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Solid-phase synthesis method of exenatide

A technology of solid-phase synthesis and exenatide, which is applied in the preparation method of peptides, chemical instruments and methods, peptides, etc., can solve problems such as condensation difficulties, fragment dissolution difficulties, and increased costs

Inactive Publication Date: 2013-02-27
NANJING UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, problems such as fragment dissolution difficulties, C-terminal racemization, and condensation difficulties caused by secondary structures are prone to problems when performing fragment condensation in liquid phase
In addition, the synthesis of each fragment must use a relatively expensive fully protected peptide resin, which greatly increases the cost

Method used

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  • Solid-phase synthesis method of exenatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Embodiment 1 prepares pseudoproline Fmoc-Leu-Ser (ψ Me,Me Pro)-OH

[0085] (1) Preparation of Fmoc-Leu-Ser(ψ Me,Me Pro)-OH

[0086] 1) Preparation of Fmoc-Leu-Ser-OBzl

[0087] Add Fmoc-Leu-OH (3.54g, 10mmol), H-Ser-OBzl·HCl (2.32g, 10mmol), HOBt (1.42g, 10.5mmol) into the flask, add DMF (100mL) under ice-cooling, and wait until the solid After dissolving, add DIPEA (3.8mL, 22mmol) to activate for 5min, finally add HBTU (3.98g, 10.5mmol), react for 10min, remove the ice bath, and react at room temperature until the reaction is complete as detected by TLC. Then extracted with ethyl acetate, the organic phase was washed with 1N HCl, saturated NaHCO 3 , washed with saturated NaCl, anhydrous Na 2 SO 4 After drying, the solvent was spin-dried to obtain 5.5 g of white solid, namely Fmoc-Leu-Ser-OBzl.

[0088] 2) Preparation of Fmoc-Leu-Ser(ψ Me,Me Pro)-OBzl

[0089] Add Fmoc-Leu-Ser-OBzl (3.2g, 5mmol), DMP (3.07mL, 25mmol), PPTS (0.377g, 1.5mmol), toluene (100mL) in...

Embodiment 2

[0093] Embodiment 2 prepares the amino acid of Hmb, Dmb or Tmb protection

[0094] (1) Preparation of Fmoc-(Dmb)Gly-OH

[0095] 1) Preparation of H-(Dmb)Gly-OH

[0096] First, the amino acid Gly (7.5g, 100mmol) was dissolved in an aqueous solution of KOH (5.6g, 100mmol), and an ethanol solution of 2,4-dimethoxybenzaldehyde (16.6g, 100mmol) was added to the aqueous solution, and at room temperature After stirring for 30min, slowly add NaBH 4 (4.1g, 101mmol) in aqueous solution (containing a small amount of 1M NaOH). Stir until reaction is complete. Adjust the pH to 4 with concentrated hydrochloric acid, and a solid precipitates out. Wash with ice water and 50% methanol / water solution to obtain 14 g of compound H-(Dmb)Gly-OH with a yield of 62.2%.

[0097] 2) Preparation of Fmoc-(Dmb)Gly-OH

[0098] Dioxane was added to an ice solution of H-(Dmb)Gly-OH (11.25g, 50mmol) until it was completely dissolved, then sodium carbonate (17g, 160mmol) was added, and Fmoc-Cl (27.2g, 10...

Embodiment 3

[0100] Example 3 Preparation of Fmoc-Gly-(Hmb)Gly-OH

[0101] 1) Preparation of H-(Hmb)Gly-OH

[0102] First, the amino acid Gly (7.5g, 100mmol) was dissolved in an aqueous solution of KOH (5.6g, 100mmol), and an ethanol solution of 2,4-dimethoxybenzaldehyde (15.2g, 100mmol) was added to the aqueous solution, and at room temperature After stirring for 30min, slowly add NaBH 4 (4.1g, 101mmol) in aqueous solution (containing a small amount of 1M NaOH). Stir until reaction is complete. Adjust the pH to 4 with concentrated hydrochloric acid, and a solid precipitates out. Wash with ice water and 50% methanol / water solution to obtain 13.8 g of compound H-(Hmb)Gly-OH with a yield of 65.4%.

[0103] 2) Preparation of Fmoc-Gly-OSu

[0104] Fmoc-Gly-OH (2.97g, 10mmol) and N-hydroxysuccinimide (1.15g, 10mmol) were dissolved in DMF, and EDC·HCl (2.30g, 10mmol) was added after cooling in an ice-water bath. The reaction was carried out at room temperature for 24 h, and the reaction wa...

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Abstract

The invention provides a solid-phase synthesis method of exenatide, which comprises the following steps: 1) preparing Fmoc-Ser(tBu)-amino resin from initial raw materials Fmoc-Ser(tBu)-OH and amino resin with the substitution degree of 0.3-1.2mmol / g; 2) after removing Fmoc protecting group from the Fmoc-Ser(tBu)-amino resin, sequentially connecting Fmoc amino resins and at least one amino-protected Fmoc amino resin or dipeptide with temporarily substituted amide N in a peptide sequence, and removing Fmoc to obtain the exenatide amino resin of which the side chain is fully protected; and 3) removing the side chain protecting group from the resin, and precipitating with ice aether, thereby obtaining the exenatide. The synthesis method has the advantages of high efficiency, simple reaction operation and easy after-treatment, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of polypeptide drug synthesis, in particular to a solid phase synthesis method of exenatide. Background technique [0002] Diabetes mellitus is an endocrine and metabolic common and frequently-occurring disease characterized by high blood sugar and multiple complications caused by absolute or relative insulin deficiency. According to the latest data released by the World Health Organization (WHO), in 2007 the global diabetes mellitus The number of patients has reached 180 million, and the incidence rate is still increasing year by year. It is predicted that by 2025, the number of diabetic patients in the world will reach 300 million, becoming the third largest killer of human beings after cardiovascular and cerebrovascular diseases and cancer. [0003] Diabetes is mainly divided into type I (insulin dependent diabetes, IDDM) and type II (non-insulin dependent diabetes, NIDDM), of which type II diabetes patie...

Claims

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Application Information

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IPC IPC(8): C07K14/575C07K1/06C07K1/04
CPCY02P20/55
Inventor 苏贤斌钱依冰毛怡春叶青董海军
Owner NANJING UNIV OF TECH
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