Method for preparing (R)-2-chlorin-1-(3-chlorphenyl) ethanol by microorganism catalysis

A catalytic preparation and microbial technology, applied in the direction of microorganism-based methods, biochemical equipment and methods, microorganisms, etc., can solve problems such as harsh reaction conditions, pollution, complex enzyme systems, etc., and achieve mild reaction conditions, high optical purity, high The effect of reaction yield

Active Publication Date: 2010-12-29
重庆博腾精细化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] It has been reported that (1R)-2-chloro-(halophenyl)ethanol was synthesized by asymmetric catalytic reduction of (1R)-2-chloro-(halophenyl)ethanone (Marc Devocelle, et.al. : Tetrahedron Letters 40, 4551-4554, 1999; Ohkuma.T, et.al.: Organic Letters, 9(2), 255-257, 2007), describe the use of rhodium (Rh) catalysts, which are expensive , high price, relatively harsh reaction conditions, complex catalyst recovery, large-scale industrial production is easy to cause pollution
Chinese patent CN1063422C (Kodama Haoxuan, etc.: 1996) discloses the product obtained by reacting racemic 2-halogenated-1-(substituted phenyl)ethanol and phthalic anhydride, and then adopts an optically active organic base as a decomposing compound Separate the ingredients to obtain an optically active intermediate, and finally hydrolyze or alcoholyze to obtain an optically active compound 2-halogenated-1-(substituted phenyl)ethanol. This method needs to start with a racemic raw material and undergo a three-step reaction to obtain the product , the yield is low, and at the same time in the resolution process, alkaloids with higher prices, multiple solvents and reagents are needed, which increases the production cost, and 50% of the useless enantiomers and some by-products are difficult to handle, resulting in environmental pollution
Chinese patent CN1228448C (Wang Yongmei et al., 2005) describes the preparation of (R)-2-halogenated-1-(substituted phenyl)ethanol using biocatalytic reduction, but as can be seen from the examples of this patent, this patent Using commercially available yeast as a biocatalyst, due to its complex enzyme system, the optical purity of the transformation product is not high, and the yield is low
And none of the above patents involves the compound (R)-2-chloro-1-(3-chlorophenyl)ethanol
There is no research report on the production of aryl chiral alcohol (R)-2-chloro-1-(3-chlorophenyl)ethanol by carbonyl reductase catalyzed by other species of microorganisms except yeast

Method used

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  • Method for preparing (R)-2-chlorin-1-(3-chlorphenyl) ethanol by microorganism catalysis
  • Method for preparing (R)-2-chlorin-1-(3-chlorphenyl) ethanol by microorganism catalysis
  • Method for preparing (R)-2-chlorin-1-(3-chlorphenyl) ethanol by microorganism catalysis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Cultivation and screening of microbial strains

[0039] Slope culture: the medium is 100mL wort (containing 10g of malt powder), 2g of agar, pH 6.0, sterilized at 121°C for 20 minutes, cooled and inoculated after sterilization, and the strains are various microbial strains shown in Table 1, 28 Cultivate for 2 days at ℃, and use as slant activated seeds.

[0040] Seed cultivation and fermentation: Yeast extract 10g / L, peptone 20g / L, glucose 20g / L, pH6.5, liquid volume is 250mL triangular bottle 50mL, sterilized at 120°C for 20 minutes, cooled and inoculated with slant seeds after sterilization, 180r / min shaker, culture at 28°C for 24-48 hours, as seeds or fermentation broth.

[0041] The amount of wet bacteria in the fermentation broth is 1.6g / 100mL, centrifuge for 10 minutes (8,000 rpm) to collect the bacteria, wash twice with potassium phosphate buffer (0.2M, pH6.5), transfer the bacteria to 5mL In the same buffer solution containing glucose (0.5M), make the cell con...

Embodiment 2

[0048] Effect of different carbon sources on transformation

[0049] Alcaligenes faecalis (Alcaligenes faecalis) ATCC 15554 was used as the transformed strain, and the strain was cultivated according to the method in Example 1, and different carbon sources were added in Example 1 instead of glucose. Inoculate the strains from the slant into 5ml liquid medium, pre-cultivate on an air shaker at 28°C, 180r / min for 24h, then transfer to 50ml medium for expansion for 24h, and centrifuge at 12000r / min for 8min at 4°C. The reaction conditions and collection method are the same as in Example 1. The results are shown in Table 2.

[0050] Table 2 Effect of different carbon sources on transformation

[0051]

[0052] It can be seen from the results in Table 2 that the sample e.e. value can reach more than 99%, and the repeatability of each parallel sample is good. Considering the conversion rate, it was determined that corn steep liquor was used as the medium carbon source in the e...

Embodiment 3

[0054] Effect of Different Nitrogen Sources on Transformation

[0055] Alcaligenes faecalis (Alcaligenes faecalis) ATCC 15554 strain was cultured according to the method of Example 1, in which different nitrogen sources (shown in Table 3) were added to the glucose medium in Example 1. Inoculate the strains from the slant into 5ml liquid medium, pre-cultivate on a shaker at 180r / min at 28°C for 24h, then transfer to 50ml medium for expansion for 24h, and centrifuge at 12000r / min for 8min at 4°C. The reaction conditions and collection method are the same as in Example 1. The results are shown in Table 3.

[0056] Table 3 Effect of different nitrogen sources on transformation

[0057]

[0058] As can be seen from the results in Table 3: with (NH 4 ) 2 SO 4 The conversion of the sample as a nitrogen source was high (80.22%) with an e.e. value of 99.79%, but there was considerable variation between levels. Considering comprehensively, yeast extract plus common peptone was ...

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Abstract

The invention provides a method for preparing (R)-2-Chloro-1-(3-chlorophenyl) ethanol through catalysis of microorganisms. The method utilizes producing strains, Vibrio fluvialis, Aureobacterium terregens, Alcaligenes faecalis, Bacillusthuringiensis, Trichosporon cutaneum, Candidaboidinii and so on of known carbonyl reductase with high enantioselectivity, to be fermented into enzyme under optimization conditions; in a single aqueous phase system or an aqueous / organic solvent biphasic system, 2-Chloro-1-(3-chlorophenyl) ethyl ketone is taken as a substrate, and glucose and macroporous resin are added; when the concentration of the substrate, 2-Chloro-1-(3-chlorophenyl) ethyl ketone, is between 50 and 140mmol / L (namely between 9.5 and 26.5 g / L), the transformation is performed for 48h, and the product (R)-2-Chloro-1-(3-chlorophenyl) ethanol is obtained after transformation conditions are optimized; the e.e value of the optical purity reaches 99.6 percent, the molar conversion rate reaches more than 99 percent, and coenzyme does not need to be added during the whole reaction process. The content of the (R)-2-Chloro-1-(3-chlorophenyl) ethanol prepared by the method reaches 99.2 percent, and the optical purity reaches 99.8 percent (e. e.).

Description

technical field [0001] The invention relates to a method for preparing (R)-2-chloro-1-(3-chlorophenyl)ethanol by microorganism catalysis, and belongs to the technical field of biocatalytic asymmetric reduction preparation of halogenated aryl chiral alcohols, which are pharmaceutical and chemical intermediates. Background technique [0002] Chiral drugs and their chiral intermediates are receiving more and more attention. For example, Fluoxetine, the first choice for antidepressants, was originally a racemic antidepressant. In 1997, its sales reached 2.7 billion US dollars. Later, it was found that its S-fluoxetine was 3 times more effective than R-fluoxetine (Ou Zhimin et al.: Journal of Wuxi University of Light Industry 2003, 22(1): 43-48), and the product was soon replaced by S-fluoxetine Instead, its important chiral intermediate is the chiral aryl alcohol 3-chloro-1-phenylpropanol. Another example is the anti-asthma drug formoterol, which is a long-acting β2 receptor ag...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P39/00C12P7/22C12R1/01C12R1/05C12R1/63C12R1/07C12R1/72C12R1/645
Inventor 居年丰朱坡虞洋秦力
Owner 重庆博腾精细化工有限公司
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