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Solid-liquid combined preparation method for liraglutide

A technology of liraglutide and solution, applied in the field of polypeptide drug preparation, can solve the problems of unsuitable industrial-scale production, found that the purity and yield are not high, and achieves the advantages of being beneficial to large-scale industrial production, having good water solubility, and solving the problem of excessive peptide impurities. Effect

Active Publication Date: 2015-12-02
JINAN KANGHE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The inventor used the existing synthetic method to prepare liraglutide, and found that the purity and yield were not high, and it was not suitable for industrial scale production

Method used

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  • Solid-liquid combined preparation method for liraglutide

Examples

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Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Synthesis of Fmoc-Lys(N-ε-(γ-Glu(N-α-Boc)-OtBu)-OH

[0031] Accurately weigh Fmoc-Lys-OH183.8g (0.5mol) and sodium carbonate 63.6 (0.6mol) and dissolve them in 1200mL of water, slowly add Boc-Glu(OSu)-OtBu tetrahydrofuran solution (200.3 g, 0.5mol) / 1000ml, stir the reaction, TLC monitors the reaction end point, after the reaction is complete, spin off the THF, add 10% citric acid aqueous solution under the ice water bath to adjust the pH value of the solution to 2~3, and extract 3 times with 1000ml ethyl acetate , the organic phases were combined, washed 3 times with 200ml saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation to 1000ml, and left to stand for crystallization to obtain Fmoc-Lys(N-ε-(γ-Glu(N-α-Boc)- OtBu)-OH 253.6g, yield 73.5%.

Embodiment 2

[0032] Embodiment 2: Synthesis of Fmoc-Gly-WangResins

[0033] Put the carrier Wang resin 400.0g (sub=0.47mmol / g) in the synthesis column, wash twice with 2400mL DMF, add 4000mL DCM to swell for 30min; after filtering off the DCM, add the mixed DCM of Fmoc-Gly-OH / DIC / HOBT Solution [Weigh 118.8g (400mmol) Fmoc-Gly-OH and 64.8g (480mmol) HOBT into the glycine activation bottle, add 2000mL of DMF and DCM mixed solution with a volume ratio of 1:1 and stir to dissolve. Add 76.4ml (480mmol) DIC, activate for 5 minutes], add 4.8g (4mmol) DMAP after 10min of reaction; react for 3h, remove the reaction solution, wash twice with 4000mL DMF, add 2400mL of capping reagent (480ml acetic anhydride and 408ml pyridine Dissolved in 1512mL DMF) reacted for 2h, filtered off the reaction solution, washed twice with DMF, DCM, methanol, and vacuum dried to obtain 436.6g of Fmoc-Gly-WangResins ； The degree of substitution was measured by sampling to be 0.30mmol / g.

Embodiment 3

[0034] Example 3: Synthesis of Fmoc-Gly-CTCResins

[0035] Weigh 50.0g (sub=0.40mmol / g) of CTC resin and place it in a synthesis column, wash it twice with 240mL DMF, add 240mL DCM to swell for 30min; DCM / DMF (3 / 1, volume ratio) solution 150ml, add DIPEA6.6ml (40mmol) after stirring, drum N 2 React for 60min, remove the reaction liquid, add DCM / CH 3 300ml of OH / DIPEA (volume ratio 17:2:1) mixed solution was capped 3 times for 10min each time; then washed twice with DMF, DCM and methanol respectively, and dried in vacuum to obtain 53.80g of Fmoc-Gly-CTCResins. The measured degree of substitution is 0.29mmol / g.

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Abstract

The invention relates to the field of peptide synthesis, especially to a solid-liquid combined chemical preparation method for liraglutide. The method provided by the invention can simplify conventional preparation process for liraglutide and improve the quality of a final product. According to the invention, dipeptide monomer Fmoc-Lys(N-epsilon-(gamma-Glu(N-Boc)-OtBu)-OH is synthesized for the first time and is applied to preparation of liraglutide; as Fmoc-Ala-Ala-OH participates in preparation of liraglutide, generation of Ala impurity peptide in which position 24 or 25 is deleted is avoided, purification difficulty is reduced and yield is improved; and trifluoro-acetylated liraglutide (unmodified) has good water-solubility, which facilitates reversed phase chromatographic purification and preparation and protects an amino group at terminal N from side reaction in the process of palmitic acid modification, so the yield of the final product is greatly improved. Through implementation of the method, the problems that related impurity peptides in the final product exceed standard and overall yield is low in conventional chemical synthesis of liraglutide are overcome; the final product with purity of greater than 99.5% and simple impurity of less than 0.1% is obtained; and production cost is lowered.

Description

technical field [0001] The invention relates to the field of polypeptide drug preparation methods, in particular to a method for preparing liraglutide by combining solid phase and liquid phase. Background technique [0002] Liraglutide (Liraglutide), trade name Victoza, developed by Novo Nordisk, Denmark, was launched in the United States on January 25, 2010, and was approved by SFDA on March 4, 2011, entering the Chinese market; for adults 2 Control blood sugar in patients with type 2 diabetes. It is suitable for patients whose blood sugar is still poorly controlled after treatment with metformin or sulfonylureas at the maximum tolerated dose. It should be used in combination with metformin or sulfonylureas. On December 23, 2014, Novo Nordisk launched Saxenda (trade name) for the treatment of obesity, with a dose of 3mg / day. [0003] Liraglutide is a GLP-1 analog with 97% sequence homology to human GLP-1, which can bind and activate GLP-1 receptors. The GLP-1 receptor is ...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/06C07K1/04
CPCC07K14/605
Inventor 张颖李同金王仁友石鑫磊南勤坤
Owner JINAN KANGHE MEDICAL TECH
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