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Process for the manufacture of glp-1 analogues

一种GLP-1、类似物的技术，应用在肽合成领域，能够解决无法获得目标肽、降低氨基酸偶联和去保护的效率等问题

Active Publication Date: 2021-06-04
BEIJING FRESENIUS KABI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This problem is particularly acute during peptide synthesis in conjunction with intramolecular peptide folding, reducing the efficiency of amino acid coupling and deprotection, leading to the formation of numerous by-products or even failure to obtain the target peptide

Method used

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  • Process for the manufacture of glp-1 analogues
  • Process for the manufacture of glp-1 analogues
  • Process for the manufacture of glp-1 analogues

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0136] In the preparation of semaglutide, a protected lysine derivative as shown below was used:

[0137]

[0138] This derivative is commercially available and its preparation is also described eg in CN104356224. This derivative is also represented as Fmoc-Lys[(tBuOOC-(CH 2 ) 16-CO-γGlu-OtBu)-AEEA-AEEA]-OH, wherein AEEA represents 2-[2-(2-aminoethoxy)ethoxy]acetyl.

[0139] The X 2 The tBu ester protecting groups of the building blocks are all removable under acidic conditions and thus cleaved at the end of the preparation process.

[0140] In a preferred aspect of the invention, said coupling step is performed in the presence of a coupling agent.

[0141] Preferably, the coupling agent is selected from N-hydroxysuccinimide (NHS), N,N'-diisopropylcarbodiimide (DIC), N,N'-dicyclohexylcarbodiimide (DCC), (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate (PyBOP), 2-(7-aza-1H-benzotriazol-1-yl)-1, 1,3,3-tetramethylurea hexafluorophosphate (HATU), 2-(1H...

Embodiment 1

[0330] Preparation of liraglutide

[0331] Step 1. Preparation of Fragment 1, Fragment D (17-31)

[0332] H-Gln(Trt) 17 -Ala-Ala-Lys(Pal-Glu-OtBu)-Glu(OtBu)-Phe-Ile-Ala-Trp(N in Boc)-Leu-Val-Arg(Pbf)-Gly-Arg(Pbf)-Gly 31 -Wang Resin

[0333]

[0334] The synthesis of the peptide fragment 1 was performed by stepwise Fmoc SPPS using 0.25 g of Wang resin (0.75 mmol / g) at room temperature. After the resin was swollen in 2ml DMF, Fmoc-Gly-OH, DIC and DMAP in DMF were added (4 eq, 2 eq and 0.1 eq relative to the resin loading, respectively). After 1h, by using DMF / DIPEA / Ac 2 The O mixture (v / v / v 5 / 2 / 1) was treated for 30 minutes to cap the unreacted hydroxyl groups of the resin. Fmoc deprotection was performed using 20% ​​piperidine in DMF (2 x 2 ml, 5 min and 15 min) and the resin was washed with DMF (4 x 2 ml). The degree of substitution was checked by UV absorbance measurement of the solution collected after Fmoc deprotection and was 0.53 mmol / g. The Fmoc-protected ami...

Embodiment 2

[0359] Preparation of semaglutide

[0360] Step 1. Preparation of Fragment 5, Fragment D (17-31)

[0361] H-Gln(Trt) 17 -Ala-Ala-Lys[(tBuOOC-(CH 2 ) 16 -CO-γGlu-OtBu)-AEEA-AEEA]-Glu(OtBu)-Phe-Ile-Ala-Trp(N in Boc)-Leu-Val-Arg(Pbf)-Gly-Arg(Pbf)-Gly 31 -O-MBH resin

[0362]

[0363] The synthesis of peptide fragment 5 was performed at room temperature using 0.5 g of H-Gly-O-MBH resin (loading 0.60 mmol / g). The resin was swollen in 3 ml DMF and used for stepwise Fmoc SPPS. Fmoc-protected amino acids (in two-fold excess relative to the resin loading) were preactivated with a mixture of DIC (2eq) and OxymaPure (2eq) for 3 min and sequentially coupled to the resin within 90 min. Arg, Val, Trp, Ala 24 The coupling of , Phe and Gln was repeated for 60 min using 1 eq coupling mixture. Using 1.5eqFmoc-Lys[(tBuOOC-(CH 2 ) 16 -CO-γGlu-OtBu)-AEEA-AEEA]-OH for the introduction of lipidated side chains in the peptide sequence, which was preactivated with 1.5eq DIC and 1.5eq O...

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Abstract

The present invention provides a process for the manufacture of GLP-1 analogues with high yield and purity by fragment condensation on the solid phase. In particular, it describes a convergent synthesis by condensation of a C-terminal pseudoproline fragment A with a fragment B bound to a solid support, followed by deprotection and cleavage from the support and final purification to yield the desired peptide. The invention further provides intermediates useful in the manufacturing process.

Description

technical field [0001] The present invention relates to peptide synthesis. In particular, the present invention relates to methods for the preparation of GLP-1 analogs. More specifically, the present invention relates to a method for the preparation of liraglutide and semaglutide by condensation of peptide fragments. Background technique [0002] Glucagon-like peptide-1 (GLP-1) is a naturally occurring peptide hormone with one of the strongest insulinotropic activities. GLP-1 is part of a longer peptide that is produced and processed into GLP-1 in the pancreas and intestine. Glucagon-like peptide 1 (GLP-1) receptor agonists, or GLP-1 analogs, are a relatively new class of injectable drugs used to treat type 2 diabetes. One of their advantages over older insulin secretagogues such as the sulfonylureas or meglitinides is their lower risk of causing hypoglycemia. [0003] Both liraglutide and semaglutide are highly similar peptides of 30 amino acids in length, which differ ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605
CPCC07K14/605C07K1/042C07K1/062
Inventor 朱塞佩娜·玛丽亚·因西沃安德烈·奥兰丁安东尼奥·里奇伊凡·古里亚诺夫沃尔特·卡布里
Owner BEIJING FRESENIUS KABI PHARM CO LTD
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