Preparation method of chiral alpha-hydroxy-beta-keto ester compound

A technology of keto esters and compounds, which is applied in the field of organic asymmetric catalysis, can solve the problems of expensive catalysts, large catalytic capacity, and low enantioselectivity, and achieve high-efficiency asymmetric synthesis, low cost, and simple synthesis

Inactive Publication Date: 2021-10-29
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The object of the present invention is to provide a kind of synthetic method of efficient preparation chiral α-hydroxyl-β-keto ester compound, to solve the low enantioselectivity proposed in the above-mentioned background technology, the catalytic amount of using catalyst is large, the reaction steps are loaded down with trivial details , expensive catalysts, etc.

Method used

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  • Preparation method of chiral alpha-hydroxy-beta-keto ester compound
  • Preparation method of chiral alpha-hydroxy-beta-keto ester compound
  • Preparation method of chiral alpha-hydroxy-beta-keto ester compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of 2-(4-methoxyphenyl)-2-oxoethyl (R)-2-hydroxyl-2-methyl-3-oxobutyrate (formula Ⅱ, wherein R 1 , R 2 is methyl, R 3 is p-methoxyacetophenone group):

[0039]

[0040] 2-(4-methoxyphenyl)-2-oxyethyl (E)-2-methylbut-2-enoic acid (formula I, where R 1 , R2 is methyl, R 3 It is p-methoxyacetophenonyl) (49.6mg, 0.20mmol), N-3,5-difluorobenzyl-O-2-bromo-3,5-di-tert-butylbenzyl quinone base quaternary The mixture of ammonium salt phase transfer catalyst Cat.1 (7.8mg, 5mol%) in toluene (4mL) was cooled to -20°C, then acetic acid (60.0mg, 5eq.), potassium permanganate (63.2mg , 2eq.) and 40% KF aqueous solution. The mixture was reacted at -20°C for 12 hours. After the starting material was completely reacted, the reaction mixture was filtered. The solvent was then evaporated again and flash purified on a silica gel column. 2-(4-Methoxyphenyl)-2-oxoethyl(R)-2-hydroxy-2-methyl-3-oxobutanoate was obtained in 96% yield and enantiomeric The ee value is 95%. ...

Embodiment 2

[0043] Preparation of 2-(4-methoxyphenyl)-2-oxoethyl (R)-2-acetyl-2-hydroxypent-4-enoate (formula II, where R 1 is allyl, R 2 is methyl, R 3 for p-methoxyacetophenone)

[0044]

[0045] 2-(4-methoxyphenyl)-2-oxyethyl (E)-2-ethylenepenta-4-enoate (formula I, where R 1 is allyl, R 2 is methyl, R 3 It is p-methoxyacetophenonyl) (54.8mg, 0.20mmol), N-3,5-difluorobenzyl-O-2-bromo-3,5-di-tert-butylbenzyl quinone base quaternary The mixture of ammonium salt phase transfer catalyst Cat.1 (7.8mg, 5mol%) in TBME (4mL) was cooled to -40°C, then acetic acid (60.0mg, 5eq.), potassium permanganate (63.2mg , 2eq.) and 40% KF aqueous solution. The mixture was reacted at -40°C for 12 hours. After the starting material was completely reacted, the reaction mixture was filtered. The solvent was then evaporated again and flash purified on a silica gel column. 2-(4-Methoxyphenyl)-2-oxoethyl(R)-2-acetyl-2-hydroxypent-4-enoate was obtained in 89% yield, and the enantiomeric ee The value ...

Embodiment 3

[0048] Preparation of 2-(4-methoxyphenyl)-2-oxoethyl (R)-2-hydroxyl-2-methyl-3-oxobutyrate (formula Ⅱ, wherein R 1 , R 2 is methyl, R 3 is p-methoxyacetophenone group):

[0049]

[0050] 2-(4-methoxyphenyl)-2-oxoethyl (R)-2-acetyl-2-hydroxypent-4-enoate (formula I, where R 1 is benzyl, R 2 is methyl, R 3 p-methoxyacetophenonyl) (49.6mg, 0.20mmol), N-3,4-difluorobenzyl-O-2-bromo-3,5-di(3,5-di-tert-butyl) The mixture of phenylbenzylcinchona base quaternary ammonium phase transfer catalyst Cat.2 (9.7mg, 5mol%) in TBME (4mL) was cooled to 0°C, and then acetic acid (60.0mg, 5eq.) was added successively thereto , potassium permanganate (63.2 mg, 2 eq.) and 200 microliters of water. The mixture was reacted at 0°C for 12 hours. After the starting material was completely reacted, the reaction mixture was filtered. The solvent was then evaporated again and flash purified on a silica gel column. 2-(4-Methoxyphenyl)-2-oxoethyl(R)-2-hydroxy-2-methyl-3-oxobutanoate was obtained ...

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Abstract

The invention discloses a preparation method of chiral alpha-hydroxy-beta-keto ester, and belongs to the technical field of organic asymmetric catalysis. The preparation method of the chiral alpha-hydroxy-beta-keto ester compound comprises the following steps: mixing alpha, beta-unsaturated ester and a cinchona alkali-derived phase transfer catalyst in an organic solvent, and adding acetic acid, potassium permanganate and a small amount of additive. reacting, after the initial raw materials completely react, filtering the reaction mixture; and then evaporating the solvent, and quickly purifying by using a silica gel column to obtain the chiral alpha-hydroxy-beta-keto ester compound with high enantioselectivity. According to the present invention, the efficient asymmetric synthesis of the chiral alpha-hydroxy-beta-keto ester is achieved, the new idea and the new method are provided for the synthesis of the chiral alpha-hydroxy-beta-keto ester, and the application range of the substrate is broadened.

Description

technical field [0001] The invention relates to the field of organic asymmetric catalysis, in particular to a synthesis method of chiral α-hydroxyl-β-ketoester. Background technique [0002] Chiral α-hydroxy-β-ketoesters are common building blocks in a variety of natural products and pharmaceuticals. This structure has a wide range of applications in the field of medicinal chemistry, among which more common drugs such as antibiotics: Kjellmanianone, Hamigeran A, etc. Chiral α-hydroxy-β-ketoesters exist in key intermediates in the synthesis of biologically active natural products, such as the anticancer drug vinca and its analogues, camptothecin, etc. Chiral α-hydroxy-β-keto esters also exist in the key intermediates for the synthesis of the pyrazoline insecticide Indoxacarb. The S configuration of this insecticide is the effective configuration of insecticide. Like chiral drugs, the use of chiral pure insecticides is more beneficial to improve the effective activity of th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/313C07C69/716C07C69/738
CPCC07C67/313C07B2200/07C07C69/716C07C69/738
Inventor 王超李娟王双双
Owner NANJING UNIV OF TECH
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