CN101240303B - Method for synthesizing natural tocopherol ester catalyzed by lipase - Google Patents
Method for synthesizing natural tocopherol ester catalyzed by lipase Download PDFInfo
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- CN101240303B CN101240303B CN2007100635796A CN200710063579A CN101240303B CN 101240303 B CN101240303 B CN 101240303B CN 2007100635796 A CN2007100635796 A CN 2007100635796A CN 200710063579 A CN200710063579 A CN 200710063579A CN 101240303 B CN101240303 B CN 101240303B
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Abstract
The invention discloses a method for catalyzing and synthesizing savageness tocofecol ester by lipase. savageness tocofecol and a unsaturated carboxylic ether in ratio range of 1:1-1:5 are added into reaction media organic solvent and lipase is used as energizing agent. The esterification rate of savageness tocofecol can be up to 9525023440n condition of 20-60 0.000000or 48-72 hours. The dosage of lipase is 0.5 times of the quantity of tocofecol and the carrier of lipase is textile fabric or colophony. Comparing with the present method in chemical catalyst, the invention has advantages such as gentle reaction condition, low energy consumption, simple product separation and less poison accessory substances.
Description
Technical field
The present invention relates to a kind of method of synthesizing natural tocopherol ester catalyzed by lipase.
Technical background
Vitamin-E (Vitamin E) is the class VITAMIN relevant with reproductive function, and chemical structure is chroman derivatives, and phenolic hydroxyl group is arranged in the structure, so also claim tocopherol.Known its mainly contains α, β, γ, δ, ε, ζ 1, eight kinds of isomer of ζ 2, η, and wherein the alpha-tocopherol activity is the strongest.Tocopherol not only plays important role on trophology, and also has quite outstanding function in prevention chronic disease function aspects, and this point is that other vitaminss are incomparable.The physiological function of tocopherol comprises antioxygenation, enhance immunity function, anticancer or function of tumor inhibition, antisterility function etc.Therefore it is widely used in fields such as medicine, food, makeup.
Tocopherol be divided into synthetic with natural two kinds, the tocopherol of synthetic utilizes some chemical intermediate condensations to form because the molecule spatial is not alternative in the condensation course, products obtained therefrom is the racemization type.Natural tocopherol is in natural resource, mainly is to extract in the vegetables oil, is generally D type (dextrorotation).Synthetic there is difference aspect security and the biological activity with natural tocopherol.Find that through the mouse oral test LD50 of synthesising complex E is 5kg/kg, natural VE then is safe, and U.S. FDA is also listed it in GRAS.Three chiral centre positions all have the R-conformation in the structure of natural tocopherol, and synthetic then is the mixture of all steric isomers, and it is many that the former biological activity ratio latter is eager to excel.ADM company relevant discovers that the effectiveness of natural product is 2 times of synthetics; Find during Henkel Corp. research VE that the pregnant woman is 3.3 times of synthetics to the specific absorption of natural VE.In addition, both Application Areass also have difference, and synthetic tocopherol is mainly used in fodder additives at present, and natural VE almost all is used for the human consumption.According to CMR prediction, synthetic VE will be with annual 3%～5% speed increment, and natural VE improves the interest of green product year by year along with people, then can increase fast with 15%～20% speed.
Tocopherol is oxidized easily in the process of preserving and using.In application, usually tocopherol is modified with certain form, obtained the higher Tocopheryl derivatives of stability.Modal is the commercialization VITAMIN E ACETATE, and it is the ester that obtains after the phenolic hydroxyl group esterification in the tocopherol.Because phenolic hydroxyl group and kinds of aromatic ring conjugation have reduced the cloud density on the Sauerstoffatom, the nucleophilicity that causes phenolic hydroxyl group than alcoholic extract hydroxyl group a little less than, so the reaction of the one-tenth ester of phenol is more difficult than alcohol.Tocopherol is difficult to carboxylic acid esterification take place directly, and under the catalysis of chemical catalyst acid or alkali, phenol can generate ester with acyl chlorides or anhydride reaction.
Both at home and abroad, the chemical process about the tocopherol acetate preparation is a lot.Can be divided into three kinds by the raw material classification: 1. Trimethylhydroquinone and isophytol condensation.2. Trimethylhydroquinone ester and isophytol condensation.3. the reaction of vitamin-E and acetic anhydride generates Vitamin E acetate.
With Trimethylhydroquinone and isophytol is that raw material is the main method of present synthesising complex E acetic ester, and employed catalyzer is not quite similar.US5523420 (1996) uses strong acid and lewis acidic mixture, and KR910000896B (1991) uses acid ion exchangers to make catalyzer, and the composition of catalyzer is ZnCl
2/ Zn/H
3PO
4Mixture.
The middle Steffen of JP2001261669 (2001) etc. mentions with the Trimethylhydroquinone diester and replaces Trimethylhydroquinone, generates Vitamin E acetate with the isophytol reaction, and catalyst system therefor is zinc halide and protonic acid.Solvent is the mixture of polar solvent or polar solvent and water.
By Trimethylhydroquinone or Trimethylhydroquinone ester and isophytol condensation, the tocopherol acetate that further esterification obtains belongs to the synthetic product.Because it is full racemization type, biological activity can not show a candle to natural product.And employed catalyzer all is a chemical catalyst in synthetic, and security of products is not high.Natural tocopherol direct esterification can obtain the high natural tocopherol acetic ester of quality.The process of the natural tocopherol esterification that patent of having reported and document are mentioned all is to come catalytic esterification with acid, alkali electroless catalyzer.
It is catalyzer that people such as Hu Chuanrong (preparation of natural VE acetic ester, modern food science and technology Vol.21No.2 (total 84)) have studied with the triethylamine, and natural mixing VE is a raw material, has synthesized the natural VE acetic ester with acetic anhydride.Total VE content is 62.31% in the raw material, wherein contains alpha-tocopherol, β tocopherol, gama tocopherol, methyltocol and is respectively 7.39%, 1.68%, 56.05%, 34.88%.Reaction is solvent with the normal hexane, and temperature is 60 ℃, and the VE esterification yield reaches 94.93%.Adopted the mode that drips in the VE solution of existing catalyzer, to add diacetyl oxide.In system, add dilute hydrochloric acid vibration washing after reaction is finished and be used for removing excessive catalyst of triethylamine, organic phase after the layering is washed with distilled water to neutrality, use anhydrous sodium sulfate drying again, dried solution is evaporated solvent with rotatory evaporator, thereby obtain vitamin-e ester.Temperature of reaction is 60 ℃, and the VE esterification yield is 94.93%.When the mixing of substrate, need control to drip the speed of acid anhydrides.Reacted system need be through overpickling, drying and other steps, complex process, and also the temperature of reaction is higher.
People such as Yang Yiwen (Chinese colleges and universities academic dissertation, 2005) having studied with concentrated hydrochloric acid/zinc oxide system is catalyzer, catalysis synthesizing natural alpha VITAMIN E ACETATE under normal temperature condition, and solvent is selected normal hexane for use, reacted mixed solution filters, and filtrate is extremely neutral with deionized water wash.With rotary evaporation the normal hexane evaporate to dryness is obtained the thick product of tocopherol acetate, mass content also needs to make with extra care if will obtain high-load product between 70%-80%.Contain high-volatile protonic acid in the catalyzer, make being recycled into of catalyzer for an important difficult problem.Among the patent application EP0850937A1, mention the catalyzer phase behind the water extractive reaction, water is concentrated again, the catalyst solution that obtains is returned to the recycling that has realized catalyzer in the reaction at 20-200 ℃.Need special pump to carry but shortcoming is the zinc halide mixture, when concentrating zinc halide, there is loss in high-volatile hydrochloric acid, and the amount of hydrochloric acid need constantly be added.
Also mentioning with HCl and zinc halide among the JP56073081 (1981) is catalyzer, and tocopherol and diacetyl oxide are raw material synthetic tocopherol acetic ester.Reaction can be carried out under lower temperature 10-30 ℃, and 0.5-2h can reach trim point, but the diacetyl oxide that reacts used is excessive, makes troubles for the purification of product.
Above-mentioned by Trimethylhydroquinone or Trimethylhydroquinone ester and isophytol condensation, the tocopherol acetate that further esterification obtains belongs to synthetic product, and biological activity is low, and employed catalyzer all is a chemical catalyst.Though the acidity of report, the Renascin product that basic catalyst esterification natural tocopherol obtains are high-quality esters.But because the acid-basicity of catalyzer and substrate acid anhydrides is excessive, need neutralization, washing, can cause a large amount of waste water like this, bring problem of environmental pollution.In addition, also have complex process, product is not easily separated, have toxic byproduct many, in industrial very difficult realization quantity-produced shortcoming.
Summary of the invention
The present invention has overcome above-mentioned shortcoming, and a kind of method of synthesizing natural tocopherol ester catalyzed by lipase is provided.The transformation efficiency height of this method can reach 95%.And also have the following advantages: reaction solvent is nontoxic, and enzyme dosage is few, and lipase all separates with product easily with reaction solvent, helps the recovery of serialization production and enzyme and solvent and utilization once more.
This synthetic method is carried out successively by following steps:
A. with natural tocopherol and a kind of undersaturated carboxylicesters, by the scope of both mol ratios at 1: 1～1: 5, join in the reaction media organic solvent, reaction is made catalyzer with lipase, under 20～60 ℃ condition, reacts 48-72 hour; Add water-retaining agent when the reaction beginning, the consumption of water-retaining agent is 7 times of tocopherol quality; The consumption of lipase is 0.5 times of tocopherol quality;
B. after reaction finishes, lipase and water-retaining agent are separated from reaction solution with filtering method;
C. the reaction solution after 60 ℃ of fractionation by distillation steams the reaction media organic solvent, obtains the product natural tocopherol ester.
Esters of unsaturated carboxylic acids is chain length C
4～C
18Esters of unsaturated carboxylic acids, specifically, can be ethene acetic ester, ethene laurate, ethene cetylate, propylene acetic ester, propylene laurate or propylene cetylate.
Described lipase is free Penicillium lipase, lipase from candida sp and esterase and by the enzyme of carrier after with above-mentioned enzyme immobilization.
Described carrier is textiles or resin, specifically can be film, cloth and particulate resins, and textiles can be a cotton.
Described natural tocopherol is α, β, γ, δ, ε, ζ 1, ζ 2, η tocopherol or its combination.
Described reaction media organic solvent is the organic solvent of LogP=2.0～4.0.Specifically, can be normal hexane, hexanaphthene, sherwood oil, normal heptane or its composition.
Used water-retaining agent is molecular sieve, discolour silica gel and the ball-type water-retaining agent with cavernous structure.Molecular sieve specifically can be 4A, 5A molecular sieve, the 13X molecular sieve.
The esterification equation that the present invention finishes in organic solvent is:
Enzyme is lived and is defined as: under 40 ℃ of conditions, the enzyme amount that hydrolysis sweet oil in the phosphate buffer solution of pH8.0, per minute discharge 1 μ mol lipid acid is an enzyme unit alive.The enzyme of the used lipase of the present invention unit alive is 250～10000U/g.
Advantage of the present invention is as follows:
(1) used catalyzer lipase is green catalyst, compares with traditional chemical catalyst to have eco-friendly characteristics.
(2) one of Fan Ying substrate unsaturated carboxylic acid belongs to organic solvent commonly used, and toxicity is little, is easy to separate.
(3) lipase is fixing, has prevented the congregation of enzyme molecule in organic solvent in the resolvase, has improved the diffusion effect of enzyme molecule, has increased the catalysis area.
(4) immobilized lipase separates with substrate and product easily, and the life-span of enzyme is longer, can reuse and serialization production.
(5) add the effect that water-retaining agent such as molecular sieve had both played water in the absorption system in the reaction process, also play the effect that promotes that reaction takes place, improved transformation efficiency greatly.
(6) the product natural tocopherol ester of gained all plays an important role in fields such as food, medicine, makeup, healthcare products.
Embodiment
Embodiment 1
It is that reaction is a catalyzer with the free lipase from candida sp (10000U/g) of 0.02g in 0.5% the sherwood oil that the natural alpha-tocopherol of two kinds of substrate 0.43g (1mmol) and 0.185ml (2mmol) ethene acetic ester are joined reaction media 10ml water content.Under 40 ℃ of conditions of temperature, shaking table vibration (180r/min), reaction 72h reaction conversion ratio reaches 50.00%.After reaction was finished, room temperature left standstill, filtering separation free lipase.Reaction solution steams organic solvent under 0.05～0.08 MPa vacuum tightness, obtain the product natural tocopherol ester.
Embodiment 2
Operation steps is with embodiment 1, and difference is: catalyzer changes Penicillium lipase into by the free lipase from candida sp, and transformation efficiency is 45.21%.
Embodiment 3
It is that reaction is a catalyzer with the immobilized lipase of 0.2g yarn fabric cotton (250U/g) in 0.5% the sherwood oil that the natural alpha-tocopherol of two kinds of substrate 0.43g (1mmol) and 0.185ml (2mmol) ethene acetic ester are joined reaction media 10ml water content.Under 40 ℃ of conditions of temperature, shaking table vibration (180r/min), reaction 72h reaction conversion ratio reaches 91.03%.Take out immobilized lipase, reaction solution steams organic solvent through after filtering under the vacuum tightness of 0.05～0.08MPa, obtain the product natural tocopherol ester.
Embodiment 4
Operation steps is with embodiment 2, and difference is: fixation support changes particulate resins into by the yarn fabric cotton, and transformation efficiency is 85.01%.
Embodiment 5
Operation steps is with embodiment 2, and difference is: petroleum ether solvent changes the normal hexane solvent into, and transformation efficiency is 85.76%.
Embodiment 6
Operation steps is with embodiment 2, and difference is: petroleum ether solvent changes cyclohexane solvent into, and transformation efficiency is 75.01%.
Embodiment 7
Operation steps is with embodiment 2, and difference is: petroleum ether solvent changes normal heptane solvent into, and transformation efficiency is 84.21%.
Embodiment 8
It is that reaction is a catalyzer with the immobilized lipase of 0.2g yarn fabric cotton (250U/g) in 0.5% the sherwood oil that the natural alpha-tocopherol of two kinds of substrate 0.43g (1mmol) and 0.185ml (2mmol) ethene acetic ester are joined reaction media 10ml water content.Adding the 3g model during reaction beginning in system is the molecular sieve of 5A, under 40 ℃ of conditions of temperature, and shaking table vibration (180r/min), reaction 72h reaction conversion ratio reaches 95.06%.Take out immobilized lipase and molecular sieve, room temperature leaves standstill, and behind the reacting liquid filtering, steams organic solvent under the vacuum tightness of 0.05～0.08MPa, obtains the product natural tocopherol ester.
Embodiment 9
Operation steps is with embodiment 8, and difference is: the 5A molecular sieve changes the 4A molecular sieve into, and transformation efficiency is 85.01%.
Embodiment 10
Operation steps is with embodiment 8, and difference is: the 5A molecular sieve changes the 13X molecular sieve into, and transformation efficiency is 93.85%.
Embodiment 11
Operation steps is with embodiment 8, and difference is: the 5A molecular sieve changes discolour silica gel into, and transformation efficiency is 91.07%.
Embodiment 12
It is that reaction is a catalyzer with the immobilized lipase of 0.2g yarn fabric cotton (250U/g) in 0.5% the sherwood oil that the natural alpha-tocopherol of substrate 0.43g (1mmol) and 0.5ml (2mmol) ethene laurate are joined reaction media 10ml water content.Under 40 ℃ of conditions of temperature, shaking table vibration (180r/min), reaction 72h, transformation efficiency is 70.71%.
Embodiment 13
It is that reaction is a catalyzer with the immobilized lipase of 0.2g yarn fabric cotton (250U/g) in 0.5% the sherwood oil that the natural alpha-tocopherol of substrate 0.43g (1mmol) and 0.675ml (2mmol) ethene cetylate are joined reaction media 10ml water content.Under 40 ℃ of conditions of temperature, shaking table vibration (180r/min), reaction 72h, transformation efficiency is 62.54%.
Embodiment 14
With 0.43g mixed tocopherol concentrated solution, wherein contain α, β, γ, methyltocol, joining the 10ml water content with 0.185ml (2mmol) ethene acetic ester is in 0.5% the sherwood oil, and reaction is a catalyzer with the immobilized lipase of 0.2g yarn fabric cotton (250U/g).Under 40 ℃ of conditions of temperature, shaking table vibration (180r/min), reaction 72h, the transformation efficiency of four kinds of tocopherols all reaches 90.00%.
More than the method for synthesizing natural tocopherol ester catalyzed by lipase provided by the present invention is described in detail, used specific case herein principle of the present invention and embodiment are set forth, the explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof; Simultaneously, for one of ordinary skill in the art, according to thought of the present invention, the part that all can change in specific embodiments and applications, in sum, this description should not be construed as limitation of the present invention.
Claims (8)
1. the method for a synthesizing natural tocopherol ester catalyzed by lipase is characterized in that, is carried out successively by following steps:
A. with natural tocopherol and a kind of undersaturated carboxylicesters, by the scope of both mol ratios at 1: 1～1: 5, join LogP and be in 2.0～4.0 the reaction media organic solvent, reaction is made catalyzer with free Penicillium lipase or lipase from candida sp, under 20～60 ℃ condition, reacted 48-72 hour; Add water-retaining agent when the reaction beginning, the consumption of water-retaining agent is 7 times of tocopherol quality; The consumption of lipase is 0.5 times of tocopherol quality;
B. after reaction finishes, lipase and water-retaining agent are separated from reaction solution with filtering method;
C. the reaction solution after 60 ℃ of fractionation by distillation steams the reaction media organic solvent, obtains the product natural tocopherol ester.
2. the method for synthesizing natural tocopherol ester catalyzed by lipase according to claim 1, it is characterized in that: described undersaturated carboxylicesters is chain length C
4～C
18Esters of unsaturated carboxylic acids.
3. the method for synthesizing natural tocopherol ester catalyzed by lipase according to claim 2, it is characterized in that: described undersaturated carboxylicesters is ethene acetic ester, ethene laurate, ethene cetylate, propylene acetic ester, propylene laurate or propylene cetylate.
4. the method for synthesizing natural tocopherol ester catalyzed by lipase according to claim 1 is characterized in that: described catalyzer also comprises by the enzyme of carrier after with free Penicillium lipase or lipase from candida sp immobilization.
5. the method for synthesizing natural tocopherol ester catalyzed by lipase according to claim 4, it is characterized in that: described carrier is textiles or resin.
6. the method for synthesizing natural tocopherol ester catalyzed by lipase according to claim 1 is characterized in that, described natural tocopherol is α, β, γ, δ, ε, ζ 1, ζ 2, η tocopherol or its combination.
7. the method for the described synthesizing natural tocopherol ester catalyzed by lipase of claim 1, it is characterized in that: described reaction media organic solvent is normal hexane, hexanaphthene, sherwood oil, normal heptane or its composition.
8. the method for the described synthesizing natural tocopherol ester catalyzed by lipase of claim 1, it is characterized in that: used water-retaining agent is molecular sieve, discolour silica gel and the ball-type water-retaining agent with cavernous structure.
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| CN102618596A (en) * | 2012-03-20 | 2012-08-01 | 中国药科大学 | Method for preparing Guanfu base G through bioconversion in nonaqueous phase system |
| CN102634552A (en) * | 2012-04-18 | 2012-08-15 | 西安海斯夫生物科技有限公司 | Synthesis method of natural alpha-tocopherol acetate |
| CN104592191A (en) * | 2014-12-25 | 2015-05-06 | 浙江新和成药业有限公司 | Method for synthesizing tocopherol succinate |
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| CN1621528A (en) * | 2003-11-28 | 2005-06-01 | 北京化工大学 | Method for catalytic synthesis of vitamin A fatty acid ester using immobilized lipase |
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| CN1621528A (en) * | 2003-11-28 | 2005-06-01 | 北京化工大学 | Method for catalytic synthesis of vitamin A fatty acid ester using immobilized lipase |
Non-Patent Citations (3)
| Title |
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| 刘涛等.脂肪酶催化合成维生素A酯.现代化工.2005,全文. * |
| 姜艳军.脂肪酶催化合成维生素A乳酸酯的研究.河北工业大学硕士论文.2006,全文. * |
| 辛嘉英等.脂肪酶催化反应纯化a-生育酚琥珀酸酯.分子催化.2005,全文. * |
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