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Method for preparing ethyl 2-oxo-4-phenylbutyrate

A technology of ethyl phenylbutyrate and halogenated phenylethane, which is applied in the field of preparation of ethyl 2-oxo-4-phenylbutyrate and can solve the problem of ethyl 2-oxo-4-phenylbutyrate Problems such as low ester purity, difficult to reach more than 97%, etc., to achieve the effects of low cost, convenient operation and high yield

Inactive Publication Date: 2013-01-09
太仓浦源医药原料有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method can produce by-product 1,6-diphenylhexane-1,6-diketone and 2-hydroxyl-2-phenylethyl-4-phenylbutyl when Grignard reagent reacts with diethyl oxalate Ethyl 2-oxo-4-phenylbutyrate can only partially remove by-products even through high vacuum distillation, resulting in a relatively low purity of the final ethyl 2-oxo-4-phenylbutyrate, which is difficult to reach more than 97%.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] (1), get the dry 500mL four-necked bottle that thermometer, reflux condenser and mechanical stirring device are housed, nitrogen flow fully blows out the air in the bottle, and add 30mL tetrahydrofuran, 7.2g new magnesium shavings (0.3 mol) and 2gβ-bromophenylethane, add three grains of elemental iodine at room temperature, stir slowly, until the color of iodine fades, and when the temperature rises slightly, it indicates that the reaction has been initiated. A mixture of 54.1g β-bromophenylethane (total 0.3mol) and 300mL methyl tert-butyl ether was slowly added dropwise at 50°C-60°C, the dropwise addition was completed in 0.5h, and stirred at the same temperature for 1h. Cool to room temperature to obtain Grignard solution containing Grignard reagent, set aside.

[0020] (2), take a dry 1000mL four-necked bottle equipped with a thermometer, a reflux condenser and a mechanical stirring device, fully blow off the air in the bottle with a nitrogen flow, and add 100mL tetr...

Embodiment 2

[0023] (1), get the dry 500mL four-neck bottle that thermometer, reflux condenser and mechanical stirrer are housed, nitrogen flow fully blows out the air in the bottle, and add 50mL methyl tetrahydrofuran, 12g new magnesium shavings ( 0.5mol) and 5gβ-chlorophenylethane, add 0.05g bromoethane at room temperature, stir slowly, when the temperature rises slightly, it indicates that the reaction has been initiated. A mixture of 65.3g β-chlorophenylethane (0.5mol in total) and 350mL isopropyl ether was slowly added dropwise at 60°C to 70°C, the dropwise addition was completed in 0.5h, and stirred at the same temperature for 1h. Cool to room temperature to obtain Grignard solution containing Grignard reagent, set aside.

[0024] (2), take a dry 1000mL four-neck bottle equipped with a thermometer, a reflux condenser and a mechanical stirring device, fully blow off the air in the bottle with a nitrogen flow, and add 180mL methyl tetrahydrofuran, 75.1g oxalyl chloride mono Ethyl este...

Embodiment 3

[0027] (1), take a dry 250mL four-neck bottle equipped with a thermometer, a reflux condenser and a mechanical stirring device, fully blow out the air in the bottle with a nitrogen flow, and add 30mL of anhydrous dioxane, 6g of freshly prepared Magnesium chips (0.25mol) and 5g β-chlorophenylethane, 0.05g ethyl bromide was added at room temperature, stirred slowly, when the temperature rose slightly, it indicated that the reaction had been initiated. A mixture of 30.2g β-chlorophenylethane (total 0.25mol) and 200mL anhydrous toluene was slowly added dropwise at 85°C-100°C, the dropwise addition was completed in 0.5h, and stirred at the same temperature for 1h. Cool to room temperature to obtain Grignard solution containing Grignard reagent, set aside.

[0028] (2), take a dry 500mL four-neck bottle equipped with a thermometer, a reflux condenser and a mechanical stirring device, fully blow out the air in the bottle with a nitrogen flow, and add 100mL of anhydrous dioxane, 38.2g...

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Abstract

The invention relates to a method for preparing ethyl 2-oxo-4-phenylbutyrate, which comprises the following steps: (1) reacting beta-halogeno ethylbenzene with magnesium in a first aprotic solvent to obtain a Grignard solution containing a Grignard reagent; (2) reacting ethyl oxalyl monochloride with one or more of CuX, Li2CuX4 and CuCN.LiX in a second aprotic solvent to obtain a solution containing a copper acyl chloride salt compound; and (3) dropwise adding the Grignard solution in the solution obtained in step (2), persevering the temperature at -20-160 DEG C, enabling the Grignard reagent to react with the cooper acyl chloride salt compound to obtain a product solution after the reaction is finished, carrying out acidic hydrolysis and alkali neutralisation on the product solution in sequence, washing, drying and removing the solvent, and obtaining the ethyl 2-oxo-4-phenylbutyrate with the purity no less than 97% after high vacuum rectification. The invention has the advantages of good reaction selectivity, high yield, easily obtained raw materials, mild reaction conditions, convenient operation and low cost.

Description

technical field [0001] The invention relates to a preparation method of ethyl 2-oxo-4-phenylbutyrate. Background technique [0002] Ethyl 2-oxo-4-phenylbutyrate (EOPB) is an important intermediate for the synthesis of the Puli series of angiotensin-converting enzyme inhibitors (ACEI), such as lisinopril, benazepril and other drugs. JP8119905A discloses a kind of preparation method of 2-oxo-4-phenylbutyric acid ethyl ester, it is first to make 2-bromoethylbenzene and metal magnesium react to obtain Grignard reagent, then make Grignard reagent and diethyl oxalate Grignard complex was obtained by ester reaction, and finally hydrolyzed to obtain ethyl 2-oxo-4-phenylbutyrate. This method can produce by-product 1,6-diphenylhexane-1,6-diketone and 2-hydroxyl-2-phenylethyl-4-phenylbutyl when Grignard reagent reacts with diethyl oxalate Ethyl butyrate can only partially remove by-products even through high vacuum rectification, resulting in lower purity of final 2-oxo-4-phenylbutyr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/738C07C67/343
Inventor 周富荣吴真邵林华朱雪根
Owner 太仓浦源医药原料有限公司
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