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Solid phase synthesis method for atosiban

A technology of solid-phase synthesis and atosiban, applied in peptide preparation methods, chemical instruments and methods, organic chemistry, etc., can solve the problems of long oxidation time, incomplete oxidation, shortening oxidation time, etc., and meet the reaction selection conditions The effect of stabilization and avoidance of loss of crude product

Active Publication Date: 2008-12-03
GL BIOCHEM SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The technical problem to be solved in the present invention is to select an oxidation method that satisfies: (1) stability in polypeptide synthesis, (2) convenient carrier reaction, and (3) avoiding the dissolution of polypeptide in air oxidation (4) can shorten the oxidation time and greatly improve the efficiency

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1: 1, Synthetic nonapeptide resin with protection

[0039] Polypeptide sequence (c[mpa-D-Tyr(Et)-Ile-Thr-Asn-Cys]-Pro-Orn-Gly-NH 2 )

[0040] Calculation of the dosage of each amino acid in the sequence and the dosage of some reagents

[0041] K=2.5×m resin×Loading=2.5×1g×0.52mmol / g=1.3mmol

[0042] Activator: m(HoBt)=M(HoBt)×K=0.135g / mmol×1.3mmol=0.176g

[0043] Condensing agent: V(DIC)=M(DIC)×K / 0.81=0.126g / mmol×1.3mmol / 0.81g / ml=0.2ml

[0044] Alkaline reagent V (collidine) = 2 × M (collidine) × K / 0.80g / ml = 2 × 0.124g / mmol × 1.3mmol / 0.80g / ml = 0.40ml

[0045] m(Gly)=M(Gly)×K=0.2973g / mmol×1.3mmol=0.386g

[0046] m(orn)=M(orn)×K=0.4545g / mmol×1.3mmol=0.591g

[0047] m(pro)=M(pro)×K=0.3374g / / mmol×1.3mmol=0.439g

[0048] m(cys)=M(cys)×K=0.5857g / mmol×1.3mmol=0.761g

[0049] m(Asn)=M(Asn)×K=0.5967g / mmol×1.3mmol=0.776g

[0050] m(Thr)=M(Thr)×K=0.3974g / mmol×1.3mmol=0.517g

[0051] m(Ile)=M(Ile)×K=0.3534g / mmol×1.3mmol=0.459g

[0052] m(D-Tyr)=M(D-Tyr)×K=0....

Embodiment 2

[0060]Take by weighing 0.67g iodine (this iodine amount is excess 5 times) and be dissolved in 10ml methanol, react with the resin of embodiment 1.

[0061] The obtained resin was added to 10 ml of a mixed solution with a volume ratio of trifluoroacetic acid: triisopropylsilane: water: p-cresol = 88: 2: 5: 5, shaken at room temperature for 1.5 hours, filtered, and washed with trifluoroacetic acid Resin was obtained twice, the filtrate was concentrated, and anhydrous ether was added to obtain a white mass, which was washed repeatedly with anhydrous ether to obtain 0.48 g of crude atosiban. ESI: 994.87 HPLC: 53.2% The final product of atosiban was obtained by separation, purification and freeze-drying.

Embodiment 3

[0063] Take by weighing 0.67g iodine (this iodine amount is excessive 5 times) and be dissolved in 10ml methanol, react with the resin of embodiment 1.1. The post-treatment was the same as in Example 2 to obtain 0.45 g of atosiban crude product. ESI: 994.45 HPLC: 78.2% The final product of atosiban was obtained by separation, purification and freeze-drying.

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PUM

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Abstract

The invention relates to a synthetic process of atosiban and solves the technical problem with poor solubility and long reaction time in the air liquid phase oxidation of the prior art. The synthetic process comprises the steps as follows: aminomethyl resin is adopted as a carrier; amino acids are combined one by one according to the Fmoc / tbu solid-phase peptide synthetic method; S-S bonds are formed by adopting the iodine oxidization method on the resin; peptides are cut from the resin with the mixed solution of trifluoroacetic acid, tri-isopropyl silicane, water and p-cresol to obtain a coarse product with S-S bonds; and the product is subjected to the HPLC purification and then frozen to obtain the atosiban. The synthetic process is simple and applicable to the large-scale synthesis of atosiban.

Description

Technical field: [0001] The invention relates to a solid phase synthesis method of atosiban. Background technique: [0002] Atosiban is a cyclic peptide oxytocin competitive antagonist of receptors in the uterus and on the decidua and fetal membranes. It is a breakthrough product in obstetric medicine and has been launched in Austria, Denmark and Sweden for delaying insufficiency month childbirth. It is estimated that it will be launched in the Netherlands, Germany and the United Kingdom in the near future. At present, there are imported products on the market in my country, but they have not yet been produced locally. The secretion is reduced to achieve the purpose of miscarriage. In China, the annual birth rate is 20 million. According to current clinical statistics, about 5-15% of pregnant women need miscarriage treatment. According to an average of 10%, the number of patients is about 2 million. Therefore, this variety has a great market prospect. [0003] Atosiban is s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/04
Inventor 徐红岩金健林薛志娟戴强
Owner GL BIOCHEM SHANGHAI
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