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Chiral alpha-quaternary carbon-alpha-hydroxy-beta-aminoketone derivative and synthesis method thereof

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, etc., to achieve the effect of wide application range of substrates, high chemoselectivity, and short steps

Active Publication Date: 2019-06-18
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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  • Chiral alpha-quaternary carbon-alpha-hydroxy-beta-aminoketone derivative and synthesis method thereof
  • Chiral alpha-quaternary carbon-alpha-hydroxy-beta-aminoketone derivative and synthesis method thereof
  • Chiral alpha-quaternary carbon-alpha-hydroxy-beta-aminoketone derivative and synthesis method thereof

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Experimental program
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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 alpha-quaternary carbon-alpha-hydroxy-beta-aminoketone. An alcohol, a diazo compound and 1,3,5-triaryl-1,3,5-triazine which are used as raw materials undergo a one-step three-component reaction in an organic solvent with Rh2(esp)2 as a catalyst, chiral phosphoric acid (CPA) as a cocatalyst and a molecular sieve as an additive to obtain the product at ahigh stereoselectivity and a high yield. The method has the advantages of good atom economy, good stereoselectivity, mild reaction conditions, high yield, and simplicity and safety in operation. Themethod realizes asymmetric Mannich reaction of hydroxyl ylides, and allows a series of optically pure alpha-quaternary carbon-alpha-hydroxy-beta-aminoketone derivatives to be 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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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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