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Method for synthesizing terlipressin by solid-phase oxidization and cyclization

A technology of terlipressin and solid-phase oxidation, which is applied to the preparation method of peptides, chemical instruments and methods, oxytocin/vasopressin, etc., can solve the problem of excessive oxidation reaction waste liquid, low application value, Unfavorable to industrial production and other issues, to achieve the effect of reducing purification costs, improving the purity of crude peptides, and speeding up the reaction time

Active Publication Date: 2010-04-14
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction time of the solid-liquid combination synthesis process is long, the total yield is low, generally about 20%, the operation is complicated, and the waste liquid of the oxidation reaction is too much, which is not conducive to industrial production and has low application value.

Method used

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  • Method for synthesizing terlipressin by solid-phase oxidization and cyclization

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The preparation of embodiment 1, Fmoc-Gly-RinkAmide resin

[0039] Add 30 grams of RinkAmide resin (1.0mmol / g) in the reaction post of 500ml, add DMF swelling 30 minutes; Wash with DMF six times. Fmoc-Gly-OH (8.91g, 30mmol), HOBt (4.1g, 30mmol) and DICPDI (3.78g, 30mmol) were dissolved in an appropriate amount of DMF and added to the above reaction column, and nitrogen was bubbled at room temperature for 60min. After the reaction was completed, the reaction solution was removed in a vacuum, washed three times with DMF, three times with DCM, and shrunk three times with methanol. The degree of substitution was 0.96 mmol / g by sampling, and the yield was 96%.

Embodiment 2

[0040] The preparation of embodiment 2, Fmoc-Gly-RinkAmide-MBHA resin

[0041] Add 75 grams of RinkAmide-MBHA resin (0.8mmol / g) in the reaction column of 1000ml, add DMF and swell for 30 minutes; Then wash six times with DMF. Fmoc-Gly-OH (17.82g, 60mmol), HOBt (8.2g, 60mmol) and DICPDI (7.56g, 60mmol) were dissolved in an appropriate amount of DMF and added to the above reaction column, and nitrogen was bubbled for 60min at room temperature. After the reaction was completed, the reaction solution was removed in a vacuum, washed three times with DMF, three times with DCM, and shrunk three times with methanol. The degree of substitution was 0.76 mmol / g by sampling, and the yield was 95%.

Embodiment 3

[0042] The preparation of embodiment 3, Fmoc-Gly-RinkAmide-BHA resin

[0043] Add 70.59 grams of RinkAmide-BHA resin (0.85mmol / g) in the reaction column of 1000ml, add DMF and swell for 30 minutes; Then wash six times with DMF. Fmoc-Gly-OH (17.82g, 60mmol), HOBt (8.2g, 60mmol) and DICPDI (7.56g, 60mmol) were dissolved in an appropriate amount of DMF and added to the above reaction column, and nitrogen was bubbled for 60min at room temperature. After the reaction was completed, the reaction solution was removed in a vacuum, washed three times with DMF, three times with DCM, and shrunk three times with methanol. The degree of substitution was 0.79 mmol / g by sampling, and the yield was 93%.

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Abstract

The invention discloses a method for synthesizing terlipressin by solid-phase oxidization and cyclization. The method comprises the following steps: (1) obtaining Fmoc-Gly-amino resins by using Fmoc-Gly-OH and amino resins; (2) coupling the Fmoc-Gly-amino resins one by one to obtain linear terlipressin-amino resins; (3) synthesizing the linear terlipressin-amino resins into terlipressin-amino resins by adopting iodine solid-phase oxidized cyclization; (4) cracking and cutting the terlipressin-amino resins to obtain raw peptides of the terlipressin; and (5) carrying out purification, salt conversion and freeze-drying on the raw peptides to obtain terlipressin acetate. The invention has the key innovations that solid-phase oxidization reduces a large amount of waste liquid brought by liquid-phase oxidization, accelerates the reaction time, belongs to process greening reformation and greatly improves the total yield.

Description

technical field [0001] The invention relates to a method for synthesizing a polypeptide, in particular to a method for synthesizing the polypeptide compound terlipressin by solid-phase oxidation and cyclization. Background technique [0002] Terlipressin is a new type of artificially synthesized long-acting vasopressin preparation, it is a prodrug, inactive in itself, in the body through the action of aminopeptidase, the 3 glycerols at its N-terminus are removed. After aminoacyl residues, active lysine vasopressin is slowly "released", so terlipressin acts as a depot from which lysine vasopressin is released at a steady rate. [0003] The molecular formula of terlipressin is: Gly-Gly-Gly-c[Cys-Tyr-Phe-Gln-Asn-Cys]-Pro-Lys-Gly-NH 2 [0004] At present, although there are reports on the synthesis process of terlipressin at home and abroad, most of them are liquid phase synthesis or solid-liquid combination synthesis process. The solid-liquid combination synthesis process ha...

Claims

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Application Information

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IPC IPC(8): C07K7/16C07K1/06C07K1/04
Inventor 刘建李红玲马亚平袁建成
Owner HYBIO PHARMA
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