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Novel method for synthesizing key intermediate of dextromethorphan through enzyme catalysis asymmetric synthesis

A technology of dextromethorphan hydrobromide and an intermediate is applied in the field of preparation of key intermediates of antitussives, and achieves the effects of mild reaction conditions, simple process route and improved yield

Active Publication Date: 2019-12-31
TIANJIN INST OF IND BIOTECH CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] We found that in the existing process, there is no enzyme-catalyzed asymmetric reduction to prepare (S)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-8 Method for Hydroisoquinoline ((S)-2)

Method used

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  • Novel method for synthesizing key intermediate of dextromethorphan through enzyme catalysis asymmetric synthesis
  • Novel method for synthesizing key intermediate of dextromethorphan through enzyme catalysis asymmetric synthesis
  • Novel method for synthesizing key intermediate of dextromethorphan through enzyme catalysis asymmetric synthesis

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Experimental program
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Effect test

Embodiment 1

[0023] Embodiment 1: the acquisition of highly expressed genetically engineered bacteria

[0024] The whole gene synthesis was completed by Shanghai Xuguan Company.

[0025] According to the gene AtIR of Amycolatopsis thermoflava (WP_027931121.1), the gene StIR of Streptomycesthermoilacinus (WP_023587323.1), the gene PmIR of Prauserella marina (WP_091804541.1), the gene SmIR of Sciscionella marina (WP_020496004.1 of Amyalcolatops gene), WP_020635634.1) and the gene ShIR (SHE96216.1) of Streptoalloteichus hindustanus were respectively codon-optimized in order to enable the gene to be expressed in the E. coli expression host. See the attached table for the sequence. And add corresponding enzyme cutting sites at both ends of the gene, and construct them into corresponding vectors to obtain genetically engineered bacteria IR1, IR2, IR3, IR4, IR5, and IR6.

[0026] Transform the prepared recombinant vector into Escherichia coli BL21, Rosetta or Origami by conventional methods to c...

Embodiment 2

[0027] The cultivation of embodiment 2 genetically engineered bacteria and the preparation of resting cells

[0028]Pick a single colony on the plate and inoculate it into 5ml of fermentation medium containing corresponding antibiotics, cultivate it for about 15 hours as a seed solution, inoculate it into 600ml of fermentation medium according to the inoculation amount of 1%, and cultivate it on a shaker at 37°C and 200rpm to OD 600 = about 0.6-0.8, add IPTG with a final concentration of 0.1 mM to induce for more than 10 h, and collect the bacteria by centrifuging the culture solution at 8000 rpm.

Embodiment 3

[0029] Embodiment 3 Utilizes the asymmetric reduction of resting cells of IR1 to catalyze formula (1) hydrochloride

[0030] Take 2.5g of IR1 resting cells and resuspend in 100mL sodium phosphate buffer (100mM, pH 7.5), add glucose (1g), NADP + (5mg), GDH enzyme powder (50mg), 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline hydrochloride (1) (0.5g) , use 10% sodium carbonate solution to control pH 7.5, react under nitrogen protection at 25°C for 24 hours, HPLC detection shows that the reaction is complete (liquid chromatography column: Daicel CHIRALPAK OJ-H (250mm×4.6mm, 5μm), mobile phase: iso Propanol (0.5% ethanolamine) / n-hexane=10:90, detection wavelength: 230nm, flow rate: 0.5mL / min), 10% sodium carbonate solution to adjust pH to 9.0, ethyl acetate extraction (100mL*3), anhydrous After drying with sodium sulfate, it was spin-dried, separated and purified by column chromatography to obtain (S)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquine The morphine ((S)-...

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Abstract

The invention discloses imine reductase AtIR(WP_027931121.1) derived from Amycolatopsis thermoflava, imine reductase StIR(WP_023587323.1) derived from Streptomyces thermolilacinus, imine reductase PmIR(WP_091804541.1) derived from Prauserella marina, imine reductase SmIR(WP_020496004.1) derived from Sciscionella marina, imine reductase AaIR(WP_020635634.1) derived from Amycolatopsis alba or iminereductase ShIR(SHE96216.1) derived from Streptoalloteichus hindustanus, and the imine reductase is adopted as a biocatalyst for preparing a key intermediate (S)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline of a central antitussive, namely dextromethorphan. A 5-50g / L substrate can be catalyzed by using corresponding imine reductase, the conversion rate is greater than 99%, and the method has remarkable characteristics of being high in yield, good in stereoselectivity, mild in reaction condition, and the like.

Description

technical field [0001] The invention relates to a new method for preparing a key intermediate of antitussive medicine, which belongs to the field of biochemical industry. It specifically relates to the preparation of the key intermediate (S)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-eight of dextromethorphan hydrobromide through enzyme-catalyzed asymmetric reduction A new approach to hydroisoquinolines. Background technique [0002] Dextromethorphan hydrobromide is also called dextromethorphan hydrobromide, the chemical name is (+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan hydrobromide monohydrate , suitable for colds, acute or chronic bronchitis, bronchial asthma, pharyngitis, tuberculosis and dry cough caused by other upper respiratory tract infections. [0003] [0004] There are many synthetic methods of dextromethorphan hydrobromide, such as Chinese patents CN201310041846, CN201310051880, CN201210405684, CN201310004262, CN201410169133 and literature [Today’s Pharmacy, 2...

Claims

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Application Information

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IPC IPC(8): C12P17/12
CPCC12P17/12
Inventor 姚培圆徐泽菲于珊珊吴洽庆朱敦明马延和
Owner TIANJIN INST OF IND BIOTECH CHINESE ACADEMY OF SCI
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