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Method for preparing amine compound having multiple chiral centers

An amine compound and chirality technology, applied in the field of chiral compound synthesis, can solve the problem of not being able to obtain products with two or more chiral centers in one step, and achieve the effects of high product purity, efficient production and cheap substrates

Active Publication Date: 2018-03-16
ASYMCHEM LIFE SCI TIANJIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The present invention aims to provide a method for preparing amine compounds with multiple chiral centers, so as to solve the technical problem that in the prior art, products with two or more chiral centers cannot be obtained in one step by chemical production.

Method used

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  • Method for preparing amine compound having multiple chiral centers
  • Method for preparing amine compound having multiple chiral centers
  • Method for preparing amine compound having multiple chiral centers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] In a 10mL reaction bottle, add 0.11g (1.86mmol) of isopropylamine into 5mL of 0.2M phosphate buffer, adjust the pH to 7.0-7.5, add 0.1g of transaminase (lyophilized powder preparation), 0.003g of pyridoxal phosphate, After mixing, add dropwise 0.1g of the main material dissolved in 0.5mL DMSO The pH of the system is 7.0-7.5, and the mixture is stirred at a constant temperature of 25°C±3°C for 20h. The pH of the system was adjusted to above 10 with 2N NaOH, extracted twice with ethyl acetate, the organic phase was dried, filtered, and concentrated to obtain the crude product Among them, 100 kinds of transaminases were screened (these 100 kinds of transaminases were all artificially synthesized from known sequences reported in the literature or the above sequences were artificially mutated), the conversion rate of the system was detected by GC, the chirality was detected by HPLC, and the reaction of most of the transaminases A large amount of raw material remained in th...

Embodiment 2

[0039] (1) Feeding: Add 0.1g of the main raw material to the 25mL reaction bottle 100uL polyethylene glycol PEG-400, 3mL phosphate buffer (100mM, pH=8.0), the raw materials are evenly dispersed in the phosphate buffer;

[0040] (2) Add transaminase: add 600uL 1M isopropylamine hydrochloride, 0.5mg pyridoxal phosphate, 0.05g transaminase ATA (lyophilized powder preparation) to the 25mL reaction bottle, and the system pH=8.0;

[0041] (3) Reaction: The system was reacted at 30°C and stirred for 24 hours;

[0042] (4) Post-treatment: adjust the pH of the system to above 10 with 2N NaOH, extract twice with ethyl acetate, dry the organic phase, filter, and concentrate to obtain the crude product After detection by GC and HPLC, the conversion rate was 47.6%, the e.e value was 97.34%, and the de value was 99.7%.

Embodiment 3

[0044] Add to a 10mL reaction bottle, 0.1g of the main raw material 2.5mL Tris-Cl buffer (100mmol / L, pH=8.5), after the raw material is dispersed, add 0.1g D-alanine, 0.22g D-glucose, 0.01g coenzyme NAD+, and 0.005g glucose dehydrogenase GDH , 1 mg of pyridoxal phosphate, after fully dissolving, add 0.1 g of transaminase ATA (lyophilized powder preparation), the pH of the system is 8.5, and stir at a constant temperature of 40 °C ± 3 °C for 20 h. The pH of the system was adjusted to above 10 with 2N NaOH, extracted twice with ethyl acetate, the organic phase was dried, filtered, and concentrated to obtain the crude product After detection by GC and HPLC, the conversion rate was 43.5%, the e.e value was 98.9%, and the de value was 99.2%.

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Abstract

The invention discloses a method for preparing an amine compound having multiple chiral centers. The method is characterized in that a compound with the formula shown in the description reacts with anamino donor under the action of transaminase to generate another compound with the formula shown the description; and in the formulas, R1 and R2 are a methyl group or an ethyl group respectively, R3is a tert-butyloxycarbonyl group or a benzyloxycarbonyl group, and n is zero or one. The transaminase stereoselectively transaminates a ketone compound used as a raw material to efficiently produce chiral amine, and selective resolution is carried out to obtain the chiral amine compound having multiple chiral centers; and the method has the characteristics cheap substrate and high product purity,and is suitable for being promoted in the industrial production of chiral amine.

Description

technical field [0001] The invention relates to the technical field of chiral compound synthesis, in particular to a method for preparing amine compounds with multiple chiral centers. Background technique [0002] Chiral amines widely exist in nature and are structural units of many important biologically active molecules. They are important intermediates for the synthesis of natural products and chiral drugs. Many chiral amines are also useful chiral auxiliaries and chiral resolution reagents. . Many chiral amines contain one or more chiral centers. The pharmacological activity, metabolic process, metabolic rate and toxicity of different chiral drugs are significantly different. Usually one enantiomer is effective, while the other enantiomer are inefficient or ineffective, or even toxic. Chiral amines containing multiple chiral centers have been intensively studied because of their unique physiological activities, extensive application value and broad application prospect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/12C12P17/10
CPCC12P17/10C12P17/12
Inventor 卢江平张娜李艳君贺晓晗刘文敬
Owner ASYMCHEM LIFE SCI TIANJIN
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