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2-(α-deuterium-α-hydroxyl-α-aryl/alkyl) azaaromatic compound and its preparation method and application

A technology for aza aromatic hydrocarbons and compounds is applied in the field of 2-aza aromatic hydrocarbon compounds and their preparation, which can solve the problems of low stereoselectivity and the like, and achieve the effects of environmental friendliness, short reaction time and less amount of photocatalyst

Active Publication Date: 2022-05-13
HENAN NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] One of the purposes of the present invention is to solve the problem of low stereoselectivity in the synthesis of chiral deuterated compounds in the prior art, and provide a 2-(α-deuterium-α-hydroxyl-α-aryl / alkyl) aza Process for the preparation of aromatic compounds

Method used

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  • 2-(α-deuterium-α-hydroxyl-α-aryl/alkyl) azaaromatic compound and its preparation method and application
  • 2-(α-deuterium-α-hydroxyl-α-aryl/alkyl) azaaromatic compound and its preparation method and application
  • 2-(α-deuterium-α-hydroxyl-α-aryl/alkyl) azaaromatic compound and its preparation method and application

Examples

Experimental program
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Effect test

Embodiment 5

[0024] The raw material 1-tert-butoxycarbonyl-2-benzoyl-benzimidazole used in Example 5, its synthesis can refer to the following documents: Sultan, S.; Rizvi, M.A.; Kumar, J.; Shah, B.A., Acyl Radicals from Terminal Alkynes:Photoredox-Catalyzed Acylation of Heteroarenes.Chemistry–A European Journal2018,24(42),10617-10620;

[0025] The synthesis of the raw materials used in the remaining examples can refer to the following documents: Wu, X.; Geng, X.; Zhao, P.; Zhang, J.; Gong, X.; Wu, Y.-d.; Wu, A.- X.,I 2 -Promoted Povarov-Type Reaction Using 1,4-Dithane-2,5-diol as an Ethylene Surrogate:Formal[4+2]Synthesis of Quinolines.Org.Lett.2017,19(7),1550-1553.

Embodiment 1

[0026] Embodiment 1: the preparation of 2-(α-deuterium-α-hydroxyl-α-phenyl)pyridine

[0027]

[0028] Preparation process: Weigh 2-benzoylpyridine (0.055g, 0.3mmol), DPZ (0.00053g, 0.0015mmol), Hans ester (0.11g, 0.45mmol), chiral spirocycle into a dry 25mL schlenk tube Phosphoric acid catalyst (0.018g, 0.003mmol), heavy water (0.8 ~ 1.6mL, 45 ~ 90mmol), sodium chloride (0.0035 ~ 0.0175g, 0.06mmol), continue to add 5mL of cyclopentyl methyl ether, at not higher than - At 78°C, use a vacuum pump to degas 2-3 times, each time for 5-10 minutes, then place it at -2-8°C, irradiate with a 3W blue light, and react for 3 hours. After the reaction, column chromatography separates ( Petroleum ether / ethyl acetate=20~4:1, volume ratio), rotary evaporation and concentration, vacuum drying (drying at 25°C for 1 hour), 2-(α-deuterium-α-hydroxyl-α-phenyl ) pyridine (0.056g, 0.3mmol), yield 96%, deuteration rate 91%. 1 H NMR (400MHz, CDCl 3 )δ8.60(d,J=4.8Hz,1H),7.65(td,J 1 =7.6Hz,J 2 =...

Embodiment 2

[0029] Embodiment 2: the preparation of 2-(α-deuterium-α-hydroxyl-α-phenyl) quinoline

[0030]

[0031] Preparation process: In a dry 25mL schlenk tube, weigh 2-benzoylquinoline (0.070g, 0.3mmol), DPZ (0.00053g, 0.0015mmol), Hansted ester (0.11g, 0.45mmol), chiral spiro Cyclic phosphoric acid catalyst (0.018g, 0.003mmol), heavy water (0.8~1.6mL, 45~90mmol), sodium chloride (0.0035~0.0175g, 0.06mmol), continue to add 5mL of cyclopentyl methyl ether, at no higher than At -78°C, use a vacuum pump to degas 2-3 times, each time for 5-10 minutes, and then place it at -2-8°C, irradiate with a 3W blue light, and react for 3 hours. After the reaction, separate by column chromatography (petroleum ether / ethyl acetate=20~4:1, volume ratio), concentrated by rotary evaporation, and vacuum dried (dried at 25°C for 1 hour) to obtain optically pure 2-(α-deuterium-α-hydroxyl-α- Phenyl)quinoline (0.068g, 0.279mmol), yield 96%, enantiomeric excess 91%, deuterated rate 91%. 1 H NMR (300MHz, C...

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Abstract

The present invention provides a kind of preparation method of 2-(α-deuterium-α-hydroxy-α-aryl / alkyl) azaaromatic compound, 2-aryl / alkanoyl azaaryl, photosensitizer DPZ, Han Stilbene ester HEH, chiral catalyst CPA, deuterium source and sodium chloride are dispersed in an organic solvent. Lamp irradiation, reaction 3~14 hours, after reaction finishes, separates and purifies and promptly obtains 2-(α-deuterium-α-hydroxyl-α-aryl / alkyl) azaaromatic compound; the enantiomer of the product obtained in the present invention The excess is about 90%, the deuterium substitution rate is over 90%, and the yield of some target products is as high as 99%, and the reaction conditions are mild, environmentally friendly, metal-free, less photocatalyst consumption, and short reaction time. It has laid a good foundation for chemical production.

Description

technical field [0001] The invention belongs to the technical field of deuterated compounds, and in particular relates to 2-(α-deuterium-α-hydroxyl-α-aryl / alkyl) azaaromatic compounds and their preparation methods and applications. Background technique [0002] Deuterium-substituted drugs replace some of the hydrogen atoms in the molecule with deuterium atoms on the basis of the original drug. We know that the C-D bond is more stable than the C-H bond, and many drugs involve the breaking of the C-H bond in the metabolic clearance mechanism of the body. Therefore, the introduction of deuterium atoms at the metabolic site of the drug can slow down or prevent the breaking of the C-D bond, so as to change the drug Metabolic rate or purpose of metabolic pathway. Compared with non-deuterated drugs, deuterium-banded drugs can slow down drug metabolism, improve pharmacokinetics, and reduce toxic metabolites. Therefore, deuterated technology is also considered to be a simple and eff...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/30C07D215/18C07D215/14C07D235/12C07D277/64C07D221/12C07D405/06C07D409/06A61P35/00
CPCC07D213/30C07D215/18C07D215/14C07D235/12C07D277/64C07D221/12C07D405/06C07D409/06A61P35/00
Inventor 江智勇
Owner HENAN NORMAL UNIV
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