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Preparation method and application of fatty dioic acid derivative

A fatty diacid and derivative technology, applied in the field of biomedicine, can solve the problems of high impurities, decomposition of insulin peptide chain, and unsuitable for industrial scale-up production.

Active Publication Date: 2015-10-28
ZHUHAI UNITED LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

N,N-dimethylformamide di-tert-butyl acetal is used as tert-butyl esterification reagent in the preparation process of hexadecanedioic acid mono-tert-butyl ester disclosed by Novo Nordisk Patent No. CN1829738, the cost is high, Not suitable for industrial scale-up; 2-succinimidyl-1,1,3,3-tetramethylurea tetrafluoroborate ( TSTU), the cost is high, and it is not suitable for industrial scale-up production; at the same time, the patent discloses hexadecanedioic acid monomethyl derivatives, because the insulin analogues prepared by this process need to be demethylated in 0.2M NaOH solution, it is easy to cause insulin Decomposition of peptide chains has many impurities, and it is also difficult to realize industrial scale-up production
Grinstaff and Zhang disclose the technology (Grinstaff And people such as Zhang, Bioconjugate chemistry, 2011,22 (4), 690-9), and the by-product hexadecanedioic acid N-acyl urea ratio that prepares hexadecanedioic acid mono-tert-butyl with this process is high, It is difficult to separate from the product, and it is also not suitable for process scale-up production

Method used

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  • Preparation method and application of fatty dioic acid derivative
  • Preparation method and application of fatty dioic acid derivative
  • Preparation method and application of fatty dioic acid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] 1. Preparation of mono-tert-butyl hexadecanedioic acid

[0087]

[0088] Hexadecanedioic acid (20.0 g, 69.8 mmol) was suspended in thionyl chloride (100 ml, 1376.8 mmol), heated to reflux at 80° C. for 3 hours, and excess thionyl chloride was distilled off under reduced pressure. Add dichloromethane (200ml) to dissolve, add tert-butanol (7.34ml, 76.81mmol) and pyridine (5.9ml, 73.32mmol), add pyridine within 2 hours, and react at 25°C for 3h. The solvent was evaporated to dryness under reduced pressure, and 600ml of DMF / water mixed solvent precooled to 0-4°C was added (DMF and water were mixed in a volume ratio of 1:2), and the precipitate was collected by filtration. Vacuum dry to constant weight, add dichloromethane (300ml) to resuspend, collect the filtrate and evaporate the solvent under reduced pressure, add petroleum ether (400ml) to resuspend, collect the filtrate and evaporate to dryness under reduced pressure, add n-heptane (80ml) for recrystallization , th...

Embodiment 2

[0112] 1. Preparation of tert-butyl tetradecanedioate

[0113]

[0114] Tetradecanedioic acid (20.0g, 77.4mmol) was suspended in dichloromethane (200ml), and catalytic equivalents of DMF (89.8μl, 1.16mmol) and thionyl chloride (33.73ml, 464.4mmol) were added respectively, at 25°C Stir overnight until dissolved. The solvent was distilled off under reduced pressure, dichloromethane (200ml) was added to dissolve, tert-butanol (8.07ml, 84.49mmol) and pyridine (6.5ml, 80.65mmol) were added, pyridine was added within 2 hours, and reacted at 20°C for 3h. The solvent was evaporated to dryness under reduced pressure, and 600ml of DMF / water mixed solvent precooled to 0-4°C was added (DMF and water were mixed in a ratio of 1:3 by volume), and the precipitate was collected by filtration. Vacuum dry to constant weight, add dichloromethane (300ml) to resuspend, collect the filtrate and evaporate the solvent under reduced pressure, add petroleum ether (400ml) to resuspend, collect the fi...

Embodiment 3

[0134] 1. Preparation of mono-tert-butyl octadecanedioate

[0135]

[0136] Suspend octadecanedioic acid (20.0g, 63.6mmol) in dichloromethane (200ml), add catalytic equivalents of DMF (73.8μl, 0.95mmol) and thionyl chloride (27.72ml, 381.6mmol) respectively, and stir at room temperature Leave overnight until dissolved. The solvent was distilled off under reduced pressure, dichloromethane (200ml) was added to dissolve, tert-butanol (6.63ml, 69.43mmol) and pyridine (5.34ml, 66.27mmol) were added. Pyridine was added within 2 hours and reacted at 25°C for 3h. The solvent was evaporated to dryness under reduced pressure, and 600ml of DMF / water mixed solvent precooled to 0-4°C was added (DMF and water were mixed in a volume ratio of 1:2), and the precipitate was collected by filtration. Vacuum dry to constant weight, add dichloromethane (200ml) to resuspend, collect the filtrate and evaporate the solvent under reduced pressure, add petroleum ether (400ml) to resuspend, collect t...

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Abstract

The present invention discloses a preparation method and application of a fatty dioic acid derivative. The method is as below: first reacting long-chain fatty dioic acid with thionyl chloride to obtain acyl chloride; reacting acyl chloride with t-butanol and removing chlorine group to obtain long-chain tert-butyl fatty dioic acid; then reacting the tert-butyl fatty dioic acid with N-hydroxy succinimide to obtain long-chain fatty dioic acid succinimidyl tert-butyl ester; reacting long-chain fatty dioic acid succinimidyl tert-butyl ester with L- glutamic acid-1-t-butyl ester to obtain tert-butyl long-chain aliphatic diacyl-L-Glu-OtBu; then reacting tert-butyl long-chain aliphatic diacyl-L-Glu-OtBu with N-hydroxysuccinimide to obtain tert-butyl long-chain aliphatic diacyl-L-Glu(OSu)-OtBu; and finally, removing the fatty dioic acid derivative in the tert-butyl long-chain aliphatic diacyl-L-Glu(OSu)-OtBu to obtain long-chain fatty dioic acid derivative. The method has the advantages of simple route operation, controllable quality, suitability for industrial scale production, low cost, simple purification, and is applicable to the preparation of high purity insulin analogues.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a method for preparing fatty diacid derivatives and its application. Background technique [0002] Fatty diacid derivatives play an important role in the research of third-generation insulin drugs, especially long-acting insulin analogs. As a blockbuster drug of long-acting insulin analogs, insulin glargine had a global sales of 7.279 billion US dollars in 2014. However, it is difficult for insulin glargine to achieve stable blood sugar control and stable pharmacokinetic curve, which directly leads to a high incidence of hypoglycemia, especially nocturnal hypoglycemia, which is life-threatening. [0003] In recent years, research on long-acting insulin analogues as insulin glargine substitutes has gradually become a hot spot in the field of diabetes treatment. Among them, the Chinese invention patent with the publication number CN1829738 and the name "New Insulin Derivatives"...

Claims

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Application Information

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IPC IPC(8): C07D207/46C07K14/62
CPCC07D207/46C07K14/62
Inventor 张伟曹春来肖拥军祝捷周翠林影
Owner ZHUHAI UNITED LAB
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