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GLP-1 derivative preparation method

A synthesis method, amino acid technology, applied in the preparation method of peptides, chemical instruments and methods, animal/human proteins, etc., can solve the problems of complex solid-phase synthesis in post-processing, unguaranteed purity of fragmented peptides, and low yield, etc., to achieve Overcoming tediousness and unfavorable industrial production, wide practical value and application prospects, and the effect of improving product purity and yield

Active Publication Date: 2017-03-08
GAN&LEE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method combines solid-liquid synthesis methods to reduce the equivalent of fragment peptides, the synthesis method is relatively cumbersome, and the purity of fragment peptides synthesized step by step in liquid phase cannot be guaranteed, and the post-treatment is obviously more complicated than solid-phase synthesis, which is not conducive to industrialization. Production
[0007] Therefore, although there have been a large number of reports on the preparation of liraglutide, due to the difficulty in determining the number and length of fragment peptides in the fragment synthesis method, there are still problems such as low yield, low purity, high synthesis cost or too long synthesis cycle. Meet the defects of industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The polypeptide fragment X is the 1st to the 4th amino acid, the polypeptide fragment Y is the 11th to the 16th amino acid, and the polypeptide fragment Z is the 24th to the 29th amino acid.

[0048] 1.1 Synthesis of polypeptide fragment X

[0049]Weigh 50g of 2-CTC resin with a degree of substitution of 1.0mmol / g, add it to the reactor of the solid-phase synthesizer, wash it twice with DMF, swell the resin with DMF for 30 minutes and then drain it, take 0.1mol Fmoc-Gly-OH for use Dissolve DMF, add to the above-mentioned reaction column with resin, add 0.4mol DIEA, drain after 6 hours of reaction, add 150ml of anhydrous methanol, seal for 1 hour, wash with DMF 6 times, and obtain Fmoc-Gly-2-CTC resin.

[0050] The Fmoc protecting group in the Fmoc-Gly-2-CTC resin was removed by DBLK twice for 15 minutes to obtain the H-Gly-2-CTC resin, which was then washed 6 times with DMF. Dissolve 0.15mol Fmoc-Glu(OtBu)-OH and 0.15mol HOBt in 150ml of DCM and DMF mixed solution wit...

Embodiment 2

[0082] The polypeptide fragment X is the 1st to the 4th amino acid, the polypeptide fragment Y is the 13th to the 16th amino acid, and the polypeptide fragment Z is the 26th to the 29th amino acid.

[0083] Using a synthesis method similar to Example 1, 53.4 g of liraglutide crude peptide was finally obtained, and the crude peptide yield was 88.1%. MALDI-TOF: (M+H)+=3752.1. Liraglutide refined peptide was obtained after purification treatment: 19.8 g, purity: 98.7%, total yield: 32.7%, and the largest single impurity was 0.12%.

Embodiment 3

[0085] The polypeptide fragment X is the 1st to the 4th amino acid, the polypeptide fragment Y is the 12th to the 16th amino acid, and the polypeptide fragment Z is the 25th to the 29th amino acid.

[0086] Using a synthesis method similar to Example 1, 53.9 g of liraglutide crude peptide was finally obtained, and the crude peptide yield was 88.1%. MALDI-TOF: (M+H)+=3752.1. Liraglutide refined peptide was obtained after purification treatment: 20.2 g, purity: 99.0%, total yield: 33.4%, largest single impurity 0.10%.

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PUM

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Abstract

The invention relates to a novel GLP-1 derivative synthesis method, wherein the synthesis of three fragments can be performed at the same time so as to substantially shorten the synthesis cycle and improve the product purity and the yield.

Description

technical field [0001] The invention relates to a novel synthesis method of liraglutide, which can simultaneously synthesize three fragments, greatly shorten the synthesis period, and improve product purity and yield. Background technique [0002] Liraglutide (trade name Victoza) is a modification of human GLP-1(7-37), which was developed by Novo Nordisk in 1996 and first launched in Denmark in 2009. From the structural point of view, liraglutide is that the 34th Lys on the GLP-1 (7-37) chain is replaced by Arg, and the glutamine modified by hexadecanoic acid is inserted into the 26th Lys. GLP-1 modified by the fatty chain increases the affinity with albumin, thereby reducing the hydrolysis rate and renal clearance rate of DPP-IV, and prolonging the biological half-life. The biological half-life of liraglutide is 11-15 hours, and only one subcutaneous injection is required per day, which greatly improves the compliance of patients. A 6-month clinical study showed that lira...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/10C07K1/06C07K1/04
CPCC07K14/605
Inventor 董长青张一宁孙海瑜
Owner GAN&LEE PHARMA
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