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Biosynthesis method of atomoxetine intermediate and carbonyl reductase

A carbonyl reductase and biosynthesis technology, applied in the field of enzyme engineering, can solve the problems of low substrate solubility and reduced catalytic rate, and achieve the effects of improving enzyme catalytic efficiency, increasing solubility, and controlling costs

Active Publication Date: 2021-02-12
JIANGSU ALPHA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Patent CN109706191A mentions a method for enzymatically introducing chiral groups. The method is novel, but the solubility of the enzyme-catalyzed substrate in the water phase is not high, which reduces the catalytic rate to a certain extent.

Method used

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  • Biosynthesis method of atomoxetine intermediate and carbonyl reductase
  • Biosynthesis method of atomoxetine intermediate and carbonyl reductase
  • Biosynthesis method of atomoxetine intermediate and carbonyl reductase

Examples

Experimental program
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Effect test

Embodiment 1

[0033] The preparation of embodiment 1 compound III

[0034] Take 30g of compound IV and add 300ml of acetone, stir at room temperature to dissolve and clarify, add 106.6g of sodium iodide and heat up to reflux reaction, about 10h, the unreacted amount of compound IV in HPLC is less than 5%, filter with suction, and concentrate the filtrate under reduced pressure to obtain 49.5g of compound III, add 150ml of n-hexane, recrystallize to get 33.34g, yield: 72%.

Embodiment 2

[0035] The preparation of embodiment 2 compound II

[0036] Take 33g of compound III prepared above, add 132ml THF, 264ml 25% monomethylamine aqueous solution, stir at room temperature, control in TLC, compound III reacts completely in about 20h, add THF under reduced pressure, add 5.6g sodium hydroxide and stir for 30min, add 400ml of toluene and 100ml of water were stirred and separated, and the aqueous phase was back-extracted with 200ml of toluene. The organic phases were combined and evaporated to dryness under reduced pressure to obtain 21.75g ​​of crude product 3-methylamino-1-phenyl-1-propanone.

[0037] Add 60ml of ethanol to dissolve, add 17g of 30% hydrochloric acid ethanol dropwise, a large amount of solids precipitate out, stir and crystallize at about 0°C for 5h, filter with suction, and dry to obtain 17.4g of white solid, that is, compound II (3-methylamino-1-benzene base-1-propanone hydrochloride).

Embodiment 3

[0038] Embodiment 3 carbonyl reductase preparation

[0039] Escherichia coli TM1908 was inoculated into 10ml LB liquid medium with an inoculum size of 1%, and the medium contained 1mg kanamycin, and cultured on a shaker at 220rpm at 37°C for 8h to obtain a seed solution.

[0040] Put the above seed liquid into the fermented enzyme production medium, the inoculum size is 1%, add kanamycin at a final concentration of 10mg / 100mL to the fermentation medium, and culture at 37°C and 220rpm shaker to OD 600 Add IPTG at a final concentration of 0.5mM at 0.6-0.8, and induce at 18°C ​​for 24h. After the induction of the fermentation broth, centrifuge at 12000rpm for 3min at 4°C to collect the cells. Wash the bacteria with 0.2 M pH7.0 PB buffer, resuspend, sonicate and freeze-dry to obtain carbonyl reductase freeze-dried enzyme powder.

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Abstract

The invention relates to the technical field of enzyme engineering and particularly relates to a biosynthesis method of a atomoxetine intermediate and carbonyl reductase, the carbonyl reductase producing strain is Escherichia coli TM1908, and the preservation number of the strain is CCTCC NO: M2019714. In the presence of a coenzyme, a coenzyme circulating enzyme, a cosolvent and a buffer solution,the carbonyl reductase is catalyzed and converted into a atomoxetine intermediate compound I. The invention further discloses a preparation method of the atomoxetine intermediate compound I. The synthesis method provided by the invention solves a problem of chemical catalysis of low-chirality products in the prior art, reduces production cost and reduces pollution. Meanwhile, the invention provides a new catalytic substrate for the preparation of the important chiral intermediate of the atomoxetine.

Description

technical field [0001] The invention relates to the field of enzyme engineering, in particular to a method for synthesizing a atomoxetine intermediate. Background technique [0002] Atomoxetine is a highly selective norepinephrine reuptake inhibitor (NRI), which selectively binds to noradrenaline (NE) on the presynaptic membrane Binds to uptake transporters, inhibits NE reuptake, and has very low affinity to other neurotransmitters. For patients with severe adverse reactions or ineffective treatment of central nervous system stimulants, there is also an alternative way to try atomoxetine. As the first non-stimulant drug used to treat attention deficit hyperactivity disorder (ADHD), atomoxetine was approved by the US FDA in 2002 and officially launched in the US in 2003. Listed and applied in many countries including my country. [0003] The research on atomoxetine has a broad market prospect and has attracted the interest of many scientific researchers at home and abroad, ...

Claims

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Application Information

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IPC IPC(8): C12N9/04C12N1/20C12P13/00C12R1/19
CPCC12N9/0006C12N1/20C12P13/001C12Y101/01184
Inventor 陈本顺叶金星何伟石利平徐春涛张维冰程瑞华孙伟振孟鑫徐秋斌刘轩豪施莉莉
Owner JIANGSU ALPHA PHARM CO LTD
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