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Method for preparing alpha-ketoamide compounds

A technology of compound and ketoamide, which is applied in the field of preparation of α-ketoamide compounds, achieves the effects of easy post-processing, favorable large-scale industrial production, and good economy

Active Publication Date: 2013-02-13
CHENGDU DIAO PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This reaction system requires the addition of a strong base pyridine, and is only suitable for primary aromatic amines

Method used

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  • Method for preparing alpha-ketoamide compounds
  • Method for preparing alpha-ketoamide compounds
  • Method for preparing alpha-ketoamide compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047]

[0048] In a 25mL round bottom flask, at room temperature, add cuprous iodide (0.19g, 1mmol), acetophenone (0.59mL, 5mmol), piperidine (1.5mL, 15mmol), and then React at 50°C for 20 hours. After the reaction was completed, cool to room temperature, add 50 mL of ethyl acetate, and extract with 25 mL of water. The ethyl acetate layer was washed with dilute hydrochloric acid (0.5 M) and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was subjected to flash column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 0.96 g of the product (light yellow solid), yield: 88%. 1 H NMR (CDCl 3 ,600MHz,ppm):δ=7.97-7.95(d,J=7.4Hz,2H),7.67-7.63(t,J=7.4Hz,1H),7.54-7.51(t,J=7.7Hz,2H), 3.72(brs,2H),3.32-3.29(t,J=5.6Hz,2H),1.72-1.70(m,4H),1.56(brs,2H); 13 C NMR (CDCl 3 ,150MHz,ppm):δ=191.9,165.5,134.6,133.3,129.6,129.0,47.0,42.2,26.2,25.5,24.4; HRMS calcd for C 13 h 15 NNaO 2 (M+Na) + 240.0995, found 240.1001.

Embodiment 2

[0050]

[0051] In a 25mL round bottom flask, at room temperature, add cuprous iodide (0.048g, 0.25mmol), toluene 10mL, p-nitroacetophenone (0.83g, 5mmol), piperidine (1mL, 10mmol), and then React at 50°C for 10 hours under an atmosphere of oxygen. After the reaction was complete, concentrate under reduced pressure to remove toluene, add 50 mL of ethyl acetate, and extract with 25 mL of water. The ethyl acetate layer was washed with dilute hydrochloric acid (0.5 M) and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrated solution was subjected to flash column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 1.19 g of the product (light yellow solid), yield: 91%. 1 H NMR (CDCl 3 ,600MHz,ppm):δ=8.36-8.34(d,J=8.8Hz,2H),8.15-8.13(d,J=8.8Hz,2H),3.74-3.72(brd,2H),3.33-3.30(t ,J=5.5Hz,2H),1.73(brs,4H),1.59(brs,2H); 13 C NMR (CDCl 3 ,150MHz,ppm):δ=189.5,164.1,151.1,137.8,130.6,124.1,47.1,42.5,26.3,25.4,24.3; HRMS calcd for C 1...

Embodiment 3

[0053]

[0054] In a 25mL round bottom flask, at room temperature, add cuprous iodide (0.19g, 1mmol), p-chloroacetophenone (0.65mL, 5mmol), piperidine (1.5mL, 15mmol), and then React at 50°C for 20 hours under oxygen. After the reaction was completed, cool to room temperature, add 50 mL of ethyl acetate, and extract with 25 mL of water. The ethyl acetate layer was washed with dilute hydrochloric acid (0.5 M) and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was subjected to flash column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 1.03 g of the product (yellow oil), yield: 82%. 1 H NMR (CDCl 3 ,600MHz,ppm):δ=7.91-7.88(d,J=8.5Hz,2H),7.50-7.47(d,J=8.5Hz,2H),3.71-3.69(t,J=5.2Hz,2H), 3.30-3.27(t,J=5.6Hz,2H),1.73-1.67(m,4H),1.58-1.53(m,2H); 13 C NMR (CDCl 3 ,150MHz,ppm):δ=190.5,164.9,141.2,131.7,130.9,129.4,47.1,42.3,26.3,25.4,24.4; HRMS calcd for C1 3 h 14 ClNNaO 2 (M+Na) + 274.0605,found 274.0604.

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Abstract

The present invention relates to a synthesis method for alpha-ketoamide compounds, wherein a plurality of alpha-ketoamide compounds can be prepared through the synthesis method. According to the present invention, cheap and easily available methyl ketone and amine are adopted as raw materials, various metal salts are adopted as catalysts, no medium solvent is required (a reaction further can be performed in an organic medium solvent), and the alpha-ketoamide compound is subjected to one step synthesis under an oxygen source condition of an atmospheric pressure; other additives such as an alkali, a ligand and the like are not used; the prepared alpha-ketoamide compound has a structure general formula represented by a formula I, wherein R1 is hydrogen atom, aryl, heteroaryl, aralkyl, alkyl, cycloalkyl and other substituted groups, and R2 and R3 are independently hydrogen atom, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl and other substituted groups; and the method is an alpha-ketoamide compound synthesis method with characteristics of simpleness, efficiency, environment protection, mild conditions, high yield and no organic solvent.

Description

technical field [0001] The invention relates to a preparation method of α-ketoamide compounds, in particular to a metal-catalyzed aerobic oxidation synthesis of α-ketoamide compounds under mild and environment-friendly conditions. Background technique [0002] α-Ketoamide compounds are not only a very important class of organic synthesis intermediates, but also the key skeleton structure of many biologically active compounds, such as immunosuppressant FK506, FKBP12, cytosolic phosphatase A 2 Inhibitors, androgen and estrogen receptors. At present, the reported synthetic methods of α-ketoamides include: [0003] 1. Acylation reaction of α-keto acid with amine (M.M.Sheha, N.M.Mahfouz, H.Y.Hassan, A.F.Youssef, T.Mimoto, Y.Kiso.Eur.J. Med Chem.2000,35,887-894.), the reaction A coupling reagent such as EDC needs to be added, and the raw keto acid is difficult to prepare. [0004] [0005] 2. Oxidation of amides and various amide derivatives such as α-hydroxyamide, α-aminoam...

Claims

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Application Information

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IPC IPC(8): C07C235/80C07C231/10
Inventor 姬建新杜丰田李伯刚
Owner CHENGDU DIAO PHARMA GROUP
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