CN101220382B - Method for producing R-(-)- benzoglycolic acid - Google Patents
Method for producing R-(-)- benzoglycolic acid Download PDFInfo
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- CN101220382B CN101220382B CN2008100522504A CN200810052250A CN101220382B CN 101220382 B CN101220382 B CN 101220382B CN 2008100522504 A CN2008100522504 A CN 2008100522504A CN 200810052250 A CN200810052250 A CN 200810052250A CN 101220382 B CN101220382 B CN 101220382B
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Abstract
The invention relates to a preparation method of R-(-)-mandelic acid and the steps are that: mandelic acid ethyl ester is taken and added in a reactor, then a ionic liquid, a tris(hydroxymethyl)aminoethane-hydrochloric acid buffer solution and a lipase catalyst are added; each milliliter of the ionic liquid is added with 0.1g to 0.3g of the mandelic acid ethyl ester, the amount of lipase is 2.5 percent to 7.5 percent of the weight of the mandelic acid ethyl ester, the ionic liquid: the buffer solution is equal to 1: 1 to 8 accounted by volume ratio, the pH scope of the buffer solution is 6 to 8.5; then reaction is carried out for 5.0 to 10 hours in a constant temperature water bath shaker, filtration is carried out for enzyme removal and water removal, the solids of the mandelic acid and the mandelic acid ethyl ester are obtained by ethyl acetate extraction and rotation evaporation; then n-hexane is added and the R-(-)-mandelic acid is obtained by filtration. The preparation method of the R-(-)-mandelic acid of the invention has simple technique, mild reaction conditions and small environmental pollution; the ionic liquid is taken as a reaction medium, thereby greatly shortening reaction time, the obtained product has high stereoselectivity, the ee value of the product is 60 percent at most, and the yield can achieve 92 percent.
Description
Technical field
Technical scheme of the present invention relates to biological process synthetic amygdalic acid, the specifically preparation method of R-(-)-amygdalic acid acid.
Background technology
Chiral drug (chiral drug) is meant the single enantiomer compound medicine with medicinal physiologically active, and often there is significant difference in the drug effect of different chiralitys at aspects such as biological activity, metabolic process and toxicity when organism.Along with the development of modern medicines investigative technique, chiral drug and correlation technique have become the research focus of current medicine and related discipline.According to incompletely statistics, the medicine of world's list marketing adds up to 1850 kinds, 523 kinds of natural and semisynthetic drugs, and wherein chiral drug is 517 kinds; 1327 kinds of synthetic drugss, wherein chiral drug is 528 kinds.Chiral drug has become one of direction of international new drug research and exploitation.
Amygdalic acid (claims the Alpha-hydroxy toluylic acid again, English name Mandelic acid), have two kinds of configurations of R, S, wherein R-(-)-amygdalic acid is a kind of important chiral intermediate, be widely used in the synthetic of multiple medicine, as be used to microbiotic, slimming medicine, antitumor drug, treatment dysthymia disorders medicine and agricultural chemicals etc. such as syncillin and head armful rhzomorph; And can be used as chiral reagent, be used to split other chipal compounds.Therefore, prepare optically pure chirality module compound and all have value widely in fields such as medicine, agricultural, material and environmental protection.
At present, the industrializing synthesis route of amygdalic acid mainly contains two, and the one, be raw material with the methyl phenyl ketone, the methyl phenyl ketone chlorination is two chloroethene phthalein benzene, gets with the diluted alkaline hydrolysis then; The 2nd, be raw material with the phenyl aldehyde, phenyl aldehyde obtains mandelonitrile after being dissolved in and adding anhydrous prussic acid reaction in the chloroform, and hydrolysis obtains product again.But traditional synthetic technology is resulting is the amygdalic acid of racemic modification, and gordian technique is the production of unicity compound, and resolution of racemic compound common methods mainly comprises in the world: chromatography, chemical method and biological process etc.Wherein, the preparation chiral chromatographic column carries out Split Method, products obtained therefrom purity height, and separated sample variable range is narrow, but owing to need expensive chiral additives, therefore only limits to detect and prepared in laboratory; The chemical method yield is low, optical purity is low, production process is numerous and diverse, energy consumption is big, environmental pollution is serious, toxicity is big, cost is high; Utilize biological process to prepare optically pure chipal compounds and have the reaction conditions gentleness, product is single, and stereoselectivity, regioselectivity and chemo-selective are higher, and can finish some chemosynthesis and be difficult to the advantages such as reaction of carrying out, and becomes the emphasis of current research.Patent " method of the asymmetric fractionation preparation of a kind of microorganism (R)-amygdalic acid " (CN1840671), at first obtain the full cell of this microorganism through fermentation culture from a kind of microorganism, split as catalyzer with this full cell again, the ee value of products therefrom reaches more than 90%, but its reaction time is longer, remove microbial cultivation process, only this step of resolution reaction just needs 24-72 hour.Patent " a kind of method of producing optical homochiral amygdalic acid " (CN1710087) adopts chemistry and biological bonded method, removes feedstock production and microbial cultivation process, and its resolution reaction needs 45-50 hour.
Summary of the invention
Technical problem to be solved by this invention is: the preparation method that a kind of R-(-)-amygdalic acid is provided, it is a kind of technology that enzyme process catalysis asymmetric hydrolysis ethyl mandelate is produced R-(-)-amygdalic acid in ionic liquid, the product that this technology has overcome chemical synthesis is the shortcoming of RS-amygdalic acid for the racemize amygdalic acid, simple to operate, environmentally friendly, the resolution reaction time only is 5.0-10 hour, and has obtained higher product ee value.
The present invention solves this technical problem the technical scheme that is adopted:
The preparation method of a kind of R-(-)-amygdalic acid the steps include:
Getting ethyl mandelate joins in the reactor, add ionic liquid again, Tutofusin tris-hydrochloric acid buffer solution (Tris-HCl buffered soln) and lipase-catalyzed dose, wherein material proportion is: add 0.1g～0.3g ethyl mandelate in every milliliter of ionic liquid, the lipase consumption is 2.5%～7.5% of an ethyl mandelate quality, in the volume ratio ionic liquid: Tutofusin tris-hydrochloric acid buffer solution=1: 1～8, Tutofusin tris-hydrochloric acid buffer solution pH scope 6～8.5, to be placed in the water bath with thermostatic control shaking table after the reactor sealing then, 50～200 rev/mins of shaking table revolutions, temperature of reaction is 20～60 ℃, 5.0～10 hours reaction times, reaction is finished after-filtration and is dezymotized, filtrate is removed moisture through rotary evaporation in vacuo, the proportioning that adds the 9ml ethyl acetate according to every milliliter of ionic liquid adds ethyl acetate extraction, extraction liquid obtains the solid of amygdalic acid and ethyl mandelate through rotary evaporation, the proportioning that adds the 10ml normal hexane according to every milliliter of ionic liquid adds normal hexane, the ethyl mandelate dissolving is filtered and is promptly got solid product R-(-)-amygdalic acid.
Among the preparation method of R-(-)-amygdalic acid, described ionic liquid is 1-butyl-3-Methylimidazole bromine ([Bmim] [Br]), 1-butyl-3-Methylimidazole chlorine ([Bmim] [Cl]), 1-butyl-3-Methylimidazole hexafluorophosphate ([Bmim] [PF in the above
6]), 1-butyl-3-methyl imidazolium tetrafluoroborate ([Bmim] [BF
4]), 1-octyl group-3-Methylimidazole hexafluorophosphate ([Omim] [PF
6]) or 1-ethyl-3-methyl imidazolium tetrafluoroborate ([Emim] [BF
4]).
Described lipase-catalyzed dose is candida antarctica lipase B (Candida antarctic lipase B), false silk column yeast (Candida Cylinder lipase), false silk rose yeast (Candida Rugosa lipase) or thermophilic fungus lipase (Lipasezyme TL IM).Described lipase-catalyzed dose is the commercial goods biological enzyme.
The invention has the beneficial effects as follows:
1. the present invention makes catalyzer because of having used commercial biological enzyme except that possessing general biological respinse catalytic efficiency height, stereoselectivity is good and reaction conditions is gentle advantage, and the full cell that obtains than fermentation culture has more stable catalytic efficiency as catalyzer; Also because of using ionic liquid as reaction medium, shortened the reaction times greatly, the resolution reaction time only is 5.0-10 hour, and has obtained higher product ee value.Ionic liquid is a kind of organic melting salt that is made of organic cation and inorganic anion, is in a liquid state during in room temperature or near room temperature, has non-volatile, the incomparable advantage of conventional organic solvents such as chemical property stable, environmentally friendly and reusable edible.
2. preparation method's technology of R-of the present invention (-)-amygdalic acid is simple, reaction conditions is gentle, environmental pollution is little; The stereoselectivity height of products therefrom, product ee value are up to 60%, and its productive rate can reach 92%.
Embodiment
Embodiment 1
Getting ethyl mandelate 0.1 restrains in the ground tool plug triangular flask that joins 50 milliliters, again with 1 milliliter of [Bmim] [Br], Tutofusin tris-hydrochloric acid buffer solution of 5 milliliters of pH7.5 (Tris-HCl buffered soln) and 7.5 milligrams of Candida antarctic lipase B enzymes join in this ground tool plug triangular flask, be placed in the water bath with thermostatic control shaking table after the bottleneck sealing with the tetrafluoroethylene seal strip, 150 rev/mins of shaking table revolutions, 50 ℃ of temperature of reaction, 6 hours reaction times, reaction is finished after-filtration and is dezymotized, filtrate is removed moisture through rotary evaporation in vacuo, surplus materials 9ml ethyl acetate extraction, extraction liquid obtains the solid of amygdalic acid and ethyl mandelate through rotary evaporation in vacuo, add the 10ml normal hexane, the ethyl mandelate dissolving is filtered and is promptly got solid product R-(-)-amygdalic acid.
The mensuration of product ee value and productive rate is used high performance liquid chromatography.Chromatographic condition: Agilent 1100 type high performance liquid chromatographs (UV detector), and CHIRALCEL OD-H chromatographic column (Φ 4.6 * 250mm, DAICEL), moving phase is normal hexane: Virahol=90: 10 (V/V), flow velocity is 0.5ml/min, and the detection wavelength is 220nm, 40 ℃ of column temperatures.The amygdalic acid that obtains of reaction adds the trimethylchlorosilane of 200 μ l and excessive methyl alcohol, and 30 ℃, 150r/min reaction obtained methyl mandelate after 24 hours in water bath chader, sample introduction again, sample size 20 μ l.(detection method following examples together)
The ee value of measuring product according to above-mentioned ee value detection method is 60.78%, and productive rate is 58.36%.
Described Tutofusin tris-hydrochloric acid buffer solution is according to " basic Biochemistry Experiment " (Wang Xiuqi, Qin Shuyuan, Gao Tianhui, Yan Huijun volume; Higher Education Publishing House; Second edition; 279) the method preparation in.(buffer preparation method following examples together.)
Embodiment 2
Getting ethyl mandelate 0.3 restrains in the ground tool plug triangular flask that joins 50 milliliters, again with 1 milliliter of [Bmim] [PF
6], Tris-HCl damping fluid and 7.5 milligrams of Candida Cylinder lipase enzymes of 7 milliliters of pH8.5 join in this ground tool plug triangular flask, be placed in the water bath with thermostatic control shaking table after the bottleneck sealing with the tetrafluoroethylene seal strip, 200 rev/mins of shaking table revolutions, 60 ℃ of temperature of reaction, 5 hours reaction times, separation method after reaction is finished obtains product R-(-)-amygdalic acid at last with embodiment 1.
The ee value of measuring product according to ee value detection method among the embodiment 1 is 35.28%, and productive rate is 67.36%.
Embodiment 3
Getting ethyl mandelate 0.2 restrains in the ground tool plug triangular flask that joins 50 milliliters, Tris-HCl damping fluid and 10 milligrams of Candida Cylinder lipase enzymes with 1 milliliter of [Bmim] [Br], 6 milliliters of pH8.5 join in this ground tool plug triangular flask again, be placed in the water bath with thermostatic control shaking table after the bottleneck sealing with the tetrafluoroethylene seal strip, 100 rev/mins of shaking table revolutions, 40 ℃ of temperature of reaction, 8 hours reaction times, the reaction finish after by above-mentioned separation method with embodiment 1, obtain product R-(-)-amygdalic acid at last.
The ee value of measuring product according to above-mentioned ee value detection method is 12.74%, and productive rate is 88.62%.
Embodiment 4
Getting ethyl mandelate 0.2 restrains in the ground tool plug triangular flask that joins 50 milliliters, again with 1 milliliter of [Bmim] [BF
4], Tris-HCl damping fluid and 10 milligrams of Candida antarctic lipase B enzymes of 5 milliliters of pH7.5 join in this ground tool plug triangular flask, be placed in the water bath with thermostatic control shaking table after the bottleneck sealing with the tetrafluoroethylene seal strip, 150 rev/mins of shaking table revolutions, 50 ℃ of temperature of reaction, 6 hours reaction times, the reaction finish after by above-mentioned separation method with embodiment 1, obtain product R-(-)-amygdalic acid at last.
The ee value of measuring product according to above-mentioned ee value detection method is 10.73%, and productive rate is 62.33%.
Embodiment 5
Getting ethyl mandelate 0.1 restrains in the ground tool plug triangular flask that joins 50 milliliters, again with 1 milliliter of [Emim] [BF
4], Tris-HCl damping fluid and 7.5 milligrams of Lipasezyme TL IM enzymes of 5 milliliters of pH6.0 join in this ground tool plug triangular flask, be placed in the water bath with thermostatic control shaking table after the bottleneck sealing with the tetrafluoroethylene seal strip, 150 rev/mins of shaking table revolutions, 30 ℃ of temperature of reaction, 10 hours reaction times, the reaction finish after by above-mentioned separation method with embodiment 1, obtain product R-(-)-amygdalic acid at last.
The ee value of measuring product according to above-mentioned ee value detection method is 10.91%, and productive rate is 92.45%.
Embodiment 6
Getting ethyl mandelate 0.3 restrains in the ground tool plug triangular flask that joins 50 milliliters, again with 1 milliliter of [Omim] [PF
6], Tris-HCl damping fluid and 15 milligrams of Candida Rugosa lipase enzymes of 4 milliliters of pH6.5 join in this ground tool plug triangular flask, be placed in the water bath with thermostatic control shaking table after the bottleneck sealing with the tetrafluoroethylene seal strip, 50 rev/mins of shaking table revolutions, 50 ℃ of temperature of reaction, 6 hours reaction times, the reaction finish after by above-mentioned separation method with embodiment 1, obtain product R-(-)-amygdalic acid at last.
The ee value of measuring product according to above-mentioned ee value detection method is 11.18%, and productive rate is 35.29%.
Embodiment 7
Getting ethyl mandelate 0.2 restrains in the ground tool plug triangular flask that joins 50 milliliters, Tris-HCl damping fluid and 12 milligrams of Lipasezyme TL IM enzymes with 1 milliliter of [Bmim] [Br], 5 milliliters of pH7.5 join in this ground tool plug triangular flask again, be placed in the water bath with thermostatic control shaking table after the bottleneck sealing with the tetrafluoroethylene seal strip, 130 rev/mins of shaking table revolutions, 60 ℃ of temperature of reaction, 7 hours reaction times, the reaction finish after by above-mentioned separation method with embodiment 1, obtain product R-(-)-amygdalic acid at last.
The ee value of measuring product according to above-mentioned ee value detection method is 10.48%, and productive rate is 90.63%.
Embodiment 8
Getting ethyl mandelate 0.3 restrains in the ground tool plug triangular flask that joins 50 milliliters, again with 1 milliliter of [Bmim] [PF
6], Tris-HCl damping fluid and 10 milligrams of Candida antarctic lipase B enzymes of 1 milliliter of pH7.5 join in this ground tool plug triangular flask, be placed in the water bath with thermostatic control shaking table after the bottleneck sealing with the tetrafluoroethylene seal strip, 110 rev/mins of shaking table revolutions, 70 ℃ of temperature of reaction, 9 hours reaction times, the reaction finish after by above-mentioned separation method with embodiment 1, obtain product R-(-)-amygdalic acid at last.
The ee value of measuring product according to above-mentioned ee value detection method is 15.96%, and productive rate is 81.03%.
Embodiment 9
Getting ethyl mandelate 0.2 restrains in the ground tool plug triangular flask that joins 50 milliliters, [the Tris-HCl damping fluid of [Bmim] [Cl], 8 milliliters of pH8.0 and 10 milligrams of Candida Cylinder lipase enzymes join in this ground tool plug triangular flask with 1 milliliter again, be placed in the water bath with thermostatic control shaking table after the bottleneck sealing with the tetrafluoroethylene seal strip, 100 rev/mins of shaking table revolutions, 20 ℃ of temperature of reaction, 7 hours reaction times, the reaction finish after by above-mentioned separation method with embodiment 1, obtain product R-(-)-amygdalic acid at last.
The ee value of measuring product according to above-mentioned ee value detection method is 21.19%, and productive rate is 64.05%.
Claims (1)
1. the preparation method of a R-(-)-amygdalic acid, it is as follows to it is characterized by preparation process:
Getting ethyl mandelate joins in the reactor, add ionic liquid again, Tutofusin tris-hydrochloric acid buffer solution and lipase-catalyzed dose, wherein material proportion is: add 0.1g～0.3g ethyl mandelate in every milliliter of ionic liquid, the lipase consumption is 2.5%～7.5% of an ethyl mandelate quality, in the volume ratio ionic liquid: Tutofusin tris-hydrochloric acid buffer solution=1: 1～8, Tutofusin tris-hydrochloric acid buffer solution pH scope 6～8.5, to be placed in the water bath with thermostatic control shaking table after the reactor sealing then, shaking table revolution 50～200rpm, temperature of reaction is 20～60 ℃, 5.0～10 hours reaction times, reaction is finished after-filtration and is dezymotized, filtrate is removed moisture through rotary evaporation in vacuo, the proportioning that adds the 9ml ethyl acetate according to every milliliter of ionic liquid adds ethyl acetate extraction, extraction liquid obtains the solid of amygdalic acid and ethyl mandelate through rotary evaporation, the proportioning that adds the 10ml normal hexane according to every milliliter of ionic liquid adds normal hexane, the ethyl mandelate dissolving is filtered and is promptly got solid product R-(-)-amygdalic acid;
Wherein, ionic liquid recited above is 1-butyl-3-Methylimidazole bromine, 1-butyl-3-Methylimidazole chlorine, 1-butyl-3-Methylimidazole hexafluorophosphate, 1-butyl-3-methyl imidazolium tetrafluoroborate, 1-octyl group-3-Methylimidazole hexafluorophosphate or 1-ethyl-3-methyl imidazolium tetrafluoroborate;
Described lipase-catalyzed dose is lipase-catalyzed dose and is candida antarctica lipase B (Candida antarcticlipase B), false silk column yeast fat enzyme (Candida Cylinder lipase), false silk rose yeast fat enzyme (Candida Rugosa lipase) or thermophilic fungus lipase (Lipasezyme TL IM).
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| CN101974604B (en) * | 2010-11-11 | 2013-04-17 | 南京工业大学 | Method for preparing paroxetine intermediate through enzymatic resolution in ionic liquid |
| CN102719496B (en) * | 2012-06-21 | 2014-08-06 | 浙江工业大学 | Preparation method of (S)-(+)-ethyl mandelate by microbial transformed ethyl benzoylformate |
| CN105349507B (en) * | 2015-12-15 | 2018-09-28 | 中国科学院南海海洋研究所 | A kind of lipase LIPDa6 and its encoding gene and application |
| CN106086090B (en) * | 2016-07-19 | 2019-05-28 | 浙江工业大学 | A kind of method that two-step microbial conversion method prepares R-MA |
| CN108546720B (en) * | 2017-10-31 | 2021-09-03 | 湖南理工学院 | Method for preparing (S) -2-phenylbutyric acid through stereoselective enzymatic hydrolysis |
| CN109321609B (en) * | 2018-10-29 | 2020-08-04 | 南京工业大学 | Method for preparing R-mandelic acid by using microchannel reaction device |
| CN109628508B (en) * | 2018-12-10 | 2021-08-10 | 华南理工大学 | Method for splitting chiral substance by enzyme method |
| CN110590973B (en) * | 2019-10-28 | 2021-11-05 | 淮北云端文化传媒有限公司 | Cyclodextrin derivatives and process for producing the same |
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| CN1840671A (en) * | 2006-01-18 | 2006-10-04 | 江南大学 | Process for preparing (R)-mandelic acid by microbial asymmetric resolution |
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| CN1840671A (en) * | 2006-01-18 | 2006-10-04 | 江南大学 | Process for preparing (R)-mandelic acid by microbial asymmetric resolution |
Non-Patent Citations (4)
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