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Preparation method of aryl propionic acid derivative

A technology of arylpropionic acid and derivatives, applied in the field of preparation of arylpropionic acid derivatives, can solve the problems of harsh reaction conditions, lengthy routes, and high requirements for production equipment

Inactive Publication Date: 2011-06-01
中国中化股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The application of this method is limited due to the need to use the noble metal palladium and the production of isomers and harsh reaction conditions
[0010] Throughout the disclosed methods for the preparation of aryl propionic acid derivatives, the sources of raw materials are difficult and expensive, and multiple oxidation and reduction reactions or the use of noble metal palladium or toxic metals nickel, manganese, and cobalt are required. The route is lengthy and the reaction conditions are harsh. Poor operability, high requirements for production equipment, high pressure on safety and environmental protection, difficult product purification, low yield, unfavorable for industrial production

Method used

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  • Preparation method of aryl propionic acid derivative
  • Preparation method of aryl propionic acid derivative
  • Preparation method of aryl propionic acid derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0054] Embodiment 1: the preparation of 3-(3-(trifluoromethyl)phenyl)propionic acid

[0055] Preparation of Diethyl 2-(3-(trifluoromethyl)benzyl)malonate

[0056] Under nitrogen protection, m-trifluoromethylbenzyl chloride (19.5 g, 0.1 mol), diethyl malonate (16 g, 0.1 mol), 100 ml of acetonitrile and potassium carbonate (27.6 g, 0.2 mol) were added to the reaction In the bottle, the reaction was stirred at reflux for 48 hours. After the reaction, cool to room temperature, evaporate acetonitrile, add 100 ml of water and 100 ml of ethyl acetate, extract and separate the organic layer, and extract the aqueous layer twice with 100 ml of ethyl acetate. All organic layers were combined and washed with 50 mL of saturated aqueous sodium chloride. Then the organic layer was dried over anhydrous sodium sulfate, concentrated, and the resulting oil was separated by silica gel column chromatography (developing solvent: petroleum ether / ethyl acetate 20:1, volume ratio) to obtain 2-(3-(tr...

Embodiment 2

[0059] Embodiment 2: the preparation of 3-(3-(trifluoromethyl)phenyl) propionic acid

[0060] Preparation of 2-(3-(trifluoromethyl)benzyl)malononitrile

[0061] Under nitrogen protection, m-trifluoromethylbenzyl chloride (19.5 g, 0.1 mol), malononitrile (6.6 g, 0.1 mol), 100 ml of toluene and potassium carbonate (27.6 g, 0.2 mol) were added to the reaction flask, The reaction was stirred at reflux for 1 hour. After the reaction, cool to room temperature, evaporate toluene, add 100 ml of water and 100 ml of ethyl acetate, separate the organic layer, and extract the water layer twice with 100 ml of ethyl acetate. All organic layers were combined and washed with 50 mL of saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, concentrated, and the resulting oil was separated by silica gel column chromatography (developing solvent: petroleum ether / ethyl acetate 20:1, volume ratio) to obtain 2-(3-(trifluoromethyl ) benzyl) malononitrile 22.2...

Embodiment 3

[0064] Embodiment 3: the preparation of 3-(3-(trifluoromethyl)phenyl)propionitrile

[0065] Preparation of ethyl 2-cyano-3-(3-(trifluoromethyl)phenyl)propionate

[0066]Under nitrogen protection, m-trifluoromethylbenzyl chloride (19.5 g, 0.1 mol), ethyl cyanoacetate (11.3 g, 0.1 mol), 100 ml of toluene and sodium carbonate (21.2 g, 0.2 mol) were added to the reaction flask In, the reaction was stirred at reflux for 12 hours. After the reaction, cool to room temperature, evaporate toluene, add 100 ml of water and 100 ml of ethyl acetate, separate the organic layer, and extract the water layer twice with 100 ml of ethyl acetate. All organic layers were combined and washed with 50 mL of saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, concentrated, and the resulting oil was separated by silica gel column chromatography (developing solvent: petroleum ether / ethyl acetate 20:1, volume ratio) to obtain 2-cyano-3-(3- (Trifluoromethyl)phe...

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Abstract

The invention relates to a preparation method of an aryl propionic acid derivative, comprising the following step of: making a compound expressed by a formula II react according to the following route so as to prepare the aryl propionic acid derivative expressed by a formula I, wherein R1, R2, R3, R4 and R5 independently express hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, halogen, trihalogenated methyl and nitryl; R7 and R8 independently express an ester group and a cyano group; R6 expresses carboxyl or a cyano group; X expresses fluorine, chlorine, bromine or iodine; when R7 and R8 both express the ester group or the cyano group, R6 expresses the carboxyl; and when R7 expresses the ester group and R8 expresses the cyano group, R6 expresses the cyano group. The preparation method of the aryl propionic acid derivative has the advantages that raw materials are easy to obtain and low in price, oxidation and reduction reaction are not needed, the route is simple, the reaction condition is moderate, the production equipment requirement is low, a small quantity of the three wastes is discharged and industrialized production can be realized easily, thereby the preparation method can be widely used for synthesizing medicaments, daily chemicals, and the like.

Description

technical field [0001] The invention relates to the field of chemical industry, in particular, the invention relates to a preparation method of aryl propionic acid derivatives. Background technique [0002] Arylpropionic acid derivatives (1) are an important class of compounds, which play a very important role in the construction of arylpropyl synthons. For example, m-trifluoromethylphenylpropionic acid derivatives (2), (3), (4) and (5) are synthetic FDA-approved not only for the treatment of secondary hyperparathyroidism in chronic kidney disease dialysis patients, but also for The key intermediate of the new drug Sensipar (cinacalcet, 6) for the treatment of hypercalcemia in patients with parathyroid carcinoma (Synthetic Communications, 2008, 38(10), 1512-1517; EP1990333; WO2008 / 058235). Cinacalcet, manufactured by Amgen, is the first drug in a new class of compounds known as calcimimetics, which activate calcium receptors in the parathyroid gland, thereby reducing parath...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/09C07C51/08C07C253/30C07C67/00C07C231/00C07C57/58C07C255/35C07C69/65C07C233/11
Inventor 陈维翁科杰宋文芳杨建军
Owner 中国中化股份有限公司
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