A chiral α-quaternary carbon-α-hydroxyl-β-amino ketone derivative and its synthesis method

A synthetic method and technology of aminoketones, applied in chemical instruments and methods, preparation of steroids, cyanide reactions, etc., can solve the problem of the inability to realize the selectivity control of α-hydroxy-β-aminoketone products and the total yield of the reaction Low cost, long synthetic route and other issues, to achieve the effect of efficient atom economy, high atom economy, and short steps

Active Publication Date: 2021-12-07
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The synthesis methods for α-hydroxy-β-aminoketone building blocks in the existing reports all have long synthetic routes, cumbersome steps (more than 5 steps), low overall reaction yields (<30%), and relatively high wastes. Many defects such as the inability to control the enantioselectivity of α-hydroxy-β-aminoketone products are unfavorable for the application of chiral α-quaternary carbon-α-hydroxy-β-aminoketone building blocks in drug synthesis

Method used

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  • A chiral α-quaternary carbon-α-hydroxyl-β-amino ketone derivative and its synthesis method
  • A chiral α-quaternary carbon-α-hydroxyl-β-amino ketone derivative and its synthesis method
  • A chiral α-quaternary carbon-α-hydroxyl-β-amino ketone derivative and its synthesis method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118]

[0119] Add metal catalyst (1mol%), CPA (5mol%) and activated Molecular sieves (100 mg) and sealed with a rubber revolving plug. Ventilate, and replace the air in the system with nitrogen. Dichloromethane (1 mL) was added to the test tube via syringe and stirred at -10°C. After that, dissolve alcohol (1equiv), diazo compound (1equiv), 1,3,5-triaryl-1,3,5-triazine (0.33equiv) in 1mL of dichloromethane and slowly add to the reaction solvent with a peristaltic pump In, the dropping rate is 1mL / h. After the dropwise addition, the stirring reaction was continued until the diazo compound was completely consumed. Stop the reaction, use a capillary to take a small amount of the reaction solution, purify it by TLC, and use it for chiral HPLC analysis, and finally purify it by column chromatography (silica gel H, eluent: EA:PE = 1:200~1:50) to obtain a white solid product 5a. Yield 81%, ee% = 78%. 1 H NMR (400MHz, CDCl 3 )δ8.00 (d,2H),7.60(d,J=7.7Hz,2H),7.44(t,J=7.4Hz...

Embodiment 2

[0121]

[0122] Add metal catalyst (1mol%), CPA (5mol%) and activated Molecular sieves (100 mg) and sealed with a rubber revolving plug. Ventilate, and replace the air in the system with nitrogen. Dichloromethane (1 mL) was added to the test tube via syringe and stirred at -10°C. After that, dissolve alcohol (1equiv), diazo compound (1equiv), 1,3,5-triaryl-1,3,5-triazine (0.33equiv) in 1mL of dichloromethane and slowly add to the reaction solvent with a peristaltic pump In, the dropping rate is 1mL / h. After the dropwise addition, the stirring reaction was continued until the diazo compound was completely consumed. Stop the reaction, use a capillary to take a small amount of the reaction solution, purify it by TLC, and use it for chiral HPLC analysis, and finally purify it by column chromatography (silica gel H, eluent: EA:PE = 1:200~1:50) to obtain a white solid product 5b. Yield 81%, ee% = 94%. 1 H NMR (400MHz, CDCl 3 )δ7.91 (s,2H),7.69–6.99(m,14H),6.70–6.47(m,3H),...

Embodiment 3

[0124]

[0125] Add metal catalyst (1mol%), CPA (5mol%) and activated Molecular sieves (100 mg) and sealed with a rubber revolving plug. Ventilate, and replace the air in the system with nitrogen. Dichloromethane (1 mL) was added to the test tube via syringe and stirred at -10°C. After that, dissolve alcohol (1equiv), diazo compound (1equiv), 1,3,5-triaryl-1,3,5-triazine (0.33equiv) in 1mL of dichloromethane and slowly add to the reaction solvent with a peristaltic pump In, the dropping rate is 1mL / h. After the dropwise addition, the stirring reaction was continued until the diazo compound was completely consumed. Stop the reaction, use a capillary to take a small amount of the reaction solution, purify it by TLC, and use it for chiral HPLC analysis, and finally purify it by column chromatography (silica gel H, eluent: EA:PE = 1:200~1:50) to obtain a white solid product 5c. Yield 76%, ee% = 90%. 1 H NMR (400MHz, CDCl 3 )δ8.03 (d, J = 7.7Hz, 2H), 7.59 (d, J = 7.6Hz, ...

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Abstract

The invention discloses a synthesis method of chiral α-quaternary carbon-α-hydroxyl-β-amino ketone, which uses alcohol, diazo compound and 1,3,5-triaryl-1,3,5-triazine as Raw materials, Rh 2 (esp) 2 As a catalyst, chiral phosphoric acid (CPA) is used as a co-catalyst, and molecular sieves are used as an additive in an organic solvent, and the product is obtained with high stereoselectivity and high yield through a one-step three-component reaction. The method of the invention has the advantages of high atom economy, good stereoselectivity, mild reaction conditions, high yield, simple and safe operation and the like. The asymmetric amine methylation reaction of hydroxy ylide was realized, and a series of optically pure α-quaternary carbon-α-hydroxy-β-aminoketone derivatives were synthesized.

Description

technical field [0001] The invention belongs to the fields of synthetic medicine and chemical industry, and relates to an optically active α-quaternary carbon-α-hydroxyl-β-aminoketone derivative and a synthesis method thereof. Background technique [0002] α-Hydroxy-β-aminoketone building blocks widely exist in biologically active compounds and natural products, and have rich compound structure diversity and biological activity diversity. a physiological activity. [0003] Three classes of compounds as shown in formula (III) have been reported to have oral antifungal activity: [0004] [0005] For example, the natural product represented by the formula (IV) exhibits certain antitumor activity, the compound represented by the formula (V) is a kind of nervous system candidate drug, and the compound represented by the formula (VI) is a kind of IDO inhibitor. [0006] [0007] The synthesis methods for α-hydroxy-β-aminoketone building blocks in the existing reports all ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C221/00C07C225/16C07D307/42C07J41/00C07C229/60C07C227/18
Inventor 邢栋车久威牛荔贾世琨胡文浩
Owner EAST CHINA NORMAL UNIV
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