Method for preparing semaglutide by fragment condensation

A fragment and peptide fragment technology, applied in the field of fragment condensation to prepare semaglutide, can solve the problems of low cost and high efficiency, low synthesis yield, high production cost, etc., to reduce the number of preparations, simple post-processing, and reduce preparation costs Effect

Active Publication Date: 2019-04-16
LANZHOU UNIVERSITY
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0006] The technical problem to be solved by the present invention is to provide a fragment in view of the shortcomings of existing methods such as low synthesis yield, high production cost, large waste liquid, difficult product purification, and inability to obtain high-purity semaglutide at low cost and high efficiency. Method for preparing semaglutide by condensation

Method used

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  • Method for preparing semaglutide by fragment condensation
  • Method for preparing semaglutide by fragment condensation
  • Method for preparing semaglutide by fragment condensation

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Embodiment

[0052] 1. Resin Preparation

[0053] 1.1 Preparation of Fmoc-Gly-2-chloro-trityl resin: 5g of 2-chloro-trityl chloride resin with a substitution value of 1.03mmol / g (1eq) was added to a polypeptide synthesizer, washed with DCM, and 1.3 dissolved in DCM was added. eq Fmoc-Gly-OH and 2.5eq DIEA, the mixture was mechanically stirred under argon protection for 1 hour and blocked with methanol. DMF, DCM and MeOH were washed, and vacuum-dried to constant weight to obtain Fmoc-Gly-2-chloro-trityl resin. The loading amount of the resin was determined to be 0.8mmol / g by ultraviolet spectrophotometry.

[0054] 1.2 Preparation of Fmoc-Ala-2-chloro-trityl resin: 5g of 2-chloro-trityl chloride resin with a substitution value of 1.03mmol / g (1eq) was added to a polypeptide synthesizer, washed with DCM, and 1.1 dissolved in DCM was added. eq Fmoc-Ala-OH and 2.2eq DIEA, the mixture was mechanically stirred under argon protection for 1 hour and blocked with methanol. DMF, DCM and MeOH were w...

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Abstract

The invention relates to a method for preparing soematoglutide. A solid-liquid phase-binding fragment condensation scheme is adopted and includes conducting solid phase synthesis to obtain side chainprotecting peptide, conducting liquid phase fragment condensation to obtain fully protected semaglutide, then conducting cleavage to obtain crude semaglutide and conducting purification salt exchangeto obtain the semaglutide. A pseudoproline strategy is adopted to reduce by-products caused by racemization. Acccording to the method, impurities are reduced, the yield is improved, the synthesis timeis reduced, the waste liquid discharge is reduced, the synthesis cost is greatly reduced, and the method is very beneficial to industrial production.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a method for preparing semaglutide by fragment condensation. Background technique [0002] Semaglutide (Semaglutide) is a new long-acting GLP-1 analog developed by Novo Nordisk, the sequence is: H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser -Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(AEEAc-AEEAc-γ-Glu-17-carboxyheptadecanoyl)-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly- Arg-Gly-OH, molecular formula: C 187 h 291 N 45 o 59 . It can inhibit the hydrolysis of DPP-4 enzyme, prolong the biological half-life, lower blood sugar for a long time, promote the regeneration of islet cells, and is used for the treatment of type 2 diabetes. [0003] Patent CN103848910, patent CN104356224, patent CN105753964, patent CN106928343, patent CN106478806, patent CN108203462, patent CN108359006, patent CN108676087 and patent CN109021092 are sequentially linked to synthesize semaglutide by Fmoc strategy solid phase metho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/06C07K1/04C07K1/02
CPCC07K14/605Y02P20/55
Inventor 常民彭雅丽王锐薛宏祥武怡菲申宇轩方泉
Owner LANZHOU UNIVERSITY
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