CN102766266A - Method for extracting and separating vitamin E polyethylene glycol succinic acid monoester and diester - Google Patents
Method for extracting and separating vitamin E polyethylene glycol succinic acid monoester and diester Download PDFInfo
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Abstract
The invention discloses a method for extracting and separating monoester and diester from a vitamin E polyethylene glycol succinic acid monoester and diester mixture. According to the method, water, hydrophilic ionic liquid, a binary mixed solvent consisting of the hydrophilic ionic liquid and the water, or a binary mixed solvent consisting of a completely water-soluble polar organic solvent and the water is taken as an extracting agent, an ester or alcohol hydrophobic organic solvent with the water solubility of more than or equal to 15g/100g is taken as a washing agent, and the monoester and the diester are efficiently separated from the mixture containing the monoester and the diester by a fractional extraction method. The method has the advantages of high separation efficiency, low solvent consumption and the like, is safe and environment-friendly and is suitable for industrial production.
Description
Technical field
The present invention relates to chemical separation process, be specifically related to a kind of method of from the vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester mixture, separating monoesters and dibasic acid esters.
Background technology
Vitamin E polyethylene glycol succinic acid ester (d-alpha-tocopherol polyethylene glycol succinate; TPGS) being a kind of soluble derivative of vitamin E, is that (PEG400～PEG2000) esterification obtains by VE-succinate and different molecular weight polyethylene glycol.Because polyoxyethylene glycol has two activity hydroxies, esterification can generate vitamin E polyethylene glycol monomester succinate and dibasic acid esters.Usually the TPGS that mentions is meant the vitamin E polyethylene glycol monomester succinate.Seeing that from molecular structure the vitamin E polyethylene glycol monomester succinate had both contained the oleophylic afterbody of vitamin E, contain the hydrophilic head of polyoxyethylene glycol again, is a kind of good non-ionics therefore.According to bibliographical information, its hydrophile-lipophile balance value (HLB value) is about 13.Because its good water-solubility and amphiphilic characteristics; TPGS is except the supplement as vitamin E; Also as the carrier of solubilizing agent, emulsifying agent, softening agent, absorption enhancer and slightly water-soluble and fat-soluble medicine; Like the carrier of solid dispersion, eye or intranasal administration, micella or other nano particle of carrying medicament, important application is arranged in medicine, makeup and food service industry.
Because TPGS monoesters and dibasic acid esters all are to have the polymkeric substance that certain molecular weight distributes, its separation and analysis have certain degree of difficulty.Existing commodity TPGS on the market; Composition and content to wherein do not elaborate; And cause the different of single dibasic acid esters content of TPGS and MWD because raw material is not quite similar with production technique between the different manufacturers, and the height of monoester content directly influences TPGS as vitamin E supplement and The Usage of Surfactant effect.All not mentioned elder generation re-uses after single dibasic acid esters is separated in many documents, and the action effect of the TPGS that obtains like this is inapt.Do not realize separating of monoesters and dibasic acid esters; Also can't obtain the exact nature of monoesters; And therefore the existence of the difference of single dibasic acid esters character and dibasic acid esters has important and practical meanings with both separation to the monoesters The properties from the mixture of vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester.
Existing document is seldom mentioned the separation problem of single dibasic acid esters, and minority mentions that the isolating method of single dibasic acid esters also mainly adopts the analysis of column chromatography perhaps to adopt simulated moving bed chromatography system to separate single dibasic acid esters with separation method.U.S. Pat 20050163828 reported with analysis mode HPLC the TPGS product content analyzed, owing to be the chromatographic system of analysis mode, so treatment capacity is very little, cost can't be realized industriallization also than higher.Collnot (E.M.Collnot, C.Baldes, M.F.Wempe; J.Hyatt, L.Navarro, K.J.Edgar; U.F.Schaefer; C.M.Lehr.Influence of vitamin E TPGS poly (ethylene glycol) chain length on apical efflux transporters in caco-2 cell monolayers [J] .Journal of Controlled Release.2006,111 (1-2): 35-40) studied preparative liquid chromatography purification monoesters, adopted C8 preparative hplc post; Methyl alcohol/acetonitrile, acetonitrile/Virahol, three kinds of solvent gradient elution purifying of Virahol monoesters are not reported for the monoesters purity that obtains, yield.In addition, still there is certain defective in preparative hplc, and is little like treatment capacity, and solvent cost is high, and industrial application has very big restriction.Chinese patent ZL200910155016.9 has reported a kind of employing simulated moving bed chromatography system, is stationary phase with the C18 post, and acetonitrile/isopropanol mixture is the method that moving phase is separated single dibasic acid esters.Although SMBC is an operate continuously process, have level of automation height, efficient height, be fit to the characteristics of suitability for industrialized production, this method facility investment is big, and C18 stationary phase cost is higher, is suitable for difficult the separation and the high product of added value.
Extraction process separates single dibasic acid esters, and to have equipment simple, easy to operate, is suitable for carrying out the characteristics of continuity large-scale industrial production.Since the complicacy and the singularity of TPGS system composition, the present report of not seeing relevant extraction process separating VE polyoxyethylene glycol mono succinate dibasic acid esters as yet.
Summary of the invention
The invention provides the method for the single dibasic acid esters of a kind of extraction process separating VE polyethanediol succinate (hereinafter to be referred as TPGS).
It is the single dibasic acid esters solvent of TPGS that the present invention adopts hydrophobic organic solvent; Binary mixed solvent of forming with water, hydrophilic ionic-liquid, hydrophilic ionic-liquid and water or water-soluble fully polar organic solvent are extraction agent with the binary mixed solvent of water composition; The extracting and separating of the single dibasic acid esters of TPGS is carried out in the process fractionation extn, may further comprise the steps:
(1) be raw material with the vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester mixture; Ester or alcohols hydrophobic organic solvent with solubleness≤15g/100g in the water are made into liquid stock; With the perhaps complete water-soluble polar organic solvent of the binary mixed solvent of water, hydrophilic ionic-liquid, hydrophilic ionic-liquid and water composition and the binary mixed solvent of water composition is extraction agent; Used hydrophobic organic solvent is a washing composition during with preparation raw material liquid, carries out fractionation extn;
(2) fractionation extn process is divided into extraction section and washing section; Extraction agent gets into the fractionation extn system from the extraction section first step; Liquid stock gets into the fractionation extn system from the last step of extraction section, and washing composition gets into the fractionation extn system from the first step of washing section, merges liquid stock at the washing section last step and gets into extraction section together; Extraction phase carries out counter current contact mutually with washing; Flow out the extraction liquid of rich in vitamin E polyoxyethylene glycol monomester succinate from the first step of washing section, flow out the raffinate of enrichment vitamin E polyethylene glycol succsinic acid dibasic acid esters, collect extraction liquid and raffinate respectively from the first step of extraction section;
(3) with extraction liquid through vacuum concentration, washing and drying, obtain vitamin E polyethylene glycol monomester succinate product, raffinate obtains vitamin E polyethylene glycol succsinic acid dibasic acid esters product through vacuum concentration, washing and drying.
The ester of solubleness≤15g/100g or alcohols hydrophobic organic solvent are methyl acetate, ETHYLE ACETATE, propyl acetate, isopropyl acetate, butylacetate, propyl carbinol, Pentyl alcohol, n-hexyl alcohol, n-Heptyl alcohol, n-Octanol, primary isoamyl alcohol, isooctyl alcohol, 2-hexanol, 2-enanthol or sec-n-octyl alcohol in the described water; Described water-soluble polar organic solvent fully is methyl alcohol, ethanol, n-propyl alcohol, Virahol, DMSO 99.8MIN., N, dinethylformamide or acetonitrile;
Described hydrophilic ionic-liquid is by positively charged ion M
+And anion N
-Two portions are formed; Positively charged ion M
+For having substituent imidazole type positively charged ion, have substituent pyridine type positively charged ion, have substituent quaternary phosphine type positively charged ion, have substituent piperidines type positively charged ion, have substituent quaternary ammonium cation or having a kind of in the substituent tetramethyleneimine type positively charged ion; Anion N
-A kind of in cl ions, bromide anion, iodide ion, tetrafluoroborate, trifluoroacetic acid root, trifluoromethanesulfonic acid root, ethylsulfonic acid root, dimethyl-phosphate radical, diethylammonium phosphate radical, dihydrogen phosphate or the amino acid group; Described substituting group is the alkyl of C1～C16, in the hydroxyethyl one or both.
The single dibasic acid esters of TPGS favorable solubility in organic solvents such as methyl alcohol, ethanol, propyl carbinol, n-Octanol, ETHYLE ACETATE, Virahol, DMSO 99.8MIN., the TPGS monoesters is water miscible, big solubleness is arranged in water, and dibasic acid esters is water-soluble hardly.Utilize both water miscible difference to make up binary mixed solvent that hydrophobic organic solvents and water, hydrophilic ionic-liquid, hydrophilic ionic-liquid and water forms or polar organic solvent and realize separating of single dibasic acid esters with the two-phase extraction system that binary mixed solvent that water is formed forms, have simple to operate, treatment capacity big, the characteristics of high efficiency separation.
The key of extraction and separation technology is selection of Extractant.
Because the textural difference of the single dibasic acid esters of TPGS is two hydroxyls of polyoxyethylene glycol in the dibasic acid esters and all generates ester with the VE-succinate reaction; And the polyoxyethylene glycol in the monoesters has only a hydroxyl and VE-succinate reaction to generate ester; Hydrophilic segment from molecule (polyoxyethylene glycol) sees that with the ratio of oleophilic moiety (vitamin E) surfactivity and the wetting ability of dibasic acid esters are more very different than monoesters.Because the shared large percentage in whole molecule of the oleophilic moiety in single dibasic acid esters, so the two is dissolved in organic solvent more easily.Monoesters was lower at the partition ratio of aqueous phase when hydrophobic organic solvent separated single dibasic acid esters with the water two-phase extraction, and adding ionic liquid or polar organic solvent can increase the distribution of monoesters in extraction phase, improves partition ratio and treatment capacity well.If use pure ionic liquid to be extraction agent, having the ionic liquid that viscosity of il is big, consumption big even have is deficiencies such as solid at normal temperatures, therefore needs to add the third solvent.The third solvent that adds should have good mutual solubility with ionic liquid, can form two-phase system with the solvent of the single dibasic acid esters of TPGS again.
The room temperature that ionic liquid is made up of zwitterion or near being liquid material under the room temperature, at separation field as one type of novel separating medium of green and noticeable.Compare as extraction agent with conventional organic solvents, ionic liquid has some unique character as extraction agent, and is good like thermostability and chemicalstability, almost do not have vp, non-volatile, not flammable etc., thereby helps the safety and environmental protection of technology; Internal cohesive energy is high, therefore forms two-phase system easily; Ionic liquid also can carry out multiple intermolecular interaction with solute, like π-π, dipole-dipole, hydrogen bond etc., therefore solute is had good solubility; Ion liquid zwitterion Adjustable structure can reach specific separating effect through the ion liquid zwitterion structure of design to regulate the mode of action and the intensity of ionic liquid and solute simultaneously.
Single dibasic acid esters total mass percentage composition is more than 40% in the vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester mixture material that the present invention adopts.According to the difference of different extraction system treatment capacities, the total concn of single dibasic acid esters is preferably 0.5 grams per liter～100 grams per liters in the liquid stock.If the concentration of single dibasic acid esters is low excessively in the liquid stock, the raw material treatment capacity is little, and solvent loss is big, is unfavorable for the economy of technology; If the excessive concentration of single dibasic acid esters is unfavorable for effective separation of single dibasic acid esters in the liquid stock.
The mass percent of hydrophilic ionic-liquid is 1%～99% in described hydrophilic ionic-liquid and the water binary mixed extractant, and the described water-soluble fully polar organic solvent and the mass percent of water binary mixed extractant Semi-polarity organic solvent are 1%～70%.The adding of ionic liquid or polar organic solvent can improve the distribution of monoesters at aqueous phase, makes it have the suitable dispensing coefficient, improves the selectivity to dibasic acid esters.
Solvent is selected homogeneous solvent for use in described washing composition and the liquid stock, when single dibasic acid esters has better dissolving power to TPGS, can form liquid-liquid two-phase system with extraction agent.
When carrying out fractionation extn, take all factors into consideration factors such as quality product, production cost, the volume flow ratio between extraction agent, washing composition, the liquid stock three is preferably 2～15: 1～5: 1.
The service temperature of described fractionation extn is advisable with 10 ℃～70 ℃.If temperature is low excessively, the viscosity of extraction agent is bigger, and rate of mass transfer reduces, and is unfavorable for production operation; If temperature is too high, solvent evaporates is serious, then can reduce the partition ratio and the selectivity of fractionation extn.
Existing fractionation extn equipment is adopted in described fractionation extn, comprises extraction section and washing section, and its synoptic diagram is as shown in Figure 1.Extraction agent gets into the fractionation extn system from the extraction section first step; Liquid stock gets into the fractionation extn system from the last step of extraction section, and washing composition gets into the fractionation extn system from the first step of washing section, merges liquid stock at the extraction section last step and gets into extraction section together; Extraction phase carries out counter current contact mutually with washing; Flow out the raffinate of enrichment TPGS dibasic acid esters from the first step of extraction section, collect raffinate, obtain TPGS dibasic acid esters product through vacuum concentration-washing-drying.Flow out the extraction liquid of TPGS monoesters from the first step of washing section, obtain TPGS monoesters product through vacuum concentration-washing-drying.
Described fractionation extn is multistage fractionation extn; The progression of extraction section and washing section is many more; The effect of fractionation extn is good more, and the purity of vitamin E polyethylene glycol monomester succinate that obtains and vitamin E polyethylene glycol succsinic acid dibasic acid esters is high more, but too much progression can cause production capacity decline, energy expenditure increase, time lengthening of fractionation extn etc. again; The extraction section of preferred fractionation extn is two to eight grades, and washing section is two to eight grades.
The content of the TPGS monoesters that obtains through separation method of the present invention is: relative content >=98%; The content of TPGS dibasic acid esters is: relative content >=98%.
The present invention adopts the content of high-efficient liquid phase chromatogram technique analysis vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester, and HPLC concrete analysis condition is: C30 post (4.6 * 250mm, particle diameter 5 μ m;
Rpaqueous), 35 ℃ of column temperatures, moving phase is acetonitrile/Virahol gradient elution (65/35; 0-10min, 30/70,10-20min; V/v); Flow velocity 1ml/min, detector are UV-detector, and wavelength is 284nm.
The method of calculation of yield and content are following among the present invention:
TPGS monoesters yield %=(TPGS monoester content in monoesters quality product * product)/(content of TPGS monoesters in raw materials quality * raw material) * 100%
TPGS dibasic acid esters yield %=(TPGS dibasic acid esters content in dibasic acid esters quality product * product)/(content of TPGS dibasic acid esters in raw materials quality * raw material) * 100%
Relative content %=(content of TPGS monoesters or dibasic acid esters in the product)/(total content of the single dibasic acid esters of TPGS in the product) * 100%
The invention has the advantages that:
1. to adopt binary mixed solvent that water, hydrophilic ionic-liquid, hydrophilic ionic-liquid and water forms or water-soluble fully polar organic solvent and the binary mixed solvent of water composition be extraction agent in the present invention; Vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester is separated; The extraction agent that is adopted not only is convenient to recycling; And than environmental protection, few to the pollution of environment, have broad application prospects;
2. the present invention adopts the fractionation extn technology, and the consumption of industrial chemicals less, production capacity is high, cost is low;
3. the inventive method adopts optimized conditions, and the relative content of vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester can reach more than 98%, and the recovery can reach more than 95%.
Description of drawings
Fig. 1 is the fractionation extn synoptic diagram.
Embodiment
TPGS1000 mixture (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 68.3%, 31.4%) and ETHYLE ACETATE are made into the liquid stock of 20 grams per liters, with ethyl imidazol(e) a tetrafluoro borate ([EMIm] [BF
4])-water mixed solvent ([EMIm] BF
4Mass percent is 50%) for extraction agent, be washing composition with ETHYLE ACETATE, extraction agent, washing composition, liquid stock three's volume flow ratio is 3: 2.7: 1, in the fractionation extn device, carries out fractionation extn under 40 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is two-stage, and washing section progression is three grades.Extraction agent gets into the fractionation extn system from the extraction section first step; Liquid stock gets into the fractionation extn system from the last step of extraction section; Washing composition gets into the fractionation extn system from the first step of washing section; Merge liquid stock at the washing section last step and get into extraction section together, extraction phase carries out counter current contact mutually with washing.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, collect extraction liquid; Flow out the raffinate of enrichment TPGS dibasic acid esters from the first step of extraction section, collect raffinate; Extraction liquid, raffinate are removed ETHYLE ACETATE through vacuum concentration, pass through repeated water washing deionizing liquid again, obtain the single dibasic acid esters product of TPGS respectively after drying dewaters.Analyze through HPLC, the monoesters relative content is 98.2% in the TPGS monoesters product, and yield is 99.7%; The dibasic acid esters relative content is 98.3% in the TPGS dibasic acid esters product, and yield is 95.4%.
TPGS400 mixture (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 70.4%, 29.4%) and butylacetate are made into the liquid stock of 0.5 grams per liter; With N-hexyl pyridinium tribromide salt ion liquid ([HPy] Br) is extraction agent; With the butylacetate is washing composition; Extraction agent, washing composition, liquid stock three's volume flow ratio is 2: 4.2: 1, in the fractionation extn device, carries out fractionation extn under 20 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is three grades, and washing section progression is three grades.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, flow out the raffinate of enrichment TPGS dibasic acid esters, collect extraction liquid and raffinate from the first step of extraction section; Extraction liquid and raffinate are removed butylacetate through vacuum concentration, pass through repeated water washing deionizing liquid again, obtain TPGS monoesters and dibasic acid esters after drying dewaters.Analyze through HPLC, the relative content of product monoesters is 98.2%, and yield is 99.7%; The relative content of dibasic acid esters is 99.5%, and yield is 99.6%.
Embodiment 3
TPGS 2000 mixtures (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 55.1%, 44.6%) and propyl carbinol are made into the liquid stock of 100 grams per liters, with tributyl ammonium villaumite ([HNBu
3] C1)-water mixed solvent ([HNBu
3] the Cl mass percent is 99%) be extraction agent, be washing composition with the propyl carbinol, extraction agent, washing composition, liquid stock three's volume flow ratio is 13: 1.7: 1, in the fractionation extn device, carries out fractionation extn under 70 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is two-stage, and washing section progression is two-stage.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, flow out the raffinate of enrichment TPGS dibasic acid esters, collect extraction liquid and raffinate from the first step of extraction section; Extraction liquid and raffinate are removed propyl carbinol through vacuum concentration, pass through repeated water washing deionizing liquid again, obtain final product after drying dewaters.Analyze through HPLC, the relative content of TPGS monoesters is 98.1% in the product, and yield is 97.7%, and the relative content of dibasic acid esters is 99.7%, and yield is 98.0%.
Embodiment 4
TPGS 600 mixtures (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 50.4%, 49.4%) and n-Octanol are made into the liquid stock of 50 grams per liters, with 1-butyl-2,3-methylimidazole fluoroform sulphonate ([BMMIm] [CF
3SO
3])-aqueous solution ([BMMIm] [CF
3SO
3] mass percent is 1%) be extraction agent, be washing composition with the n-Octanol, extraction agent, washing composition, liquid stock three's volume flow ratio is 15: 2: 1, in the fractionation extn device, carries out fractionation extn under 10 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is three grades, and washing section progression is two-stage.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, flow out the raffinate of enrichment TPGS dibasic acid esters, collect extraction liquid and raffinate from the first step of extraction section; Extraction liquid, raffinate are removed n-Octanol through vacuum concentration, pass through repeated water washing deionizing liquid again, obtain final product after drying dewaters.Analyze through HPLC, the relative content of TPGS monoesters is 98.9% in the product, and yield is 97.8%, and the relative content of TPGS dibasic acid esters is 98.3%, and yield is 96.2%.
Embodiment 5
TPGS 1200 mixtures (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 58.7%, 40.1%) and ETHYLE ACETATE are made into the liquid stock of 85 grams per liters, with 1-hydroxyethyl pyridine diethyl phosphate ([HOEtPy] [C
2H
5PO
4])-water mixed solvent ([HOEtPy] [C
2H
5PO
4] mass percent is 20%) be extraction agent, be washing composition with ETHYLE ACETATE, extraction agent, washing composition, liquid stock three's volume flow ratio is 6.3: 2: 1, in the fractionation extn device, carries out fractionation extn under 60 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is three grades, and washing section progression is three grades.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, flow out the raffinate of enrichment TPGS dibasic acid esters, collect extraction liquid and raffinate from the first step of extraction section; Extraction liquid and raffinate are removed ETHYLE ACETATE through vacuum concentration, pass through repeated water washing deionizing liquid again, obtain final product after drying dewaters.Analyze through HPLC, the relative content of TPGS monoesters is 98.7% in the product, and yield is 98.8%, and the relative content of TPGS dibasic acid esters is 98.6%, and yield is 97.9%.
Embodiment 6
With TPGS 600 mixtures, composition is identical with embodiment 4 with content, is made into the liquid stock of 3 grams per liters with n-Heptyl alcohol, with N, and N, N-trimethylammonium-N-Bing Ji Phosphonium lysine salt ([P
3111] [Lys])-water mixed solvent ([P
3111] [Lys] mass percent is 15%) be extraction agent, be washing composition with the n-Heptyl alcohol, extraction agent, washing composition, liquid stock three's volume flow ratio is 2: 1.5: 1, in the fractionation extn device, carries out fractionation extn under 25 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is three grades, and washing section progression is level Four.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, flow out the raffinate of enrichment TPGS dibasic acid esters, collect extraction liquid and raffinate from the first step of extraction section; Extraction liquid, raffinate are removed n-Heptyl alcohol through vacuum concentration, pass through repeated water washing deionizing liquid again, obtain final product after drying dewaters.Analyze through HPLC, the relative content of TPGS monoesters is 99.3% in the product, and yield is 99.8%, and the relative content of TPGS dibasic acid esters is 99.6%, and yield is 99.4%.
Embodiment 7
With TPGS 1000 mixtures, composition is identical with embodiment 1 with content, is made into the liquid stock of 70 grams per liters with n-hexyl alcohol, with tributyl ammonium trifluoroacetate ([HNBu
3] [CF
3CO
2])-water mixed solvent ([HNBu
3] [CF
3CO
2] mass percent is 5%) be extraction agent, be washing composition with the n-hexyl alcohol, extraction agent, washing composition, liquid stock three's volume flow ratio is 14: 5: 1, in the fractionation extn device, carries out fractionation extn under 50 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is level Four, and washing section progression is three grades.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, flow out the raffinate of enrichment TPGS dibasic acid esters, collect extraction liquid and raffinate from the first step of extraction section; Extraction liquid and raffinate are removed n-hexyl alcohol through vacuum concentration, pass through repeated water washing deionizing liquid again, obtain final product after drying dewaters.Analyze through HPLC, the relative content of TPGS monoesters is 98.0% in the product, and yield is 99.1%; The relative content of TPGS dibasic acid esters is 98.4%, and yield is 98.5%.
Embodiment 8
With the TPGS400 mixture; Composition is identical with embodiment 2 with content; Being made into the liquid stock of 5 grams per liters with the 2-hexanol, is extraction agent with 1-butyl-1-methyl piperidine iodine ([BMPi] I)-water mixed solvent ([BMPi] I mass percent is 80%), is washing composition with the 2-hexanol; Extraction agent, washing composition, liquid stock three's volume flow ratio is 2.5: 1: 1, in the fractionation extn device, carries out fractionation extn under 50 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is three grades, and washing section progression is three grades.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, flow out the raffinate of enrichment TPGS dibasic acid esters, collect extraction liquid and raffinate from the first step of extraction section; Extraction liquid and raffinate are removed the 2-hexanol through vacuum concentration, pass through repeated water washing deionizing liquid again, obtain final product after drying dewaters.Analyze through HPLC, the relative content of TPGS monoesters is 99.6% in the product, and yield is 97.8%; The relative content of TPGS dibasic acid esters is 98.4%, and yield is 97.5%.
Embodiment 9
With TPGS 1000 mixtures, composition is identical with embodiment 1 with content, is made into the liquid stock of 1 grams per liter with isooctyl alcohol, with 1-dodecyl-3-Methylimidazole bromine salt ([C
12MIm] Br)-water mixed solvent ([C
12MIm] the Br mass percent is 71%) be extraction agent, be washing composition with the isooctyl alcohol, extraction agent, washing composition, liquid stock three's volume flow ratio is 4: 2.3: 1, in the fractionation extn device, carries out fractionation extn under 30 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is level Four, and washing section progression is level Four.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, flow out the raffinate of enrichment TPGS dibasic acid esters, collect extraction liquid and raffinate from the first step of extraction section; Extraction liquid and raffinate are removed isooctyl alcohol through vacuum concentration, pass through repeated water washing deionizing liquid again, obtain final product after drying dewaters.Analyze through HPLC, the relative content of TPGS monoesters is 98.2% in the product, and yield is 98.9%; The relative content of TPGS dibasic acid esters is 99.3%, and yield is 96.7%.
Embodiment 10
With TPGS 1000 mixtures (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 71.7%, 20.1%); Be made into the liquid stock of 40 grams per liters with primary isoamyl alcohol; With water is extraction agent; With the primary isoamyl alcohol is washing composition, and extraction agent, washing composition, liquid stock three's volume flow ratio is 12: 3.3: 1, in the fractionation extn device, carries out fractionation extn under 45 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is seven grades, and washing section progression is eight grades.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, flow out the raffinate of enrichment TPGS dibasic acid esters, collect extraction liquid, raffinate from the first step of extraction section; Extraction liquid, raffinate are removed primary isoamyl alcohol, water through vacuum concentration, after the dry product that obtains TPGS monoesters and dibasic acid esters.HPLC analyzes, and the relative content of TPGS monoesters is 98.9%, and yield is 99.2%, and the relative content of TPGS dibasic acid esters is 99.3%, and yield is 99.3%.
Embodiment 11
With TPGS 2000 mixtures (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 80%, 15%); Be made into the liquid stock of 10 grams per liters with n-Heptyl alcohol; With DMSO 99.8MIN.-water mixed solvent (the DMSO 99.8MIN. mass percent is 40%) is extraction agent; With the n-Heptyl alcohol is washing composition, and extraction agent, washing composition, liquid stock three's volume flow ratio is 2.9: 2.7: 1, in the fractionation extn device, carries out fractionation extn under 30 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is six grades, and washing section progression is six grades.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, flow out the raffinate of enrichment TPGS dibasic acid esters, collect extraction liquid and raffinate from the first step of extraction section; Extraction liquid, raffinate are removed n-Heptyl alcohol, water, DMSO 99.8MIN. through vacuum concentration, after drying obtains final product.Analyze through HPLC, the relative content of TPGS monoesters is 98.8% in the product, and yield is 99.8%, and the relative content of TPGS dibasic acid esters is 98.6%, and yield is 99.7%.
Embodiment 12
With TPGS 1200 mixtures; Composition is identical with embodiment 5 with content, is made into the liquid stock of 60 grams per liters with Pentyl alcohol, is extraction agent with ethanol-water mixed solvent (the ethanol mass percent is 5%); With the Pentyl alcohol is washing composition; Extraction agent, washing composition, liquid stock three's volume flow ratio is 5: 4: 1, in the fractionation extn device, carries out fractionation extn under 35 ℃, flows out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section.Fractionation extn is divided into extraction section and washing section, and extraction section progression is Pyatyi, and washing section progression is level Four.Flow out the raffinate of enrichment TPGS dibasic acid esters from the first step of extraction section, collect extraction liquid, raffinate; Extraction liquid, raffinate are removed Pentyl alcohol, ethanol, water through vacuum concentration, obtain final product through drying.Analyze through HPLC, the relative content of TPGS monoesters is 99.0% in the product, and yield is 99.2%, and the relative content of TPGS dibasic acid esters is 99.3%, and yield is 99.7%.
Embodiment 13
With TPGS 1200 mixtures; Composition is identical with embodiment 5 with content; Being made into the liquid stock of 60 grams per liters with methyl acetate, is extraction agent with methanol-water mixed solvent (methanol quality percentage ratio is 1%), is washing composition with the methyl acetate; Extraction agent, washing composition, liquid stock three's volume flow ratio is 5: 4: 1, in the fractionation extn device, carries out fractionation extn under 35 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is Pyatyi, and washing section progression is Pyatyi.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, flow out the raffinate of enrichment TPGS dibasic acid esters, collect extraction liquid, raffinate from the first step of extraction section; Extraction liquid, raffinate are removed methyl acetate, methyl alcohol, water through vacuum concentration, obtain final product through drying.Analyze through HPLC, the relative content of TPGS monoesters is 98.3% in the product, and yield is 99.2%, and the relative content of TPGS dibasic acid esters is 99.0%, and yield is 98.7%.
Embodiment 14
With TPGS 1000 mixtures (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 30.2%, 9.8%), be made into the liquid stock of 40 grams per liters with n-hexyl alcohol, with tributyl ammonium trifluoroacetate ([HNBu
3] [CF
3CO
2])-water mixed solvent ([HNBu
3] [CF
3CO
2] mass percent is 5%) be extraction agent, be washing composition with the n-hexyl alcohol, extraction agent, washing composition, liquid stock three's volume flow ratio is 11: 5: 1, in the fractionation extn device, carries out fractionation extn under 40 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is two-stage, and washing section progression is three grades.Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, flow out the raffinate of enrichment TPGS dibasic acid esters, collect extraction liquid and raffinate from the first step of extraction section; Extraction liquid and raffinate are removed n-hexyl alcohol through vacuum concentration, pass through repeated water washing deionizing liquid again, obtain final product after drying dewaters.Analyze through HPLC, the relative content of TPGS monoesters is 98.1% in the product, and yield is 98.3%; The relative content of TPGS dibasic acid esters is 98.6%, and yield is 98.1%.
Embodiment 15
TPGS1000 mixture (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 48.0%, 21.6%) and propyl acetate are made into the liquid stock of 26 grams per liters, with ethyl imidazol(e) a tetrafluoro borate ([EMIm] [BF
4])-water mixed solvent ([EMIm] BF
4Mass percent is 50%) for extraction agent, be washing composition with the propyl acetate, extraction agent, washing composition, liquid stock three's volume flow ratio is 3: 3.7: 1, in the fractionation extn device, carries out fractionation extn under 40 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is three grades, and washing section progression is three grades.Extraction agent gets into the fractionation extn system from the extraction section first step; Liquid stock gets into the fractionation extn system from the last step of extraction section; Washing composition gets into the fractionation extn system from the first step of washing section, merges liquid stock at the washing section last step and gets into extraction section together, and extraction phase carries out counter current contact mutually with washing; Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, collect extraction liquid; Flow out the raffinate of enrichment TPGS dibasic acid esters from the first step of extraction section, collect raffinate; Extraction liquid, raffinate are removed propyl acetate through vacuum concentration, pass through repeated water washing deionizing liquid again, obtain the single dibasic acid esters product of TPGS respectively after drying dewaters.Analyze through HPLC, the monoesters relative content is 98.5% in the TPGS monoesters product, and yield is 99.6%; The dibasic acid esters relative content is 98.7% in the TPGS dibasic acid esters product, and yield is 96.7%.
Embodiment 16
TPGS1000 mixture (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 78.0%, 21.5%) and 2-enanthol are made into the liquid stock of 27 grams per liters; With n-propyl alcohol-water mixed solvent (the n-propyl alcohol mass percent is 20%) is extraction agent; With the 2-enanthol is washing composition; Extraction agent, washing composition, liquid stock three's volume flow ratio is 3: 3.7: 1, in the fractionation extn device, carries out fractionation extn under 40 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is six grades, and washing section progression is seven grades.Extraction agent gets into the fractionation extn system from the extraction section first step; Liquid stock gets into the fractionation extn system from the last step of extraction section; Washing composition gets into the fractionation extn system from the first step of washing section, merges liquid stock at the washing section last step and gets into extraction section together, and extraction phase carries out counter current contact mutually with washing; Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, collect extraction liquid; Flow out the raffinate of enrichment TPGS dibasic acid esters from the first step of extraction section, collect raffinate; Extraction liquid, raffinate are removed 2-enanthol etc. through vacuum concentration, obtain the single dibasic acid esters product of TPGS respectively after drying dewaters.Analyze through HPLC, the monoesters relative content is 99.0% in the TPGS monoesters product, and yield is 99.3%; The dibasic acid esters relative content is 98.9% in the TPGS dibasic acid esters product, and yield is 97.7%.
Embodiment 17
TPGS1000 mixture (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 78.0%, 21.5%) and sec-n-octyl alcohol are made into the liquid stock of 30 grams per liters; With Virahol-water mixed solvent (the Virahol mass percent is 21%) is extraction agent; With the sec-n-octyl alcohol is washing composition; Extraction agent, washing composition, liquid stock three's volume flow ratio is 3.1: 3.7: 1, in the fractionation extn device, carries out fractionation extn under 45 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is eight grades, and washing section progression is seven grades.Extraction agent gets into the fractionation extn system from the extraction section first step; Liquid stock gets into the fractionation extn system from the last step of extraction section; Washing composition gets into the fractionation extn system from the first step of washing section, merges liquid stock at the washing section last step and gets into extraction section together, and extraction phase carries out counter current contact mutually with washing; Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, collect extraction liquid; Flow out the raffinate of enrichment TPGS dibasic acid esters from the first step of extraction section, collect raffinate; Extraction liquid, raffinate are removed sec-n-octyl alcohol etc. through vacuum concentration, obtain the single dibasic acid esters product of TPGS respectively after drying dewaters.Analyze through HPLC, the monoesters relative content is 99.1% in the TPGS monoesters product, and yield is 99.4%; The dibasic acid esters relative content is 99.0% in the TPGS dibasic acid esters product, and yield is 97.8%.
Embodiment 18
TPGS1000 mixture (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 78.0%, 21.5%) and isopropyl acetate are made into the liquid stock of 20 grams per liters; With N; Dinethylformamide-water mixed solvent (N, dinethylformamide mass percent are 10%) is an extraction agent, is washing composition with the isopropyl acetate; Extraction agent, washing composition, liquid stock three's volume flow ratio is 3.5: 3.9: 1, in the fractionation extn device, carries out fractionation extn under 30 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is level Four, and washing section progression is Pyatyi.Extraction agent gets into the fractionation extn system from the extraction section first step; Liquid stock gets into the fractionation extn system from the last step of extraction section; Washing composition gets into the fractionation extn system from the first step of washing section, merges liquid stock at the washing section last step and gets into extraction section together, and extraction phase carries out counter current contact mutually with washing; Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, collect extraction liquid; Flow out the raffinate of enrichment TPGS dibasic acid esters from the first step of extraction section, collect raffinate; Extraction liquid, raffinate are removed isopropyl acetate etc. through vacuum concentration, obtain the single dibasic acid esters product of TPGS respectively after drying dewaters.Analyze through HPLC, the monoesters relative content is 98.7% in the TPGS monoesters product, and yield is 98.5%; The dibasic acid esters relative content is 99.1% in the TPGS dibasic acid esters product, and yield is 98.6%.
Embodiment 19
TPGS1000 mixture (wherein the quality percentage composition of monoesters, dibasic acid esters is respectively 78.0%, 21.5%) and 2-enanthol are made into the liquid stock of 35 grams per liters; With acetonitrile-water mixed solvent (the acetonitrile mass percent is 70%) is extraction agent; With the 2-enanthol is washing composition; Extraction agent, washing composition, liquid stock three's volume flow ratio is 3: 3.7: 1, in the fractionation extn device, carries out fractionation extn under 40 ℃.Fractionation extn is divided into extraction section and washing section, and extraction section progression is Pyatyi, and washing section progression is Pyatyi.Extraction agent gets into the fractionation extn system from the extraction section first step; Liquid stock gets into the fractionation extn system from the last step of extraction section; Washing composition gets into the fractionation extn system from the first step of washing section, merges liquid stock at the washing section last step and gets into extraction section together, and extraction phase carries out counter current contact mutually with washing; Flow out the extraction liquid that is rich in the TPGS monoesters from the first step of washing section, collect extraction liquid; Flow out the raffinate of enrichment TPGS dibasic acid esters from the first step of extraction section, collect raffinate; Extraction liquid, raffinate are removed 2-enanthol etc. through vacuum concentration, obtain the single dibasic acid esters product of TPGS respectively after drying dewaters.Analyze through HPLC, the monoesters relative content is 98.9% in the TPGS monoesters product, and yield is 98.8%; The dibasic acid esters relative content is 98.7% in the TPGS dibasic acid esters product, and yield is 98.1%.
Claims (10)
1. the method for an extracting and separating vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester is characterized in that, may further comprise the steps:
(1) be raw material with the vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester mixture; Ester or alcohols hydrophobic organic solvent with solubleness≤15g/100g in the water are made into liquid stock; With the perhaps complete water-soluble polar organic solvent of the binary mixed solvent of water, hydrophilic ionic-liquid, hydrophilic ionic-liquid and water composition and the binary mixed solvent of water composition is extraction agent; Used hydrophobic organic solvent is a washing composition during with preparation raw material liquid, carries out fractionation extn;
(2) fractionation extn process is divided into extraction section and washing section; Extraction agent gets into the fractionation extn system from the extraction section first step; Liquid stock gets into the fractionation extn system from the last step of extraction section, and washing composition gets into the fractionation extn system from the first step of washing section, merges liquid stock at the washing section last step and gets into extraction section together; Extraction phase carries out counter current contact mutually with washing; Flow out the extraction liquid of rich in vitamin E polyoxyethylene glycol monomester succinate from the first step of washing section, flow out the raffinate of enrichment vitamin E polyethylene glycol succsinic acid dibasic acid esters, collect extraction liquid and raffinate respectively from the first step of extraction section;
(3) with extraction liquid through vacuum concentration, washing and drying, obtain vitamin E polyethylene glycol monomester succinate product, raffinate obtains vitamin E polyethylene glycol succsinic acid dibasic acid esters product through vacuum concentration, washing and drying.
2. the method for extracting and separating vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester as claimed in claim 1; It is characterized in that the ester of solubleness≤15g/100g or alcohols hydrophobic organic solvent are methyl acetate, ETHYLE ACETATE, propyl acetate, isopropyl acetate, butylacetate, propyl carbinol, Pentyl alcohol, n-hexyl alcohol, n-Heptyl alcohol, n-Octanol, primary isoamyl alcohol, isooctyl alcohol, 2-hexanol, 2-enanthol or sec-n-octyl alcohol in the described water.
3. the method for extracting and separating vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester as claimed in claim 1; It is characterized in that; Described water-soluble polar organic solvent fully is methyl alcohol, ethanol, n-propyl alcohol, Virahol, DMSO 99.8MIN., N, dinethylformamide or acetonitrile.
4. the method for extracting and separating vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester as claimed in claim 1 is characterized in that, described hydrophilic ionic-liquid is by positively charged ion M
+And anion N
-Two portions are formed; Positively charged ion M
+For having substituent imidazole type positively charged ion, have substituent pyridine type positively charged ion, have substituent quaternary phosphine type positively charged ion, have substituent piperidines type positively charged ion, have substituent quaternary ammonium cation or having a kind of in the substituent tetramethyleneimine type positively charged ion; Anion N
-A kind of in cl ions, bromide anion, iodide ion, tetrafluoroborate, trifluoroacetic acid root, trifluoromethanesulfonic acid root, ethylsulfonic acid root, dimethyl-phosphate radical, diethylammonium phosphate radical, dihydrogen phosphate or the amino acid group; Described substituting group is C
1～C
16Alkyl, in the hydroxyethyl one or both.
5. the method for extracting and separating vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester as claimed in claim 1 is characterized in that, the total concn of single dibasic acid esters is 0.5 grams per liter～100 grams per liters in the described liquid stock.
6. the method for extracting and separating vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester as claimed in claim 1 is characterized in that, the mass percent of the binary mixed extractant intermediate ion liquid that described hydrophilic ionic-liquid and water are formed is 1%～99%.
7. the method for extracting and separating vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester as claimed in claim 1; It is characterized in that described fully water-soluble polar organic solvent is 1%～70% with the mass percent of the binary mixed extractant Semi-polarity organic solvent of water composition.
8. the method for extracting and separating vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester as claimed in claim 1 is characterized in that, the service temperature of described fractionation extn is 10 ℃～70 ℃.
9. the method for extracting and separating vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester as claimed in claim 1 is characterized in that, the volume flow ratio between extraction agent, washing composition, the liquid stock three is 2～15: 1～5: 1.
10. the method for extracting and separating vitamin E polyethylene glycol succinate monoester from vitamin E polyethylene glycol succinate diester as claimed in claim 1 is characterized in that, the extraction section of described fractionation extn is two to eight grades, and washing section is two to eight grades.
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| CN103288870A (en) * | 2013-05-08 | 2013-09-11 | 浙江大学 | Preparation method of injection grade high-purity phosphatidyl choline |
| CN103342820A (en) * | 2013-06-27 | 2013-10-09 | 浙江大学 | Method for extracting and separating polyehtylne glycol fatty acid monoester and diester |
| WO2016150025A1 (en) * | 2015-03-24 | 2016-09-29 | 浙江大学 | Method for preparing high-content mixed tocopherols through lyotropic liquid crystal extraction and separation |
| CN107474238A (en) * | 2017-08-15 | 2017-12-15 | 武汉桀升生物科技有限公司 | A kind of method of separating VE polyethylene glycol mono succinate dibasic acid esters |
| CN109254102A (en) * | 2017-07-14 | 2019-01-22 | 上海联陆实业股份有限公司 | A kind of efficient liquid phase detection method of watermiscible vitamin E derivative |
| CN109422873A (en) * | 2017-09-04 | 2019-03-05 | 广东东阳光药业有限公司 | A kind of post-processing approach of VE succinic acid macrogol ester |
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