Preparation method of lixisenatide

A lixisenatide and resin technology, applied in the field of medicine, can solve the problems of increasing the difficulty of purification, reducing the yield of the product, and reducing the purity of crude peptides, etc.

Inactive Publication Date: 2016-06-29
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The inventors have found that the conventional Fmoc / tBu strategy has the following problems in the step-by-step coupling: due to the obvious shrinkage of the resin solid phase coupling, the five amino acids (Glu 15 、Glu 16 、Glu 17 、Ala 18 、Vla 19 ), these five amino acids are likely to produce defective peptides with incomplete coupling, thereby reducing the purity of the crude peptide, increasing the difficulty of purification and further reducing the product yield

Method used

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  • Preparation method of lixisenatide
  • Preparation method of lixisenatide
  • Preparation method of lixisenatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] H-Arg(pbf)-Leu-Phe-Ile-Glu(OtBu)-Trp(Boc)-Leu-Lys(Boc)-Asn(Trt)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu) -Synthesis of Gly-Ala-Pro-Pro-Ser(tBu)-Lys(Boc)-Lys(Boc)-Lys(Boc)-Lys(Boc)-Lys(Boc)-Lys(Boc)-RinkAmideResin

[0094] Weigh 100g of RinkAmideResin (purchased from Tianjin Nankai Hecheng) with a substitution degree of 0.1mmol / g and add it to the solid-phase reaction column, wash twice with DMF of one volume of resin bed, and wash twice with DMF of one volume of resin bed. Swell the resin for 30 minutes. Add one volume of resin bed layer 20% piperidine / DMF, remove Fmoc by 10min+10min. The reaction solution was drained, and the resin was washed 6 times with DMF of one volume of the resin bed. Weigh 14.055g Fmoc-Lys(Boc)-OH (30mmol), 4.053gHOBt (30mmol) and dissolve in the minimum volume mixed solution of DCM and DMF with a volume ratio of 1:1, add 5.19ml DIC (33mmol) under ice-water bath for activation for 3min, then add In a solid-phase reaction column, react at room temperatur...

Embodiment 2

[0096] H-Arg(pbf)-Leu-Phe-Ile-Glu(OtBu)-Trp(Boc)-Leu-Lys(Boc)-Asn(Trt)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu) -Synthesis of Gly-Ala-Pro-Pro-Ser(tBu)-Lys(Boc)-Lys(Boc)-Lys(Boc)-Lys(Boc)-Lys(Boc)-Lys(Boc)--RinkAmideResin

[0097]Weigh 25g of RinkAmideResin (purchased from Tianjin Nankai Hecheng) with a substitution degree of 0.4mmol / g, add it to the solid-phase reaction column, wash twice with DMF of double the volume of the resin bed, wash twice with double the volume of the resin bed DMF swells the resin for 30 minutes. Add 20% piperidine / DMF to double the volume of the resin bed, and remove Fmoc in the manner of 10min+10min. The reaction solution was drained, and the resin was washed 6 times with DMF of one volume of the resin bed. Weigh 14.055g Fmoc-Lys(Boc)-OH (30mmol), 4.053gHOBt (30mmol) and dissolve in the minimum volume mixed solution of DCM and DMF with a volume ratio of 1:1, add 5.19ml DIC (33mmol) under ice-water bath for activation for 3min, then add In a solid-phase reac...

Embodiment 3

[0099] H-Arg(pbf)-Leu-Phe-Ile-Glu(OtBu)-Trp(Boc)-Leu-Lys(Boc)-Asn(Trt)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu) -Synthesis of Gly-Ala-Pro-Pro-Ser(tBu)-Lys(Boc)-Lys(Boc)-Lys(Boc)-Lys(Boc)-Lys(Boc)-Lys(Boc)-RinkAmideResin

[0100] Weigh 50g of RinkAmideResin (Tianjin Nankai Hecheng) with a substitution degree of 0.2mmol / g, add it to the solid-phase reaction column, wash twice with DMF of one volume of resin bed, and swell with DMF of one volume of resin bed Resin 30 minutes. Add one volume of resin bed layer 20% piperidine / DMF, remove Fmoc by 10min+10min. The reaction solution was drained and the resin was washed 6 times with DMF. Weigh 14.055g Fmoc-Lys(Boc)-OH (30mmol), 4.053gHOBt (30mmol) and dissolve in the minimum volume mixed solution of DCM and DMF with a volume ratio of 1:1, add 5.19ml DIC (33mmol) under ice-water bath for activation for 3min, then add In a solid-phase reaction column, react at room temperature for 2 hours. Use the ninhydrin method to detect and judge the reacti...

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Abstract

The invention relates to a preparation method of lixisenatide. Lixisenatide is synthesized through a fragment condensation method. Specifically, fragment 20-24 peptide resin and fragment 15-19 are used to carry out solid phase condensation, and then residual amino acids are coupled gradually until the solid phase synthesis is finished. Compared with the conventional step-by-step coupling, the purity and purification yield of coarse peptide are improved.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for preparing lixisenatide. Background technique [0002] Diabetes mellitus (Diabetes Mellitus) is a chronic comprehensive disease mainly caused by the disorder of glucose metabolism caused by absolute or relative insulin deficiency or decreased sensitivity of target cells to insulin, which seriously affects the health and quality of life of patients. Clinically, diabetes is divided into insulin-dependent diabetes (type I diabetes) and non-insulin-dependent diabetes (type II diabetes), of which type II diabetes accounts for more than 90%. Lixisenatide (lixisenatide) is the fourth listed incretin analogue in the world, and its indication is once a day, combined with oral hypoglycemic drugs or basal insulin to treat adults with type 2 diabetes. [0003] Clinical studies have shown that for patients with type II diabetes poorly controlled by metformin, adminis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/575C07K1/06C07K1/04
Inventor 张文治聂涛马亚平袁建成
Owner HYBIO PHARMA
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