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Method for preparing long-chain fatty diacid monobenzyl ester and application thereof

A technology of monobenzyl diacid and chain dibenzyl ester, applied in the field of biopharmaceuticals, can solve the problems of difficulty in purification, difficulty in realizing industrial scale up, complicated post-processing and the like

Active Publication Date: 2022-07-26
DONGGUAN HEC BIOPHARMACEUTICAL R&D CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Although long aliphatic chain diacid derivatives can be used in the research and development of long-acting insulin drugs through the general technology of protein modification, in the prior art, the preparation process of long aliphatic chain diacid derivatives involves high cost of chemical reagents, poor selectivity, and side effects. There are many products and it is difficult to purify, and it is difficult to achieve industrial scale-up; however, the methods suitable for industrial scale-up have low yield, long reaction time, cumbersome post-treatment, high preparation cost, large loss of reagents, many "solid wastes" and high processing costs. question

Method used

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  • Method for preparing long-chain fatty diacid monobenzyl ester and application thereof
  • Method for preparing long-chain fatty diacid monobenzyl ester and application thereof
  • Method for preparing long-chain fatty diacid monobenzyl ester and application thereof

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preparation example Construction

[0053] The method for preparing long-chain fatty diacid monobenzyl ester according to an embodiment of the present invention can be described as follows:

[0054]

[0055] 1-1) Compound A, benzyl alcohol, catalyst a are prepared in solvent b to obtain intermediate A', the reaction is completed, the temperature is lowered to room temperature, then reverse solvent c is added to the reaction system, and the temperature is continued to be about 0°C for crystallization, Filter, rinse the filter cake with reverse solvent c to obtain compound B with a purity of more than 95%, which can be used in the next step after drying.

[0056] 1-2) Compound A', (acid) base d are stirred and reacted in solvent e, and the reaction is completed, (if the reaction is hydrolyzed with acid, acid free and solvent extraction can be skipped) After acid f is free, solvent g is extracted, and the reaction is carried out at room temperature. In the organic phase, reverse solvent h is added for crystalliz...

Embodiment 1

[0087] Example 1 Synthesis of dibenzyl hexadecanedioate

[0088]

[0089] Hexadecanedioic acid (100.0g, 349.4mmol), benzyl alcohol (167.4g, 1547.8mmol), TsOH (6.0g, 34.9mmol) and 1000mL of toluene were added to a 3000mL three-necked flask and placed in a 120°C stirring reaction for 24h, the reaction ended , cooled to room temperature with 0.5M Na 2 CO 3 .aq (35 ml, 17 mmol) was used to wash the reaction system, and the aqueous phase was separated and discarded. 1000ml of n-heptane was added to the organic phase under stirring. With the addition of n-heptane in the system, solids gradually precipitated in the system. After the dropwise addition of n-heptane, the stirring was continued for 0.5 h, and the reaction system was transferred to a low temperature. The crystallization continued in the tank, and the low temperature tank was gradually cooled to -5 °C. When the system was cooled to -5 °C, the system was kept stirring for 1 h to make the system crystallize completely. ...

Embodiment 2

[0092] Synthesis of hexadecanedioic acid monobenzyl ester (a)

[0093]

[0094]Dibenzyl hexadecanedioate (4.7g, 10mmol) and benzyl alcohol (25ml) were added to a 100mL single-necked flask, and after stirring at room temperature to dissolve, under stirring at room temperature, KOH (0.55g, 11mmol) was added dropwise to the reaction system. A solution of benzyl alcohol (10 ml) was added dropwise and stirred at room temperature overnight. Adjust the pH of the reaction system: 1-2 with 1M HCl.aq (25ml), filter, and separate the aqueous phase. At room temperature, n-heptane (40 ml) was added dropwise to the organic phase, and a white solid began to precipitate in the system with the addition of n-heptane. The reaction system was transferred to a low-temperature tank at 0°C, and the temperature was continued to decrease for crystallization. After the system was cooled to 0°C, more solids were precipitated in the reaction flask, and the stirring was continued for 0.5 h. Filter at...

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Abstract

The invention provides a method for preparing long-chain fatty diacid monobenzyl ester. The method comprises: 1) carrying out an esterification reaction with a long aliphatic chain diacid to obtain a long aliphatic chain dibenzyl ester; 2) carrying out a hydrolysis reaction of the long aliphatic chain dibenzyl ester so as to obtain a long chain aliphatic diacid monobenzyl ester; Wherein, the long aliphatic chain diacid has a structure represented by formula (A), and X is an integer of 6-32. Compared with the prior art, the method has the advantages of cheap and easily available reaction reagents, simple operation, low product-related impurity content, simple purification of intermediates, short production cycle, high yield, low cost, less "waste liquid" and no solid waste. Generated, low environmental pressure. .

Description

technical field [0001] The present invention relates to the field of biopharmaceuticals, in particular to a method for preparing long-chain fatty diacid monobenzyl ester and its application. Background technique [0002] Long-acting insulins are classified according to insulin action time, and the action time is longer (24h or more), which is used for the treatment of type 1 and type 2 diabetes. Usually only 1 injection per day, there is no obvious peak of action in the body, mainly to provide basal insulin. The current mainstream long-acting insulins include insulin glargine, insulin detemir and insulin degludec, the latter two are obtained by using long-chain fatty acid modification technology. [0003] Although long aliphatic chain diacid derivatives can be used in the research and development of long-acting insulin drugs through the general protein modification technology, in the prior art, the preparation process of long aliphatic chain diacid derivatives requires high...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/08C07C69/34C07C67/313C07C69/67C07D207/48A61K47/54A61K38/28A61K38/26A61P3/10
CPCC07C67/08C07C67/313C07D207/48A61K47/545A61K47/543A61K38/28A61K38/26A61P3/10C07C69/34C07C69/67
Inventor 杨福斌李松王海龙王仲清郑宝液郭林峰李平珠
Owner DONGGUAN HEC BIOPHARMACEUTICAL R&D CO LTD
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