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

The technology of monobenzyl diacid and chain dibenzyl ester is applied in the field of biopharmaceuticals, and can solve the problems of difficulty in realizing industrial scale-up, high cost of chemical reagents, large preparation cost, etc., and achieves low post-processing cost, low preparation cost, low cost effect

Active Publication Date: 2020-06-26
DONGGUAN HEC BIOPHARMACEUTICAL R&D CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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

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preparation example Construction

[0054] The method for preparing long-chain fatty diacid monobenzyl ester according to an embodiment of the present invention can be as follows:

[0055]

[0056] 1-1) Compound A, benzyl alcohol, and catalyst a are prepared in solvent b to obtain intermediate A'. After the reaction is completed, cool down to room temperature, then add reverse solvent c to the reaction system, and continue to cool down to about 0°C to crystallize. Filter and wash 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.

[0057] 1-2) Compound A' and (acid) base d are stirred and reacted in solvent e. After the reaction is completed, (acid free and solvent extraction can be skipped if the reaction is hydrolyzed with acid) after acid f is free, solvent g is extracted, and the Add the reverse solvent h to the organic phase to crystallize, filter, rinse the filter cake with the reverse solvent h, and dry the filter...

Embodiment 1

[0088] The synthesis of embodiment 1 hexadecanedioic acid dibenzyl ester

[0089]

[0090] Add hexadecanedioic acid (100.0g, 349.4mmol), benzyl alcohol (167.4g, 1547.8mmol), TsOH (6.0g, 34.9mmol) and 1000mL toluene into a 3000mL three-necked flask, place it at 120°C and stir for 24h, the reaction is over , cooled to room temperature, with 0.5M Na 2 CO 3 .aq (35ml, 17mmol) washes the reaction system, separates and discards the aqueous phase. Add 1000ml of n-heptane to the organic phase under stirring. With the addition of n-heptane in the system, solids are gradually precipitated in the system. The crystallization continued in the tank, and the temperature of the low-temperature tank was gradually lowered to -5°C. When the temperature of the system dropped to -5°C, the system was kept and stirred for 1 hour to allow the system to crystallize completely. After filtering, the filter cake was washed with 200 ml of n-heptane, and the filter cake was vacuum-dried at 40° C. for...

Embodiment 2

[0093] Synthesis of Monobenzyl Hexadecandioate (a)

[0094]

[0095]Add dibenzyl hexadecanedioate (4.7g, 10mmol) and benzyl alcohol (25ml) into a 100mL one-necked flask, stir and dissolve at room temperature, then add KOH (0.55g, 11mmol) dropwise to the reaction system under stirring at room temperature Benzyl alcohol (10ml) solution, after the dropwise addition, was stirred overnight at room temperature. Use 1M HCl.aq (25ml) to adjust the pH of the reaction system: 1-2, filter, separate and discard the aqueous phase. At room temperature, n-heptane (40ml) was added dropwise to the organic phase, and a white solid began to precipitate out in the system along with the addition of n-heptane. Transfer the reaction system to a low-temperature tank at 0°C, and continue to cool down to crystallize. After the system cools down to 0°C, more solids are precipitated in the reaction bottle, and continue to heat and stir for 0.5h. Filter at low temperature and rinse twice with n-hepta...

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Abstract

The invention provides a method for preparing long-chain fatty acid monobenzyl ester. The method comprises the following steps: 1) carrying out esterification reaction on long-chain fatty diacid to obtain long-aliphatic chain dibenzyl ester; and 2) carrying out hydrolysis reaction on the long-aliphatic chain dibenzyl ester to obtain long-chain fatty diacid monobenzyl ester; wherein the long-chainfatty diacid has a structure shown as 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 reagent, simple operation, low product related impurity content, simple intermediate purification, short production period, high yield, low cost, little generated waste liquid, no generation of solid waste and low environmental protection pressure.

Description

technical field [0001] The 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 insulin is classified according to the insulin action time, a type of insulin with a longer action time (24h or more), and is used for the treatment of type 1 and type 2 diabetes. Usually only one injection per day is needed, and 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, and 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 technology of protein modification, in the prior art, the preparation process of long aliphatic chain dia...

Claims

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Application Information

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Patent Type & Authority Applications(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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