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New polypeptide fragment of somalutide and preparation method thereof

A peptide fragment and fragment technology, applied in the field of peptide drug synthesis, can solve the problems of reduced coupling efficiency, increased amino acid racemization, decreased product purity and yield, etc., to improve coupling efficiency, reduce the degree of racemization, and improve product quality. quality effect

Active Publication Date: 2019-10-11
QILU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Solid-phase synthesis of peptide fragments with protective groups does not reduce the high cost factor that naturally exists in solid-phase peptide synthesis; the obtained fragments have low purity, and directly react with other fragments without purification, and the impurities brought into the product also increase; The phase method condenses amino acids one by one to obtain fragments. Each condensation and deprotection process is cumbersome, and it will increase the possibility of amino acid racemization, resulting in racemization impurities.
In particular, solid-phase peptide synthesis is used to gradually couple amino acids to synthesize semaglutide. After the introduction of the amino acid Aib with large steric hindrance, it brings great challenges to the subsequent coupling of His. The steric hindrance leads to coupling efficiency. Reduce the fragment impurities associated with the lack of His, and at the same time the coupling efficiency results in the high racemization of histidine
These reasons all can lead to the decline of product purity and yield, even can't produce qualified product

Method used

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  • New polypeptide fragment of somalutide and preparation method thereof
  • New polypeptide fragment of somalutide and preparation method thereof
  • New polypeptide fragment of somalutide and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1, the preparation of Fmoc-His(Boc)-Aib-Glu(OtBu)-Gly-OH

[0040] Dissolve Cbz-Glu(OtBu)-OH (67.5g, 200mmol) and glycine methyl ester hydrochloride (25.1g, 200mmol) in 550ml THF, add dicyclohexylcarbodiimide (45.4g, 220mmol) and HOBt (40.5g, 300mmol), stirred at room temperature for 18 hours. After the reaction, filter the reaction solution, wash the filter cake with tetrahydrofuran, combine the filtrates, concentrate under reduced pressure, and then re-dissolve in dichloromethane, leave the solution at 0°C for 30 minutes, then filter, and wash the solid with dichloromethane , concentrated under pressure after the filtrate was combined to obtain Cbz-Glu(OtBu)-Gly-OMe (76.6g, 93.8%), Ms=408.19 (M+H + ).

[0041] Cbz-Glu(OtBu)-Gly-OMe (75g, 183.6mmol) was dissolved in 600ml of dichloromethane containing 11.4ml of HCl, nitrogen was evacuated and Pd / C catalyst was added, followed by hydrogen for reduction reaction. After the reaction is finished, the catalyst ...

Embodiment 2

[0045] Embodiment 2, the preparation of Boc-His-Aib-Glu(OtBu)-Gly-OSu

[0046] Cbz-Glu(OtBu)-OH (50.6g, 150mmol) and glycine methyl ester (18.8g, 150mmol) were dissolved in 500ml tetrahydrofuran, and dicyclohexylcarbodiimide (34g, 165mmol) and HOBt (30.4g, 225mmol), stirred at room temperature for 18 hours. After the reaction, filter the reaction solution, wash the filter cake with tetrahydrofuran, combine the filtrates, concentrate under reduced pressure, and then re-dissolve in dichloromethane, leave the solution at 0°C for 30 minutes, then filter, and wash the solid with dichloromethane , combined the filtrates and concentrated under pressure to obtain Cbz-Glu(OtBu)-Gly-OMe (57.2 g, 93.3%). Ms=408.19(M+H + ).

[0047] Cbz-Glu(OtBu)-Gly-OMe (56g, 137.1mmol) was dissolved in 500ml of dichloromethane containing 8.5ml of HCl, nitrogen was evacuated and Pd / C catalyst was added, followed by hydrogen for reduction reaction. After the reaction is finished, the catalyst is remov...

Embodiment 3

[0052] Embodiment 3, the preparation of Fmoc-His(Fmoc)-Aib-Glu(OtBu)-Gly-OH

[0053] Weigh Cbz-Glu(OtBu)-OH (16.9g, 50mmol) and glycine methyl ester (6.3g, 50mmol) and dissolve in 150ml tetrahydrofuran, add dicyclohexylcarbodiimide (11.4g, 55mmol) and HOBt (10.1 g, 75mmol), stirred at room temperature for 18 hours. After the reaction, filter the reaction solution, wash the filter cake with tetrahydrofuran, combine the filtrates, concentrate under reduced pressure, and then re-dissolve in dichloromethane, leave the solution at 0°C for 30 minutes, then filter, and wash the solid with dichloromethane , combined the filtrates and concentrated under pressure to obtain Cbz-Glu(OtBu)-Gly-OMe (18.9 g, 92.4%). Ms=408.19(M+H + ).

[0054] Cbz-Glu(OtBu)-Gly-OMe (16g, 39.2mmol) was dissolved in 150ml of dichloromethane containing 2.4ml of HCl, nitrogen was evacuated and Pd / C catalyst was added, followed by hydrogen for reduction reaction. After the reaction is finished, the catalyst i...

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Abstract

The invention relates to the field of polypeptide drug synthesis, in particular to a somalutide polypeptide fragment with a protective group and a preparation method thereof. When the new polypeptidefragment is used for synthesizing somalutide, impurities in the fragment are reduced, and the purity of the final product is improved.

Description

technical field [0001] The invention relates to the field of polypeptide drug synthesis, in particular to a polypeptide fragment with a protective group used for preparing semaglutide. The polypeptide fragment reduces missing peptide fragment impurities and racemic impurities in the synthesis of semaglutide, and improves the purity of the final product. [0002] technical background [0003] Glucagon-like peptide 1 (GLP-1) is an "incretin" naturally secreted by the human gastrointestinal mucosa, which can bind to receptors on islet cells and stimulate insulin secretion, thereby reducing blood sugar. . The advantages of GLP-1 receptor agonist hypoglycemic drugs are that the incidence of hypoglycemic events is significantly lower than that of insulin, and they can reduce food intake and delay gastric emptying, which is beneficial to weight control and can protect the function of pancreatic β cells. [0004] Sermaglutide, a novel long-acting glucagon-like peptide-1 (GLP-1) ana...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/02
CPCC07K14/605Y02P20/55
Inventor 田振平石鑫磊韩荣刚薛琛琛彭海涛匡德琦
Owner QILU PHARMA
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