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Novel method for preparing chiral alpha-hydroxy-beta-dicarbonyl compound by using quinine C-2' derivative as catalyst

A technology of dicarbonyl compound and cinchona base is applied in the field of efficient preparation of chiral α-hydroxy-β-dicarbonyl compound and achieves the effect of high catalytic activity

Active Publication Date: 2015-12-16
DALIAN UNIV OF TECH
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Problems solved by technology

However, cinchonine can only obtain the oxidation product of 50% ee, and modify the cheap and easy-to-obtain cinchonine to obtain a more efficient organic catalyst, obtain higher enantioselectivity, and a wider range of substrates, especially when using the same catalyst It is still a great challenge to efficiently obtain two oxidation products with different configurations

Method used

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  • Novel method for preparing chiral alpha-hydroxy-beta-dicarbonyl compound by using quinine C-2' derivative as catalyst
  • Novel method for preparing chiral alpha-hydroxy-beta-dicarbonyl compound by using quinine C-2' derivative as catalyst
  • Novel method for preparing chiral alpha-hydroxy-beta-dicarbonyl compound by using quinine C-2' derivative as catalyst

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Experimental program
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Effect test

Embodiment 1

[0043] Embodiment 1: 2 '-bromo-dihydroquinine preparation (formula Ia, R 2 for Br, R 1 For Me): Weigh 3.26 g of dihydroquinine, dissolve in 45 mL of chloroform, and cool to 0°C. Subsequently, 5.08 g of m-chloroperoxybenzoic acid with a mass fraction of 85% was added and stirred for half an hour. Subsequently, it was raised to room temperature, and stirring was continued for 3 hours until the reaction was complete. A 10% aqueous NaOH solution was added to the reaction solution until the pH of the aqueous layer=10. The aqueous phase was extracted 5 times with chloroform / methanol=10:1 mixed solution. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was suspended to dry to obtain dihydroquinine bis-N-O compound (3.55 g, 99% yield) as light yellow solid. The crude product was directly used in the next reaction. Weigh 2.60gNaHSO 3, add 20 mL of 1mol / L HCl, and stir for one hour. Subsequently, the temperature was lowered to 0°C. The dihyd...

Embodiment 2

[0044] Embodiment 2: 2'-bromo-6'-hydroxyl-dihydro cinchonidine (formula Ia, R 2 for Br, R 1 For the preparation of H):

[0045] Weigh 2'-bromo-dihydroquinine (0.48g) and place it in a 25mL three-necked flask, and add 5mL of 40% mass fraction of hydrobromic acid. The mixture was reacted at 110°C for 16 hours. Cool down and adjust pH=9 using solid NaOH. The mixture was extracted 4 times with dichloromethane / methanol=15:1 mixture, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (40% ethyl acetate, 15% methanol, 2% triethylamine , 43% petroleum ether) to obtain 0.39 g of 2`-bromo-6`-hydroxyl-dihydrocinchonidine, with a yield of 85%. 1HNMR (500MHz, Methanol-d4) δ7.83(dd, J=9.0, 1.5Hz, 1H), 7.68(s, 1H), 7.33(ddd, J=9.2, 2.6, 1.2Hz, 1H), 7.24(d ,J=2.6Hz,1H),5.47(d,J=3.3Hz,1H),3.70(dtd,J=8.1,5.3,2.5Hz,1H),3.21–3.03(m,2H),2.74(qd, J=7.4,3.4Hz,3H),2.49–2.36(m,1H),1.97–1.79(m,3H),1.62–1.49(m,2H),1.48–1.38(m...

Embodiment 3

[0046] Embodiment 3: 2 '-chloro-dihydroquinine (formula Ia, R 2 for Cl, R 1 Preparation of Me): at 0°C, weigh 0.34 g of dihydroquinine mono-N-O compound, add 5 mL of chloroform, and add 0.61 g of phosphorus oxychloride under nitrogen protection. After stirring for 30 minutes, the temperature was raised to 70° C., and the reaction was refluxed for 2.5 hours. After the reaction, 15 mL of ice water was added, and the pH was adjusted to 10 with ammonia water. The mixture was extracted four times with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated. Column chromatography separation (40% ethyl acetate, 5% methanol, 2% triethylamine, 53% petroleum ether) gave 0.30 g of 2'-chloro-dihydroquinine with a yield of 83%. 1 HNMR (500MHz, Methanol-d 4 )δ8.00–7.82(m,1H),7.64(d,J=2.9Hz,1H),7.54–7.34(m,2H),5.55–5.44(m,1H),4.12–3.88(m,3H) ,3.71(s,1H),3.15(s,2H),2.97(q,J=7.3Hz,1H),2.77(s,1H),2.47(d,J=12.4Hz,1H),1.99–1.76( m,3H), 1.22...

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Abstract

The invention belongs to the technical field of organic synthesis, and provides a novel method for preparing a chiral alpha-hydroxy-beta-dicarbonyl compound by using quinine C-2' derivative as a catalyst. The quinine C-2' derivative, of which the amount is 0.5-50 mol%, is used as the catalyst to react with a substrate and an oxidizer in an inert reaction solvent to prepare the chiral alpha-hydroxy-beta-dicarbonyl compound, wherein the maximum yield is 99%, and the maximum enantiomeric excess value is 98%. The inert solvent comprises halohydrocarbon, aromatic hydrocarbon, alkane and the like. The oxidizer is common organic peroxide. The ratio of the oxidizer to the beta-dicarbonyl compound is 1-20, and the reaction temperature is -70 to 50 DEG C. The organic peroxide or oxydol can be used as the oxidizer to respectively obtain two alpha-hydroxylation products in different configuration.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to a method for efficiently preparing chiral α-hydroxyl-β-dicarbonyl compounds using cinchona base C-2′ derivatives as catalysts. Background technique [0002] Optically active ɑ-hydroxy-β-dicarbonyl compounds are a very important structural unit, which widely exist in natural products, chiral pharmaceuticals and pesticide intermediates. It is worth mentioning that (S)-5-chloro-1-oxoindene-2-hydroxy-2-carboxylic acid methyl ester is an important intermediate of the pesticide indoxacarb. Davis first reported the method of using Davis reagent to obtain chiral α-hydroxyl-β-dicarbonyl compound in 1981 (Tetrahedron Lett.1981, 22, 4385-4388), but the method is cumbersome to operate, the reaction conditions are relatively harsh, and excessive use of Chiral oxidizing agent has high cost and is not suitable for production application. [0003] In recent years, researchers have repo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/82C07C231/12C07C69/757C07C67/31B01J31/02C07D453/04
Inventor 孟庆伟王亚坤刘广志杨帆陈帅唐晓飞
Owner DALIAN UNIV OF TECH
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