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Method for preparing chemical compounds of interest by nucleophilic aromatic substitution of aromatic carboxylic acid derivatives supporting at least one electro-attractive group

A technology for aromatic carboxylic acids and carboxylic acid derivatives, which is applied in the preparation of carboxylate, the preparation of organic compounds, the preparation of cyanide reactions, etc.

Inactive Publication Date: 2013-03-20
曼恩大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, it has widely reported disadvantages, notably the need to use a catalyst, and the need for the carboxyl functional group (CO 2 H) for protection / deprotection, which is necessary as a carbon fixation site for subsequent chemical functionalization reactions

Method used

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  • Method for preparing chemical compounds of interest by nucleophilic aromatic substitution of aromatic carboxylic acid derivatives supporting at least one electro-attractive group
  • Method for preparing chemical compounds of interest by nucleophilic aromatic substitution of aromatic carboxylic acid derivatives supporting at least one electro-attractive group
  • Method for preparing chemical compounds of interest by nucleophilic aromatic substitution of aromatic carboxylic acid derivatives supporting at least one electro-attractive group

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specific example

[0049] Presence of asymmetric carbon

[0050] According to a preferred embodiment, there is an asymmetric carbon on the aromatic carboxylic acid derivative, preferably on the benzoic acid derivative of the general formula (II) and / or on the nucleophile, and the obtained general formula Compounds of (I) are asymmetric. Very advantageously, the aromatic carboxylic acid derivative, preferably the benzoic acid derivative of general formula (II), has at least one chiral leaving group.

[0051] Use of Chiral Ligands

[0052] In a particular embodiment, a chiral ligand is added to the reaction mixture; this ligand serves to impart chirality to the reaction product (I) of the invention.

[0053] According to the present invention, the chiral ligand can be selected from chiral diamines, chiral diethers, chiral amino ethers, multi-point binding chiral amino ethers and bis Bisoxazoline ligands. Examples of chiral ligands that can be used are described in Table 1.

[0054]

...

Embodiment 1

[0125] Embodiment 1-preparation of 2-n-butyl-6-fluorobenzoic acid

[0126]

[0127] n-BuLi (6.9 mL, 11 mmol, 1.6M in hexane) was added to a solution of 2,6-difluorobenzoic acid (791 mg, 5 mmol) in anhydrous THF (30 mL) at -78 °C. The reaction mixture was stirred at this temperature for 2 h, then iodomethane (1.25 mL, 12 mmol) was added. The solution was hydrolyzed with water (20 mL) at room temperature and the two phases were separated. The aqueous phase was washed with ethyl acetate (3 x 40 mL). The aqueous phase was then acidified to pH 1 and extracted with ethyl acetate (3 x 40 mL). Combined organic phases in MgSO 4 Dry over and concentrate under vacuum. The residue was purified by silica gel chromatography (cyclohexane: ethyl acetate 95:5) to give 2-butyl-6-fluorobenzoic acid (425 mg, 2.17 mmol, 43%) as a yellow oil. Adding iodomethane before hydrolysis did not change the reaction outcome. 1 H NMR (400MHz, CDCl 3 )δ: 11.04(s large, 1H), 7.35(td, JHF=5.7Hz, J=8....

Embodiment 2

[0128] Embodiment 2-preparation 2,6-di-sec-butylbenzoic acid

[0129]

[0130] This compound was prepared according to the procedure of Example 1 from 2,6-difluorobenzoic acid (791 mg, 5 mmol) and s-BuLi (10.7 mL, 15.0 mmol, 1.4M in cyclohexane). The reaction mixture was stirred at 0 °C for 4 h. Purification by recrystallization (cyclohexane / ethyl acetate) afforded 2,6-di-sec-butylbenzoic acid (650 mg, 2.77 mmol, 55%) as a white solid (mp 125-126°C). Adding iodomethane before hydrolysis did not change the reaction outcome. 1 H NMR (400MHz, CDCl 3 )δ: 7.36(t, J=7.8Hz, 1H), 7.13(d, J=7.8Hz, 2H), 2.73(sext, J=7.0Hz, 2H), 1.75-1.55(m, 4H), 1.27( dd, J=1.6Hz, J=6.8Hz, 6H), 0.85(t, J=7.4Hz, 6H). 13 C NMR (100MHz, CDCl 3 )δ: 176.2, 143.2, 133.4, 129.5, 122.8, 38.7, 30.9, 22.0, 12.1. IR (ATR, cm -1 ): 2955, 2925, 2864, 1705, 1594, 1585, 1456, 1390, 1379, 1260, 1134, 1003, 908, 803, 764, 699, 609.C 15 h 26 NO 2 HRMS[M+NH 4 ] + Calculated: 252.1964, Measured: 252.1963.

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Abstract

The present invention relates to a method for preparing aromatic carboxylic acid derivatives by nucleophilic aromatic substitution, which involves reacting an aromatic carboxylic acid derivative supporting only one carboxyl function, or one of the salts thereof, said carboxylic acid derivative supporting, orthogonally to the carboxyl function, a splitting group which is an atom of fluorine or chlorine or an alcoxy group, chiral or otherwise and, in the latter case, a methoxy group is preferred; said carboxylic acid derivative being substituted by at least one electro-attractive group other than the splitting group, preferably by a fluorine atom, with a MNu reagent, wherein M is a metal and Nu is an optionally chiral nucleophile, said nucleophilic aromatic substitution reaction being carried out without a catalyst and without a step of protecting / unprotecting the acid function of the initial compound, said method being selective in that the reaction leads to the formation of ketone derivatives in a very minority fashion during the reaction.

Description

technical field [0001] The present invention relates to the field of chemical synthesis, and in particular, the present invention proposes a novel method capable of nucleophilic aromatic substitution of aromatic carboxylic acid derivatives carrying at least one electron-withdrawing group in addition to the leaving group , the nucleophilic aromatic substitution is carried out without a catalyst and without a protection / deprotection step of the acid function of the starting compound. Background technique [0002] Nucleophilic aromatic substitution is a well-known and widely used reaction in industry. However, it has widely reported disadvantages, notably the need to use a catalyst, and the need for the carboxyl functional group (CO 2 H) Protection / deprotection, which is necessary as a carbon fixation site for subsequent chemical functionalization reactions. [0003] The use of the catalyst is limited because it must be trapped and removed at the end of the reaction. Catalys...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/353C07C227/08C07D295/155C07C229/56C07C229/58C07C229/64C07C229/68
CPCC07B37/04C07C51/353C07C227/08C07B43/04C07C63/04C07C63/70C07C63/331C07C229/56C07C229/58C07C63/72
Inventor 雅克·莫尔捷安-苏菲·卡斯塔奈阿诺·诺里迈克尔·比罗德-罗特尔
Owner 曼恩大学
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