CN101085990B - Method for preparing chiral aryl secondary alcohol - Google Patents
Method for preparing chiral aryl secondary alcohol Download PDFInfo
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- CN101085990B CN101085990B CN200710042880A CN200710042880A CN101085990B CN 101085990 B CN101085990 B CN 101085990B CN 200710042880 A CN200710042880 A CN 200710042880A CN 200710042880 A CN200710042880 A CN 200710042880A CN 101085990 B CN101085990 B CN 101085990B
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- secondary alcohol
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- alcohol
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Abstract
The invention discloses a method for preparing chiral aromatic secondary alcohol. It comprises following steps: a. oxiding racemic aromatic secondary alcohol in beta- cyclodextrin containing water phase into relevant aromatic acetone by using chemical oxidant, reaction time is 6- 24 hours; b. adding reducant additive for reaction for 30 minutes, adding basic substance to moderate pH to 7.0; c. putting the quiescent cell of Rhodotorula sp.)ECU316-1 CGMCC NO.1735 into said solution to catalyze and oxide aromatic acetone into (S)- aromatic secondary alcohol; d. isolating and purifying reaction solution and getting target product. The invention combines chemical and biological method to converse racemic aromatic secondary alcohol to chiral aromatic secondary alcohol with high optical purity (above 99%). It is characterized by temperate reaction condition, simple operation, easy to prepare catalysy and good industrial development prospect.
Description
Technical field
The present invention relates to the preparation method of aryl alcohol, relate to a kind of in particular by the method for chemistry with biocatalysis combined preparation chiral aryl secondary alcohol.
Background technology
Chiral alcohol is the important chipal compounds of a class, can be used as important chiral intermediate and raw material and is applied to the synthetic of medicine and fine chemicals.Its synthetic method generally can be divided into two kinds: the asymmetric reduction of the kinetic resolution of raceme alcohol and precursor ketone (method that comprises biocatalysis and chemical catalysis).The theoretical yield that general dynamics splits has only 50%, and the method for asymmetric reduction can be in theory obtains optically pure chiral alcohol compound with 100% productive rate.But the easier acquisition of the alcohol of racemization in some cases, and precursor ketone is difficult for obtaining and costing an arm and a leg.In this case, as target substrates, exploring the novel method that obtains 100%ee value chiral alcohol with 100% theoretical yield just becomes the interested goal in research of people with the alcohol of racemization.From current bibliographical information, mainly containing two kinds of methods reaches and cause this target: one is Dynamic Kinetic Resolution, mainly be the racemization that in organic phase, utilizes a substrate alcohol of in-situ coupling in the process of transesterification resolution reaction of lytic enzyme catalytic alcohol, the catalysis racemization be generally the heavy metal coordination catalyst.Another kind method is to utilize one or both microorganisms to go racemization to change the chiral alcohol of single configuration into the alcohol of racemization, and it is realized by two oxydo-reductase of selectivity complementary in the microbe are coupled.This process can realize that the theoretical yield with 100% prepares optically pure chiral alcohol.Yet how finding fast and effectively at specific substrate suitable can catalysis goes the microbial strains of racemization reaction to become the key that can this process successful.Generally speaking, it is actually rare that the microorganism alcohol oxidase of highly-solid selectively is reported, the micro-reduction enzyme then has a lot of reports, for example, Tetrahedron:Asymmetry 2006,17:1769-1774, Yang Wei etc. once reported rhodotorula Rhodotorula sp.AS2.2241, and a series of aryl ketones of reduction that can highly-solid selectively are the aryl secondary alcohol of chirality.
Liquid alcohol oxidation system aldehydes or ketones is very important organic chemical reactions process, has a wide range of applications in the production of extensive chemical industry production and fine chemical product.In recent years, because the raising that the energy, environment etc. require, gentle, the alcohol compound oxidizing reaction becomes the focus of research gradually efficiently.Also successfully develop the oxidation reaction process of a series of gentlenesses, comprising the mild oxidation reaction system in aqueous media (Dorit, Adv.Synth.Catal.2004,346,339-345).
At above-mentioned prior art background, we think might be converted into (S)-aryl alcohol accordingly with the aryl alcohol of racemization with 100% theoretical yield with chemical oxidation and enzyme process reduction combination, split the theoretical limit that obtains 50% chiral aryl alcohol thereby break through traditional power, have application promise in clinical practice.(Adv.Synth.Catal.2006 such as Busto, 348,2626-2632) reported that recently a kind of chemical oxidation is combined with biological reducing prepares 1-(3-pyridyl) alcoholic acid method, this method is to utilize chromium trioxide at first the alcohol of racemization to be oxidized to corresponding ketone for oxygenant in acetone, utilizes bread yeast that ketone is reduced to chiral alcohol afterwards again.So just realized by the conversion of the alcohol of racemization to chiral alcohol.But this method has following shortcoming: at first, the first step chemical oxidation reaction carries out in organic solvent, and is obviously unfavorable to environment; Secondly, will pass through being used further to second behind the pure product that precipitation, filtration, washing and a plurality of steps of fractionation by distillation purifying obtain ketone and going on foot biological reducing after the first step oxidizing reaction finishes, the entire operation process is more loaded down with trivial details.Therefore be necessary to develop the method for a kind of gentleness chemo-enzymatic process combined preparation chiral alcohol efficient, simple to operate.
Summary of the invention
Technical problem to be solved by this invention provide a kind of by racemization the aryl alcohol after chemical reaction and biocatalysis with the method for produced in high yields chiral aryl alcohol.
The technical solution used in the present invention: the present invention is based on that such imagination realizes, promptly at first utilize a kind of chemical oxidizing agent under the mild conditions in aqueous media high chemo-selective ground oxidation racemization aryl alcohol be corresponding aryl ketones, directly add a small amount of additive then and eliminate the remaining micro-oxygenant of the first step reaction, adding highly-solid selectively reductase enzyme or cell catalysis the first step oxidation products aryl ketones asymmetric reduction are chiral aryl alcohol in this reaction mixture again, by said process, can realize that the chemical-biological combined method changes the raceme aryl alcohol into the chiral aryl alcohol of single configuration.A kind of method for preparing chiral aryl secondary alcohol comprises the following steps:
A. utilize chemical oxidizing agent at the aqueous phase that adds beta-cyclodextrin the raceme aryl secondary alcohol to be oxidized to corresponding aryl ketones, the reaction times is 6～24 hours, and the general structure of wherein said raceme aryl secondary alcohol is: R
1CH (OH) CH
3, substituent R
1For-C
6H
4X, substituent X wherein is selected from-H ,-CH
3,-F ,-Cl ,-Br ,-I ,-OH ,-NH
2Or-NO
2One of them;
B. in above-mentioned solution, added the reductibility additive reaction 30 minutes, add alkaline matter again, the pH value to 7.0 of conditioned reaction liquid, wherein said reductibility additive be selected from Sulfothiorine, S-WAT or sodium bisulfite one of them;
C. the resting cell of rhodotorula (Rhodotorula sp.) ECU316-1 CGMCC NO.1735 being placed above-mentioned pH value is 7.0 reaction solution, and the asymmetric reduction of the above-mentioned oxidation products aryl ketones of catalysis is (S)-aryl secondary alcohol;
D. reaction solution obtains target product optical purity (S)-aryl secondary alcohol after separation and purification.
Chemical oxidizing agent described in the step a is selected from and is N-bromo-succinimide (NBS) or 2-iodoxy phenylformic acid (IBX).
Alkaline matter described in the step b is selected from sodium hydroxide or dipotassium hydrogen phosphate.
Temperature of reaction is controlled to be 20～50 ℃ in the step c catalyzed reaction, and the reaction times is 12～72 hours.
Beneficial effect of the present invention, the present invention has designed the method for a kind of novelty " two-step approach; treat different things alike ", and promptly at first utilizing the oxidation racemization alcohol of a kind of chemical oxidizing agent (for example can at room temperature, in the aqueous media) high chemo-selective under mild conditions is corresponding ketone; Next adds the reductibility additive and reacts the injury of the micro-oxygenant of remnants to enzyme or cell with the abundant elimination the first step, forms the extraordinary reaction system of a kind of biocompatibility, so just can give full play to the catalytic performance of biological catalyst; The asymmetric reduction that directly adds highly-solid selectively oxydo-reductase catalysis of carbonyl afterwards again in this reaction mixture is a chiral alcohol.By said process, can reduce the usage quantity of organic solvent greatly, realize that very easily " chemo-enzymatic process " combination of " treating different things alike " changes raceme into the chiral alcohol of single configuration.The method that the present invention adopts the combination of above-mentioned chemical-biological method changes the raceme aryl secondary alcohol chiral aryl secondary alcohol of high-optical-purity (＞99%) into, and reaction conditions gentleness, catalyzer are easy to preparation, have certain industrial application DEVELOPMENT PROSPECT.
Embodiment
Below by embodiment the present invention is described in further detail: a kind of method for preparing chiral aryl secondary alcohol, comprise the following steps: that a. utilizes chemical oxidizing agent at the aqueous phase that adds beta-cyclodextrin the raceme aryl secondary alcohol to be oxidized to corresponding aryl ketones, reaction times is 6～24 hours, and the general structure of wherein said raceme aryl secondary alcohol is: R
1CH (OH) CH
3, substituent R
1For-C
6H
4X, substituent X wherein is selected from-H ,-CH
3,-F ,-Cl ,-Br ,-I ,-OH ,-NH
2Or-NO
2One of them; B. in above-mentioned solution, added the reductibility additive reaction 30 minutes, add alkaline matter again, the pH value to 7.0 of conditioned reaction liquid, wherein said reductibility additive be selected from Sulfothiorine, S-WAT or sodium bisulfite one of them; C. the resting cell of rhodotorula (Rhodotorula sp.) ECU316-1 CGMCC NO.1735 being placed above-mentioned pH value is 7.0 reaction solution, and the asymmetric reduction of the above-mentioned oxidation products aryl ketones of catalysis is (S)-aryl secondary alcohol; D. reaction solution obtains target product optical purity (S)-aryl secondary alcohol after separation and purification.Chemical oxidizing agent described in the step a is selected from and is N-bromo-succinimide (NBS) or 2-iodoxy phenylformic acid (IBX).Alkaline matter described in the step b is selected from sodium hydroxide or dipotassium hydrogen phosphate.Temperature of reaction is controlled to be 20～50 ℃ in the step c catalyzed reaction, and the reaction times is 12～72 hours.The mol ratio of chemical oxidizing agent described in the step a and described aryl secondary alcohol can be 1: 1～1: 10 for the mol ratio of beta-cyclodextrin described in 1: 1～5: 1 step a and described aryl secondary alcohol.The concentration of red yeast cell described in the step c can be 10～100g (weight in wet base)/L.
Embodiment 1
The chemical oxidation of aryl secondary alcohol (is example with the 1-phenylethyl alcohol).In the 15ml deionized water, add the 1mmol beta-cyclodextrin, be heated to 50～60 ℃ and make it molten entirely, slowly add the methanol solution 1ml of 1mmol racemization 1-phenylethyl alcohol, to be cooled after room temperature, slowly add NBS 1 mmol, react 24h under the room temperature.The transformation efficiency of 1-phenylethyl alcohol is greater than 99%.
Embodiment 2
The chemical oxidation of aryl secondary alcohol (is example with the 1-phenylethyl alcohol).In the 15ml deionized water, add the 0.1mmol beta-cyclodextrin, slowly add the methanol solution 1ml of 1mmol racemization 1-phenylethyl alcohol, to be cooled after room temperature, slowly add IBX 1.2mmol, react 24h under the room temperature.The transformation efficiency of 1-phenylethyl alcohol is greater than 99%.
Embodiment 3
The fermentation culture of rhodotorula (Rhodotorula sp.) ECU316-1 CGMCC NO.1735.Culture medium prescription is: glucose 15.0g/L, yeast extract paste 5.0g/L, peptone 5.0g/L, KH
2PO
41.0g/L, K
2HPO
43H
2O 0.5g/L, NaCl 1.0g/L, MgSO
40.5g/L pH 7.0.Get the rhodotorula slant strains of 4 ℃ of preservations, picking one ring is seeded to the 250ml that the 50ml substratum is housed and shakes in the bottle, and under 30 ℃, 48h, centrifugal cell harvesting are cultivated in the 160rpm jolting.The fermentation broth enzyme vigor is about 20～40U/L, and the about 10～20g of cell concn (weight in wet base)/L, the enzyme activity of unit cell are the 2U/g wet cell.Cell viability unit is defined as: at 30 ℃, under the condition of pH 7.0, the reduction of per minute catalysis methyl phenyl ketone generates the required cell concentration of 1.0 μ mol 1-phenylethyl alcohols.
Embodiment 4
Chemical oxidation and biocatalysis reductive coupling preparation (S)-1-phenylethyl alcohol.According to embodiment 1 described method, utilize NBS with the oxidation of 1mmol 1-phenylethyl alcohol, in reaction solution, add 0.1mmol Sulfothiorine behind the reaction 24h and continue reaction 30 minutes, the pH value that adds the dipotassium hydrogen phosphate 0.3ml accent reaction solution of 1mol/L then is 7.0, and add PH7.0 potassium phosphate salt buffered soln (0.1mol/L) and make reaction volume be diluted to 60ml, add the red yeast cell that 4 methods according to embodiment 3 that restrain weight in wet bases are cultivated afterwards, reaction mixture is at 30 ℃, jolting reaction on the constant temperature shaking table of 160r/min, intermittent sampling is with ethyl acetate extraction, with the enantiomeric excess value and the productive rate of chirality gas-chromatography (chromatographic column is β-DEX120 kapillary chirality gas chromatographic column) assay products.React after 48 hours, use equal-volume ethyl acetate extraction reaction solution 3 times, the combined ethyl acetate phase adds anhydrous sodium sulfate drying and spends the night, decompression and solvent recovery, and residuum carries out column chromatography purification.(S)-the analysis productive rate of 1-phenylethyl alcohol is 95% (separation yield is 75%), ee＞99%.
Embodiment 5
Chemical oxidation and biocatalysis reductive coupling preparation (S)-1-(2-fluorophenyl) ethanol.Method according to embodiment 2 described chemical oxidations, utilize IBX with 1mmol 1-(2-fluorophenyl) oxidation of ethanol, in reaction solution, add the 0.1mmol S-WAT behind the reaction 24h and continue reaction 30 minutes, the pH value that adds the aqueous sodium hydroxide solution 0.25ml accent reaction solution of 1mol/L then is 7.0, and add PH7.0 potassium phosphate salt buffered soln (0.1mol/L) and make reaction volume be diluted to 60ml, add the red yeast cell that 4 methods according to embodiment 3 that restrain weight in wet bases are cultivated afterwards, reaction mixture is at 30 ℃, jolting reaction on the constant temperature shaking table of 160r/min, intermittent sampling is with ethyl acetate extraction, with the enantiomeric excess value and the productive rate of chirality gas-chromatography (chromatographic column is β-DEX120 kapillary chirality gas chromatographic column) assay products.React after 36 hours, use equal-volume ethyl acetate extraction reaction solution 3 times, the combined ethyl acetate phase adds anhydrous sodium sulfate drying and spends the night, decompression and solvent recovery, and residuum carries out column chromatography purification.(S)-1-(2-fluorophenyl) alcoholic acid analysis productive rate is 96% (separation yield is 82%), ee＞99%.
Embodiment 6
Chemical oxidation and biocatalysis reductive coupling preparation (S)-1-(3-chloro-phenyl-) ethanol.Method according to embodiment 1 described chemical oxidation, utilize NBS with 1mmol 1-(3-chloro-phenyl-) oxidation of ethanol, in reaction solution, add 0.1mmol Sulfothiorine behind the reaction 12h and continue reaction 30 minutes, the pH value that adds the dipotassium hydrogen phosphate 0.3ml accent reaction solution of 1mol/L then is 7.0, add the red yeast cell that 4 methods according to embodiment 3 that restrain weight in wet bases are cultivated afterwards, reaction mixture is at 30 ℃, jolting reaction on the constant temperature shaking table of 160r/min, intermittent sampling is with ethyl acetate extraction, with the enantiomeric excess value and the productive rate of chirality gas-chromatography (chromatographic column is β-DEX120 kapillary chirality gas chromatographic column) assay products.React after 36 hours, use equal-volume ethyl acetate extraction reaction solution 3 times, the combined ethyl acetate phase adds anhydrous sodium sulfate drying and spends the night, decompression and solvent recovery, and residuum carries out column chromatography purification.(S)-1-(3-chloro-phenyl-) alcoholic acid analysis productive rate is 93% (separation yield is 80%), ee＞99%.
Above said content only is the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.
Claims (2)
1. a method for preparing chiral aryl secondary alcohol comprises the following steps:
A. utilize N-bromo-succinimide NBS or 2-iodoxy phenylformic acid IBX at the aqueous phase that adds beta-cyclodextrin the raceme aryl secondary alcohol to be oxidized to corresponding aryl ketones, the reaction times is 6～24 hours, and the general structure of wherein said raceme aryl secondary alcohol is: R
1CH (OH) CH
3, substituent R
1For-C
6H
4X, substituent X wherein is selected from-H ,-CH
3,-F ,-Cl ,-Br ,-I ,-OH ,-NH
2Or-NO
2One of them;
B. in above-mentioned solution, added the reductibility additive reaction 30 minutes, add sodium hydroxide or dipotassium hydrogen phosphate again, the pH value to 7.0 of conditioned reaction liquid, wherein said reductibility additive be selected from Sulfothiorine, S-WAT or sodium bisulfite one of them;
C. the resting cell of rhodotorula (Rhodotorula sp.) ECU316-1CGMCC NO.1735 being placed above-mentioned pH value is 7.0 reaction solution, and the above-mentioned oxidation products aryl ketones of catalysis asymmetric reduction is (S)-aryl secondary alcohol;
D. reaction solution obtains target product optical purity (S)-aryl secondary alcohol after separation and purification.
2. according to the described method for preparing chiral aryl secondary alcohol of claim 1, it is characterized in that: temperature of reaction is controlled to be 20～50 ℃ in the step c catalyzed reaction, and the reaction times is 12～72 hours.
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| CN101085990B true CN101085990B (en) | 2010-05-19 |
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| CN101240299B (en) * | 2008-03-17 | 2012-04-18 | 江南大学 | Method for preparing optical activity alcohol by using yeast cell to catalytically reduce aromatic ketone |
| CN101570775B (en) * | 2008-05-04 | 2012-03-21 | 上海医药工业研究院 | Method for preparing 3 beta, 7 beta-dihydroxy-15 beta, 16 beta-methylene-5-androstene-17-ketone by microbial transformation method |
| CN104561136B (en) * | 2014-12-08 | 2018-07-06 | 上海应用技术学院 | A kind of method that raceme aryl vicinal diamines are converted into chiral aryl vicinal diamines |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1869197A (en) * | 2006-06-29 | 2006-11-29 | 华东理工大学 | Red yeast cell and method of producing optically pure chiral tertiary alcohol |
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| CN1869197A (en) * | 2006-06-29 | 2006-11-29 | 华东理工大学 | Red yeast cell and method of producing optically pure chiral tertiary alcohol |
Non-Patent Citations (4)
| Title |
|---|
| E. Busto 等.Enantioselective Synthesis of 4-(Dimethylamino)pyridinesthrough a Chemical Oxidation-Enzymatic ReductionSequence. Application in Asymmetric Catalysis.Advanced Synthesis and Catalysis348 18.2006,348(18),2626-2632. |
| E.Busto 等.Enantioselective Synthesis of 4-(Dimethylamino)pyridinesthrough a Chemical Oxidation-Enzymatic ReductionSequence. Application in Asymmetric Catalysis.Advanced Synthesis and Catalysis348 18.2006,348(18),2626-2632. * |
| 刘湘等.酵母细胞催化芳香酮的不对称还原反应.催化学报27 1.2006,27(1),20-24. |
| 刘湘等.酵母细胞催化芳香酮的不对称还原反应.催化学报27 1.2006,27(1),20-24. * |
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