CN102363606A - 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 compound method of Vitamin A Palmitate 1.7 M.I.U/Gram.
Background technology
Vitamin A Palmitate 1.7 M.I.U/Gram is a 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 compound method.These methods comprise that by retinol or vitamin A low-grade fatty acid ester be the method for feedstock production Vitamin A Palmitate 1.7 M.I.U/Gram; Said method relates to multiple reaction scheme; Wherein Japanese Patent JP 62,248495 disclosed synthetic routes are: and palmitinic acid obtain Vitamin A Palmitate 1.7 M.I.U/Gram under action of lipase.English Patent GB 816224 disclosed synthetic routes are: and palmitinic acid alkyl ester obtain Vitamin A Palmitate 1.7 M.I.U/Gram under the effect of sodium methylate.English Patent GB 1293041 disclosed synthetic routes are: retinol and palmityl chloride obtain Vitamin A Palmitate 1.7 M.I.U/Gram in the presence of triethylamine.
The above-mentioned method for preparing Vitamin A Palmitate 1.7 M.I.U/Gram has following point:
Japanese Patent JP 62,248495 disclosed methods:, process Vitamin A Palmitate 1.7 M.I.U/Gram by and palmitinic acid reaction through lipase-catalyzed.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 lypase in the reaction product and makes difficulty of later separation, is difficult to obtain the Vitamin A Palmitate 1.7 M.I.U/Gram of the high yield of high quality.
English Patent GB 816224 disclosed methods: 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 under the condition of alkalescence and heating, to carry out, reaction product quality is relatively poor, and color is darker.
English Patent GB 1293041 disclosed methods: retinol and palmityl chloride prepared in reaction Vitamin A Palmitate 1.7 M.I.U/Gram.This method is swift in response in the presence of organic bases, fully, can obtain the light-coloured prods of better quality.But the retinol height is unstable, under the acidic medium influence, is destroyed easily to form axerophthene and reverse vitamin A:
Summary of the invention
The purpose of this invention is to provide that a kind of yield is higher, the quality compound method of Vitamin A Palmitate 1.7 M.I.U/Gram preferably.
The structural formula of said Vitamin A Palmitate 1.7 M.I.U/Gram (being designated as compound (I)) is following:
Said Vitamin A Palmitate 1.7 M.I.U/Gram is made through the reaction of two steps by retinol; The compound method of said Vitamin A Palmitate 1.7 M.I.U/Gram may further comprise the steps:
1) retinol (compound (II)) is dissolved in the organic solvent with halogen acid amide (compound (III)); Add phosphorus compound (compound (IV)) again and carry out the halogen replacement(metathesis)reaction; Remove by filter the by product that reaction process produces, filtrating is cooled to crystallization, obtains vitamin A halides (compound (V));
2) vitamin A halides (compound (V)) and palmitate (compound (VI)) are dissolved in the organic solvent, add organic bases (compound (VII)) reaction again after, add the water washing organic layer, the reduction vaporization organic solvent obtains Vitamin A Palmitate 1.7 M.I.U/Gram.
In step 1); The mass ratio of said retinol, halogen acid amide, 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) is preferably: retinol: halogen acid amide: organic solvent: phosphorus compound=1: (0.5～0.7): (3～5): (0.7～1.2); Said organic solvent can be selected from alkane, aromatic hydrocarbons, and haloalkane, a kind of in the ethers etc., said alkane can be selected from the alkane with 1～12 carbon atom; Said aromatic hydrocarbons can be selected from has 0～2 substituent aromatic hydrocarbons; Said haloalkane can be selected from the haloalkane with 1～2 carbon atom and 1～4 halogen; Said ethers can be selected from the ethers with 2～4 carbon atoms; Said organic solvent preferably is selected from benzene, toluene, normal hexane, hexanaphthene, heptane, THF, methylene dichloride, a kind of in the chloroform etc., preferred benzene and normal hexane etc.; Said phosphorus compound can be selected from triphenylphosphine or triple phenoxyl phosphine etc.; The temperature of said 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; Said refrigerative temperature can be-20 ℃.
In step 2) in; The mass ratio of said vitamin A halides, palmitate, 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); Be preferably: vitamin A halides: palmitate: organic solvent: organic bases=1: (0.9～1.1): (3～7): (0.3～0.7) is preferably: vitamin A halides: palmitate: organic solvent: organic bases=1: (0.9～1.1): (3～5): (0.3～0.6); Said organic solvent can be selected from alkane, aromatic hydrocarbons, and haloalkane, a kind of in the ethers etc., said alkane can be selected from the alkane with 1～12 carbon atom; Said aromatic hydrocarbons can be selected from has 0～2 substituent aromatic hydrocarbons; Said haloalkane can be selected from the haloalkane with 1～2 carbon atom and 1～4 halogen; Said ethers can be selected from the ethers with 2～4 carbon atoms; Said organic solvent preferably is selected from benzene, toluene, normal hexane, hexanaphthene, heptane, THF, methylene dichloride, a kind of in the chloroform etc., preferred benzene and normal hexane etc.; Said organic bases can be selected from alkyl amine, pyridines, and a kind of in the quinoline etc., said 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; Said pyridines can be selected from has 1～3 substituting group on the pyridine ring, substituting group is hydroxyl or the alkyl with 1～4 carbon atom; Said 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; Said organic bases preferably is selected from diethylamine, triethylamine, pyridine, α-Jia Jibiding, 1; A kind of in 2-lutidine, 4-hydroxy-2-methyl pyridine, γ-trimethylpyridine, quinoline, the dimethyl quinoline etc., a kind of in preferred triethylamine, pyridine, α-Jia Jibiding, the γ-trimethylpyridine etc.; The temperature of said reaction can be 0～50 ℃, and preferred 10～30 ℃, the time of reaction can be 1～10h, preferred 2～4h.
The structural formula of said compound (II) is:
The structural formula of said compound (III) is:
R’-NH-X (III)
Wherein R '-NH is a carboxamido-group, and X is a halogen.Use the example of the acid amides that R '-NH representes to comprise succinic diamide, succimide and glycolylurea, preferred succimide and glycolylurea.The example of the halogen of representing with X comprises F, Cl, Br and I, preferred Cl and Br.
The structural formula of said compound (IV) is:
Wherein R is an aryl, and the example of the aryl of representing with R comprises phenyl and phenoxy.
The structural formula of said compound (V) is:
The example of the halogen of wherein representing with X comprises F, Cl, Br and I, preferred Cl and Br.
The structural formula of said compound (VI) is:
The alkali-metal example of wherein representing with M comprises K, Na and Mg, preferred K and Na.
The organic bases of said 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 the 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-Jia Jibiding, 1,2-lutidine, 4-hydroxy-2-methyl pyridine, γ-trimethylpyridine, quinoline and dimethyl quinoline.More preferably triethylamine, pyridine, α-Jia Jibiding and γ-trimethylpyridine.
In the prior art, lipase-catalyzed method throughput is low, contains lypase in the reaction product and makes difficulty of later separation, 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 under the condition of alkalescence and heating, to carry out; Reaction product quality is relatively poor, and color is darker.Acylation reaction is destroyed easily under the acidic medium influence and forms axerophthene and reverse vitamin A.And the present invention is starting raw material with the retinol, and the compound halogenating agent of forming with N-halogen acid amide and phosphorus compound carries out the halogen replacement(metathesis)reaction and prepares the vitamin A halides.This method is suitable for resembling the halogen replacement(metathesis)reaction of this type of vitamin A to the unsettled alcohol of acid especially, can not damage vitamin A.
It is raw material that the present invention adopts more stable vitamin A halides and the palmitate sodium that obtains easily; 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 compound 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 unsettled by products such as axerophthene and reverse vitamin A.
Through the Vitamin A Palmitate 1.7 M.I.U/Gram of the present invention's preparation, outward appearance is faint yellow oily thing.Adopt the method for USP 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 through the inventive method can be widely used as medicine, fodder additives, foodstuff additive etc.
Embodiment
Following examples will be further described the present invention, 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) is dissolved in the sherwood oil (20ml), and solution is cooled to 10 ℃.At 10 ℃, use 20min, (11.35g, 43.29mmol) drips of solution in sherwood oil (20ml) is added in the refrigerative solution of front with triphenylphosphine.After adding finishes, mixture is stirred 1h under same temperature, then removing by filter the succimide that reaction process produces.After filtrating is cooled to-20 ℃, stir 1h, filtering separation gained crystal, drying under reduced pressure obtain light yellow crystal (10.52g).The gained crystal is used liquid-phase chromatographic analysis, and the 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) is dissolved in the sherwood oil (45ml), and solution is heated to 30 ℃.At 30 ℃, and adding γ-trimethylpyridine (4.48g, 36.77mmol).After adding finishes, mixture is being stirred 3h under same temperature, it is two-layer so that mixture is divided into then to add water (40ml).Organic layer water (120ml) divides three washings, uses anhydrous sodium sulfate drying.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 USP USP28.The 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) is dissolved in the sherwood oil (20ml), and solution is cooled to 10 ℃.At 10 ℃, use 20min, (7.28g, 23.46mmol) drips of solution in sherwood oil (20ml) is added in the refrigerative solution of front with the triple phenoxyl phosphine.After adding finishes, mixture is stirred 1h under same temperature, then removing by filter the glycolylurea that reaction process produces.After filtrating is cooled to-20 ℃, stir 1h, filtering separation gained crystal, drying under reduced pressure obtain light yellow crystal (11.01g).The gained crystal is used liquid-phase chromatographic analysis, and the 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) is dissolved in the toluene (35ml), and solution is heated to 30 ℃.At 30 ℃, and adding γ-trimethylpyridine (4.48g, 36.77mmol).After adding finishes, mixture is being stirred 3h under same temperature, it is two-layer so that mixture is divided into then to add water (40ml).Organic layer water (120ml) divides three washings, uses anhydrous sodium sulfate drying.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 USP USP28.The 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) is dissolved in the sherwood oil (20ml), and solution is cooled to 10 ℃.At 10 ℃, use 20min, (7.28g, 23.46mmol) drips of solution in sherwood oil (20ml) is added in the refrigerative solution of front with the triple phenoxyl phosphine.After adding finishes, mixture is stirred 1h under same temperature, then removing by filter the glycolylurea that reaction process produces.After filtrating is cooled to-20 ℃, stir 1h, filtering separation gained crystal, drying under reduced pressure obtain light yellow crystal (10.98g).The gained crystal is used liquid-phase chromatographic analysis, and the 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) is dissolved in the sherwood oil (40ml), and solution is heated to 30 ℃.At 30 ℃, and the adding triethylamine (3.89g, 38.44mmol).After adding finishes, mixture is being stirred 3.5h under same temperature, it is two-layer so that mixture is divided into then to add water (40ml).Organic layer water (120ml) divides three washings, uses anhydrous sodium sulfate drying.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 USP USP28.The 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) is dissolved in the toluene (15ml), and solution is cooled to 15 ℃.At 15 ℃, use 20min, (11.37g, 43.35mmol) drips of solution in toluene (15ml) is added in the refrigerative solution of front with triphenylphosphine.After adding finishes, mixture is stirred 1h under same temperature, then removing by filter the succimide that reaction process produces.After filtrating is cooled to-20 ℃, stir 1h, filtering separation gained crystal, drying under reduced pressure obtain light yellow crystal (9.14g).The gained crystal is used liquid-phase chromatographic analysis, and the 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) is dissolved in the sherwood oil (45ml), and solution is heated to 35 ℃.At 35 ℃, and adding γ-trimethylpyridine (5.09g, 41.77mmol).After adding finishes, mixture is being stirred 4h under same temperature, it is two-layer so that mixture is divided into then to add water (40ml).Organic layer water (120ml) divides three washings, uses anhydrous sodium sulfate drying.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 USP USP28.The 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) is dissolved in the toluene (15ml), and solution is cooled to 15 ℃.At 15 ℃, use 20min, (7.28g, 23.46mmol) drips of solution in toluene (15ml) is added in the refrigerative solution of front with the triple phenoxyl phosphine.After adding finishes, mixture is stirred 1h under same temperature, then removing by filter the succimide that reaction process produces.After filtrating is cooled to-20 ℃, stir 1h, filtering separation gained crystal, drying under reduced pressure obtain light yellow crystal (9.58g).The gained crystal is used liquid-phase chromatographic analysis, and the 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) is dissolved in the toluene (35ml), and solution is heated to 35 ℃.At 35 ℃, and adding γ-trimethylpyridine (5.09g, 41.77mmol).After adding finishes, mixture is being stirred 4h under same temperature, it is two-layer so that mixture is divided into then to add water (40ml).Organic layer water (120ml) divides three washings, uses anhydrous sodium sulfate drying.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 USP USP28.The 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 (10)
1. the compound method of Vitamin A Palmitate 1.7 M.I.U/Gram is characterized in that said Vitamin A Palmitate 1.7 M.I.U/Gram, is designated as compound (I), and its structural formula is following:
Said compound method may further comprise the steps:
1) retinol and halogen acid amide are dissolved in the organic solvent, add phosphorus compound again and carry out the halogen replacement(metathesis)reaction, remove by filter the by product that reaction process produces, and filtrating is cooled to crystallization, obtains the vitamin A halides;
2) vitamin A halides and palmitate are dissolved in the organic solvent, add organic bases reaction again after, add the water washing organic layer, the reduction vaporization organic solvent obtains Vitamin A Palmitate 1.7 M.I.U/Gram.
2. the compound 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 said 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); Be preferably: retinol: halogen acid amide: organic solvent: phosphorus compound=1: (0.5～0.8): (2～7): (0.5～1.3) is preferably: retinol: halogen acid amide: organic solvent: phosphorus compound=1: (0.5～0.7): (3～5): (0.7～1.2).
3. the compound method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1 is characterized in that in step 1), and said organic solvent is selected from alkane, aromatic hydrocarbons, and haloalkane, a kind of in the ethers, said alkane can be selected from the alkane with 1～12 carbon atom; Said aromatic hydrocarbons can be selected from has 0～2 substituent aromatic hydrocarbons; Said haloalkane can be selected from the haloalkane with 1～2 carbon atom and 1～4 halogen; Said ethers can be selected from the ethers with 2～4 carbon atoms.
4. the compound method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1 is characterized in that in step 1), and said organic solvent is selected from benzene, toluene, normal hexane, hexanaphthene, heptane, THF, methylene dichloride, a kind of in the chloroform, preferred benzene and normal hexane.
5. the compound method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1 is characterized in that in step 1), and said phosphorus compound is selected from triphenylphosphine or triple phenoxyl phosphine.
6. the compound method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1 is characterized in that in step 1), and the temperature of said halogen replacement(metathesis)reaction is 0～50 ℃, and preferred 0～30 ℃, the time of halogen replacement(metathesis)reaction is 1～10h, preferred 1～5h; Said refrigerative temperature is-20 ℃.
7. the compound 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 said 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); Be preferably: vitamin A halides: palmitate: organic solvent: organic bases=1: (0.9～11): (3～7): (0.3～0.7) is preferably: vitamin A halides: palmitate: organic solvent: organic bases=1: (0.9～11): (3～5): (0.3～0.6).
8. the compound method of Vitamin A Palmitate 1.7 M.I.U/Gram as claimed in claim 1 is characterized in that in step 2) in, said organic solvent is selected from alkane, aromatic hydrocarbons, and haloalkane, a kind of in the ethers, said alkane can be selected from the alkane with 1～12 carbon atom; Said aromatic hydrocarbons can be selected from has 0～2 substituent aromatic hydrocarbons; Said haloalkane can be selected from the haloalkane with 1～2 carbon atom and 1～4 halogen; Said ethers can be selected from the ethers with 2～4 carbon atoms; Said organic solvent preferably is selected from benzene, toluene, normal hexane, hexanaphthene, heptane, THF, methylene dichloride, a kind of in the chloroform, preferred benzene and normal hexane.
9. the compound 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; Said organic bases is selected from alkyl amine, pyridines, a kind of in the quinoline; Said 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; Said pyridines can be selected from has 1～3 substituting group on the pyridine ring, substituting group is hydroxyl or the alkyl with 1～4 carbon atom; Said 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; Said organic bases preferably is selected from diethylamine, triethylamine, pyridine, α-Jia Jibiding, 1; A kind of in 2-lutidine, 4-hydroxy-2-methyl pyridine, γ-trimethylpyridine, quinoline, the dimethyl quinoline, a kind of in preferred triethylamine, pyridine, α-Jia Jibiding, the γ-trimethylpyridine.
10. the compound 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 said reaction is 0～50 ℃, preferred 10～30 ℃, the time of reaction is 1～10h, preferred 2～4h.
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| CN 201110343281 CN102363606B (en) | 2011-11-03 | 2011-11-03 | Method for synthesizing vitamin A palmitate |
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| CN 201110343281 CN102363606B (en) | 2011-11-03 | 2011-11-03 | Method for synthesizing vitamin A palmitate |
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| CN102363606A true CN102363606A (en) | 2012-02-29 |
| CN102363606B CN102363606B (en) | 2013-06-19 |
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| CN 201110343281 Active CN102363606B (en) | 2011-11-03 | 2011-11-03 | Method for synthesizing vitamin A palmitate |
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| CN115160200A (en) * | 2022-08-17 | 2022-10-11 | 上海仁尚医药科技有限公司 | Preparation method of vitamin A palmitate |
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| 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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| 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 |
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| V. AZAIS.BRAESCO,ET AL.: "Rapid Synthesis and Purification of Vitamin A Esters", 《JOURNAL OF THE AMERICAN OIL CHEMISTRY SOCIETY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115160200A (en) * | 2022-08-17 | 2022-10-11 | 上海仁尚医药科技有限公司 | Preparation method of vitamin A palmitate |
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Effective date of registration: 20160620 Address after: 361022 35 Xinchang Road, Xinyang Industrial Area, Haicang investment zone, Xiamen, Fujian Patentee after: XIAMEN KINGDOMWAY VITAMIN CO., LTD. Patentee after: Xiamen Kingdomway Group Company Address before: 361022 35 Xinchang Road, Xinyang Industrial Area, Haicang investment zone, Xiamen, Fujian Patentee before: Xiamen Kingdomway Group Company |