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Salan ligand, metal-Salan complex and preparation method of chiral alpha-hydroxy-beta-keto ester compound

A technology of keto esters and complexes, which is applied in the field of organic synthesis catalysis, can solve problems such as not optimistic, and achieve the effects of high enantiomeric excess value, good application prospects, and mild reaction conditions

Inactive Publication Date: 2019-05-21
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Document (J.Org.Chem. 2004,69,8165-8167) discloses a kind of method that directly uses cinchona base and its derivatives as catalyst to prepare α-hydroxyl-β-ketoester, and the yield of this method is generally At 80-90%, but the enantiomeric excess value is around 80%, which is relatively not optimistic
Meng et al. (Org. Lett. 2017, 19, 448-451) prepared chiral α-hydroxy-β-ketoesters by organotransition metal complexes, and achieved good results, with a yield of 99%, enantiomeric excess value Also up to 98%, however, the catalyst consumption reported in this document is used as 10mol%, which is relatively high

Method used

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  • Salan ligand, metal-Salan complex and preparation method of chiral alpha-hydroxy-beta-keto ester compound
  • Salan ligand, metal-Salan complex and preparation method of chiral alpha-hydroxy-beta-keto ester compound
  • Salan ligand, metal-Salan complex and preparation method of chiral alpha-hydroxy-beta-keto ester compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of ligand L3 (R is 2-methoxyphenyl)

[0028]

[0029] Under argon protection, dissolve (1S,2S)-1,2-diphenylethylenediamine (1.0mmol, 212mg, 1.0equiv) in 50mL of absolute ethanol, and then add 3-(2-methoxy)benzene Base salicylaldehyde (2.0mmol, 456mg, 2.0equiv), continue to stir for 10min, then add 5 drops of acetic acid successively, Molecular sieve. The reaction solution was refluxed overnight. Cool down to 0°C, add NaBH in batches 4 (3.0 mmol, 113 mg, 3.0 equiv), stirred overnight at room temperature. After the reaction was completed, the resulting mixed solution was evaporated to dryness, and then the resulting solid was added with NH 4 Cl quenched, stirred for 30min, CH 2 Cl 2 Extract 3 times. Wash twice with saturated saline, anhydrous NaSO 4 Dry, evaporate the solvent to dryness, and recrystallize from ethanol to obtain L3 (541 mg, 0.85 mmol, 85% yield).

[0030] (c=0.5, CHCl 3 );

[0031] 1 H NMR (600MHz, CDCl 3 )δ9.73(s,2H),7.33(td...

Embodiment 2

[0036] Optimization of reaction conditions

[0037]

[0038] Dissolve metal compound (5.0mol%) and ligand (5.5mol%) in 2mL organic solvent, stir at room temperature for 30min, then add methyl 5-chloroindanone formate (1.0equiv.) and oxidizing agent (1.5equiv.) successively, Continue to react for 4h. After the reaction is complete, use CH 2 Cl 2 Extracted 3 times, and the organic phase was washed 2 times with saturated brine. with anhydrous Na 2 SO 4 After drying, filtering, and evaporating the resulting solution to dryness, a crude product was obtained, which was separated by column chromatography to obtain a pure product.

[0039] Table 1 condition optimization

[0040]

[0041]

[0042] a 0°C; b 50°C; c 30%H 2 o 2 ; d tert-butyl hydroperoxide (TBHP);e Add additive acetic acid; f HPLC: OD-H (5μm, 250 mm×4.6mm), 25℃, hexane / i-PrOH=90 / 10, 1mL / min, 254nm, t R1 (major)=12.5min,t R2 (minor) = 15.7 min.

[0043] We know from Table 1 that the corresponding...

Embodiment 3

[0045] Preparation of Chiral α-Hydroxy-β-Ketoesters

[0046]

[0047] The above formula shows the preparation process of α-hydroxy-β-ketoester: Dissolve L3 (5.5mol%, 3.5mg, 0.055equiv.) in 2 mL toluene, add Zr(acac) 4 (5.0mol%, 2.4mg, 0.05equiv.), stirred at room temperature for 30min to prepare the Zr(IV)-Salan complex, and then added I (0.1mmol, 1.0equiv.), cumene hydroperoxide (CHP; 80 %wt, 0.15mmol, 28.5 mg, 1.5equiv.), and continued stirring at room temperature for 4h. After the reaction was completed, α-hydroxy-β-ketoester II was separated by column chromatography (petroleum ether / ethyl acetate=8 / 1). The product yield, ee value and detection method thereof are shown in Table 2.

[0048] Table 2 α-Hydroxy-β-keto ester data analysis

[0049]

[0050]

[0051]

[0052] From Table 2, we found that the yield and ee value of the obtained α-hydroxy-β-ketoester were between 92–99% and 90–99%, respectively, without considering the influence of electron-withdrawing ...

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Abstract

The invention discloses a Salan ligand, metal-Salan complex and a preparation method of a chiral alpha-hydroxy-beta-keto ester compound. The preparation method comprises the following steps that (1S,2S)-1,2-Diphenylethylenediamine-derived Salan ligand is used as a chiral source and is coordinated with metal ions to prepare the metal-Salan complex, the prepared metal-Salan complex reacts with a substrate and an oxidant in an organic solvent to obtain the chiral alpha-hydroxy-beta-keto ester compound. The yield is up to 99% and the enantiomeric excess is up to 99% which is the highest enantioselectivity to date. The method has the advantages of mild reaction conditions, less catalyst consumption, simple operation, high enantiomeric excess and good application prospects.

Description

technical field [0001] The invention belongs to the field of organic synthesis catalysis, and specifically relates to a Salan ligand, a metal-Salan complex and a method for preparing chiral α-hydroxyl-β-keto ester compounds. Background technique [0002] Chirality is one of the essential properties of nature. In recent years, with the development of organic synthesis, more and more chiral compounds can be obtained by chemical synthesis. Asymmetric catalysis has become an important method for the synthesis of chiral substances, and it is one of the key technologies that must be broken through in the industrial production of chiral drugs. [0003] Indoxacarb, a high-efficiency insecticide developed by DuPont Corporation of the United States, its key intermediate (+)-5-chloro-2,3-dihydro-2-hydroxy-1-oxo-2H-indene-2-carboxylic acid methyl ester It is obtained by α-hydroxylation of methyl 5-chloroindanone formate. In addition, chiral α-hydroxy-β-ketoesters are ubiquitous and i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/58C07C67/31B01J31/22C07C69/757C07C213/02C07C213/08
Inventor 王斌郑庚修陈洁谷海洋朱学英
Owner UNIV OF JINAN
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