CN102517342A - Method for catalytic synthesis of R-2-bromo-1-aryl alcohol using carrot root whole cells - Google Patents
Method for catalytic synthesis of R-2-bromo-1-aryl alcohol using carrot root whole cells Download PDFInfo
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Abstract
The invention discloses a method for catalytic synthesis of R-2-bromo-1-aryl alcohol using carrot root whole cells. As shown in the formula, the method uses carrot root whole cells as a biocatalyst which catalyzes asymmetric reduction of alpha-bromo-aryl ethyl ketone under a proper condition to synthesize the corresponding R-2-bromo-1-aryl alcohol, the enantiomer excess is over 82.5%, and in the formula, R is H, p-CH3, p-OCH3, p-Cl, p-NO2, m-Cl and other different substituent groups. The chiral halogenated alcohol R-2-bromo-1-aryl alcohol synthesized using the method of the invention is an important chiral synthesis building block, and can also be transformed to chiral synthesis building block with alpha site being another group, so that R-2-bromo-1-aryl alcohol has high application value in synthesis of medicines, pesticides, additives and other chiral compounds.
Description
Technical field
The present invention relates to the technical field that the biocatalysis method prepares optical activity alcohol, particularly a kind of novel preparation method of optical activity R-2-bromo-1-aryl alcohol.
Background technology
In recent decades, asymmetric synthesis research has obtained development rapidly because of this great value in practical application of its synthetic product.The alpha-brominated aromatic alcohol of optical activity is one type of important chiral building block; Can obtain of the synthetic building block of α position through some simple chemical conversions, therefore aspect chipal compounds such as medicine, agricultural chemicals, additive synthetic, bigger using value arranged for the chirality aromatic alcohol of other group.
Chipal compounds except by some physical methods with outside the body that disappears chemical process is separated obtains, major part is to take asymmetric synthesis to obtain, and comprises asymmetric chemical catalysis synthesis method and asymmetric biocatalysis synthesis method, the both has certain application.It is one of research focus of green chemical industry as the process that catalyzer carries out asymmetric chemical conversion that wherein asymmetric biocatalysis is promptly utilized enzyme or biological organism (full cell, organoid, tissue etc.).The asymmetric conversion of biocatalysis carbonyl containing compound occupies very consequence in asymmetric synthesis, wherein the vegetable cell asymmetric reduction that is used for the catalyzing ketone compound is that research early also is one type of more reaction of research to generate corresponding chiral alcohol.The advantage that has full cell response with plant as catalyzer; Promptly majority need not carry out the purification of enzyme; Need not add the expensive coenzyme and the energy that keeps reaction to carry out, the source is abundant, cost is low, efficient is high and the product enantio-selectivity is good and advantage such as reaction process environmental friendliness.At present, the substrate scope of research is more and more wider, as the kind of the plant of catalyzer also in continuous increase.
Existing research report about the alpha-brominated aromatic alcohol of biocatalysis synthesis of optically active.Document (Letters in Organic Chemistry; 2006; 3,613-618) reported that a kind of mikrobe (C.lunata) can become corresponding R-2-bromo-1-phenylethyl alcohol and S-2-bromo-1-p-nitrophenyl ethanol, ee value＞94% by the alpha-brominated methyl phenyl ketone of catalysis with alpha-brominated p-nitroacetophenone; Document (Tetrahedron:Asymmetry, 2006,17:2287-2291) the then contrast through different plant tissues, the Radix Dauci Sativae root cells has unique advantages aspect also in that the catalysis of carbonyl compound is asymmetric.The biological catalyst of the alpha-brominated aromatic alcohol of biocatalysis synthesis of optically active mainly concentrates on microorganism field at present, comprises yeast, fungi and bacterium etc.The whole cell of plant is applied to the synthetic of the alpha-brominated aromatic alcohol of optical activity as biological catalyst then not to appear in the newspapers.Consider the meliority of Radix Dauci Sativae aspect the catalysis of carbonyl compound, it is the process for catalytic synthesis that the whole cell of Radix Dauci Sativae is applied to the alpha-brominated aromatic alcohol of optical activity that the present invention has introduced a kind of new bio catalyzer.
Summary of the invention
The purpose of this invention is to provide the method that the alpha-brominated aryl methyl ketone of a kind of vegetable cell catalytic reduction prepares optical activity R-2-bromo-1-aryl alcohol; Substrate to different is selected proper reaction conditions for use, can obviously improve the transformation efficiency of the alpha-brominated aryl methyl ketone of substrate and the enantiomeric excess value of corresponding product R-2-bromo-1-aryl alcohol.
The whole cell of plant of the present invention is selected the Radix Dauci Sativae root cells for use, and the technical scheme of employing is following:
(1) the whole cell activation in reaction medium of plant: reaction medium is pH 6.4～7.2 phosphate buffer solns; The whole concentration of cell in medium of Radix Dauci Sativae root is 100～300g/L; Activation temperature is 24～36 ℃, and hunting speed is 120r/min during activation, and soak time is 0.2～1h;
(2) add alpha-brominated aryl methyl ketone in the system after activation; Carry out the bioconversion reaction of the alpha-brominated aryl methyl ketone of catalytic asymmetric reduction; The alpha-brominated aryl methyl ketone concentration of substrate is 0.1～1.0g/L, and the whole cell consumption of plant is: the reaction medium of 50mL adds the whole cell of 5～15g plant, and temperature of reaction is 28～36 ℃; Hunting speed is 120r/min during reaction, and the reaction times is 24～36h;
(3) reaction finishes the back with solvent ethyl acetate extracting and separating reactant, analyzing and testing gained optical activity R-2-bromo-1-aryl alcohol.Reaction finishes the back with an amount of solvent ethyl acetate extraction back spinning; Extraction liquid concentrates the back and utilizes the high performance liquid chromatograph that Chiralcel OB-H chiral column or Chiralcel OD-H chiral column are housed to detect, and calculates the enantiomeric excess value of substrate conversion efficiency and product.
Beneficial effect of the present invention: the present invention utilizes the whole cell of plant as the alpha-brominated aryl methyl ketone of biological catalyst catalytic asymmetric reduction.Utilize the present invention when concentration of substrate is 0.1～1.0g/L; Select different vegetable cell catalytic conditions according to different substrates; The transformation efficiency of the alpha-brominated aryl methyl ketone of substrate reaches more than 61.5%; The enantiomeric excess value of product optical activity R-2-bromo-1-aryl alcohol reaches more than 82.5%; The R-2-bromo-1-aryl alcohol that optical purity is high is the synthetic intermediate of a lot of natural products and the synthetic precursor of chiral drug, and use be cheap plant as catalyzer, so the method that the present invention prepares optical activity R-2-bromo-1-aryl alcohol has higher using value.
Embodiment
Following embodiment can make those skilled in the art comprehensively understand the present invention, but does not limit the present invention in any way.
Embodiment 1: in an Erlenmeyer flask, add the phosphate buffered saline buffer 50mL of 0.1mol/L, pH=7.0 and the Radix Dauci Sativae root cells of 10g chopping; (120r/min) 20min vibrates in the constant temperature water bath shaker under 32 ℃ of conditions; Make the activation of Radix Dauci Sativae root cells; Add the alpha-brominated methyl phenyl ketone of 0.02g (0.4g/L) then, oscillatory reaction 24h under uniform temp.After reaction finishes; 40mL ETHYLE ACETATE is joined in the reaction solution; Spinning behind the oscillation extraction; Tell extraction liquid, extraction liquid concentrates the back and detects with the high performance liquid chromatograph that Chiralcel OD-H chiral column is housed, and the enantiomeric excess value of the transformation efficiency of the alpha-brominated methyl phenyl ketone of substrate and product R-2-bromo-1-phenylethyl alcohol is respectively 83.6% and 88.5%.
Embodiment 2: in an Erlenmeyer flask, add the phosphate buffered saline buffer 50mL of 0.1mol/L, pH=6.4 and the Radix Dauci Sativae root cells of 10g chopping; (120r/min) 20min vibrates in the constant temperature water bath shaker under 32 ℃ of conditions; Make the activation of Radix Dauci Sativae root cells; Add the alpha-brominated p-methyl aceto phenone of 0.02g (0.4g/L) then, oscillatory reaction 28h under uniform temp.After reaction finishes; 40mL ETHYLE ACETATE is joined in the reaction solution; Spinning behind the oscillation extraction; Tell extraction liquid, extraction liquid concentrates the back and detects with the high performance liquid chromatograph that Chiralcel OD-H chiral column is housed, and the transformation efficiency of the alpha-brominated p-methyl aceto phenone of substrate and product R-2-bromo-1-are respectively 63.1% and 88.9% to methylbenzene alcoholic acid enantiomeric excess value.
Embodiment 3: the phosphate buffered saline buffer 50mL and the 15g Radix Dauci Sativae root cells that in an Erlenmeyer flask, add 0.1mol/L, pH=6.4; (120r/min) 20min vibrates in the constant temperature water bath shaker under 30 ℃ of conditions; Make the activation of Radix Dauci Sativae root cells; Add the alpha-brominated p-methoxy-acetophenone of 0.02g (0.4g/L) then, oscillatory reaction 30h under uniform temp.After reaction finishes; 40mL ETHYLE ACETATE is joined in the reaction solution; Spinning behind the oscillation extraction; Tell extraction liquid, extraction liquid concentrates the back and detects with the high performance liquid chromatograph that Chiralcel OD-H chiral column is housed, and the transformation efficiency of the alpha-brominated p-methoxy-acetophenone of substrate and product R-2-bromo-1-are respectively 61.5% and 87.7% to anisole alcoholic acid enantiomeric excess value.
Embodiment 4: the phosphate buffered saline buffer 50mL and the 10g Radix Dauci Sativae root cells that in an Erlenmeyer flask, add 0.1mol/L, pH=7.0; (120r/min) 30min vibrates in the constant temperature water bath shaker under 32 ℃ of conditions; Make the activation of Radix Dauci Sativae root cells; Add the alpha-brominated parachloroacetophenone of 0.025g (0.5g/L) then, oscillatory reaction 34h under uniform temp.After reaction finishes; 40mL ETHYLE ACETATE is joined in the reaction solution; Spinning behind the oscillation extraction; Tell extraction liquid, extraction liquid concentrates the back and detects with the high performance liquid chromatograph that Chiralcel OB-H chiral column is housed, and the transformation efficiency of the alpha-brominated parachloroacetophenone of substrate and product R-2-bromo-1-are respectively 76.3% and 84.3% to the enantiomeric excess value of chlorophenethylol.
Embodiment 5: the phosphate buffered saline buffer 50mL and the 10g Radix Dauci Sativae root cells that in an Erlenmeyer flask, add 0.1mol/L, pH=7.0; (120r/min) 30min vibrates in the constant temperature water bath shaker under 30 ℃ of conditions; Make the activation of Radix Dauci Sativae root cells; Add the alpha-brominated m chloroacetophenone of 0.025g (0.5g/L) then, oscillatory reaction 28h under uniform temp.After reaction finishes; 40mL ETHYLE ACETATE is joined in the reaction solution; Spinning behind the oscillation extraction; Tell extraction liquid, extraction liquid concentrates the back and detects with the high performance liquid chromatograph that Chiralcel OB-H chiral column is housed, and the enantiomeric excess value of chlorophenethylol is respectively 77.5% and 84.1% between the transformation efficiency of the alpha-brominated m chloroacetophenone of substrate and product R-2-bromo-1-.
Embodiment 6: the phosphate buffered saline buffer 50mL and the 10g Radix Dauci Sativae root cells that in an Erlenmeyer flask, add 0.1mol/L, pH=7.0; (120r/min) 30min vibrates in the constant temperature water bath shaker under 32 ℃ of conditions; Make the activation of Radix Dauci Sativae root cells; Add the alpha-brominated p-nitroacetophenone of 0.025g (0.5g/L) then, oscillatory reaction 34h under uniform temp.After reaction finishes; 40mL ETHYLE ACETATE is joined in the reaction solution; Spinning behind the oscillation extraction; Tell extraction liquid, extraction liquid concentrates the back and detects with the high performance liquid chromatograph that Chiralcel OB-H chiral column is housed, and the transformation efficiency of the alpha-brominated p-nitroacetophenone of substrate and product R-2-bromo-1-p-nitrophenyl alcoholic acid enantiomeric excess value are respectively 82.3% and 82.5%.
Claims (3)
1. the preparation method of chirality halohydrin R-2-bromo-1-aryl alcohol is characterized in that: utilize the whole cell of Radix Dauci Sativae root to prepare R-2-bromo-1-aryl alcohol as the alpha-brominated aryl methyl ketone of biological catalyst catalytic asymmetric reduction, reaction formula is following:
In the formula, R is respectively H, p-CH
3, p-OCH
3, p-Cl, p-NO
2, different substituting group such as m-Cl.
Chiral intermediate R-2-bromo-1-aryl alcohol preparation method of the present invention is following:
(1) the whole cell activation in reaction medium of Radix Dauci Sativae root: reaction medium is pH 6.0～7.2 phosphate buffer solns; The whole concentration of cell in medium of Radix Dauci Sativae root is 100～300g/L; Activation temperature is 28～36 ℃, and hunting speed is 120r/min during activation, and soak time is 0.2～1h;
(2) add alpha-brominated aryl methyl ketone in the system after activation; Carry out the bioconversion reaction of the alpha-brominated aromatic ketone of catalytic asymmetric reduction; The alpha-brominated aryl methyl ketone concentration of substrate is 0.1～1.0g/L, and the whole cell consumption of Radix Dauci Sativae root is: add the whole cell of 100～300g Radix Dauci Sativae root in the reaction medium of every 1L, temperature of reaction is 28～36 ℃; Hunting speed is 120r/min during reaction, and the reaction times is 24～36h;
(3) reaction finishes the back with solvent ethyl acetate extracting and separating reactant, analyzing and testing gained optical activity R-2-bromo-1-aryl alcohol.
2. according to the said method of claim 1; It is characterized in that substrate is alpha-brominated aryl methyl ketone; Be respectively alpha-brominated methyl phenyl ketone, alpha-brominated p-methyl aceto phenone, alpha-brominated p-methoxy-acetophenone, alpha-brominated m chloroacetophenone or alpha-brominated parachloroacetophenone or alpha-brominated p-nitroacetophenone, product is optically active R-2-bromo-1-aryl alcohol, be respectively R-2-bromo-1-phenylethyl alcohol, R-2-bromo-1-to methylbenzene ethanol, R-2-bromo-1-to chlorophenethylol, R-2-bromo-1-between anisole ethanol, R-2-bromo-1-to chlorophenethylol or R-2-bromo-1-p-nitrophenyl ethanol.
3. according to the said method of claim 1, it is characterized in that biological catalyst is the whole cell of Radix Dauci Sativae root.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104531785A (en) * | 2014-12-09 | 2015-04-22 | 江南大学 | Method for catalytically synthesizing ethyl (R)-4-aryl-3-hydroxybutyrate by utilizing potato whole cell |
Citations (2)
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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 |
| CN101696433A (en) * | 2009-10-13 | 2010-04-21 | 常熟理工学院 | Method for catalyzing organic reduction reaction through plant biocatalyst |
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Patent Citations (2)
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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 |
| CN101696433A (en) * | 2009-10-13 | 2010-04-21 | 常熟理工学院 | Method for catalyzing organic reduction reaction through plant biocatalyst |
Non-Patent Citations (3)
| Title |
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| 《Tetrahedron: Asymmetry》 20051231 Dina Scarpi等 Selectivity of Daucus carota roots and baker_s yeast in the enantioselective reduction of gamma-nitroketones 第16卷, * |
| DINA SCARPI等: "Selectivity of Daucus carota roots and baker_s yeast in the enantioselective reduction of γ-nitroketones", 《TETRAHEDRON: ASYMMETRY》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104531785A (en) * | 2014-12-09 | 2015-04-22 | 江南大学 | Method for catalytically synthesizing ethyl (R)-4-aryl-3-hydroxybutyrate by utilizing potato whole cell |
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