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

A ketoester and compound technology, applied in the field of organic asymmetric catalysis, can solve the problems of expensive catalyst, large catalytic amount of catalyst, low enantioselectivity, etc., and achieve the effects of efficient asymmetric synthesis, low cost and simple synthesis

Active Publication Date: 2022-07-29
NANJING TECH UNIV
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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
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Effect test

Embodiment 1

[0038] Preparation of 2-(4-Methoxyphenyl)-2-oxoethyl (S)-2-hydroxy-2-methyl-3-oxobutyrate (Formula II, wherein R 1 ,R 2 is methyl, R 3 For p-methoxyacetophenone group):

[0039]

[0040] 2-(4-Methoxyphenyl)-2-oxoethyl (E)-2-methylbut-2-enoic acid (formula I, wherein R 1,R 2 is methyl, R 3 For p-methoxyacetophenone) (49.6mg, 0.20mmol), N-3,5-difluorobenzyl-O-2-bromo-3,5-di-tert-butylbenzyl quinaline quaternary A mixture of ammonium salt phase transfer catalyst Cat.1 (7.8 mg, 5 mol%) in toluene (4 mL) was cooled to -20°C, and then acetic acid (60.0 mg, 5 eq.), potassium permanganate (63.2 mg) were added to it sequentially , 2eq.) and 40% aqueous KF. The mixture was reacted at -20°C for 12 hours. After the complete reaction of the starting materials, the reaction mixture was filtered. The solvent was then re-evaporated and purified rapidly with a silica gel column. 2-(4-Methoxyphenyl)-2-oxoethyl (S)-2-hydroxy-2-methyl-3-oxobutyrate gave 96% yield with enantiomeric Th...

Embodiment 2

[0050] Preparation of 2-(4-Methoxyphenyl)-2-oxoethyl (S)-2-acetyl-2-hydroxypent-4-enoate (Formula II, wherein R 1 is allyl, R 2 is methyl, R 3 for p-methoxyacetophenone group)

[0051]

[0052] 2-(4-Methoxyphenyl)-2-oxoethyl (E)-2-ethylenepent-4-enoate (Formula I, where R 1 is allyl, R 2 is methyl, R 3 For p-methoxyacetophenone) (54.8mg, 0.20mmol), N-3,5-difluorobenzyl-O-2-bromo-3,5-di-tert-butylbenzyl quinaline quaternary A mixture of ammonium salt phase transfer catalyst Cat.1 (7.8 mg, 5 mol%) in TBME (4 mL) was cooled to -40°C, and then acetic acid (60.0 mg, 5 eq.), potassium permanganate (63.2 mg) were added to it sequentially , 2eq.) and 40% aqueous KF. The mixture was reacted at -40°C for 12 hours. After the complete reaction of the starting materials, the reaction mixture was filtered. The solvent was then re-evaporated and purified rapidly with a silica gel column. 2-(4-Methoxyphenyl)-2-oxoethyl (S)-2-acetyl-2-hydroxypent-4-enoate gave 89% yield with enanti...

Embodiment 3

[0055] Preparation of 2-(4-Methoxyphenyl)-2-oxoethyl (S)-2-hydroxy-2-methyl-3-oxobutyrate (Formula II, wherein R 1 ,R 2 is methyl, R 3 For p-methoxyacetophenone group):

[0056]

[0057] 2-(4-Methoxyphenyl)-2-oxoethyl (S)-2-acetyl-2-hydroxypent-4-enoate (formula I, wherein R 1 is benzyl, R 2 is methyl, R 3 as p-methoxyacetophenone) (49.6 mg, 0.20 mmol), N-3,4-difluorobenzyl-O-2-bromo-3,5-bis(3,5-di-tert-butyl) A mixture of phenylbenzyl bromide cinchona-based quaternary ammonium salt phase transfer catalyst Cat.2 (9.7 mg, 5 mol%) in TBME (4 mL) was cooled to 0°C, and then acetic acid (60.0 mg, 5 eq.) was sequentially added 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 complete reaction of the starting materials, the reaction mixture was filtered. The solvent was then re-evaporated and purified rapidly with a silica gel column. 2-(4-Methoxyphenyl)-2-oxoethyl (S)-2-hydroxy-2-methyl...

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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. And reaction: 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 method for synthesizing a chiral α-hydroxy-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 the 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 vinblastine and its analogs, camptothecin, etc. Chiral α-hydroxy-β-ketoesters also exist in the key intermediates in the synthesis of pyrazoline insecticides Indoxacarb. The S configuration of this insecticide is the effective configuration for insecticide. Like chiral drugs, the use of chiral pure pesticides is more beneficial to improve the effective activit...

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 TECH UNIV
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