CN115141166A - Preparation method of vitamin C tetraisopalmitate - Google Patents
Preparation method of vitamin C tetraisopalmitate Download PDFInfo
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- CN115141166A CN115141166A CN202210981234.3A CN202210981234A CN115141166A CN 115141166 A CN115141166 A CN 115141166A CN 202210981234 A CN202210981234 A CN 202210981234A CN 115141166 A CN115141166 A CN 115141166A
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- CN
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- Prior art keywords
- vitamin
- tetraisopalmitate
- acid
- lipase
- preparing
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- HQPBOBUGXWYNEZ-QLMRWRAFSA-N [(2S)-2-[(2R)-3,4-bis(14-methylpentadecanoyloxy)-5-oxo-2H-furan-2-yl]-2-(14-methylpentadecanoyloxy)ethyl] 14-methylpentadecanoate Chemical compound CC(C)CCCCCCCCCCCCC(=O)OC[C@H](OC(=O)CCCCCCCCCCCCC(C)C)[C@H]1OC(=O)C(OC(=O)CCCCCCCCCCCCC(C)C)=C1OC(=O)CCCCCCCCCCCCC(C)C HQPBOBUGXWYNEZ-QLMRWRAFSA-N 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims description 4
- 239000011718 vitamin C Substances 0.000 claims abstract description 47
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 29
- 229950004531 hexyldecanoic acid Drugs 0.000 claims abstract description 22
- JMOLZNNXZPAGBH-UHFFFAOYSA-N hexyldecanoic acid Chemical compound CCCCCCCCC(C(O)=O)CCCCCC JMOLZNNXZPAGBH-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 17
- MHEDPJJXDOOCQO-UHFFFAOYSA-N 2-hexyldecanoyl chloride Chemical compound CCCCCCCCC(C(Cl)=O)CCCCCC MHEDPJJXDOOCQO-UHFFFAOYSA-N 0.000 claims abstract description 15
- ZONJATNKKGGVSU-UHFFFAOYSA-M 14-methylpentadecanoate Chemical compound CC(C)CCCCCCCCCCCCC([O-])=O ZONJATNKKGGVSU-UHFFFAOYSA-M 0.000 claims abstract description 14
- 108090001060 Lipase Proteins 0.000 claims abstract description 13
- 239000004367 Lipase Substances 0.000 claims abstract description 13
- 102000004882 Lipase Human genes 0.000 claims abstract description 13
- 235000019421 lipase Nutrition 0.000 claims abstract description 13
- 239000011230 binding agent Substances 0.000 claims abstract description 11
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002808 molecular sieve Substances 0.000 claims description 9
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 9
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 108010084311 Novozyme 435 Proteins 0.000 claims description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- -1 characterized by Chemical compound 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- OEWBEINAQKIQLZ-CMRBMDBWSA-N [(2s)-2-[(2r)-3,4-bis(2-hexyldecanoyloxy)-5-oxo-2h-furan-2-yl]-2-(2-hexyldecanoyloxy)ethyl] 2-hexyldecanoate Chemical compound CCCCCCCCC(CCCCCC)C(=O)OC[C@H](OC(=O)C(CCCCCC)CCCCCCCC)[C@H]1OC(=O)C(OC(=O)C(CCCCCC)CCCCCCCC)=C1OC(=O)C(CCCCCC)CCCCCCCC OEWBEINAQKIQLZ-CMRBMDBWSA-N 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000002516 radical scavenger Substances 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 51
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 24
- 229930003268 Vitamin C Natural products 0.000 description 24
- 235000019154 vitamin C Nutrition 0.000 description 24
- 239000000243 solution Substances 0.000 description 21
- 239000000047 product Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- 238000001035 drying Methods 0.000 description 11
- 239000012535 impurity Substances 0.000 description 11
- 238000005406 washing Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000002537 cosmetic Substances 0.000 description 5
- 150000003700 vitamin C derivatives Chemical class 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002087 whitening effect Effects 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- BGCSXGUJVNUOSD-UHFFFAOYSA-N 1,4-dimethyl-1H-triazol-1-ium chloride Chemical compound CC1=C[NH+](N=N1)C.[Cl-] BGCSXGUJVNUOSD-UHFFFAOYSA-N 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- KTSFKUSRYVFNFU-UHFFFAOYSA-N 2-hexyldecanal Chemical compound CCCCCCCCC(C=O)CCCCCC KTSFKUSRYVFNFU-UHFFFAOYSA-N 0.000 description 1
- 206010002482 Angiosclerosis Diseases 0.000 description 1
- 150000000996 L-ascorbic acids Chemical class 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 102000003425 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 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
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/62—Three oxygen atoms, e.g. ascorbic acid
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
Abstract
The invention discloses a method for preparing vitamin C tetraisopalmitate, which is characterized in that 2-hexyldecanoic acid and L-vitamin C react in a non-aqueous reagent under the catalysis of lipase to generate 6-vitamin C isopalmitate, and the obtained intermediate is prepared into the vitamin C tetraisopalmitate through 2-hexyldecanoyl chloride in the presence of an acid binding agent. The invention firstly invents a method for synthesizing high-purity vitamin C tetraisopalmitate by using lipase; the method has the advantages of high reaction selectivity and high product purity; the environment is protected; simple operation and easy industrial production.
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to a preparation method of high-purity vitamin C tetraisopalmitate.
Background
Vitamin C tetraisopalmitate (CAS: 183476-82-6) has the following structure:
vitamin C tetraisopalmitate is an important ascorbic acid derivative, is a fat-soluble antioxidant, not only retains the pharmacological actions of the ascorbic acid, namely vitamin C, in resisting oxidation, preventing angiosclerosis and treating septicemia, but also has fat solubility, increases the application range of the product, and is a high-efficiency and multifunctional additive. Antioxidants, stabilizers, synergists used as medicines in the pharmaceutical field; in the aspect of health-care food, the product is mainly used as a human body antioxidant and a nutrition enhancer; additives for cosmetics are used mainly in the cosmetic field.
The vitamin C tetraisopalmitate is stable at high temperature, has good solubility in oil, and excellent transdermal absorption capacity, and can be decomposed into free vitamin C in skin to realize physiological function. Since vitamin C has various physiological activities such as whitening, anti-aging, etc., it is used as an active ingredient in various fields of cosmetics. In particular, the whitening effect of vitamin C is widely known to general consumers, and various vitamin C derivatives have been developed. However, most of them are water-soluble vitamin C derivatives, and there are problems in skin absorbability and stability. Vitamin C tetraisopalmitate is a stable vitamin C derivative which is excellent in skin absorbability, is excellent in compatibility with oil, unlike conventional vitamin C derivatives. Absorbed by living body, the vitamin C derivative and ester are combined and cut off by enzyme in living body to become vitamin C, which exerts various physiological functions, inhibits the activity of tyrosinase in cell and melanin generation, and has whitening effect widely applied in various cosmetics.
Two methods are currently known for the synthesis of vitamin C tetraisopalmitate. JP-Kokai No. 6-247956 and CN108069926A both report a method for synthesizing vitamin C tetraisopalmitate, which utilizes 2-hexyldecanoyl chloride to react with vitamin C to generate vitamin C tetraisopalmitate; the vitamin C tetraisopalmitate is prepared by post-treatment such as extraction, water washing, drying, concentration, purification and the like. The method has the disadvantages of complicated steps, environmental pollution and low product purity. Similarly, the chinese patent application "method for synthesizing L-vitamin C polyester" (CN 03129677.7) discloses adding ascorbic acid into a reaction flask of tetrahydrofuran and water, adding isopalmitoyl chloride and sodium hydroxide solution dropwise, reacting to maintain pH at 6-8, adding ethyl acetate after reaction, and stirring to extract the reactant. The method needs to keep the pH value of the reaction liquid between 6 and 8, when the pH value of the reaction liquid is lower than 6, ethyl acetate is added, an organic phase and a water phase are not easy to separate, so that the product loss is large, impurities in the water phase are not easy to remove, and the product purity is reduced.
CN 113493428A is a synthesis method of vitamin C tetraisopalmitate, which comprises mixing vitamin C, alkali solution and cyclohexane, performing ice bath treatment, and then dropwise adding 2-hexyldecanoyl chloride for heat preservation reaction to obtain reaction liquid; standing and layering the reaction solution, and taking the upper layer to obtain an upper layer solution A; adding an oxalic acid aqueous solution into the upper layer liquid A for layering, and taking the upper layer to obtain an upper layer liquid B; adding petroleum ether and saturated sodium bicarbonate solution into the supernatant B for layering, and then adding saturated sodium chloride solution for washing to obtain a clear solution; and adding calcium carbonate viscous liquid into the clear solution, stirring, separating liquid, and then adding activated carbon for purification to obtain the vitamin C tetraisopalmitate. The product in the reaction is decomposed into a plurality of intermediate derivatives due to strong alkalinity, fat-soluble intermediate impurities cannot be washed away in the subsequent washing process, and the product has low purity and low yield.
In addition, CN109320479A discloses a simple synthesis method of vitamin C tetraisopalmitate. 2-hexyldecanal and vitamin C are directly reacted under the action of a catalyst, 1, 4-dimethyl triazole chloride, cesium carbonate and an oxidant (sodium persulfate, tert-butyl peroxy alcohol and potassium hydrogen persulfate) to generate vitamin C tetraisopalmitate; the vitamin C tetraisopalmitate is prepared by post-treatment such as extraction, water washing, drying, concentration, purification and the like. However, the method uses column chromatography for purification, and the yield is about 80 percent and is general.
The product obtained by the method has low purity, cannot meet the increasing quality requirements of cosmetic raw materials or needs to be purified by a column chromatography method, and is not suitable for industrial production.
Vitamin C has four hydroxyl groups in its molecular structure, and the target molecule, vitamin C tetraisopalmitate, is an esterified product of all four hydroxyl groups in the vitamin C molecule. The hydroxyl groups in vitamin C molecules can be divided into two types according to the structural characteristics, wherein the 2, 3-position hydroxyl group can be regarded as a phenolic hydroxyl group and has certain acidity, and the 2, 3-position hydroxyl group has obviously different acidity; the hydroxyl group at the 5,6-position is an alcoholic hydroxyl group, and the hydroxyl group at the 5,6-position is more likely to undergo an esterification reaction than the hydroxyl group at the 2,3-position. When the esterification reaction of the isopalmitoyl chloride and the vitamin C occurs, due to the difference of the reactivity of the hydroxyl groups, the steric hindrance is different or the reaction speed is different, so that the tri-substituted vitamin C isopalmitic acid derivatives with partially different substitution positions are available besides the final product vitamin C tetraisopalmitic acid ester. Since these trisubstituted isopalmitate derivatives are structurally similar to vitamin C isopalmitate, the physical and chemical properties are also very close and very difficult to remove. In addition, the inventor of the patent application has no way to change the selectivity of the acylation reaction by trying to change the material ratio and the material adding mode, changing the reaction temperature and the like. Therefore, these tri-substituted isopalmitate derivative impurities are generated, resulting in a lower purity of the final product. At present, the purity of the products on the market is generally only about 90 percent, and the highest purity is about 96 percent. And 3-4% of the impurities, even about 10% of the impurities, not only reduce the purity of the product, but also bring about deterioration to the appearance, smell and stability of the product. Therefore, a synthetic process for preparing high-purity vitamin C isopalmitate remains to be solved.
Disclosure of Invention
The invention aims to provide a method for synthesizing high-purity vitamin C tetraisopalmitate.
In order to achieve the purpose of the invention, the technical scheme is as follows:
a method for synthesizing vitamin C tetraisopalmitate comprises the following steps: reacting 2-hexyldecanoic acid with L-vitamin C (vitamin C) under the catalysis of lipase to generate 6-vitamin C isopalmitate, and then preparing the vitamin C tetraisopalmitate by 2-hexyldecanoyl chloride in the presence of an acid-binding agent. The reaction formula is as follows:
step I
Step II
In the research process of researching the synthesis process of high-purity vitamin C isopalmitate, 6-vitamin C isopalmitate is synthesized by using lipase catalysis, and the obtained product is prepared into vitamin C tetraisopalmitate by 2-hexyldecanoyl chloride in the presence of an acid binding agent. We used synthetic 6-ascorbic acid isopalmitate as a raw material, and since the 6-position hydroxyl group had formed an ester group (protected), when the subsequent acyl chloride was acylated, the esterification reaction occurred in turn according to the reactivity of the hydroxyl group, unexpectedly the reaction proceeded almost quantitatively, and almost no additional impurities were generated. We have fortunately succeeded in synthesizing high-purity vitamin tetraisopalmitate, the purity of which reaches more than 99%. The method has the advantages of high selectivity, few side reactions, mild reaction conditions, relatively simple downstream separation operation of products, low requirement on equipment and the like, accords with the development trends of clean production and green chemical industry, and is very suitable for industrial production.
Preferably, 2-hexyldecanoic acid reacts with L-vitamin C under the catalysis of lipase to synthesize 6-vitamin C isopalmitate, which is then separated, dewatered or directly dewatered without separation, and then mixed with 2-hexyldecanoyl chloride in the presence of an acid-binding agent to prepare the vitamin C tetraisopalmitate.
Preferably, the lipase is Novozym435.
Preferably, 2-hexyldecanoic acid is reacted with L-vitamin C in a non-aqueous solvent. The non-aqueous solvent is one of ethanol, ethylene glycol, tert-butyl alcohol, tert-amyl alcohol, cyclohexanol, normal hexane, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, dimethylformamide, acetone and butanone or a mixture of the two substances.
Preferably, the calcium molecular sieve is added into the reaction system of the 2-hexyldecanoic acid and the L-vitamin C. More preferably, the calcium molecular sieve is a 5A molecular sieve. The mass ratio of the addition amount of the calcium molecular sieve to the addition amount of the 2-hexyldecanoic acid is 0.5-1.
The reaction temperature in step I is 0 to 80 ℃, preferably 20 to 60 ℃, and more preferably 30 to 60 ℃.
The reaction temperature in step II is 0 to 40 ℃, preferably 20 to 30 ℃.
The reaction time in step I is 10 to 40 hours, preferably 15 to 30 hours.
Preferably, the acid-binding agent includes organic bases such as triethylamine and pyridine, and inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate. Preferably, the acid-binding agent is added in an amount of 1 to 4 times the molar amount of the 2-hexyldecanoic acid. Further, when sodium carbonate and potassium carbonate are selected as acid-binding agents, the adding amount is 1-2 times of the molar amount of the 2-hexyldecanoic acid; when triethylamine, pyridine, sodium bicarbonate and potassium bicarbonate are selected as acid-binding agents, the adding amount is 3-4 times of the molar amount of the 2-hexyldecanoic acid.
Preferably, the molar ratio of the 2-hexyldecanoic acid to the L-vitamin C is 1-8: 1, preferably 1-2: 1; more preferably 1 to 1.5; the specific preferred ratio is 1:1. the optimal dosage of the lipase is less than 5% (by mass with the substrate L-vitamin C).
Preferably, the molar ratio of the 2-hexyldecanoic acid acyl chloride to the L-vitamin C is 3-4: 1.
the advantages of the invention are as follows:
the invention utilizes 2-hexyldecanoic acid to react with L-vitamin C under the catalysis of lipase to generate 6-vitamin C isopalmitate, and the obtained intermediate is prepared into vitamin C tetraisopalmitate by 2-hexyldecanoyl chloride in the presence of an acid-binding agent, with the yield of 95-98%.
The invention firstly invents a method for synthesizing high-purity vitamin C tetraisopalmitate by using lipase; the method has the advantages of high reaction selectivity and high product purity; the environment is protected; simple operation and easy industrial production.
The product obtained by the method has the characteristics of high purity, less impurities, light color, no color change, no odor, environmental protection, simple and convenient operation and the like, and is easy to industrially implement.
Drawings
FIG. 1 is an HPLC chart of vitamin C tetraisopalmitate (comparative example one).
FIG. 2 is an HPLC chart of vitamin C tetraisopalmitate (comparative example two).
FIG. 3 is an HPLC chart of vitamin C tetraisopalmitate (example two).
FIG. 4 is a NMR spectrum of vitamin C tetraisopalmitate.
FIG. 5 is an infrared spectrum of vitamin C tetraisopalmitate.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible, embodiments accompanied with specific embodiments of the present invention are described in detail below for clarity and completeness of description. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
Comparative example 1
Mixing 1mol of vitamin C, 550mL of aqueous solution of sodium hydroxide 2mol/L and 7mol of cyclohexane for 30min, dropwise adding 5mol of 2-hexyldecanoyl chloride at 0 ℃ for reaction for 24h while controlling the dropwise addition within 4h, and simultaneously supplementing the aqueous solution of sodium hydroxide 2mol/L to ensure that the pH of the reaction is 9.5 to obtain a reaction solution. And pouring the reaction solution into a separating funnel, standing for layering for 0.1h to obtain an upper layer solution A. Adding oxalic acid aqueous solution with the mass concentration of 1% into the upper layer liquid A for layering to obtain an upper layer liquid B; adding 2mol of petroleum ether and 2mol/L of sodium bicarbonate solution into the upper-layer solution B for layering, and then adding 2mol/L of sodium chloride solution for washing to obtain a clear solution; and adding 0.05mol of calcium carbonate viscous liquid into the clear solution, stirring, separating liquid, adding activated carbon accounting for 4% of the solution mass, placing at the temperature of 60 ℃ for refluxing for 1 hour, and then carrying out suction filtration and reduced pressure distillation treatment to obtain the vitamin C tetraisopalmitate. Yield: 80.0 percent. HPLC: (236 nm) (as shown in FIG. 1). MS [ M + H ]] + ＝1130。
1 HNMR(400MHz,CDCl 3 ):δ(ppm):5.4(m,1H,C4-H),4.27–4.45(m,3H,C5,C6-H),0.90–2.40(m,124H)。
IR(cm -1 ):722,1097,1133,1339,1378,1464,1708,1743，1779,1799,2865,2923and2954。
Chromatographic conditions are as follows: an ultraviolet detector; a chromatographic column: c18 column (250 mm. Times.4.6mm, 4.5um); an agilent chromatography data workstation; the detection wavelength is 236nm; mobile phase: the volume ratio of methanol to chloroform is 80:20, flow rate: 1mL/min; and (4) an external standard method. The following liquid phase conditions were the same.
Comparative example No. two
A1000 mL three-necked flask was charged with vitamin C22.02g (125 mmol), 2-hexyldecanoic acid 144.13g (562.5 mmol), novozym435 lipase (1 g) and t-amyl alcohol (200 mL), and the reaction was stirred at 55 ℃ for 30 hours. After the reaction, filtering to separate out enzyme and unreacted vitamin C, separating the filtrate to remove tert-amyl alcohol, washing the obtained oily substance with distilled water, and Na 2 SO 4 Drying and filtering again. Colorless oil was obtained, yield: 85.2 percent. HPLC:93.7% (236 nm). (as shown in FIG. 2) MS [ M + H] + ＝1130。
1 HNMR(400MHz,CDCl 3 ):δ(ppm):5.4(m,1H,C4-H),4.27–4.45(m,3H,C5,C6-H),0.90–2.40(m,124H)。
IR(cm -1 ):722,1097,1133,1339,1378,1464,1708,1743，1779,1799,2865,2923and2954。
Example one
A1000 mL three-necked flask was charged with 22.02g of vitamin C, 32.05 g of 2-hexyldecanoic acid, 1g of Novozym435, 200mL of acetone, and 20 g of 5A molecular sieves. The reaction was stirred at 50 ℃ for 30 hours. After the reaction is finished, impurities and excessive acid are removed through drying, filtering and high vacuum. 250 g of dimethylformamide and 128.6 g of 2-hexyldecanoyl chloride were directly charged, and 47.4 g of triethylamine was added dropwise. Stirring for 5 hours at 20-30 ℃, adding 400 g of petroleum ether for extraction, washing, decoloring, drying, allowing the petroleum ether solution of the crude product to flow through a 30 cm silica gel column under negative pressure, and concentrating the solvent. An almost colorless or yellowish oil was obtained. Yield: 97 percent. HPLC:99.3% (236 nm). MS [ M + H ]] + ＝1130。
1 HNMR(400MHz,CDCl 3 ):δ(ppm):5.4(m,1H,C4-H),4.27–4.45(m,3H,C5,C6-H),0.90–2.40(m,124H)。
IR(cm -1 ):722,1097,1133,1339,1378,1464,1708,1743，1779,1799,2865,2923and2954。
Example two
1000mL three-portA bottle was charged with 22.02g of vitamin C, 32.05 g of 2-hexyldecanoic acid, 1g of Novozym435 lipase, 200ml of t-butanol and 20 g of 5A molecular sieves. The reaction was stirred at 50 ℃ for 30 hours. After the reaction is finished, impurities and excessive acid are removed through drying, filtering and high vacuum. 250 g of dimethylformamide and 141.5 g of 2-hexyldecanoyl chloride, 32 g of potassium carbonate powder were directly charged. Stirring for 5 hours at 20-30 ℃, adding 400 g of normal hexane for extraction, washing, decoloring and drying, enabling petroleum ether solution of a crude product to flow through a 30 cm silica gel column under negative pressure, and concentrating a solvent to obtain almost colorless or light yellow oily substances. Yield: 96 percent. HPLC:99.5% (236 nm). (see FIG. 3 for details) MS [ M + H ]] + ＝1130。
1 HNMR(400MHz,CDCl 3 ):δ(ppm):5.4(m,1H,C4-H),4.27–4.45(m,3H,C5,C6-H),0.90–2.40(m,124H)。
IR(cm -1 ):722,1097,1133,1339,1378,1464,1708,1743，1779,1799,2865,2923and2954。
EXAMPLE III
A1000 mL three-necked flask was charged with 22.02g vitamin C, 32.05 g 2-hexyldecanoic acid, 1g Novozym435 lipase, 200mL acetone, and 20 g 5A molecular sieves. The reaction was stirred at 55 ℃ for 30 hours. After the reaction is finished, impurities and excessive acid are removed through drying, filtering and high vacuum. 250 g of dimethylformamide and 128.6 g of 2-hexyldecanoyl chloride were directly added, and 37.1 g of pyridine was added dropwise. Stirring for 5 hours at 20-30 ℃, adding 400 g of n-heptane for extraction, washing, decoloring, drying, allowing a petroleum ether solution of a crude product to flow through a 30 cm silica gel column under negative pressure, and concentrating a solvent to obtain almost colorless or light yellow oily matter. Yield: 98 percent. HPLC:99.0% (236 nm). MS [ M + H ]] + ＝1130。
1 HNMR(400MHz,CDCl 3 ):δ(ppm):5.4(m,1H,C4-H),4.27–4.45(m,3H,C5,C6-H),0.90–2.40(m,124H)。
IR(cm -1 ):722,097,1133,1339,1378,1464,1708,17431779,1799,2865,2923and2954。
Example four
A1000 mL three-necked flask was charged with 22.02g of vitamin C, 32.05 g of 2-hexyldecanoic acid, 1g of Novozym435 lipase, and 200 mmL tetrahydrofuran and 20 g of 5A molecular sieve. The reaction was stirred at 50 ℃ for 30 hours. After the reaction is finished, impurities and excessive acid are removed through drying, filtering and high vacuum. 250 g of dimethylformamide and 128.6 g of 2-hexyldecanoyl chloride, 32 g of sodium carbonate powder were directly charged. Stirring for 5 hours at 20-30 ℃, adding 400 g of normal hexane for extraction, washing, decoloring and drying, enabling petroleum ether solution of a crude product to flow through a 30 cm silica gel column under negative pressure, and concentrating a solvent to obtain almost colorless or light yellow oily substances. Yield: 95 percent. HPLC:99.5% (236 nm). MS [ M + H ]] + ＝1130。
1 HNMR(400MHz,CDCl 3 ):δ(ppm):5.4(m,1H,C4-H),4.27–4.45(m,3H,C5,C6-H),0.90–2.40(m,124H)。
IR(cm -1 ):722,1097,1133,1339,1378,1464,1708,1743，1779,1799,2865,2923and2954。
Claims (10)
1. A method for preparing vitamin C tetraisopalmitate, characterized by, 2-hexyl decanoic acid reacts with L-vitamin C under the catalysis of lipase in nonaqueous reagent, produce 6-vitamin C isopalmitate, the midbody got is made vitamin C tetraisopalmitate under the existence of acid-binding agent again through 2-hexyl decanoyl chloride; the structure of the 6-vitamin C isopalmitate is as follows:
2. the method for preparing vitamin C tetraisopalmitate according to claim 1, wherein 2-hexyldecanoic acid is reacted with L-vitamin C under lipase catalysis to synthesize 6-vitamin C isopalmitate, which is then separated, dehydrated or directly dehydrated without separation, and then reacted with 2-hexyldecanoyl chloride in the presence of an acid-binding agent to obtain vitamin C tetraisopalmitate.
3. The process for the preparation of vitamin C tetraisopalmitate according to claim 1, characterized in that said lipase is Novozym435 lipase.
4. The method for preparing vitamin C tetraisopalmitate according to claim 1, wherein said lipase is used in an amount less than 5%, and the molar ratio of 2-hexyldecanoic acid to L-vitamin C is 1-1.5: 1.
5. The method for preparing vitamin C tetraisopalmitate according to claim 4, characterized in that said molar ratio of 2-hexyldecanoic acid chloride to L-vitamin C is 3 to 4:1.
6. the method of claim 1, wherein the non-aqueous reagent is one of ethanol, ethylene glycol, t-butanol, t-amyl alcohol, cyclohexanol, n-hexane, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, dimethylformamide, acetone or a mixture of two substances.
7. The method of claim 1, wherein the acid scavenger comprises one or more of triethylamine, pyridine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate; the adding amount is 1 to 4 times of the molar amount of the 2-hexyldecanoic acid.
8. The method of producing ascorbyl tetraisopalmitate according to claim 1, characterized in that the reaction temperature for producing 6-ascorbyl isopalmitate is 0 to 80 ℃; the reaction temperature for preparing the vitamin C tetraisopalmitate is 0-40 ℃.
9. The method of producing ascorbyl tetraisopalmitate according to claim 8, characterized in that the reaction temperature for producing 6-ascorbyl isopalmitate is 20 to 60 ℃; the reaction temperature for preparing the vitamin C tetraisopalmitate is 20-30 ℃.
10. The method for preparing vitamin C tetraisopalmitate according to claim 1, wherein the reaction system of 2-hexyldecanoic acid with L-vitamin C is added with a calcium molecular sieve.
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