NON type chiral bisoxazoline ligand nd synthesis method and application thereof

A bisoxazoline and synthesis method technology, which is applied in the field of NON-type chiral bisoxazoline ligands and its synthesis, can solve the problems of insufficient synthesis method, harsh synthesis conditions, and few reaction types, etc.

Active Publication Date: 2020-06-05
SHANGHAI NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these developed NON oxazoline ligands have achieved good results in the corresponding asymmetric catalytic reactions, there are not many types of reactions that can be applied to them, and the synthesis methods are not efficient enough, the synthesis conditions are harsh, and the raw materials More expensive and other limitations

Method used

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  • NON type chiral bisoxazoline ligand nd synthesis method and application thereof
  • NON type chiral bisoxazoline ligand nd synthesis method and application thereof
  • NON type chiral bisoxazoline ligand nd synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1: Synthesis of Intermediate 4.

[0060]

[0061] Under anhydrous and oxygen-free conditions, o-iodobenzoic acid compound 2 (4.96g, 20mmol, 1 equiv) was added to the reactor, nitrogen was replaced three times, then 80mL of dry dichloromethane was added to the reactor, and stirred at 0°C for 2 ~3 minutes, after the internal and external temperature stabilized, add two drops of N,N-dimethylformamide, and finally add oxalyl chloride (1.86mL, 22mmol, 1.1equiv) dropwise into the system using a constant pressure dropping funnel, half The drop was completed within hours, and finally the reactor was transferred to room temperature for reaction. After the reaction solution became transparent, TLC monitored it. After 6-7 hours, the reaction stopped, and was directly spin-dried to obtain o-iodobenzoyl chloride compounds. Under anhydrous and oxygen-free conditions, add methyl acetate 3 (6.4mL, 80mmol, 4equiv) into a 500mL reactor, then add 120mL of dry tetrahydrofuran or...

Embodiment 2

[0063] Example 2: Synthesis of Intermediate 5.

[0064]

[0065] Under anhydrous and oxygen-free conditions, the intermediate 4 (6.08g, 20mmol, 1equiv), cuprous iodide (381mg, 2mmol, 0.1equiv), and tetrakis (triphenylphosphine) palladium (1.156g, 1mmol, 0.05 equiv) were added to the reactor respectively, nitrogen was replaced three times, then propargyl alcohol (4.6mL, 80mmol, 4equiv) and triethylamine (8.3mL, 60mmol, 3equiv) were added to the reactor, and finally 200mL of dry tetrahydrofuran was added to the reactor , stirred at 50°C for 18h, TLC monitored R f=0.2 (ethyl acetate:petroleum ether=1:1, UV) the reaction was completed, and after the reaction device returned to room temperature, filter it directly with diatomaceous earth, and spin the filtrate to dryness. Intermediate 5 (3.99 g, 86%) was obtained by column chromatography separation with ethyl acetate:petroleum ether=1:5 or 1:1.

[0066] white solid. 1 H NMR (400MHz, CDCl 3 )δ7.62(d, J=3.8Hz, 1H), 7.60(d, J=3...

Embodiment 3

[0067] Example 3: Synthesis of Intermediate 6.

[0068]

[0069] under anhydrous and oxygen-free conditions. Intermediate 5 (4.64g, 20mmol, 1equiv) and Molecular sieves (6g) were added to the reactor, nitrogen was replaced three times, then 180mL of dry dichloromethane was added, and stirred at 0°C for 10 minutes. After the internal and external temperatures were stabilized, Dess-Martin reagent (8.48g, 20mmol, 1equiv) was slowly added to the reaction system. TLC monitoring reaction R f =0.5 (ethyl acetate:petroleum ether=1:1, UV), 5~10h after the reaction is over, return the reaction device to room temperature, filter directly with diatomaceous earth, slowly add sodium thiosulfate solution to the filtrate, stir for 30 minutes, Extract with ethyl acetate, combine the organic phases, add saturated sodium bicarbonate solution, wash twice with saturated sodium chloride solution, dry over anhydrous magnesium sulfate, and spin the filtrate to dryness. Using ethyl acetate:pet...

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Abstract

The invention relates to an NON type chiral bisoxazoline ligand and a synthesis method and application thereof. The ligand has a bisoxazoline structure as shown in a general formula 1, the synthesis method of the NON type chiral bisoxazoline ligand comprises the following steps: taking an o-iodobenzoic acid compound as an initial raw material, performing acylating chlorination on a benzoisofuranylalkylene dicarboxylic acid skeleton prepared through multi-step reaction, performing condensation with chiral amino alcohol, and finally performing cyclization to obtain a ligand 1 which is used for catalytic synthesis of chiral fluorinated beta-ketone ester. Compared with the prior art, the synthesis method disclosed by the invention is simple and efficient, mild in synthesis condition and easy to operate and good in repeatability, and the corresponding metal complex shows good catalytic activity and stereoselectivity in the asymmetric fluorination reaction of beta-ketone ester.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to a NON-type chiral bisoxazoline ligand and a synthesis method and application thereof. Background technique [0002] Asymmetric catalysis has become a frontier in organic synthesis and organometallic chemistry. Chiral ligands play a vital role in the development of chiral drugs, chiral materials and other chemicals. Chiral oxazoline ligands have been proven to be one of the dominant chiral ligands with excellent stereoselectivity. Since many excellent ligands and catalysts have been protected by patents, and the types of ligands currently developed are limited, most of them are ligands of the same type of skeleton, which are generally only suitable for specific reaction types, and their industrial applications and medical research have great potential. Very restrictive. Therefore, designing and synthesizing bisoxazoline chiral ligands with new skeletons with independent...

Claims

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Application Information

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IPC IPC(8): C07D413/14B01J31/22C07C67/307C07C69/757
CPCC07D413/14B01J31/2217C07C67/307C07B2200/07C07C2602/08B01J2531/26B01J2531/0241C07C69/757
Inventor 邓清海任冰涛刘炎开江岭峰
Owner SHANGHAI NORMAL UNIVERSITY
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