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Method for preparing alkyl diacid monobenzyl ester

A technology for alkyl diacid monobenzyl ester and alkyl diacid, which is applied in the field of preparing alkyl diacid monobenzyl ester, can solve the problems of unsatisfactory yield, complicated operation, high cost and the like, and achieves the advantages of implementing and selecting Good performance and easy operation

Active Publication Date: 2019-12-10
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the synthesis of alkyl diacid monobenzyl ester is mostly based on the esterification reaction of alkyl diacid, and the two carboxylic acids of alkyl diacid have the same reactivity, so it is inevitable to obtain double esterification products in the reaction process. The diesterification product in the reaction not only increases the difficulty of operation but also reduces the reaction yield. In the prior art, potassium hydroxide methanol solution and phase transfer catalyst are used to prepare the method of alkyl dioic acid monobenzyl ester, and its operation is more loaded down with trivial details, and The yield is also not ideal, and other methods with higher yields have problems such as high cost and difficult implementation

Method used

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  • Method for preparing alkyl diacid monobenzyl ester
  • Method for preparing alkyl diacid monobenzyl ester

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Sodium carbonate (424mg, 4.0mmol) and water (14.3g, 794.4mmol) were added to the reaction flask, and hexadecanedioic acid (1.43g, 5.0mmol), 2-methyltetrahydrofuran (35.0g) and Benzyl bromide (1.37g, 8.0mmol), the reaction system was heated to 75°C, stirred for 22h to stop the reaction. Add hydrochloric acid to the system to make the pH of the aqueous phase reach 1-3, separate the layers, and spin the organic layer to obtain a solid residue. The rotary evaporation residue was slurried with dichloromethane (28 g), filtered, and the filtrate was spin-dried to obtain a solid residue. The rotary evaporation residue was recrystallized from isopropanol (3 g) to obtain 1046 mg of white solid, yield 55.6%. 1H NMR (400MHz, DMSO) δ11.95(s, 1H), 7.44-7.20(m, 5H), 5.08(s, 2H), 2.33(t, J=7.3Hz, 2H), 2.17(t, J= 7.4Hz, 2H), 1.60-1.41(m, 4H), 1.22(s, 20H); MS, m / z: [M-H] - = 375.2.

Embodiment 2

[0030] Hexadecanedioic acid (1.43g, 5.0mmol), tetrahydrofuran (18.0g), benzyl chloride (1.01g, 8.0mmol), potassium carbonate (1037mg, 7.5mmol) and water (14.3g, 794.4mmol) were added to the reaction flask ), the reaction system was heated to 80°C and stirred for 40h to stop the reaction. Add hydrochloric acid to the system to make the pH of the aqueous phase reach 1-3, separate the layers, and spin the organic layer to obtain a solid residue. The rotary evaporation residue was slurried with dichloromethane (28 g), filtered, and the filtrate was spin-dried to obtain a solid residue. The rotary evaporation residue was recrystallized from isopropanol (3 g) to obtain 941 mg of white solid, yield 50.0%. 1H NMR (400MHz, DMSO) δ11.95(s, 1H), 7.44-7.20(m, 5H), 5.08(s, 2H), 2.33(t, J=7.3Hz, 2H), 2.17(t, J= 7.4Hz, 2H), 1.60-1.41(m, 4H), 1.22(s, 20H); MS, m / z: [M-H] - = 375.2.

Embodiment 3

[0032]Potassium bicarbonate (901mg, 9.0mmol) and water (15.7g, 872.2mmol) were added to the reaction flask, and after stirring and dissolving, octadecanedioic acid (1.57g, 5.0mmol) and 2-methyltetrahydrofuran (15.7g) were added and benzyl bromide (1.37g, 8.0mmol), the reaction system was heated to 75°C and stirred for 30h to stop the reaction. Add hydrochloric acid to the system to make the pH of the aqueous phase reach 1-3, separate the layers, and spin the organic layer to obtain a solid residue. The rotary evaporation residue was slurried with dichloromethane (30 g), filtered, and the filtrate was spin-dried to obtain a solid residue. The rotary evaporation residue was recrystallized from isopropanol (3 g) to obtain 1177 mg of white solid, yield 58.2%. 1H NMR (400MHz, CDCl 3 )δ11.22(s,1H),7.40-7.29(m,5H),5.11(s,2H),2.35(td,J=7.5,2.5Hz,4H),1.63(s,4H),1.25(s ,24H); MS, m / z: [M-H] - = 403.3.

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Abstract

The invention relates to a method for preparing an alkyl diacid monobenzyl ester, and belongs to the technical field of chemical engineering. According to the method provided by the invention, an alkyl diacid is used as a raw material and is subjected to esterification reaction with benzyl bromide or benzyl chloride in a mixed system of an organic solvent and water under the action of an alkali toobtain the alkyl diacid monobenzyl ester. The method is good in selectivity, convenient to operate, high in yield, low in cost and beneficial to implementation.

Description

technical field [0001] The invention relates to a method for preparing alkyldiacid monobenzyl ester, which belongs to the technical field of chemical industry. Background technique [0002] Alkyl dioic acid monobenzyl ester is a very important structural unit in medicinal chemistry and fine chemicals, such as hexadecanedioic acid monobenzyl ester is a key intermediate for the preparation of insulin degludec, and the length of the alkyl chain can be The derivatization of drugs brings more possibilities, so it is of great significance to synthesize alkyldioic acid monobenzyl esters with high selectivity and high yield. At present, the synthesis of alkyl diacid monobenzyl ester is mostly based on the esterification reaction of alkyl diacid, and the two carboxylic acids of alkyl diacid have the same reactivity, so it is inevitable to obtain double esterification products in the reaction process. The diesterification product in the reaction not only increases the difficulty of o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/11C07C69/34
CPCC07C67/11C07C69/34Y02P20/55
Inventor 赖金强丰亚辉麦健聪钟镇涛王仲清罗忠华黄芳芳
Owner SUNSHINE LAKE PHARM CO LTD