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A kind of synthetic method of chiral aminoalcohol compound

A compound, amino alcohol technology, applied in the field of synthesis of chiral amino alcohol compounds, can solve problems such as low safety factor, conversion rate of only 50%, harsh reaction conditions, etc., achieve good industrial application prospects, high optical purity of products, easy operation convenient effect

Active Publication Date: 2021-12-28
TIANJIN INST OF IND BIOTECH CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2019, Zhang et al. reported the "one-pot" synthesis of (S)-2-aminobutanol through a multi-enzyme cascade reaction of epoxyhydrolase, alcohol dehydrogenase and transaminase, but the conversion rate was relatively low, less than 50%. (Zhang et al, Catal. Sci. Technol, 2019, 9, 70)
[0007] The synthetic method of above (S)-2-amino-1-butanol and (R)-3-aminobutanol, chemical method needs high temperature, high pressure and metal catalyst, harsh reaction conditions, big pollution, low safety factor
The biological method has mild reaction conditions and good stereoselectivity, but the conversion rate is only 50%, and the yield is low

Method used

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  • A kind of synthetic method of chiral aminoalcohol compound
  • A kind of synthetic method of chiral aminoalcohol compound
  • A kind of synthetic method of chiral aminoalcohol compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Example 1. Screening of amine dehydrogenase for biocatalytic preparation of chiral aminoalcohol compounds

[0083] 1. Preparation of recombinant bacteria expressing amine dehydrogenase

[0084] 1. Recombinant plasmid expressing amine dehydrogenase

[0085]The recombinant plasmid expressing amine dehydrogenase is to replace the NdeI and XhoI of the corresponding expression vector (column 3 in Table 2) with the coding gene of each amine dehydrogenase in the amine dehydrogenase library in Table 2 (column 5 of Table 2) A DNA molecule between the sites, resulting in a vector expressing a recombinant protein with a His tag fused to the C-terminus of each amine dehydrogenase.

[0086] The vectors pET22b, pET28a, pET24a, and pET21b all have his tags on them. pET22b, pET21b are ampicillin-resistant, and pET28a, pET24a are kana-resistant.

[0087] Table 2 is the amine dehydrogenase library information table

[0088]

[0089]

[0090]

[0091] 2. Recombinant bacteria e...

Embodiment 2

[0127] Example 2, Condition optimization for the preparation of chiral aminoalcohol compounds by amine dehydrogenase biocatalysis

[0128] One, the preparation of pure amine dehydrogenase

[0129] Whole cells expressing recombinant EsAmDH prepared in Example 1, whole cells expressing recombinant BsAmDH1, whole cells expressing recombinant TiAmDH, whole cells expressing recombinant BcAmDH, whole cells expressing recombinant SpAmDH, whole cells expressing recombinant LsAmDH1 The whole cells were ultrasonically disrupted, centrifuged at 12,000rpm, 60min, 4°C to collect the supernatant, filtered through a 0.45μm water filter membrane, and then purified with an ATKA protein purifier. The chromatographic column used was HisTrap HP 5mL prepacked column (GE) , Cat. No. 17524802. Loading and equilibration buffer A (50mM potassium phosphate buffer, 0.5M NaCl, 20mM imidazole, pH 8.0); Elution buffer B (50mM potassium phosphate buffer, 0.5M NaCl, 500mM imidazole, pH 8.0), elution flow ra...

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Abstract

The invention discloses a synthesis method of a chiral aminoalcohol compound. The application of the biological material comprising amine dehydrogenase provided by the present invention in at least one of the following A1-A6); A1) catalyzing 1-hydroxyl-2-butanone to generate (S)-2-amino-1-butanol ; A2) catalyzing 4-hydroxyl-2-butanone to generate (R)-3-amino-1-butanol; A3) synthesis or preparation of chiral amino alcohol compounds; A4) synthesis or preparation of 2-amino-1-butanol and 3‑amino‑1‑butanol; A5) synthesis or preparation of (S)‑2‑amino‑1‑butanol and (R)‑3‑amino‑1‑butanol; A6) catalysis of hydroxyketone substrates to generate aminoalcohol compounds The experiment proves that the method provided by the present invention has the advantages of mild reaction conditions, good stereoselectivity, high yield and simple operation.

Description

technical field [0001] The invention belongs to the field of biotechnology, and relates to a synthesis method of a chiral aminoalcohol compound. Background technique [0002] Chiral amino alcohols are structural units of many bioactive molecules, and are important pharmaceutical and fine chemical intermediates, among which (S)-2-aminobutanol is an important pharmaceutical intermediate, mainly used in the synthesis of ethambutol hydrochloride (Ethambutol ), has long been used as a first-line drug against Mycobacterium tuberculosis (Wilkinson et al., 1961; Pablos-Mendez et al., 1998). (R)-3-Aminobutanol is an important raw material for the synthesis of new drug Dolutegravir (CN:102245572A, CN:101212903A). Dolutegravir is an anti-AIDS integrase inhibitor developed by GlaxoSmithKline. [0003] At present (S)-2-aminobutanol chemical synthesis method has: take butyraldehyde, dibenyl azodicarboxylate and D-proline as raw material, in NaBH 4 、H 2 Synthesis of (S)-2-aminobutanol ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N9/06C12N15/53C12P13/00
CPCC12N9/0014C12P13/001C12Y104/99003
Inventor 孙周通王红月刘贝贝
Owner TIANJIN INST OF IND BIOTECH CHINESE ACADEMY OF SCI
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