CN105315185B - A kind of synthetic method of vitamin A high-grade aliphatic ester - Google Patents
A kind of synthetic method of vitamin A high-grade aliphatic ester Download PDFInfo
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- CN105315185B CN105315185B CN201410298234.9A CN201410298234A CN105315185B CN 105315185 B CN105315185 B CN 105315185B CN 201410298234 A CN201410298234 A CN 201410298234A CN 105315185 B CN105315185 B CN 105315185B
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- vitamin
- aliphatic ester
- grade aliphatic
- synthetic method
- retinol
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- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 title claims abstract description 120
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 title claims abstract description 79
- -1 aliphatic ester Chemical class 0.000 title claims abstract description 50
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 title claims abstract description 40
- 235000019155 vitamin A Nutrition 0.000 title claims abstract description 40
- 239000011719 vitamin A Substances 0.000 title claims abstract description 40
- 229940045997 vitamin a Drugs 0.000 title claims abstract description 40
- 238000010189 synthetic method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 239000011607 retinol Substances 0.000 claims abstract description 39
- 229960003471 retinol Drugs 0.000 claims abstract description 39
- 235000020944 retinol Nutrition 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 36
- 229910044991 metal oxide Inorganic materials 0.000 claims abstract description 11
- 150000004706 metal oxides Chemical class 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 230000032050 esterification Effects 0.000 claims abstract 2
- 238000005886 esterification reaction Methods 0.000 claims abstract 2
- 239000003513 alkali Substances 0.000 claims description 26
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 20
- 239000000706 filtrate Substances 0.000 claims description 18
- 238000001556 precipitation Methods 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 16
- 239000003208 petroleum Substances 0.000 claims description 15
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 14
- 239000000194 fatty acid Substances 0.000 claims description 14
- 229930195729 fatty acid Natural products 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 150000004665 fatty acids Chemical class 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 4
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 3
- 238000012805 post-processing Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000292 calcium oxide Substances 0.000 claims description 2
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 2
- 239000000395 magnesium oxide Substances 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- 230000006837 decompression Effects 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 27
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 abstract description 22
- 238000002360 preparation method Methods 0.000 abstract description 19
- 238000001514 detection method Methods 0.000 abstract description 17
- 229940108325 retinyl palmitate Drugs 0.000 abstract description 11
- 235000019172 retinyl palmitate Nutrition 0.000 abstract description 11
- 239000011769 retinyl palmitate Substances 0.000 abstract description 11
- 230000008901 benefit Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 3
- 235000013373 food additive Nutrition 0.000 abstract description 2
- 239000002778 food additive Substances 0.000 abstract description 2
- 238000012545 processing Methods 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract 1
- 239000007791 liquid phase Substances 0.000 description 22
- 230000004913 activation Effects 0.000 description 17
- 101000939467 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 28 Proteins 0.000 description 15
- 102100029821 Ubiquitin carboxyl-terminal hydrolase 28 Human genes 0.000 description 15
- 238000009413 insulation Methods 0.000 description 15
- 239000008236 heating water Substances 0.000 description 14
- 239000012263 liquid product Substances 0.000 description 14
- 238000011282 treatment Methods 0.000 description 14
- NGEZPLCPKXKLQQ-VOTSOKGWSA-N (e)-4-(3-methoxyphenyl)but-3-en-2-one Chemical compound COC1=CC=CC(\C=C\C(C)=O)=C1 NGEZPLCPKXKLQQ-VOTSOKGWSA-N 0.000 description 9
- 150000002148 esters Chemical group 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 6
- 229910052782 aluminium Inorganic materials 0.000 description 5
- 239000004411 aluminium Substances 0.000 description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 125000001033 ether group Chemical group 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- FLIACVVOZYBSBS-UHFFFAOYSA-N Methyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC FLIACVVOZYBSBS-UHFFFAOYSA-N 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 108010084311 Novozyme 435 Proteins 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- ZGISOPBIAXHOTQ-OUGXGHBNSA-N all-trans-retinyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C ZGISOPBIAXHOTQ-OUGXGHBNSA-N 0.000 description 1
- WIYYXLSPNGTKOH-OGBLRLSYSA-N all-trans-retinyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C WIYYXLSPNGTKOH-OGBLRLSYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- ZPOLOEWJWXZUSP-WAYWQWQTSA-N bis(prop-2-enyl) (z)-but-2-enedioate Chemical compound C=CCOC(=O)\C=C/C(=O)OCC=C ZPOLOEWJWXZUSP-WAYWQWQTSA-N 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 244000222991 cardamomo Species 0.000 description 1
- 235000005300 cardamomo Nutrition 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- NWADXBLMWHFGGU-UHFFFAOYSA-N dodecanoic anhydride Chemical compound CCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCC NWADXBLMWHFGGU-UHFFFAOYSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N methyl undecanoic acid Natural products CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000002927 oxygen compounds Chemical class 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Abstract
The invention discloses a kind of synthetic method of vitamin A high-grade aliphatic ester, including：Under the catalysis of alkaline metal oxide, with higher aliphatic acid anhydrides esterification occurs in organic solvent for retinol, and described vitamin A high-grade aliphatic ester is obtained through processing later after reaction completely.The preparation method has byproduct of reaction few, and product purity is high, the measured advantage of matter, using high performance liquid chromatography detection content more than 97.5%, yield more than 96.5%.Obtained vitamin A high-grade aliphatic ester is more convenient for the storing and application of vitamin A.Prepared Retinol Palmitate is analyzed using the method for pharmacopeia, and biological value is 175~1,780,000 IU/g, and high performance liquid chromatography detection content more than 97.5% can be widely used in medicine, feed addictive, food additives directly as merchandise sales.
Description
Technical field
The invention belongs to vitamin synthesis field, and in particular to a kind of synthetic method of vitamin A high-grade aliphatic ester.
Background technology
Retinol is poor because of its stability, is difficult storing, and in actual application, retinol is usually converted into phase
To more stable vitamin A higher fatty acids carboxylate.The synthetic method of vitamin A higher fatty acids carboxylate is quite a lot of, but
There is shortcoming, be at present after higher fatty acids is acylated through thionyl chloride, to be tied up with retinol using more production technologies
React and prepare in the presence of sour agent (triethylamine, pyridine etc.), the method has energy consumption big, seriously polluted, process route length, acid binding agent
The shortcomings of hardly possible separation, poor product quality.
Shown in the structure of vitamin A high-grade aliphatic ester such as formula (I)：
In formula (I), R is C9~15Linear paraffin.
Shown in the structure of retinol such as formula (III)：
Patent WO2014/23772 discloses a kind of preparation method of Retinol Palmitate, and the preparation method is in highly basic
Property under the conditions of, methyl hexadecanoate and vitamine A acetate carry out ester exchange, and methyl acetate is evaporated off, so as to be prepared into vitamin A palm fibre
The higher fatty acids methyl esters purity obtained in glycerin monostearate, the method is not high, most of unrealized industrialized production, and alkali is in the product
Residual make the stability and poor appearance of product.
Enzymatic clarification vitamin A high-grade aliphatic ester also has been reported that (Liu Yuan, " enzyme process prepares vitamin A palmitic acid in recent years
The research of ester ", Collects The American University's Master's thesis, on April 15th, 2011), using fatty acid enzyme Novozyme435 or Amberlyst
A21, vitamine A acetate directly reaction can prepare vitamin A higher fatty acids carboxylate with higher fatty acids, and this method is present
The cost of enzyme, the problems such as separation with enzyme and activation, and yield only 78% are applied mechanically, without any cost advantage.
The content of the invention
The invention provides a kind of synthetic method of vitamin A high-grade aliphatic ester, the synthetic method is environmentally friendly, instead
Answer temperature relatively low, energy consumption is small, the molecule utilization rate of supplementary material is high, high income.
A kind of synthetic method of vitamin A high-grade aliphatic ester, including：
Under the catalysis of alkaline metal oxide, retinol is esterified in organic solvent with higher aliphatic acid anhydrides
Reaction, described vitamin A high-grade aliphatic ester is obtained after reaction completely through processing later；
Shown in the structure of vitamin A high-grade aliphatic ester such as formula (I)：
Shown in the structure such as formula (II) of described higher aliphatic acid anhydrides：
In formula (I), R is C9~C15Alkyl, preferably C9~C15Straight chained alkyl.
The present invention enters for the shortcoming in the synthetic method of current vitamin A higher fatty acids carboxylate to synthetic method
Optimization is gone, using alkaline metal oxide as catalyst, using higher aliphatic acid anhydrides as acylating reagent, with higher receipts
Rate has obtained vitamin A high-grade aliphatic ester, and the purity of obtained product is high, and outward appearance is good.
In addition, also there is document report (" acid gama-alumina catalyzes and synthesizes diallyl maleate "《Fine chemical material
And intermediate》One army of king the 9th phase in 2005) ester is catalyzed and synthesized using acidic metal oxide, but vitamin A is in acid condition
Extremely unstable, during synthesis for vitamin A higher fatty acids carboxylate, accessory substance is more, does not possess actual application value；This
Invention carries out being processed into alkalescence to metal oxide, is used further to synthetic vitamin A higher fatty acids carboxylates, neither the life of destruction dimension
Plain A has reached catalytic effect again.
Preferably, described alkaline metal oxide is at least one of calcium oxide, magnesia and aluminum oxide, wherein
200 mesh alkali alumina (gamma-alumina) catalytic effects are best.
Accessory substance acetic acid can be evaporated off by corresponding higher fatty acids and acetic acid anhydride reactant in described higher aliphatic acid anhydrides
After obtain.Preferably, described higher aliphatic acid anhydrides is preferably palmitic anhydride.
Organic solvent of the present invention is pyridine, acetonitrile, benzene, toluene, petroleum ether, normal hexane, normal heptane, dichloromethane
One or more of mixtures in alkane, chloroform equal solvent.The solvent effect of pyridine is best during reaction, but its post processing fiber crops
It is tired, pyridine residual can be caused more；Benzene, toluene are unfriendly to environment, belong to carcinogenic solvent, are not suitable for big production；Acetonitrile, just
Because there is H in hexane, normal heptane, chloroform+Or-CH3Group can suppress the solvation of reaction product, hinder reaction to positive direction
Carry out.Integrated economics benefit, environment-friendly and solvent effect, petroleum ether, dichloromethane are most preferred solvent, now, reclaim energy
Consumption is small.
Preferably, described alkaline metal oxide is alkali alumina (gamma-alumina), mesh number is 100~300 mesh；
Described organic solvent is petroleum ether or dichloromethane, now, the yield highest of reaction.
As it is further preferably, described alkali alumina is activated using preceding adopting with the following method：
Commercially available gamma-alumina is soaked 2~3 hours in 10~15% sodium hydrate aqueous solutions at room temperature, then subtracted
80~90 DEG C are dried 20~24 hours in pressure baking oven.
Preferably, reaction temperature is 10~80 DEG C, the reaction time is 1~4 hour；It is used as further preferred, reaction
Temperature is 40~50 DEG C, and the reaction time is 2.5 hours.
Preferably, the mol ratio of described retinol and described higher aliphatic acid anhydrides is 1：1.05~2；As
Further preferred, described retinol and the mol ratio of described higher aliphatic acid anhydrides are 1：1.1~1.5.
Preferably, the mass ratio of described retinol, organic solvent, catalyst is 1：3~10：0.1~0.2；Make
Mass ratio for further preferred, described retinol, organic solvent, catalyst is 1：3.5~5：0.15.
Preferably, described post-processing operation is as follows：Reaction solution after reaction completely is first filtered to remove alkalinous metal oxygen
Compound, is subsequently cooled to -10~-15 DEG C, insulation is filtrated to get filtrate again after 1~2 hour, obtains described after the filtrate precipitation
Vitamin A high-grade aliphatic ester.It can make what higher aliphatic acid anhydrides excessive in reaction system and reaction were produced by cooling
Higher fatty acids is separated out, and is further removed by filtration, and excessive higher aliphatic acid anhydrides can with accessory substance higher fatty acids
To apply mechanically the preparation of higher aliphatic acid anhydrides.
Compared with the existing technology, beneficial effects of the present invention are embodied in：
Very well, impurity is few for vitamin A high-grade aliphatic ester stability prepared by the present invention, and outward appearance is faint yellow to colourless
It is more than oily liquids, high performance liquid chromatography positive detection level 97.5% (alltrans).Especially Retinol Palmitate is used
U.S. medicine song USP28 method is analyzed, the IU/g of biological value 176~1,780,000, content more than 98%；Advised with NF
Fixed method is analyzed, and the IU/g of biological value 175~1,780,000, content more than 98% can be widely applied to medicine, feed and add
Plus agent and food additives.
Embodiment
By following experiment, the present invention is further illustrated, is not the concrete restriction to the scope of the invention, emphasis
It has studied the preparation of Retinol Palmitate.
The preparation of the Retinol Palmitate of embodiment 1
(59.5g, 0.12mol) palmitic anhydride is put into (28.6g, 0.1mol) retinol and 240g petroleum ethers
In the solution of composition, slow 40 DEG C of heating water bath adds 4.29g and activates 200 mesh alkali aluminas.Insulation reaction 2 hours, liquid
Phase tracing detection retinol residual≤0.3% stops reaction, filters out alkali alumina, -12 DEG C of cold treatments filter out filter residue,
Filtrate carries out precipitation, obtains pale yellow oily liquid product (51.2g, molar yield 97.62%).Product liquid-phase chromatographic analysis with
Standard items feature is consistent, and is analyzed using American Pharmacopeia USP28 method：Product biological value is 178.1 ten thousand IU/g, content
98.3%.
Wherein, the activation method of 200 mesh alkali aluminas is as follows：
200 mesh gamma-aluminas soak 2 hours in 10% sodium hydrate aqueous solution at room temperature, then depressurize 85 DEG C of bakings in baking railway carriage or compartment
24 hours.
The preparation of the Retinol Palmitate of embodiment 2
(59.5g, 0.12mol) palmitic anhydride is put into (28.6g, 0.1mol) retinol and 240g petroleum ether groups
Into solution in, slow 40 DEG C of heating water bath adds 2.86g and activates 200 mesh alkali aluminas (activation method and embodiment 1
It is identical).Insulation reaction 2 hours, liquid phase tracing detection retinol residual≤0.3% stops reaction, filters out alkali alumina ,-
12 DEG C of cold treatments, filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid product (50.7g, molar yield
96.75%).Product liquid-phase chromatographic analysis is consistent with standard items feature, is analyzed using American Pharmacopeia USP28 method：Product is given birth to
Thing potency is 176.1 ten thousand IU/g, content 98.01%.
Embodiment 3-dimensional gives birth to the preparation of element A palmitates
(59.5g, 0.12mol) palmitic anhydride is put into (28.6g, 0.1mol) retinol and 240g petroleum ether groups
Into solution in, slow 40 DEG C of heating water bath, adding the 200 mesh alkali aluminas that 5.72g activated, (activation method is with implementing
Example 1 is identical).Insulation reaction 2 hours, liquid phase tracing detection retinol residual≤0.3% stops reaction, filters out alkaline oxygenated
Aluminium, -12 DEG C of cold treatments filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid product (50.9g, molar yield
97.14%).Product liquid-phase chromatographic analysis is consistent with standard items feature, is analyzed using American Pharmacopeia USP28 method：Product is given birth to
Thing potency is 176.3 ten thousand IU/g, content 98.07%.
The preparation of the Retinol Palmitate of embodiment 4
(59.5g, 0.12mol) palmitic anhydride is put into (28.6g, 0.1mol) retinol and 240g petroleum ether groups
Into solution in, slow 40 DEG C of heating water bath adds 4.5g (100~300 mesh) alkaline oxygenated calcium.Insulation reaction 2 hours, liquid
Phase tracing detection retinol residual≤0.3% stops reaction, filters out alkaline oxygenated calcium, -12 DEG C of cold treatments filter out filter residue,
Filtrate carries out precipitation, obtains pale yellow oily liquid product (49.9g, molar yield 95.23%).Product liquid-phase chromatographic analysis with
Standard items feature is consistent, and is analyzed using American Pharmacopeia USP28 method：Product biological value is 171.3 ten thousand IU/g, content
97.07%.
The preparation of the Retinol Palmitate of embodiment 5
(59.5g, 0.12mol) palmitic anhydride is put into (28.6g, 0.1mol) retinol and 240g petroleum ether groups
Into solution in, slow 40 DEG C of heating water bath adds 4.5g (100~300 mesh) alkaline oxygenated magnesium.Insulation reaction 2 hours, liquid
Phase tracing detection retinol residual≤0.3% stops reaction, filters out alkaline oxygenated magnesium, -12 DEG C of cold treatments filter out filter residue,
Filtrate carries out precipitation, obtains pale yellow oily liquid product (47.3g, molar yield 90.26%).Product liquid-phase chromatographic analysis with
Standard items feature is consistent, and is analyzed using American Pharmacopeia USP28 method：Product biological value is 173.3 ten thousand IU/g, content
97.87%.
The preparation of the Retinol Palmitate of embodiment 6
(59.5g, 0.12mol) palmitic anhydride is put into (28.6g, 0.1mol) retinol and 300g pyridines composition
Solution in, slow 40 DEG C of heating water bath, add 4.29g activation 200 mesh alkali aluminas (activation method and the phase of embodiment 1
Together).Insulation reaction 2 hours, liquid phase tracing detection retinol residual≤0.3% stops reaction, filters out alkali alumina, -12
DEG C cold treatment, filters out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid product (45.1g, molar yield
86.06%).Product liquid-phase chromatographic analysis is consistent with standard items feature, is analyzed using American Pharmacopeia USP28 method：Product is given birth to
Thing potency is 171.8 ten thousand IU/g, content 95.31%.
The preparation of the Retinol Palmitate of embodiment 7
(59.5g, 0.12mol) palmitic anhydride is put into (28.6g, 0.1mol) retinol and 300g acetonitriles composition
Solution in, slow 40 DEG C of heating water bath, add 4.29g activation 200 mesh alkali aluminas (activation method and the phase of embodiment 1
Together).Insulation reaction 2 hours, liquid phase tracing detection retinol residual≤0.3% stops reaction, filters out alkali alumina, -12
DEG C cold treatment, filters out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid product (46.7g, molar yield
89.12%).Product liquid-phase chromatographic analysis is consistent with standard items feature, is analyzed using American Pharmacopeia USP28 method：Product is given birth to
Thing potency is 172.4 ten thousand IU/g, content 96.72%.
The preparation of the Retinol Palmitate of embodiment 8
(59.5g, 0.12mol) palmitic anhydride is put into (28.6g, 0.1mol) retinol and 300g normal heptane shapes
Into solution in, slow 40 DEG C of heating water bath adds 4.29g and activates 200 mesh alkali aluminas (activation method and embodiment 1
It is identical).Insulation reaction 2 hours, liquid phase tracing detection retinol residual≤0.3% stops reaction, filters out alkali alumina ,-
12 DEG C of cold treatments, filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid product (47.5g, molar yield
90.64%).Product liquid-phase chromatographic analysis is consistent with standard items feature, is analyzed using American Pharmacopeia USP28 method：Product is given birth to
Thing potency is 173.0 ten thousand IU/g, content 97.26%.
The preparation of the vitamin A certain herbaceous plants with big flowers acid esters (ten carbonic esters) of embodiment 9
(39.1g, 0.12mol) capric anhydrid is put into (28.6g, 0.1mol) retinol and 240g petroleum ethers are formed
Solution in, slow 40 DEG C of heating water bath adds 200 mesh alkali aluminas (activation method and the embodiment 1 of 4.29g activation
It is identical).Insulation reaction 2 hours, liquid phase tracing detection retinol residual≤0.3% stops reaction, filters out alkali alumina ,-
15 DEG C of cold treatments, filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid product (42.6g, molar yield
96.73%).With reference to American Pharmacopeia USP28 method analysis, product biological value is 221.6 ten thousand IU/g, content 98.53%.
The preparation of the vitamin A hendecoic acid ester of embodiment 10
(42.6g, 0.12mol) hendecoic acid acid anhydride is put into (28.6g, 0.1mol) retinol and 240g petroleum ethers
In the solution of formation, slow 40 DEG C of heating water bath adds 4.29g and activates 200 mesh alkali alumina (activation method and embodiments
1 is identical).Insulation reaction 2 hours, liquid phase tracing detection retinol residual≤0.3% stops reaction, filters out alkaline oxygenated
Aluminium, -15 DEG C of cold treatments filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid product (44.9g, 98.73%).
With reference to American Pharmacopeia USP28 method analysis, product biological value is 214.1 ten thousand IU/g, content 98.64%.
The preparation of the vitamin A laurate of embodiment 11 (lauric acid ester)
(45.9g, 0.12mol) lauric anhydride is put into (28.6g, 0.1mol) retinol and 240g petroleum ether shapes
Into solution in, slow 40 DEG C of heating water bath, add 4.29g activation 200 mesh alkali alumina (activation method and embodiments
1 is identical).Insulation reaction 2 hours, liquid phase tracing detection retinol residual≤0.3% stops reaction, filters out alkaline oxygenated
Aluminium, -15 DEG C of cold treatments filter out filter residue, and filtrate carries out precipitation, obtain pale yellow oily liquid product (45.4g,
96.85%).With reference to American Pharmacopeia USP28 method analysis, product biological value is 205.4 ten thousand IU/g, content 98.27%.
The preparation of the vitamin A ficocerylic acid ester of embodiment 12
(49.3g, 0.12mol) ficocerylic acid acid anhydride is put into (28.6g, 0.1mol) retinol and 240g petroleum ethers
In the solution of formation, slow 40 DEG C of heating water bath adds 4.29g and activates 200 mesh alkali alumina (activation method and embodiments
1 is identical).Insulation reaction 2 hours, liquid phase tracing detection retinol residual≤0.3% stops reaction, filters out alkaline oxygenated
Aluminium, -15 DEG C of cold treatments filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid product (46.8g, 97.01%).
With reference to American Pharmacopeia USP28 method analysis, product biological value is 198.7 ten thousand IU/g, content 98.36%.
The preparation of the vitamin A myristate of embodiment 13 (ten tetra-carbonic esters)
(52.7g, 0.12mol) cardamom acid anhydrides is put into (28.6g, 0.1mol) retinol and 240g petroleum ether shapes
Into solution in, slow 40 DEG C of heating water bath adds 4.29g and activates 200 mesh alkali aluminas (activation method and embodiment 1
It is identical).Insulation reaction 2 hours, liquid phase tracing detection retinol residual≤0.3% stops reaction, filters out alkali alumina ,-
15 DEG C of cold treatments, filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid product (48.2g, 97.09%).Reference
American Pharmacopeia USP28 method analysis, product biological value is 195.4 ten thousand IU/g, content 98.24%.
The preparation of the carbonic ester of 14 vitamin A of embodiment 15
(56.0g, 0.12mol) 15 carbonic anhydride is put into (28.6g, 0.1mol) retinol and 240g petroleum ethers
In the solution of formation, slow 40 DEG C of heating water bath adds 4.29g and activates 200 mesh alkali alumina (activation method and embodiments
1 is identical).Insulation reaction 2 hours, liquid phase tracing detection retinol residual≤0.3% stops reaction, filters out alkaline oxygenated
Aluminium, -15 DEG C of cold treatments filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid product (49.8g, 97.48%).
With reference to American Pharmacopeia USP28 method analysis, product biological value is 184.5 ten thousand IU/g, content 98.3%.
Claims (8)
1. a kind of synthetic method of vitamin A high-grade aliphatic ester, it is characterised in that including：
Under the catalysis of alkaline metal oxide, with higher aliphatic acid anhydrides esterification occurs in organic solvent for retinol,
Described vitamin A high-grade aliphatic ester is obtained by post processing；Described alkaline metal oxide be calcium oxide, magnesia and
At least one of aluminum oxide；
Shown in the structure such as formula (I) of described vitamin A high-grade aliphatic ester：
Shown in the structure such as formula (II) of described higher aliphatic acid anhydrides：
In formula (I), R is C9~C15Alkyl；
Described higher aliphatic acid anhydrides is obtained by corresponding higher fatty acids and acetic acid anhydride reactant after accessory substance acetic acid is evaporated off.
2. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, it is characterised in that described is organic
Solvent is the one or more in pyridine, acetonitrile, benzene, toluene, petroleum ether, normal hexane, normal heptane, dichloromethane, chloroform
Mixture.
3. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, it is characterised in that described alkalescence
Metal oxide is alkali alumina, and mesh number is 100~300 mesh.
4. the synthetic method of the vitamin A high-grade aliphatic ester according to claim 1 or 3, it is characterised in that described alkali
Property aluminum oxide is activated using preceding adopting with the following method：
At room temperature by gamma-alumina mass percent concentration be 10~15% sodium hydrate aqueous solutions in soak 2~3 hours, so
Afterwards decompression baking oven in 80~90 DEG C dry 20~24 hours.
5. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, it is characterised in that reaction temperature is
10~80 DEG C, the reaction time is 1~4 hour.
6. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, it is characterised in that described dimension life
The mol ratio of plain A alcohol and described higher aliphatic acid anhydrides is 1：1.05~2.
7. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, it is characterised in that described dimension life
Plain A alcohol, organic solvent, the mass ratio of catalyst are 1：3~10：0.1~0.2.
8. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, it is characterised in that described rear place
Reason operation is as follows：Reaction solution after reaction completely is first filtered to remove alkaline metal oxide, is subsequently cooled to -10~-15 DEG C, guarantor
Temperature is filtrated to get filtrate again after 1~2 hour, and described vitamin A high-grade aliphatic ester is obtained after the filtrate precipitation.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2971966A (en) * | 1957-08-30 | 1961-02-14 | Pfizer & Co C | Process of preparing vitamin a esters |
| US20130171240A1 (en) * | 2004-12-22 | 2013-07-04 | Nitto Denko Corporation | Drug carrier and drug carrier kit for inhibiting fibrosis |
-
2014
- 2014-06-26 CN CN201410298234.9A patent/CN105315185B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2971966A (en) * | 1957-08-30 | 1961-02-14 | Pfizer & Co C | Process of preparing vitamin a esters |
| US20130171240A1 (en) * | 2004-12-22 | 2013-07-04 | Nitto Denko Corporation | Drug carrier and drug carrier kit for inhibiting fibrosis |
Non-Patent Citations (2)
| Title |
|---|
| SYNTHESIS OF TRI-, TETRA-, AND PENTA-DEUTERATED FORMS OF VITAMIN A;H. Robert Bergen, et al.;《Journal of labelled compounds and radiopharmaceuticals》;19881231;第XXV卷(第I期);11-21 * |
| 氧化钙氧化镁催化菜籽油与甲醇醋交换反应动力学的研究;姚建，等;《精细石油化工》;20080731;第25卷(第4期);39-42 * |
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Application publication date: 20160210 Assignee: ZHEJIANG NHU PHARMACEUTICAL Co.,Ltd. Assignor: SHANGYU NHU BIO-CHEM Co.,Ltd. Contract record no.: X2023980043734 Denomination of invention: A Synthesis Method of Vitamin A Advanced Fatty Esters Granted publication date: 20171031 License type: Common License Record date: 20231019 |