CN105315185A - Synthesis method of vitamin A higher fatty acid ester - Google Patents
Synthesis method of vitamin A higher fatty acid ester Download PDFInfo
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- CN105315185A CN105315185A CN201410298234.9A CN201410298234A CN105315185A CN 105315185 A CN105315185 A CN 105315185A CN 201410298234 A CN201410298234 A CN 201410298234A CN 105315185 A CN105315185 A CN 105315185A
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- Prior art keywords
- vitamin
- aliphatic ester
- synthetic method
- grade aliphatic
- 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 122
- 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 80
- -1 fatty acid ester Chemical class 0.000 title claims abstract description 47
- 235000019155 vitamin A Nutrition 0.000 title claims abstract description 40
- 239000011719 vitamin A Substances 0.000 title claims abstract description 40
- 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 39
- 229940045997 vitamin a Drugs 0.000 title claims abstract description 39
- 235000014113 dietary fatty acids Nutrition 0.000 title abstract description 17
- 239000000194 fatty acid Substances 0.000 title abstract description 17
- 229930195729 fatty acid Natural products 0.000 title abstract description 17
- 238000001308 synthesis method Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 37
- 229910044991 metal oxide Inorganic materials 0.000 claims abstract description 12
- 150000004706 metal oxides Chemical class 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- 239000011607 retinol Substances 0.000 claims description 40
- 229960003471 retinol Drugs 0.000 claims description 40
- 235000020944 retinol Nutrition 0.000 claims description 40
- 239000003513 alkali Substances 0.000 claims description 31
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 22
- 239000000706 filtrate Substances 0.000 claims description 18
- 238000010189 synthetic method Methods 0.000 claims description 17
- 238000001556 precipitation Methods 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 229960001701 chloroform Drugs 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 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
- 230000032050 esterification Effects 0.000 claims description 2
- 239000000395 magnesium oxide Substances 0.000 claims description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 2
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 43
- 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 30
- 238000001514 detection method Methods 0.000 abstract description 17
- VYGQUTWHTHXGQB-UHFFFAOYSA-N Retinol hexadecanoate Natural products CCCCCCCCCCCCCCCC(=O)OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-UHFFFAOYSA-N 0.000 abstract description 15
- 229940108325 retinyl palmitate Drugs 0.000 abstract description 15
- 235000019172 retinyl palmitate Nutrition 0.000 abstract description 15
- 239000011769 retinyl palmitate Substances 0.000 abstract description 15
- 150000004665 fatty acids Chemical class 0.000 abstract description 7
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 3
- 235000019169 all-trans-retinol Nutrition 0.000 abstract 1
- 239000011717 all-trans-retinol Substances 0.000 abstract 1
- 238000004458 analytical method Methods 0.000 abstract 1
- 239000003674 animal food additive Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 235000013373 food additive Nutrition 0.000 abstract 1
- 239000002778 food additive Substances 0.000 abstract 1
- 239000007791 liquid phase Substances 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 19
- 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
- 239000007788 liquid Substances 0.000 description 15
- 101100493710 Caenorhabditis elegans bath-40 gene Proteins 0.000 description 14
- 230000004913 activation Effects 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 14
- 238000009413 insulation Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 239000002253 acid Substances 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 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
- 238000004519 manufacturing process Methods 0.000 description 3
- 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
- 239000000654 additive Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- FLIACVVOZYBSBS-UHFFFAOYSA-N Methyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC FLIACVVOZYBSBS-UHFFFAOYSA-N 0.000 description 1
- 108010084311 Novozyme 435 Proteins 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000000996 additive effect Effects 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
- 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
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 244000222991 cardamomo Species 0.000 description 1
- 235000005300 cardamomo Nutrition 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
- NWADXBLMWHFGGU-UHFFFAOYSA-N dodecanoic anhydride Chemical compound CCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCC NWADXBLMWHFGGU-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019387 fatty acid methyl ester Nutrition 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N methyl undecanoic acid Natural products CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940099204 ritalin Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 230000032258 transport Effects 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 synthesis method of vitamin A higher fatty acid ester, which includes the following steps: a) performing an esterification reaction to vitamin A alcohol and higher fatty acid anhydride in an organic solvent under catalysis of an alkaline metal oxide; and b) performing after treatment after the reaction is finished to obtain the vitamin A higher fatty acid ester. The method is less in reaction by-products, is high in product purity and is good in product quality. The product is more than 97.5% in content and is more than 96.5% in yield through high performance liquid chromatography detection. The vitamin A higher fatty acid ester enables storage, transportation and application of vitamin A to be more convenient. An analytic method in pharmacopeia proves that vitamin A palmitate is 1750000-1780000 IU/g in biological titer and is more than 97.5% in content through the high performance liquid chromatography detection, so that the vitamin A palmitate can be marketed as commodity directly, and is widely applied in the fields of medicines, feed additives and food additives.
Description
Technical field
The invention belongs to VITAMIN synthesis field, be specifically related to a kind of synthetic method of vitamin A high-grade aliphatic ester.
Background technology
Retinol, because of its poor stability, not easily stores and transports, and in the application of reality, usually retinol is converted into relatively more stable vitamin A higher fatty acid carboxylate.The synthetic method of vitamin A higher fatty acid carboxylate is quite a lot of; but there is shortcoming; the many production technique of current employing is that higher fatty acid is after sulfur oxychloride acidylate; under the existence of acid binding agent (triethylamine, pyridine etc.), preparation is reacted with retinol; this method has energy consumption large; seriously polluted, operational path is long, the difficult separation of acid binding agent, the shortcomings such as poor product quality.
The structure of vitamin A high-grade aliphatic ester is as shown in formula I:
In formula I, R is C
9~
15straight-chain paraffin.
The structure of retinol is as shown in formula III:
Patent WO2014/23772 discloses a kind of preparation method of Vitamin A Palmitate 1.7 M.I.U/Gram, this preparation method under strongly alkaline conditions, Uniphat A60 and carry out transesterify, steam except ritalin, thus be prepared into Vitamin A Palmitate 1.7 M.I.U/Gram, the higher fatty acid methyl esters purity obtained in this method is not high, most of unrealized suitability for industrialized production, alkali residual stability and the appearance poor making product in the product.
Enzymatic clarification vitamin A high-grade aliphatic ester also has report (Liu Yuan in recent years, " enzyme process prepares the research of Vitamin A Palmitate 1.7 M.I.U/Gram ", Collects The American University's Master's thesis, on April 15th, 2011), adopt fatty acid enzyme Novozyme435 or AmberlystA21, and higher fatty acid can prepare vitamin A higher fatty acid carboxylate by direct reaction, this method exist enzyme cost, apply mechanically and being separated and the difficult problem such as activating of enzyme, and yield only 78%, without any cost advantage.
Summary of the invention
The invention provides a kind of synthetic method of vitamin A high-grade aliphatic ester, this synthetic method is environmentally friendly, and temperature of reaction is lower, and energy consumption is little, and the molecule utilization ratio of supplementary material is high, and yield is high.
A synthetic method for vitamin A high-grade aliphatic ester, comprising:
Under the catalysis of alkaline metal oxide, there is esterification in retinol and higher aliphatic acid anhydrides in organic solvent, obtains described vitamin A high-grade aliphatic ester after reacting completely through process later;
The structure of vitamin A high-grade aliphatic ester is as shown in formula I:
The structure of described higher aliphatic acid anhydrides is as shown in formula II:
In formula I, R is C
9~ C
15alkyl, is preferably C
9~ C
15straight chained alkyl.
The present invention is directed to the shortcoming in the synthetic method of current vitamin A higher fatty acid carboxylate; synthetic method is optimized; adopt alkaline metal oxide as catalyzer; adopt higher aliphatic acid anhydrides as acylating reagent; vitamin A high-grade aliphatic ester is obtained with higher yield; the purity of the product obtained is high, and outward appearance is good.
In addition, also bibliographical information (" acid gama-alumina catalyzes and synthesizes diallyl maleate " " fine chemical material and intermediate " king one army the 9th phase in 2005) is had to adopt acidic metal oxide to catalyze and synthesize ester, but vitamin A is extremely unstable in acid condition, during synthesis for vitamin A higher fatty acid carboxylate, by product is many, does not possess actual using value; The present invention is processed into alkalescence to metal oxide, is used further to synthesise vitamins A higher fatty acid carboxylate, neither destroys vitamin A and reaches catalytic effect again.
As preferably, described alkaline metal oxide is at least one in calcium oxide, magnesium oxide and aluminum oxide, and wherein 200 order alkali alumina (gamma-alumina) catalytic effects are best.
Described higher aliphatic acid anhydrides can be reacted by corresponding higher fatty acid and acetic anhydride, steams and obtains except after by product acetic acid.As preferably, described higher aliphatic acid anhydrides is preferably palmitic anhydride.
Organic solvent of the present invention is one or more mixtures in pyridine, acetonitrile, benzene, toluene, sherwood oil, normal hexane, normal heptane, methylene dichloride, trichloromethane equal solvent.During reaction, the solvent effect of pyridine is best, but its aftertreatment trouble, pyridine can be caused to remain more; Benzene, toluene are unfriendly to environment, belong to carcinogenic solvent, are not suitable for large production; Because there is H in acetonitrile, normal hexane, normal heptane, trichloromethane
+or-CH
3the solvation of group meeting inhibited reaction product, hinders reaction to carry out to positive dirction.Integrated economics benefit, environmental friendliness and solvent effect, sherwood oil, methylene dichloride are most preferred solvent, now, reclaim energy consumption little.
As preferably, described alkaline metal oxide is alkali alumina (gamma-alumina), and order number is 100 ~ 300 orders;
Described organic solvent is sherwood oil or methylene dichloride, and now, the yield of reaction is the highest.
As further preferred, described alkali alumina is adopted before using and is activated with the following method:
Under room temperature, commercially available gamma-alumina is soaked 2 ~ 3 hours in 10 ~ 15% aqueous sodium hydroxide solutions, then decompression baking oven in 80 ~ 90 DEG C dry 20 ~ 24 hours.
As preferably, temperature of reaction is 10 ~ 80 DEG C, and the reaction times is 1 ~ 4 hour; As further preferred, temperature of reaction is 40 ~ 50 DEG C, and the reaction times is 2.5 hours.
As preferably, the mol ratio of described retinol and described higher aliphatic acid anhydrides is 1:1.05 ~ 2; As further preferred, the mol ratio of described retinol and described higher aliphatic acid anhydrides is 1:1.1 ~ 1.5.
As preferably, the mass ratio of described retinol, organic solvent, catalyzer is 1:3 ~ 10:0.1 ~ 0.2; As further preferred, the mass ratio of described retinol, organic solvent, catalyzer is 1:3.5 ~ 5:0.15.
As preferably, described post-processing operation is as follows: the reaction solution after reacting completely first is crossed and filtered alkaline metal oxide, then be cooled to-10 ~-15 DEG C, be incubated after 1 ~ 2 hour again to filter and obtain filtrate, after this filtrate precipitation, obtain described vitamin A high-grade aliphatic ester.The higher fatty acid that higher aliphatic acid anhydrides excessive in reaction system and reaction can be made to produce by cooling is separated out, and filter, and excessive higher aliphatic acid anhydrides and by product higher fatty acid can apply mechanically the preparation of higher aliphatic acid anhydrides further by crossing.
Compared with the existing technology, beneficial effect of the present invention is embodied in:
Vitamin A high-grade aliphatic ester stability prepared by the present invention is fine, and impurity is few, and outward appearance is faint yellow to colourless oily liquids, more than high performance liquid chromatography positive detection level 97.5% (alltrans).Especially Vitamin A Palmitate 1.7 M.I.U/Gram adopts the method for the bent USP28 of U.S.'s medicine to analyze, biological value 176 ~ 1,780,000 IU/g, content more than 98%; Analyze by the method that state-promulgated pharmacopoeia specifies, biological value 175 ~ 1,780,000 IU/g, content more than 98%, can be widely used in medicine, fodder additives and foodstuff additive.
Embodiment
By following experiment, the present invention is further illustrated, be not the concrete restriction to the scope of the invention, the primary study preparation of Vitamin A Palmitate 1.7 M.I.U/Gram.
The preparation of embodiment 1 Vitamin A Palmitate 1.7 M.I.U/Gram
(59.5g, 0.12mol) palmitic anhydride is put in the solution of the composition of (28.6g, 0.1mol) retinol and 240g sherwood oil, slow heating in water bath 40 DEG C, then add 4.29g and activate 200 order alkali aluminas.Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, filtering alkali alumina,-12 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtain pale yellow oily liquid body product (51.2g, molar yield 97.62%).Product liquid-phase chromatographic analysis conforms to standard substance feature, adopts the methods analyst of American Pharmacopeia USP28: product biological value is 178.1 ten thousand IU/g, content 98.3%.
Wherein, the activation method of 200 order alkali aluminas is as follows:
Under room temperature, 200 order gamma-aluminas soak 2 hours in 10% aqueous sodium hydroxide solution, then decompression to be dried in railway carriage or compartment 85 DEG C and dried 24 hours.
The preparation of embodiment 2 Vitamin A Palmitate 1.7 M.I.U/Gram
By (59.5g, 0.12mol) palmitic anhydride puts into (28.6g, in the solution of 0.1mol) retinol and 240g sherwood oil composition, slow heating in water bath 40 DEG C, then add 2.86g and activate 200 order alkali aluminas (activation method is identical with embodiment 1).Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, filtering alkali alumina,-12 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtain pale yellow oily liquid body product (50.7g, molar yield 96.75%).Product liquid-phase chromatographic analysis conforms to standard substance feature, adopts the methods analyst of American Pharmacopeia USP28: product biological value is 176.1 ten thousand IU/g, content 98.01%.
The preparation of embodiment 3 Vitamin A Palmitate 1.7 M.I.U/Gram
By (59.5g, 0.12mol) palmitic anhydride puts into (28.6g, in the solution that 0.1mol) retinol and 240g sherwood oil form, slow heating in water bath 40 DEG C, then the 200 order alkali aluminas (activation method is identical with embodiment 1) adding that 5.72g activates.Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, filtering alkali alumina,-12 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtain pale yellow oily liquid body product (50.9g, molar yield 97.14%).Product liquid-phase chromatographic analysis conforms to standard substance feature, adopts the methods analyst of American Pharmacopeia USP28: product biological value is 176.3 ten thousand IU/g, content 98.07%.
The preparation of embodiment 4 Vitamin A Palmitate 1.7 M.I.U/Gram
(59.5g, 0.12mol) palmitic anhydride is put in the solution of (28.6g, 0.1mol) retinol and 240g sherwood oil composition, slow heating in water bath 40 DEG C, then add 4.5g (100 ~ 300 order) alkaline oxygenated calcium.Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, the alkaline oxygenated calcium of filtering,-12 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtain pale yellow oily liquid body product (49.9g, molar yield 95.23%).Product liquid-phase chromatographic analysis conforms to standard substance feature, adopts the methods analyst of American Pharmacopeia USP28: product biological value is 171.3 ten thousand IU/g, content 97.07%.
The preparation of embodiment 5 Vitamin A Palmitate 1.7 M.I.U/Gram
(59.5g, 0.12mol) palmitic anhydride is put in the solution of (28.6g, 0.1mol) retinol and 240g sherwood oil composition, slow heating in water bath 40 DEG C, then add 4.5g (100 ~ 300 order) alkaline oxygenated magnesium.Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, the alkaline oxygenated magnesium of filtering,-12 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtain pale yellow oily liquid body product (47.3g, molar yield 90.26%).Product liquid-phase chromatographic analysis conforms to standard substance feature, adopts the methods analyst of American Pharmacopeia USP28: product biological value is 173.3 ten thousand IU/g, content 97.87%.
The preparation of embodiment 6 Vitamin A Palmitate 1.7 M.I.U/Gram
By (59.5g, 0.12mol) palmitic anhydride puts into (28.6g, in the solution of 0.1mol) retinol and 300g pyridine composition, slow heating in water bath 40 DEG C, then add 4.29g and activate 200 order alkali aluminas (activation method is identical with embodiment 1).Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, filtering alkali alumina,-12 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtain pale yellow oily liquid body product (45.1g, molar yield 86.06%).Product liquid-phase chromatographic analysis conforms to standard substance feature, adopts the methods analyst of American Pharmacopeia USP28: product biological value is 171.8 ten thousand IU/g, content 95.31%.
The preparation of embodiment 7 Vitamin A Palmitate 1.7 M.I.U/Gram
By (59.5g, 0.12mol) palmitic anhydride puts into (28.6g, in the solution of 0.1mol) retinol and 300g acetonitrile composition, slow heating in water bath 40 DEG C, then add 4.29g and activate 200 order alkali aluminas (activation method is identical with embodiment 1).Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, filtering alkali alumina,-12 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtain pale yellow oily liquid body product (46.7g, molar yield 89.12%).Product liquid-phase chromatographic analysis conforms to standard substance feature, adopts the methods analyst of American Pharmacopeia USP28: product biological value is 172.4 ten thousand IU/g, content 96.72%.
The preparation of embodiment 8 Vitamin A Palmitate 1.7 M.I.U/Gram
By (59.5g, 0.12mol) palmitic anhydride puts into (28.6g, in the solution that 0.1mol) retinol and 300g normal heptane are formed, slow heating in water bath 40 DEG C, then add 4.29g and activate 200 order alkali aluminas (activation method is identical with embodiment 1).Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, filtering alkali alumina,-12 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtain pale yellow oily liquid body product (47.5g, molar yield 90.64%).Product liquid-phase chromatographic analysis conforms to standard substance feature, adopts the methods analyst of American Pharmacopeia USP28: product biological value is 173.0 ten thousand IU/g, content 97.26%.
The preparation of embodiment 9 vitamin A certain herbaceous plants with big flowers acid esters (ten carbonic ethers)
By (39.1g, 0.12mol) capric anhydrid puts into (28.6g, in the solution that 0.1mol) retinol and 240g sherwood oil are formed, slow heating in water bath 40 DEG C, then the 200 order alkali aluminas (activation method is identical with embodiment 1) adding 4.29g activation.Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, filtering alkali alumina,-15 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtain pale yellow oily liquid body product (42.6g, molar yield 96.73%).With reference to the methods analyst of American Pharmacopeia USP28, product biological value is 221.6 ten thousand IU/g, content 98.53%.
The preparation of embodiment 10 vitamin A hendecoic acid ester
By (42.6g, 0.12mol) hendecoic acid acid anhydride puts into (28.6g, in the solution that 0.1mol) retinol and 240g sherwood oil are formed, slow heating in water bath 40 DEG C, then add 4.29g and activate 200 order alkali aluminas (activation method is identical with embodiment 1).Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, filtering alkali alumina, and-15 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid body product (44.9g, 98.73%).With reference to the methods analyst of American Pharmacopeia USP28, product biological value is 214.1 ten thousand IU/g, content 98.64%.
The preparation of embodiment 11 vitamin A laurate (lauric acid ester)
By (45.9g, 0.12mol) lauric anhydride puts into (28.6g, in the solution that 0.1mol) retinol and 240g sherwood oil are formed, slow heating in water bath 40 DEG C, then the 200 order alkali aluminas (activation method is identical with embodiment 1) adding 4.29g activation.Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, filtering alkali alumina, and-15 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid body product (45.4g, 96.85%).With reference to the methods analyst of American Pharmacopeia USP28, product biological value is 205.4 ten thousand IU/g, content 98.27%.
The preparation of embodiment 12 vitamin A ficocerylic acid ester
By (49.3g, 0.12mol) ficocerylic acid acid anhydride puts into (28.6g, in the solution that 0.1mol) retinol and 240g sherwood oil are formed, slow heating in water bath 40 DEG C, then add 4.29g and activate 200 order alkali aluminas (activation method is identical with embodiment 1).Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, filtering alkali alumina, and-15 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid body product (46.8g, 97.01%).With reference to the methods analyst of American Pharmacopeia USP28, product biological value is 198.7 ten thousand IU/g, content 98.36%.
The preparation of embodiment 13 vitamin A myristate (ten tetra-carbonic esters)
By (52.7g, 0.12mol) cardamom acid anhydrides puts into (28.6g, in the solution that 0.1mol) retinol and 240g sherwood oil are formed, slow heating in water bath 40 DEG C, then add 4.29g and activate 200 order alkali aluminas (activation method is identical with embodiment 1).Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, filtering alkali alumina, and-15 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid body product (48.2g, 97.09%).With reference to the methods analyst of American Pharmacopeia USP28, product biological value is 195.4 ten thousand IU/g, content 98.24%.
The preparation of embodiment 14 vitamin A 15 carbonic ether
By (56.0g, 0.12mol) 15 carbonic anhydrides put into (28.6g, in the solution that 0.1mol) retinol and 240g sherwood oil are formed, slow heating in water bath 40 DEG C, then add 4.29g and activate 200 order alkali aluminas (activation method is identical with embodiment 1).Insulation reaction 2 hours, liquid phase tracing detection retinol remains≤0.3% stopped reaction, filtering alkali alumina, and-15 DEG C of deepfreezes, filter out filter residue, and filtrate carries out precipitation, obtains pale yellow oily liquid body product (49.8g, 97.48%).With reference to the methods analyst of American Pharmacopeia USP28, product biological value is 184.5 ten thousand IU/g, content 98.3%.
Claims (9)
1. a synthetic method for vitamin A high-grade aliphatic ester, is characterized in that, comprising:
Under the catalysis of alkaline metal oxide, there is esterification in retinol and higher aliphatic acid anhydrides in organic solvent, obtains described vitamin A high-grade aliphatic ester through aftertreatment;
The structure of described vitamin A high-grade aliphatic ester is as shown in formula I:
The structure of described higher aliphatic acid anhydrides is as shown in formula II:
In formula I, R is C
9~ C
15alkyl.
2. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, is characterized in that, described alkaline metal oxide is at least one in calcium oxide, magnesium oxide and aluminum oxide.
3. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, it is characterized in that, described organic solvent is one or more mixtures in pyridine, acetonitrile, benzene, toluene, sherwood oil, normal hexane, normal heptane, methylene dichloride, trichloromethane.
4. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, is characterized in that, described alkaline metal oxide is alkali alumina, and order number is 100 ~ 300 orders.
5. the synthetic method of the vitamin A high-grade aliphatic ester according to claim 2 or 4, is characterized in that, described alkali alumina is adopted before using and activated with the following method:
Under room temperature by gamma-alumina mass percent concentration be in 10 ~ 15% aqueous sodium hydroxide solutions soak 2 ~ 3 hours, then decompression baking oven in 80 ~ 90 DEG C dry 20 ~ 24 hours.
6. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, is characterized in that, temperature of reaction is 10 ~ 80 DEG C, and the reaction times is 1 ~ 4 hour.
7. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, is characterized in that, the mol ratio of described retinol and described higher aliphatic acid anhydrides is 1:1.05 ~ 2.
8. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, is characterized in that, the mass ratio of described retinol, organic solvent, catalyzer is 1:3 ~ 10:0.1 ~ 0.2.
9. the synthetic method of vitamin A high-grade aliphatic ester according to claim 1, it is characterized in that, described post-processing operation is as follows: the reaction solution after reacting completely first is crossed and filtered alkaline metal oxide, then-10 ~-15 DEG C are cooled to, to be incubated after 1 ~ 2 hour again to filter and to obtain filtrate, after this filtrate precipitation, obtain described vitamin A high-grade aliphatic ester.
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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 |
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2014
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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 |
|---|
| H. ROBERT BERGEN, ET AL.: "SYNTHESIS OF TRI-, TETRA-, AND PENTA-DEUTERATED FORMS OF VITAMIN A", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS》 * |
| 姚建，等: "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", 《精细石油化工》 * |
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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 |
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