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Solid-phase preparation method for exenatide crude product

A technique for the preparation of exenatide and solid phase, which is applied to the preparation methods of peptides, chemical instruments and methods, peptides, etc., and can solve problems such as difficult stability, many control items, and complicated steps of exenatide

Inactive Publication Date: 2013-05-29
SHANGHAI AMBIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The steps of solid-liquid phase synthesis of exenatide are complicated, GMP production has many control items, it is not easy to be stable, and there are many by-products produced
The removal of impurities requires multiple washings or other means of purification, resulting in high cost

Method used

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Examples

Experimental program
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preparation example Construction

[0084] In one example of the present invention, the preparation method of solid-phase synthesis of exenatide by the polypeptide of the present invention comprises the following steps:

[0085] The first step, the synthesis of Fmoc-linker:

[0086] Use 1.0-5.0 times the amount of Fmoc-Linker, 1.0-5.0 times the amount of HOBt, and 1.0-5.0 times the amount of DIC reagent, and dissolve it in a DMF solvent of 5ml-10ml / g resin. Add it into a reaction kettle equipped with PLAM or MBHA resin, react for 30-60 minutes, then add 1.0-5.0 times the amount of DIC reagent, and react for 3 hours at room temperature. After the reaction, it was washed three times with DMF / MeOH successively. End-capped with Ac2O / Pyridine / DMF;

[0087] The second step, the synthesis of amino acid residue 39#-31#:

[0088]Treat the solid in the reaction kettle twice with a deprotecting agent, wash with DMF / MeOH for 1-3 times, and then add 1.0-5.0 times the amount of Fmoc-protected amino acids (such as: Fmoc-Ser...

Embodiment 1

[0117] Synthesis of Crude Exenatide 1

[0118] Synthesis of Fmoc-linker:

[0119] Use 2.0 times the amount of Fmoc-Linker, 2.0 times the amount of HOBt, and 2.0 times the amount of DIC reagent, and dissolve them in a DMF solvent of 8ml / g resin. Add it into a reaction kettle equipped with 5.5 grams of MBHA resin (substitution rate 0.9mmol / g), react for 30 minutes, then add 2.0 times the amount of DIC reagent, and react for 3 hours at room temperature. After the reaction, it was washed three times with DMF / MeOH successively. Capped with Ac2O / Pyridine / DMF.

[0120] Synthesis of amino acid residues 39#-31#:

[0121] Treat the solid in the reaction kettle twice with a deprotecting agent, wash it three times with DMF / MeOH, add 2.5 times the amount of Fmoc protected amino acids, 2.5 times the amount of HOBt, and 2.5 times the amount of DIC reagent, and dissolve them in 8ml / g Mixed solution of resin in DMF solvent. After reacting for 30 minutes, add 2.5 times the amount of DIC re...

Embodiment 2

[0137] Synthesis of Crude Exenatide 2

[0138] Synthesis of Fmoc-linker:

[0139] Use 2.0 times the amount of Fmoc-Linker, 2.0 times the amount of HOBt, and 2.0 times the amount of DIC reagent, and dissolve them in a DMF solvent of 8ml / g resin. Add it into a reaction kettle equipped with 2.22 grams of PLAM resin (substitution rate 0.9mmol / g), react for 30 minutes, then add 2.0 times the amount of DIC reagent, and react for 3 hours at room temperature. After the reaction, it was washed three times with DMF / MeOH successively. Capped with Ac2O / Pyridine / DMF.

[0140] Synthesis of amino acid residues 39#-31#:

[0141] Treat the solid in the reaction kettle twice with a deprotecting agent, wash it three times with DMF / MeOH, add 2.5 times the amount of Fmoc protected amino acids, 2.5 times the amount of HOBt, and 2.5 times the amount of DIC reagent, and dissolve them in 8ml / g Mixed solution of resin in DMF solvent. After reacting for 30 minutes, add 2.5 times the amount of DIC r...

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Abstract

The invention discloses a solid-phase preparation method for an exenatide crude product. The method comprises the following steps of: taking solid-phase synthetic resin as a starting material; sequentially connecting amino acids or polypeptides with Fmoc protecting groups according to a solid-phase synthesis method, so as to obtain the protected nonatriaconta-peptide resin; sequentially removing the Fmoc protecting groups during the process; taking any one of TBTU / HOBt, HBTU / HOBt, BOP / HOBt, HBTU / HOAt, HBTU / HOAt, DIC / HOBt or BOP / HOAt as a condensing agent, and performing peptide grafting reaction to obtain the protected nonatriaconta-peptide resin; and synchronously removing side-chain protecting groups and cutting peptide to obtain the exenatide crude product. The steps have the following characteristics that: 1, the polypeptides with the Fmoc protecting groups are Fmoc-Gly-Gly-OH; and 2, synthesis for residue 20-19 and residue 17-11 is performed by taking HATU / HOBt as a condensing agent.

Description

technical field [0001] The invention relates to the chemical synthesis of medicinal polypeptide raw materials, in particular to a solid-phase preparation method of crude exenatide. Background technique [0002] Exenatide (Exenatide), which is a polypeptide composed of 39 amino acids, is the first incretin drug. Incretin drugs are a new type of treatment for type 2 diabetes, which can mimic the anti-diabetic response of natural gastrointestinal hormones in the body or the response of reducing glucose concentration. These responses include stimulating the body to produce insulin when blood sugar rises , inhibits the secretion of glucagon after meals, slows down the rate of blood uptake of nutrients and reduces food intake. Exenatide (Exenatide) is a new type of drug for the treatment of type Ⅱ diabetes. Subcutaneous injection, 2 times a day, for patients with type Ⅱ diabetes mellitus whose blood sugar cannot be adequately controlled by metformin, sulfonylureas or the combina...

Claims

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Application Information

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IPC IPC(8): C07K14/575C07K1/06C07K1/04
CPCY02P20/55
Inventor 白俊才张国庆张若平方路
Owner SHANGHAI AMBIOPHARM
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