CN102517342B - 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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- CN102517342B CN102517342B CN201110419273.6A CN201110419273A CN102517342B CN 102517342 B CN102517342 B CN 102517342B CN 201110419273 A CN201110419273 A CN 201110419273A CN 102517342 B CN102517342 B CN 102517342B
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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 Biocatalysis method and prepare the technical field of optical activity alcohol, particularly the novel preparation method of the bromo-1-aryl alcohol of a kind of optical activity R-2-.
Background technology
In recent decades, asymmetric synthesis research develops because its synthetic product great value in actual applications itself has obtained rapidly.The alpha-brominated aromatic alcohol of optical activity is the important chiral building block of a class, through some simple chemical conversions, can obtain the building block that α position is the chiral aromatic alcohols of other group, therefore aspect the chipal compounds such as medicine, agricultural chemicals, additive synthetic, have larger using value.
Chipal compounds disappears outside body obtains except separated with chemical process by some physical methods, and major part is to take asymmetric synthesis to obtain, and comprises asymmetric chemistry catalysis synthesis process and asymmetric biocatalysis synthesis method, both has certain application.The process that wherein asymmetric biocatalysis utilizes enzyme or biological organism (full cell, organoid, tissue etc.) to carry out asymmetric chemistry conversion as catalyzer is one of study hotspot of green chemical industry.The asymmetric conversion of biocatalysis carbonyl containing compound occupies very consequence in asymmetric synthesis, and wherein vegetable cell is that to study be also early a more class reaction of research for the asymmetric reduction of catalyzing ketone compound to generate corresponding chiral alcohol.With plant, as catalyzer, there is full cell response, majority need not carry out the purification of enzyme, the energy that need not add expensive coenzyme and keep reaction to carry out, source is abundant, cost is low, efficiency is high and product enantio-selectivity is good and the 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.
The existing report of the research 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 microorganism (C.lunata) can become the bromo-1-phenylethyl alcohol of corresponding R-2-and the bromo-1-p-nitrophenyl of S-2-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) by the contrast of different plant tissues, Carrot Roots cell has unique superiority aspect also 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, fungus and bacterium etc.Using the whole cell of plant as biological catalyst, be applied to the synthetic report that has no of the alpha-brominated aromatic alcohol of optical activity.Consider the superiority of Radix Dauci Sativae aspect 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 biocatalyst.
Summary of the invention
The object of this invention is to provide the alpha-brominated aryl methyl ketone of a kind of vegetable cell catalytic reduction and prepare the method for the bromo-1-aryl alcohol of optical activity R-2-, for different substrates, select suitable reaction conditions, can obviously improve the transformation efficiency of the alpha-brominated aryl methyl ketone of substrate and the enantiomeric excess value of the bromo-1-aryl alcohol of corresponding product R-2-.
The whole cell of plant of the present invention is selected Carrot Roots cell, and the technical scheme of employing is as follows:
(1) the whole cell of plant activates in reaction medium: reaction medium is pH 6.4～7.2 phosphate buffer solns, the concentration of the whole cell of Carrot Roots in medium is 100～300g/L, activation temperature is 24～36 ℃, and during activation, hunting speed is 120r/min, and soak time is 0.2～1h;
(2) in the system after activation, add alpha-brominated aryl methyl ketone, 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, the whole cell consumption of plant is: the reaction medium of 50mL adds the whole cell of 5～15g plant, temperature of reaction is 28～36 ℃, during reaction, hunting speed is 120r/min, and the reaction times is 24～36h;
(3) reaction finishes rear with solvent ethyl acetate extracting and separating reactant, the bromo-1-aryl alcohol of analyzing and testing gained optical activity R-2-.Reaction finishes the rear centrifugation of the appropriate solvent ethyl acetate extraction of rear use, after extraction liquid is concentrated, utilize the high performance liquid chromatograph that Chiralcel OB-H chiral column or Chiralcel OD-H chiral column are housed to detect, calculate 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, according to different substrates, select different vegetable cell catalytic conditions, the transformation efficiency of the alpha-brominated aryl methyl ketone of substrate reaches more than 61.5%, the enantiomeric excess value of the bromo-1-aryl alcohol of product optical activity R-2-reaches more than 82.5%, the synthetic intermediate that the bromo-1-aryl alcohol of R-2-that optical purity is high is a lot of natural products and the synthetic precursor of chiral drug, and what use is that cheap plant is as catalyzer, therefore the method that the present invention prepares the bromo-1-aryl alcohol of optical activity R-2-has higher using value.
Embodiment
Embodiment can make those skilled in the art comprehensively understand the present invention below, 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 Carrot Roots cell of 10g chopping, (120r/min) 20min vibrates under 32 ℃ of conditions in constant temperature water bath shaker, make Carrot Roots cell activation, then add the alpha-brominated methyl phenyl ketone of 0.02g (0.4g/L), at the same temperature oscillatory reaction 24h.After reaction finishes, 40mL ethyl acetate is joined in reaction solution, centrifugation after oscillation extraction, separate extraction liquid, after extraction liquid is concentrated, with the high performance liquid chromatograph that Chiralcel OD-H chiral column is housed, detect, the enantiomeric excess value of the transformation efficiency of the alpha-brominated methyl phenyl ketone of substrate and the bromo-1-phenylethyl alcohol of product R-2-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 Carrot Roots cell of 10g chopping, (120r/min) 20min vibrates under 32 ℃ of conditions in constant temperature water bath shaker, make Carrot Roots cell activation, then add the alpha-brominated p-methyl aceto phenone of 0.02g (0.4g/L), at the same temperature oscillatory reaction 28h.After reaction finishes, 40mL ethyl acetate is joined in reaction solution, centrifugation after oscillation extraction, separate extraction liquid, after extraction liquid is concentrated, with the high performance liquid chromatograph that Chiralcel OD-H chiral column is housed, detect, the transformation efficiency of the alpha-brominated p-methyl aceto phenone of substrate and the bromo-1-of product R-2-are respectively 63.1% and 88.9% to the enantiomeric excess value of methylbenzene ethanol.
Embodiment 3: the phosphate buffered saline buffer 50mL and the 15g Carrot Roots cell that in an Erlenmeyer flask, add 0.1mol/L, pH=6.4, (120r/min) 20min vibrates under 30 ℃ of conditions in constant temperature water bath shaker, make Carrot Roots cell activation, then add the alpha-brominated p-methoxy-acetophenone of 0.02g (0.4g/L), at the same temperature oscillatory reaction 30h.After reaction finishes, 40mL ethyl acetate is joined in reaction solution, centrifugation after oscillation extraction, separate extraction liquid, after extraction liquid is concentrated, with the high performance liquid chromatograph that Chiralcel OD-H chiral column is housed, detect, the transformation efficiency of the alpha-brominated p-methoxy-acetophenone of substrate and the bromo-1-of product R-2-are respectively 61.5% and 87.7% to the enantiomeric excess value of anisole ethanol.
Embodiment 4: the phosphate buffered saline buffer 50mL and the 10g Carrot Roots cell that in an Erlenmeyer flask, add 0.1mol/L, pH=7.0, (120r/min) 30min vibrates under 32 ℃ of conditions in constant temperature water bath shaker, make Carrot Roots cell activation, then add the alpha-brominated parachloroacetophenone of 0.025g (0.5g/L), at the same temperature oscillatory reaction 34h.After reaction finishes, 40mL ethyl acetate is joined in reaction solution, centrifugation after oscillation extraction, separate extraction liquid, after extraction liquid is concentrated, with the high performance liquid chromatograph that Chiralcel OB-H chiral column is housed, detect, the transformation efficiency of the alpha-brominated parachloroacetophenone of substrate and the bromo-1-of product R-2-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 Carrot Roots cell that in an Erlenmeyer flask, add 0.1mol/L, pH=7.0, (120r/min) 30min vibrates under 30 ℃ of conditions in constant temperature water bath shaker, make Carrot Roots cell activation, then add the alpha-brominated m chloroacetophenone of 0.025g (0.5g/L), at the same temperature oscillatory reaction 28h.After reaction finishes, 40mL ethyl acetate is joined in reaction solution, centrifugation after oscillation extraction, separate extraction liquid, after extraction liquid is concentrated, with the high performance liquid chromatograph that Chiralcel OB-H chiral column is housed, detect, between the transformation efficiency of the alpha-brominated m chloroacetophenone of substrate and the bromo-1-of product R-2-, the enantiomeric excess value of chlorophenethylol is respectively 77.5% and 84.1%.
Embodiment 6: the phosphate buffered saline buffer 50mL and the 10g Carrot Roots cell that in an Erlenmeyer flask, add 0.1mol/L, pH=7.0, (120r/min) 30min vibrates under 32 ℃ of conditions in constant temperature water bath shaker, make Carrot Roots cell activation, then add the alpha-brominated p-nitroacetophenone of 0.025g (0.5g/L), at the same temperature oscillatory reaction 34h.After reaction finishes, 40mL ethyl acetate is joined in reaction solution, centrifugation after oscillation extraction, separate extraction liquid, after extraction liquid is concentrated, with the high performance liquid chromatograph that Chiralcel OB-H chiral column is housed, detect, the enantiomeric excess value of the transformation efficiency of the alpha-brominated p-nitroacetophenone of substrate and the bromo-1-p-nitrophenyl of product R-2-ethanol is respectively 82.3% and 82.5%.
Claims (3)
1. the preparation method of the bromo-1-aryl alcohol of chirality halohydrin R-2-, is characterized in that: utilize the whole cell of Carrot Roots to prepare the bromo-1-aryl alcohol of R-2-as the alpha-brominated aryl methyl ketone of biological catalyst catalytic asymmetric reduction, reaction formula is as follows:
In formula, R is respectively H, p-CH
3, p-OCH
3, p-Cl, p-NO
2, substituting group that m-Cl is different;
Preparation method is as follows for the bromo-1-aryl alcohol of chiral intermediate R-2-:
(1) the whole cell of Carrot Roots activates in reaction medium: reaction medium is pH6.0～7.2 phosphate buffer soln, the concentration of the whole cell of Carrot Roots in medium is 100～300g/L, activation temperature is 28～36 ℃, and during activation, hunting speed is 120r/min, and soak time is 0.2～1h;
(2) in the system after activation, add alpha-brominated aryl methyl ketone, 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, the whole cell consumption of Carrot Roots is: in the reaction medium of every 1L, add the whole cell of 100～300g Carrot Roots, temperature of reaction is 28～36 ℃, during reaction, hunting speed is 120r/min, and the reaction times is 24～36h;
(3) reaction finishes rear with solvent ethyl acetate extracting and separating reactant, the bromo-1-aryl alcohol of analyzing and testing gained optical activity R-2-.
2. method according to 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 the bromo-1-aryl alcohol of optically active R-2-, be respectively the bromo-1-phenylethyl alcohol of R-2-, the bromo-1-of R-2-is to methylbenzene ethanol, the bromo-1-of R-2-is to anisole ethanol, chlorophenethylol between the bromo-1-of R-2-, the bromo-1-of R-2-is to chlorophenethylol or the bromo-1-p-nitrophenyl of R-2-ethanol.
3. method according to claim 1, is characterized in that biological catalyst is the whole cell of Carrot Roots.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (4)
| Title |
|---|
| Dina Scarpi等.Selectivity of Daucus carota roots and baker_s yeast in the enantioselective reduction of γ-nitroketones.《Tetrahedron: Asymmetry》.2005,第16卷 |
| Enantioselective reduction of bromo- and methoxy-acetophenone derivatives using carrot and celeriac enzymatic system;Wanda K.等;《Tetrahedron: Asymmetry》;20041231;第15卷;第1965-1967页 * |
| Selectivity of Daucus carota roots and baker_s yeast in the enantioselective reduction of γ-nitroketones;Dina Scarpi等;《Tetrahedron: Asymmetry》;20051231;第16卷;第1479-1483页 * |
| Wanda K.等.Enantioselective reduction of bromo- and methoxy-acetophenone derivatives using carrot and celeriac enzymatic system.《Tetrahedron: Asymmetry》.2004,第15卷 |
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