosphorus oxybromide; in step (2), the esterifying reagent is selected from sodium formate, potassium formate, sodium acetate, potassium acetate, magnesium acetate, sodium benzoate, or potassium benzoate; in step (3), the base is selected from triethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate, the alcohol used for the alcoholysis is selected from methanol, ethanol, n-propanol or isopropanol, and the separation comprises further purification, and the purification method comprises column chromatography and distillation.
2. Preparation of all-racemic vitamin represented by formula II from all-racemic phytol composition prepared by the preparation method of claim 1K 1 Comprising:
(i) Converting the full racemic phytol composition of formula VII into a composition of formula IX in the presence of a chlorinating or brominating agent,
(ii) Reacting the composition of formula IX with a compound of formula IV in the presence of a base to produce a composition of formula VI,
(iii) Removing cyclopentadiene from the composition shown in the formula VI to obtain a composition shown in the formula II,
wherein in step (i), the chlorinating agent is selected from phosphorus trichloride, hydrochloric acid, thionyl chloride or phosphorus oxychloride; the brominating reagent is selected from phosphorus tribromide, hydrobromic acid, dibromosulfoxide or phosphorus tribromide; in step (ii), the base is selected from potassium tert-butoxide, sodium tert-butoxide, potassium isopropoxide, sodium isopropoxide or sodium amide;
the full racemization plant alcohol composition shown in the formula VII is prepared by the following steps:
(1) Carrying out halogenation reaction on isophytol shown in a formula III and a halogenating reagent to convert the isophytol into a composition shown in a formula V,
(2) The composition shown in the formula V is subjected to esterification reaction with an esterification reagent to be converted into a composition shown in the formula VIII,
(3) The composition shown in the formula VIII is subjected to hydrolysis or alcoholysis de-esterification reaction in the presence of alkali, and is separated to obtain the full racemization plant alcohol composition shown in the formula VII,
the formula VII comprises a Z-type configuration and an E-type configuration, wherein Z/(Z+E) is less than or equal to 15%; the E-type and Z-type configurations are respectively shown as formulas VII-1 and VII-2:
x in the composition shown in the formula V is selected from fluorine, chlorine, bromine and iodine; r in the composition shown in the formula VIII is selected from methyl, ethyl, propyl or phenyl; in the step (1), the halogenating reagent is selected from phosphorus trichloride, phosphorus tribromide, hydrochloric acid, hydrobromic acid, hydroiodic acid, thionyl chloride, dibromosulfoxide, phosphorus oxychloride or phosphorus oxybromide; in step (2), the esterifying reagent is selected from sodium formate, potassium formate, sodium acetate, potassium acetate, magnesium acetate, sodium benzoate, or potassium benzoate; in step (3), the base is selected from triethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate, the alcohol used for the alcoholysis is selected from methanol, ethanol, n-propanol or isopropanol, and the separation comprises further purification, and the purification method comprises column chromatography and distillation.
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| US3026249A (en) * | 1960-06-30 | 1962-03-20 | Eastman Kodak Co | Preparation of stable aqueous isomeric vitamin a compositions |
| EP1122236A2 (en) * | 1996-07-05 | 2001-08-08 | Kuraray Co., Ltd., Kurashiki Plant | Process for producing 6-methyl-3-hepten-2-one, and process for producing phyton or isophytol |
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| US3026249A (en) * | 1960-06-30 | 1962-03-20 | Eastman Kodak Co | Preparation of stable aqueous isomeric vitamin a compositions |
| EP1122236A2 (en) * | 1996-07-05 | 2001-08-08 | Kuraray Co., Ltd., Kurashiki Plant | Process for producing 6-methyl-3-hepten-2-one, and process for producing phyton or isophytol |
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