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Applications of alcohol dehydrogenase in asymmetric reduction

An alcohol dehydrogenase, asymmetric technology, applied in atomoxetine, the field of preparation of single-configuration oxetine drugs, can solve the problems of unfriendly environment, low reaction yield, unsuitable for large-scale industrial production and the like, To achieve the effects of environmental friendliness, high product concentration, and good industrial application prospects

Active Publication Date: 2015-07-29
ABIOCHEM BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For chiral hydroxyl compounds, in the prior art, ruthenium or rhodium metal catalysts are mainly used for asymmetric reduction preparation, but this type of method has low reaction yields, wastes need to be discharged, is not friendly to the environment, and is not suitable for large-scale industrial production and other shortcomings

Method used

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  • Applications of alcohol dehydrogenase in asymmetric reduction
  • Applications of alcohol dehydrogenase in asymmetric reduction
  • Applications of alcohol dehydrogenase in asymmetric reduction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Dissolve 163g of 3-(methylamino)-1-phenylpropan-1-one in 150mL of isopropanol, add 400mL of sodium phosphate buffer and adjust the pH to 7.0 with 20% (w / v) NaOH solution, add 450mL of the whole bacteria lysate was stirred at 30°C for reaction, and the reaction progress was detected by TLC. After the reaction, dilute hydrochloric acid was added to adjust the pH to 2 to precipitate the protein, and then filtered with diatomaceous earth, the filtrate was adjusted to pH 12 with 20% (w / v) sodium hydroxide solution, extracted three times with equal volume of ethyl acetate, The organic phases were combined, dried and spin-dried to obtain the product. The weight of the product is 150.1 g, and the molar yield is 91.0%.

[0043] The structure of the product was confirmed by proton nuclear magnetic resonance spectroscopy and ee value determination:

[0044]

[0045] 1 H NMR (300MHz, CDCl 3 ):δ7.19(5H,s,Ar-H),4.50(1H,t,-CHOH),2.55(2H,t,-CH 2 NHCH 3 ),2.47(3H,s,-CH3 ),2.0(1...

Embodiment 2-5

[0048] Referring to the method of Example 1, in combination with the parameters in Table 1, the compounds of Examples 2-5 were prepared. Wherein, when NADP+ is used in the reaction system, NADP+ and the whole bacterial lysate are added to the reaction system at the same time.

[0049] Table 1

[0050]

[0051]

[0052] The detection and structural characterization results of the product are as follows.

Embodiment 2

[0054]

[0055] The weight of the product is 92.0 g, and the molar yield is 91.0%.

[0056] 1 H NMR (300MHz, CDCl3): δ7.19(5H, s, Ar-H), 4.50(1H, t, -CH(OH)), 2.36(2H, t, -CH 2 NMe 2 ),2.27(6H,s,-N(CH 3 ) 2 ),2.0(1H,s,-OH).1.87(2H,m,-C(OH)CH 2 -),

[0057] ee value >99%.

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PUM

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Abstract

The invention discloses an enzyme-chemical synthetic method used for preparing chiral alcohol via asymmetric reduction with alcohol dehydrogenase, and further discloses a method used for preparing medicines, especially tomoxetine, of single configuration, with the chiral alcohol, wherein the medicines possesses a 3-aryloxy-3-aryl propylamine structure. Reaction conditions are mild; raw material cost is low; the method is friendly to the environment; reaction yield is high; product optical purity is high; and the method possesses obvious advantages compared with conventional asymmetric reduction preparation methods.

Description

technical field [0001] The invention belongs to the field of biochemical engineering, and in particular relates to an enzymatic-chemical synthesis method for preparing chiral alcohols through asymmetric reduction reaction catalyzed by alcohol dehydrogenase, and further using the chiral alcohols to prepare single-configuration cetines Drugs especially atomoxetine approach. Background technique [0002] Selective serotonin reuptake inhibitors and norepinephrine reuptake inhibitors are mostly cetines containing 3-aryloxy-3-arylpropylamine structure, such as fluoxetine, The structures of Nisoxetine and Tomoxetine are as follows: [0003] [0004] Atomoxetine is the first non-central nervous system stimulant drug approved by the US Food and Drug Administration, mainly for the treatment of ADHD in children and adolescents. It is not a central nervous system stimulant, is not addictive, and is not a controlled drug. The main pharmacological effect is to increase the chemical s...

Claims

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Application Information

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IPC IPC(8): C12P13/00C12P7/22
Inventor 罗煜丁时澄瞿旭东王海涛
Owner ABIOCHEM BIOTECH CO LTD
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