CN102363606B - Method for synthesizing vitamin A palmitate - Google Patents
Method for synthesizing vitamin A palmitate Download PDFInfo
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Abstract
The invention discloses a method for synthesizing vitamin A palmitate, which relates to a vitamin A. The invention provides the method for synthesizing vitamin A palmitate, which has high yield and can ensure high quality. The method comprises: dissolving vitamin A alcohol and haloacetamide in an organic solvent; adding a phosphorous compound to perform a halogen displacement reaction; filtering to remove byproducts produced in a reaction process; cooling filtrate till crystals are formed, and obtaining vitamin A halide; and dissolving the vitamin A halide and palmitate in an organic solvent, adding an organic alkali, reacting, adding water to washing an organic layer, evaporating the organic solvent under reduced pressure, and obtaining the vitamin A palmitate. In the invention, the reaction conditions are mild, and unstable byproducts such as dehydro vitamin A and reverse vitamin A are avoided. The prepared vitamin A palmitate appears yellowish and oily. According analysis by a method from United States Pharmacopeia (USP) 28, the titer of the vitamin A palmitate is 1.75 to 1.76 million IU/g, namely the content is 96 to 97 percent. The vitamin A palmitate can be widely used as a medicine, feed additive, food additive and the like.
Description
Technical field
The present invention relates to a kind of vitamin A, especially relate to a kind of synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram.
Background technology
Vitamin A Palmitate 1.7 M.I.U/Gram is known compound, and its structural formula is:
Vitamin A Palmitate 1.7 M.I.U/Gram has been widely used as medicine, foodstuff additive and fodder additives etc., the relevant report of existing multiple synthetic method.These methods comprise that by retinol or vitamin A low-grade fatty acid ester be the method that raw material prepares Vitamin A Palmitate 1.7 M.I.U/Gram, described method relates to multiple reaction scheme, wherein the disclosed synthetic route of Japanese Patent JP 62,248495 is: and palmitinic acid obtain Vitamin A Palmitate 1.7 M.I.U/Gram under the effect of lipase.The disclosed synthetic route of English Patent GB 816224 is: and palmitinic acid alkyl ester obtain Vitamin A Palmitate 1.7 M.I.U/Gram under the effect of sodium methylate.The disclosed synthetic route of English Patent GB 1293041 is: retinol and palmityl chloride obtain Vitamin A Palmitate 1.7 M.I.U/Gram under the existence of triethylamine.
The above-mentioned method for preparing Vitamin A Palmitate 1.7 M.I.U/Gram has following point:
The disclosed method of Japanese Patent JP 62,248495: by lipase-catalyzed, make Vitamin A Palmitate 1.7 M.I.U/Gram by and palmitinic acid reaction.Reaction can at room temperature be carried out, and can avoid vitamin A to wreck.But enzymatic method must be carried out in lower concentration, and throughput is low, contains lipase in reaction product and makes later separation more difficult, is difficult to obtain the Vitamin A Palmitate 1.7 M.I.U/Gram of the high yield of high quality.
The disclosed method of English Patent GB 816224: the transesterification reaction of palmitinic acid alkyl ester and retinol is a reversible reaction.The alkyl alcohol that reaction process generates must in time distill to be removed just and can disequilibrate, and therefore reaction is difficult to carry out fully.Because reaction is to carry out under the condition of alkalescence and heating, reaction product quality is relatively poor, and color is darker.
The disclosed method of English Patent GB 1293041: retinol and palmityl chloride reaction preparation Vitamin A Palmitate 1.7 M.I.U/Gram.This method is swift in response under organic bases exists, fully, can obtain the light-coloured prods of better quality.But retinol is highly unstable, easy destroyed formation axerophthene and reverse vitamin A under the acidic medium impact:
Summary of the invention
The purpose of this invention is to provide that a kind of yield is higher, the quality synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram preferably.
The structural formula of described Vitamin A Palmitate 1.7 M.I.U/Gram (being designated as compound (I)) is as follows:
Described Vitamin A Palmitate 1.7 M.I.U/Gram is made by the reaction of two steps by retinol; The synthetic method of described Vitamin A Palmitate 1.7 M.I.U/Gram comprises the following steps:
1) retinol (compound (II)) is dissolved in organic solvent with halogen acid amide (compound (III)), add again phosphorus compound (compound (IV)) to carry out the halogen replacement(metathesis)reaction, remove by filter the by product that reaction process produces, filtrate is cooled to crystallization, obtains vitamin A halides (compound (V));
2) vitamin A halides (compound (V)) and palmitate (compound (VI)) are dissolved in organic solvent, after adding again organic bases (compound (VII)) reaction, add the water washing organic layer, the reduction vaporization organic solvent obtains Vitamin A Palmitate 1.7 M.I.U/Gram.
in step 1) in, described retinol, halogen acid amide, the mass ratio of organic solvent and phosphorus compound can be: retinol: halogen acid amide: organic solvent: phosphorus compound=1: (0.5～1): (2～10): (0.5～1.5), be preferably: retinol: halogen acid amide: organic solvent: phosphorus compound=1: (0.5～0.8): (2～7): (0.5～1.3), be preferably: retinol: halogen acid amide: organic solvent: phosphorus compound=1: (0.5～0.7): (3～5): (0.7～1.2), described organic solvent can be selected from alkane, aromatic hydrocarbons, and haloalkane, a kind of in ethers etc., described alkane can be selected from the alkane with 1～12 carbon atom, described aromatic hydrocarbons can be selected from has 0～2 substituent aromatic hydrocarbons, described haloalkane can be selected from the haloalkane with 1～2 carbon atom and 1～4 halogen, described ethers can be selected from the ethers with 2～4 carbon atoms, described organic solvent preferably is selected from benzene, toluene, normal hexane, hexanaphthene, heptane, tetrahydrofuran (THF), methylene dichloride, a kind of in chloroform etc., preferred benzene and normal hexane etc., described phosphorus compound can be selected from triphenylphosphine or triple phenoxyl phosphine etc., the temperature of described halogen replacement(metathesis)reaction can be 0～50 ℃, and preferred 0～30 ℃, the time of halogen replacement(metathesis)reaction can be 1～10h, preferred 1～5h, described cooling temperature can be-20 ℃.
in step 2) in, described vitamin A halides, palmitate, the mass ratio of organic solvent and organic bases can be: vitamin A halides: palmitate: organic solvent: organic bases=1: (0.9～1.2): (3～10): (0.2～1), preferably: vitamin A halides: palmitate: organic solvent: organic bases=1: (0.9～1.1): (3～7): (0.3～0.7), be preferably: vitamin A halides: palmitate: organic solvent: organic bases=1: (0.9～1.1): (3～5): (0.3～0.6), described organic solvent can be selected from alkane, aromatic hydrocarbons, and haloalkane, a kind of in ethers etc., described alkane can be selected from the alkane with 1～12 carbon atom, described aromatic hydrocarbons can be selected from has 0～2 substituent aromatic hydrocarbons, described haloalkane can be selected from the haloalkane with 1～2 carbon atom and 1～4 halogen, described ethers can be selected from the ethers with 2～4 carbon atoms, described organic solvent preferably is selected from benzene, toluene, normal hexane, hexanaphthene, heptane, tetrahydrofuran (THF), methylene dichloride, a kind of in chloroform etc., preferred benzene and normal hexane etc., described organic bases can be selected from alkyl amine, pyridines, and a kind of in quinoline etc., described alkyl amine can be selected from has 1～3 substituent organic amine compound on the N atom, or substituting group is the alkyl with 1～4 carbon atom, described pyridines can be selected from has 1～3 substituting group on pyridine ring, substituting group is hydroxyl or the alkyl with 1～4 carbon atom, described quinoline can be selected from has 1～3 substituting group on the quinoline ring, substituting group is hydroxyl or the alkyl with 1～4 carbon atom, described organic bases preferably is selected from diethylamine, triethylamine, pyridine, α-methylpyridine, 1, a kind of in 2-lutidine, 4-hydroxy-2-methyl pyridine, γ-trimethylpyridine, quinoline, dimethyl quinoline etc., a kind of in preferred triethylamine, pyridine, α-methylpyridine, γ-trimethylpyridine etc., the temperature of described reaction can be 0～50 ℃, and preferred 10～30 ℃, the time of reaction can be 1～10h, preferred 2～4h.
The structural formula of described compound (II) is:
The structural formula of described compound (III) is:
R’-NH-X (III)
Wherein R '-NH is amide group, and X is halogen.Use the example of the acid amides that R '-NH represents to comprise succinic diamide, succimide and glycolylurea, preferred succimide and glycolylurea.The example of the halogen that represents with X comprises F, Cl, Br and I, preferred Cl and Br.
The structural formula of described compound (IV) is:
Wherein R is aryl, and the example of the aryl that represents with R comprises phenyl and phenoxy group.
The structural formula of described compound (V) is:
The example of the halogen that wherein represents with X comprises F, Cl, Br and I, preferred Cl and Br.
The structural formula of described compound (VI) is:
The alkali-metal example that wherein represents with M comprises K, Na and Mg, preferred K and Na.
The organic bases of described compound (VII) comprises alkyl amine, for example has 1 to 3 substituent organic amine compound on the N atom, and substituting group is the alkyl with 1 to 4 carbon atom; Pyridines for example has 1 to 3 substituting group on pyridine ring, substituting group is hydroxyl or the alkyl with 1 to 4 carbon atom; And quinoline, for example having 1 to 3 substituting group on the quinoline ring, substituting group is hydroxyl or the alkyl with 1 to 4 carbon atom.Wherein preferred diethylamine, triethylamine, pyridine, α-methylpyridine, 1,2-lutidine, 4-hydroxy-2-methyl pyridine, γ-trimethylpyridine, quinoline and dimethyl quinoline.More preferably triethylamine, pyridine, α-methylpyridine and γ-trimethylpyridine.
In prior art, lipase-catalyzed method throughput is low, contains lipase in reaction product and makes later separation more difficult, is difficult to obtain the Vitamin A Palmitate 1.7 M.I.U/Gram of the high yield of high quality.The transesterification reaction of alcohol is a reversible reaction, the alkyl alcohol that reaction process generates must in time distill to be removed just and can disequilibrate, and therefore reaction is difficult to carry out fully, because reaction is to carry out under the condition of alkalescence and heating, reaction product quality is relatively poor, and color is darker.Acylation reaction is easy destroyed formation axerophthene and reverse vitamin A under the acidic medium impact.And the present invention is take retinol as starting raw material, and the compound halogenating agent that forms with N-halogen acid amide and phosphorus compound carries out the halogen replacement(metathesis)reaction and prepares the vitamin A halides.This method is particularly suitable for resembling this class of vitamin A to the halogen replacement(metathesis)reaction of the unsettled alcohol of acid, can not damage vitamin A.
The present invention adopts more stable vitamin A halides and holds facile palmitate sodium is raw material, the classical reaction principle of utilizing haloalkane and carboxylate salt effect to prepare ester prepares Vitamin A Palmitate 1.7 M.I.U/Gram, the defective of having avoided aforementioned 3 kinds of Vitamin A Palmitate 1.7 M.I.U/Gram synthetic methods to exist.It is gentle that the present invention prepares the reaction conditions of Vitamin A Palmitate 1.7 M.I.U/Gram, can not produce the unsettled by products such as axerophthene and reverse vitamin A.
By the Vitamin A Palmitate 1.7 M.I.U/Gram that the present invention prepares, outward appearance is faint yellow oily thing.Adopt the method for American Pharmacopeia USP28 to analyze, tiring is 175～1,760,000 IU/g, is equivalent to content 96%～97%.
The Vitamin A Palmitate 1.7 M.I.U/Gram that makes by the inventive method can be widely used as medicine, fodder additives, foodstuff additive etc.
Embodiment
The present invention is further illustrated for following examples, do not limit the scope of the present invention but should not be misinterpreted as.
Embodiment 1
The preparation of a vitamin A bromo-derivative
With 3,7-dimethyl-9-(2,6,6-trimethylammonium-1-cyclohexenyl)-2,4,6,8-tetraene in the ninth of the ten Heavenly Stems-1-alcohol (10g, purity 93.94%, 32.79mmol) and bromo-succinimide (7.00g, 39.35mmol) be dissolved in sherwood oil (20ml), and solution is cooled to 10 ℃.At 10 ℃, use 20min, the solution of triphenylphosphine (11.35g, 43.29mmol) in sherwood oil (20ml) is added drop-wise in the cooling solution in front.Add complete after, mixture is being stirred 1h at same temperature, then remove by filter the succimide that reaction process produces.After filtrate is cooled to-20 ℃, stir 1h, filtering separation gained crystal, drying under reduced pressure obtain light yellow crystal (10.52g).With gained crystal liquid-phase chromatographic analysis, result shows that the purity of vitamin A bromo-derivative is 96.83%.Pure yield is 88.66%.
The preparation of b Vitamin A Palmitate 1.7 M.I.U/Gram
With 3,7-dimethyl-9-(2,6,6-trimethylammonium-1-cyclohexenyl)-2,4,6,8-tetraene in the ninth of the ten Heavenly Stems-1-bromine (10g, purity 97.13%, 27.80mmol) and potassium palmitate (9.42g, 31.97mmol) be dissolved in sherwood oil (45ml), and solution is heated to 30 ℃.At 30 ℃, add γ-trimethylpyridine (4.48g, 36.77mmol).Add complete after, mixture is stirred 3h at same temperature, then add water (40ml) two-layer so that mixture is divided into.Anhydrous sodium sulfate drying is used in organic layer water (120ml) minute three washings.Remove by filter sodium sulfate.Solvent evaporated under reduced pressure obtains faint yellow oily thing (14.12g).Gained oily matter is analyzed according to the method for American Pharmacopeia USP28.Result shows that the purity of Vitamin A Palmitate 1.7 M.I.U/Gram is 175.86 ten thousand IU/g, is equivalent to content 96.73%.Pure yield is 93.61%.
Embodiment 2
The preparation of a vitamin A bromo-derivative
With 3,7-dimethyl-9-(2,6,6-trimethylammonium-1-cyclohexenyl)-2,4,6,8-tetraene in the ninth of the ten Heavenly Stems-1-alcohol (10g, purity 93.94%, 32.79mmol) and C5H6Br2N2O2 (5.84g, 21.32mmol) be dissolved in sherwood oil (20ml), and solution is cooled to 10 ℃.At 10 ℃, use 20min, the solution of triple phenoxyl phosphine (7.28g, 23.46mmol) in sherwood oil (20ml) is added drop-wise in the cooling solution in front.Add complete after, mixture is being stirred 1h at same temperature, then remove by filter the glycolylurea that reaction process produces.After filtrate is cooled to-20 ℃, stir 1h, filtering separation gained crystal, drying under reduced pressure obtain light yellow crystal (11.01g).With gained crystal liquid-phase chromatographic analysis, result shows that the purity of vitamin A bromo-derivative is 97.69%.Pure yield is 93.63%.
The preparation of b Vitamin A Palmitate 1.7 M.I.U/Gram
With 3,7-dimethyl-9-(2,6,6-trimethylammonium-1-cyclohexenyl)-2,4,6,8-tetraene in the ninth of the ten Heavenly Stems-1-bromine (10g, purity 97.13%, 27.80mmol) and potassium palmitate (9.42g, 31.97mmol) be dissolved in toluene (35ml), and solution is heated to 30 ℃.At 30 ℃, add γ-trimethylpyridine (4.48g, 36.77mmol).Add complete after, mixture is stirred 3h at same temperature, then add water (40ml) two-layer so that mixture is divided into.Anhydrous sodium sulfate drying is used in organic layer water (120ml) minute three washings.Remove by filter sodium sulfate.Solvent evaporated under reduced pressure obtains faint yellow oily thing (13.61g).Gained oily matter is analyzed according to the method for American Pharmacopeia USP28.Result shows that the purity of Vitamin A Palmitate 1.7 M.I.U/Gram is 176.36 ten thousand IU/g, is equivalent to content 97.01%.Pure yield is 90.49%.
Embodiment 3
The preparation of a vitamin A bromo-derivative
With 3,7-dimethyl-9-(2,6,6-trimethylammonium-1-cyclohexenyl)-2,4,6,8-tetraene in the ninth of the ten Heavenly Stems-1-alcohol (10g, purity 93.94%, 32.79mmol) and bromo-succinimide (7.00g, 39.35mmol) be dissolved in sherwood oil (20ml), and solution is cooled to 10 ℃.At 10 ℃, use 20min, the solution of triple phenoxyl phosphine (7.28g, 23.46mmol) in sherwood oil (20ml) is added drop-wise in the cooling solution in front.Add complete after, mixture is being stirred 1h at same temperature, then remove by filter the glycolylurea that reaction process produces.After filtrate is cooled to-20 ℃, stir 1h, filtering separation gained crystal, drying under reduced pressure obtain light yellow crystal (10.98g).With gained crystal liquid-phase chromatographic analysis, result shows that the purity of vitamin A bromo-derivative is 97.12%.Pure yield is 92.83%.
The preparation of b Vitamin A Palmitate 1.7 M.I.U/Gram
With 3,7-dimethyl-9-(2,6,6-trimethylammonium-1-cyclohexenyl)-2,4,6,8-tetraene in the ninth of the ten Heavenly Stems-1-bromine (10g, purity 97.13%, 27.80mmol) and Sodium pentadecanecarboxylate (9.29g, 33.37mmol) be dissolved in sherwood oil (40ml), and solution is heated to 30 ℃.At 30 ℃, add triethylamine (3.89g, 38.44mmol).Add complete after, mixture is stirred 3.5h at same temperature, then add water (40ml) two-layer so that mixture is divided into.Anhydrous sodium sulfate drying is used in organic layer water (120ml) minute three washings.Remove by filter sodium sulfate.Solvent evaporated under reduced pressure obtains faint yellow oily thing (13.87g).Gained oily matter is analyzed according to the method for American Pharmacopeia USP28.Result shows that the purity of Vitamin A Palmitate 1.7 M.I.U/Gram is 172.34 ten thousand IU/g, is equivalent to content 94.80%.Pure yield is 90.11%.
Embodiment 4
The preparation of a vitamin A chloro thing
With 3,7-dimethyl-9-(2,6,6-trimethylammonium-1-cyclohexenyl)-2,4,6,8-tetraene in the ninth of the ten Heavenly Stems-1-alcohol (10g, purity 93.94%, 32.79mmol) and chlorosuccinimide (5.26g, 39.39mmol) be dissolved in toluene (15ml), and solution is cooled to 15 ℃.At 15 ℃, use 20min, the solution of triphenylphosphine (11.37g, 43.35mmol) in toluene (15ml) is added drop-wise in the cooling solution in front.Add complete after, mixture is being stirred 1h at same temperature, then remove by filter the succimide that reaction process produces.After filtrate is cooled to-20 ℃, stir 1h, filtering separation gained crystal, drying under reduced pressure obtain light yellow crystal (9.14g).With gained crystal liquid-phase chromatographic analysis, result shows that the purity of vitamin A chloro thing is 96.54%.Pure yield is 87.95%.
The preparation of b Vitamin A Palmitate 1.7 M.I.U/Gram
With 3,7-dimethyl-9-(2,6,6-trimethylammonium-1-cyclohexenyl)-2,4,6,8-tetraene in the ninth of the ten Heavenly Stems-1-chlorine (10g, purity 96.35%, 31.60mmol) and potassium palmitate (10.70g, 36.33mmol) be dissolved in sherwood oil (45ml), and solution is heated to 35 ℃.At 35 ℃, add γ-trimethylpyridine (5.09g, 41.77mmol).Add complete after, mixture is stirred 4h at same temperature, then add water (40ml) two-layer so that mixture is divided into.Anhydrous sodium sulfate drying is used in organic layer water (120ml) minute three washings.Remove by filter sodium sulfate.Solvent evaporated under reduced pressure obtains faint yellow oily thing (15.82g).Gained oily matter is analyzed according to the method for American Pharmacopeia USP28.Result shows that the purity of Vitamin A Palmitate 1.7 M.I.U/Gram is 171.96 ten thousand IU/g, is equivalent to content 94.59%.Pure yield is 90.22%.
Bromo-succinimide (7.00g, 39.35mmol)
Embodiment 5
The preparation of a vitamin A chloro thing
With 3,7-dimethyl-9-(2,6,6-trimethylammonium-1-cyclohexenyl)-2,4,6,8-tetraene in the ninth of the ten Heavenly Stems-1-alcohol (10g, purity 93.94%, 32.79mmol) and chlorosuccinimide (5.26g, 39.39mmol) be dissolved in toluene (15ml), and solution is cooled to 15 ℃.At 15 ℃, use 20min, the solution of triple phenoxyl phosphine (7.28g, 23.46mmol) in toluene (15ml) is added drop-wise in the cooling solution in front.Add complete after, mixture is being stirred 1h at same temperature, then remove by filter the succimide that reaction process produces.After filtrate is cooled to-20 ℃, stir 1h, filtering separation gained crystal, drying under reduced pressure obtain light yellow crystal (9.58g).With gained crystal liquid-phase chromatographic analysis, result shows that the purity of vitamin A chloro thing is 96.78%.Pure yield is 92.44%.
The preparation of b Vitamin A Palmitate 1.7 M.I.U/Gram
With 3,7-dimethyl-9-(2,6,6-trimethylammonium-1-cyclohexenyl)-2,4,6,8-tetraene in the ninth of the ten Heavenly Stems-1-chlorine (10g, purity 96.35%, 31.60mmol) and potassium palmitate (10.70g, 36.33mmol) be dissolved in toluene (35ml), and solution is heated to 35 ℃.At 35 ℃, add γ-trimethylpyridine (5.09g, 41.77mmol).Add complete after, mixture is stirred 4h at same temperature, then add water (40ml) two-layer so that mixture is divided into.Anhydrous sodium sulfate drying is used in organic layer water (120ml) minute three washings.Remove by filter sodium sulfate.Solvent evaporated under reduced pressure obtains faint yellow oily thing (15.13g).Gained oily matter is analyzed according to the method for American Pharmacopeia USP28.Result shows that the purity of Vitamin A Palmitate 1.7 M.I.U/Gram is 175.68 ten thousand IU/g, is equivalent to content 96.63%.Pure yield is 88.15%.
Claims (29)
1. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram, is characterized in that described Vitamin A Palmitate 1.7 M.I.U/Gram, is designated as compound (I), and its structural formula is as follows:
Described synthetic method comprises the following steps:
1) retinol and halogen acid amide are dissolved in organic solvent, then add phosphorus compound to carry out the halogen replacement(metathesis)reaction, remove by filter the by product that reaction process produces, and filtrate is cooled to crystallization, obtains the vitamin A halides; Described phosphorus compound is selected from triphenylphosphine or triple phenoxyl phosphine;
2) vitamin A halides and palmitate are dissolved in organic solvent, then after adding the organic bases reaction, add the water washing organic layer, the reduction vaporization organic solvent obtains Vitamin A Palmitate 1.7 M.I.U/Gram.
2. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1, it is characterized in that in step 1), the mass ratio of described retinol, halogen acid amide, organic solvent and phosphorus compound is: retinol: halogen acid amide: organic solvent: phosphorus compound=1: (0.5～1): (2～10): (0.5～1.5).
3. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 2, is characterized in that the mass ratio of described retinol, halogen acid amide, organic solvent and phosphorus compound is: retinol: halogen acid amide: organic solvent: phosphorus compound=1: (0.5～0.8): (2～7): (0.5～1.3).
4. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 3, is characterized in that the mass ratio of described retinol, halogen acid amide, organic solvent and phosphorus compound is: retinol: halogen acid amide: organic solvent: phosphorus compound=1: (0.5～0.7): (3～5): (0.7～1.2).
5. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1, is characterized in that in step 1), and described organic solvent is selected from alkane, aromatic hydrocarbons, haloalkane, a kind of in ethers.
6. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 5, is characterized in that described alkane is selected from the alkane with 1～12 carbon atom.
7. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 5 is characterized in that described aromatic hydrocarbons is selected from and has 0～2 substituent aromatic hydrocarbons.
8. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 5, is characterized in that described haloalkane is selected from the haloalkane with 1～2 carbon atom and 1～4 halogen.
9. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 5, is characterized in that described ethers is selected from the ethers with 2～4 carbon atoms.
10. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1, is characterized in that in step 1), and described organic solvent is selected from benzene, toluene, normal hexane, cyclohexane, heptane, tetrahydrofuran (THF), methylene dichloride, a kind of in chloroform.
11. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 10 is characterized in that described organic solvent is selected from benzene and normal hexane.
12. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1 is characterized in that in step 1), the temperature of described halogen replacement(metathesis)reaction is 0～50 ℃, and the time of halogen replacement(metathesis)reaction is 1～10h, and described cooling temperature is-20 ℃.
13. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 12, the temperature that it is characterized in that described halogen replacement(metathesis)reaction is 0～30 ℃, and the time of halogen replacement(metathesis)reaction is 1～5h.
14. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1, it is characterized in that in step 2) in, the mass ratio of described vitamin A halides, palmitate, organic solvent and organic bases is: vitamin A halides: palmitate: organic solvent: organic bases=1: (0.9～1.2): (3～10): (0.2～1).
15. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 14 is characterized in that the mass ratio of described vitamin A halides, palmitate, organic solvent and organic bases is: vitamin A halides: palmitate: organic solvent: organic bases=1: (0.9～1.1): (3～7): (0.3～0.7).
16. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1, it is characterized in that in step 2) in, the mass ratio of described vitamin A halides, palmitate, organic solvent and organic bases is: vitamin A halides: palmitate: organic solvent: organic bases=1: (0.9～1.1): (3～5): (0.3～0.6).
17. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1 is characterized in that in step 2) in, described organic solvent is selected from alkane, aromatic hydrocarbons, haloalkane, a kind of in ethers.
18. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 17 is characterized in that described alkane is selected from the alkane with 1～12 carbon atom.
19. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 17 is characterized in that described aromatic hydrocarbons is selected from and has 0～2 substituent aromatic hydrocarbons.
20. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 17 is characterized in that described haloalkane is selected from the haloalkane with 1～2 carbon atom and 1～4 halogen.
21. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 17 is characterized in that described ethers is selected from the ethers with 2～4 carbon atoms.
22. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 17 is characterized in that described organic solvent is selected from benzene, toluene, normal hexane, cyclohexane, heptane, tetrahydrofuran (THF), methylene dichloride, a kind of in chloroform.
23. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 22 is characterized in that described organic solvent is selected from benzene and normal hexane.
24. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1 is characterized in that in step 2) in, described organic bases is selected from alkyl amine, pyridines, a kind of in quinoline.
25. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 24 is characterized in that in step 2) in, described alkyl amine is selected from has 1～3 substituent organic amine compound on the N atom, and substituting group is the alkyl with 1～4 carbon atom; Described pyridines is selected from has 1～3 substituting group on pyridine ring, substituting group is hydroxyl or the alkyl with 1～4 carbon atom; Described quinoline is selected from has 1～3 substituting group on the quinoline ring, substituting group is hydroxyl or the alkyl with 1～4 carbon atom.
26. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 24, it is characterized in that in step 2) in, described organic bases is selected from diethylamine, triethylamine, pyridine, α-methylpyridine, 1, a kind of in 2-lutidine, 4-hydroxy-2-methyl pyridine, γ-trimethylpyridine, quinoline, dimethyl quinoline.
27. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 26 is characterized in that described organic bases is selected from a kind of in triethylamine, pyridine, α-methylpyridine, γ-trimethylpyridine.
28. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1 is characterized in that in step 2) in, the temperature of described reaction is 0～50 ℃, the time of reaction is 1～10h.
29. the synthetic method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 28, the temperature that it is characterized in that described reaction is 10～30 ℃, and the time of reaction is 2～4h.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4876400A (en) * | 1985-01-10 | 1989-10-24 | Kuraray Co., Ltd. | Process for producing vitamin A or its carboxylic acid esters, and itermediate compounds useful for the process |
| CN101200740A (en) * | 2007-12-18 | 2008-06-18 | 北京化工大学 | Method for preparing vitamin A fatty acid ester by lipase catalysis |
| CN101553574A (en) * | 2006-10-06 | 2009-10-07 | 伊士曼化工公司 | Preparation of retinyl esters |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4876400A (en) * | 1985-01-10 | 1989-10-24 | Kuraray Co., Ltd. | Process for producing vitamin A or its carboxylic acid esters, and itermediate compounds useful for the process |
| CN101553574A (en) * | 2006-10-06 | 2009-10-07 | 伊士曼化工公司 | Preparation of retinyl esters |
| CN101200740A (en) * | 2007-12-18 | 2008-06-18 | 北京化工大学 | Method for preparing vitamin A fatty acid ester by lipase catalysis |
Non-Patent Citations (2)
| Title |
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| Rapid Synthesis and Purification of Vitamin A Esters;V. Azais.Braesco,et al.;《Journal of the American Oil Chemistry Society》;19921231;第69卷(第12期);1272-1273 * |
| V. Azais.Braesco,et al..Rapid Synthesis and Purification of Vitamin A Esters.《Journal of the American Oil Chemistry Society》.1992,第69卷(第12期),1272-1273. |
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