A kind of solid phase synthesis atosiban method

A technology of atosiban and solid-phase synthesis, which is applied in the preparation methods of peptides, chemical instruments and methods, organic chemistry, etc., can solve the problems of increasing the risk of product quality, affecting the production schedule, and production operation restrictions, and reducing the Loss of target product, low production cost, and the effect of reducing waste of solvent

Active Publication Date: 2012-02-15
HAINAN ZHONGHE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are several problems in this synthetic method: one, the low-temperature operation requirement of ammonium solution is long, and the product purity is not high, and the equipment requirements are complicated; two, metal sodium is used for the side chain protection group, which has hidden dangers in safety. There are relatively large restrictions on production operations; 3. The steps are relatively cumbersome, which affects the production progress and increases the risk of product quality

Method used

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  • A kind of solid phase synthesis atosiban method
  • A kind of solid phase synthesis atosiban method
  • A kind of solid phase synthesis atosiban method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1 Preparation of Fmoc-Gly-resin

[0055] Add 100.00 g of Rink Amide resin to the reaction column, add 550 ml of DCM / wash for 3 times, then add 550 ml of DMF / wash for 3 times, add 550 ml of prepared 30% piperidine / DMF solution to the glass reaction column, and stir. The reaction was carried out for 30 min, the reaction solution was removed, 550 ml of DMF was added for washing 6 times, and the deprotection effect was detected with 5% ninhydrin ethanol solution. Weigh 23.79g of Fmoc-Gly-OH and 10.80g of HOBT, add N, N-dimethylformamide (DMF) and stir to dissolve, add 12ml of DIPCDI after complete dissolution, stir evenly and add to the glass reaction column, stir and react 24 Hour. After the completion of the reaction, the reaction solution was removed, washed 3 times with 550 ml of DMF, then washed 3 times with 550 ml of DCM, and finally washed 3 times with 550 ml of methanol, drained, poured out, and dried in a vacuum drying box. 12h. It was taken out and weig...

Embodiment 2

[0056] Example 2 Preparation of Fmoc-Orn(Boc)-Gly-resin

[0057] 103.19 g of Fmoc-Gly-resin was added to the reaction column, 550 ml of DCM was added to wash 3 times, and 550 ml of DMF was added to wash 3 times. Add 550ml of prepared 30% piperidine / DMF solution to the glass reaction column, stir for 30min, remove the reaction solution, add 550ml of DMF / wash for 6 times, use 5% ninhydrin ethanol solution to detect the deprotection effect . Weigh 108.34 g of Fmoc-Orn(Boc)-OH and 32.21 g of HOBT, add DMF and stir to dissolve, after complete dissolution, add 37 ml of DMF solution of 1 mmol / ml DIPCDI, and stir evenly. The prepared amino acid coupling solution was added to the reaction column, and the reaction was stirred for 90 min. The reaction solution was removed, washed 6 times with DMF 550ml / time, and the coupling effect was detected with 5% ninhydrin ethanol solution.

Embodiment 3

[0058] Example 3 Preparation of Fmoc-Pro-Orn(Boc)-Gly-resin:

[0059] Add 550ml of prepared 30% piperidine / DMF solution to the glass reaction column, stir for 30min, remove the reaction solution, add 550ml of DMF / wash for 6 times, use 5% ninhydrin ethanol solution to detect the deprotection effect . Weigh 32.21 g of Fmoc-Pro-OH and HOBT, add DMF and stir to dissolve, and after complete dissolution, add 37 ml of a DMF solution of 1 mmol / ml DIPCDI, and stir evenly. The prepared amino acid coupling solution was added to the reaction column, and the reaction was stirred for 90 min. The reaction solution was removed, washed 6 times with DMF550ml / time, and the coupling effect was detected by sampling with 5% ninhydrin ethanol solution.

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Abstract

The present invention relates to a method for solid-phase synthesis of atosiban, comprising the following steps: 1) taking Rink Amide resin as a carrier, and obtaining H2N-Rink Amide resin after removing Fmoc-protection; 2) using HOBT and DIPCI as condensation reagents, and The carboxyl group of Fmoc-Gly-OH is connected with the amino group of the resin to obtain Fmoc-Gly (resin); 3) adopt the Fmoc strategy to synthesize the remaining amino acids in the solid phase sequence sequentially; 4) carry out solid phase cyclization with iodine; 5) then use the cleavage reagent ( Trifluoroacetic acid / thioanisole / 1,2-ethanedithiol / water) cleavage and ether precipitation to obtain crude atosiban peptide; 6) the crude product was prepared and separated by HPLC to obtain pure atosiban.

Description

Technical field: [0001] The invention relates to a method for synthesizing active polypeptide raw materials, in particular to a method for synthesizing atosiban in solid phase. Background technique: [0002] Atosiban (atosiban), its chemical name is: 1-(3-thiolpropanolate)-2-(O-ethyl-D-tyrosine)-4-L-threonine-8-L -Ornithine-oxytocin. [0003] Its structural formula is: [0004] [0005] Atosiban is an oxytocin analog, a synthetic cyclic polypeptide, and a competitive oxytocin antagonist for receptors in the uterus, decidua, and fetal membranes. Its acetate is used clinically to treat premature labor. . Atosiban Acetate Injection was developed by Ferring AB and was first listed in Austria on March 23, 2000 under the trade name: [0006] Relevant literature reports that the synthesis method of atosiban is to prepare amino acid resin by Boc-protected glycine (Gly) and chloromethyl resin, and then coupling the remaining protected amino acids through cyclic condensation ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/16C07K1/06C07K1/04C07K1/20
Inventor 崔学云周宗贞杨平马中刚蒋明更
Owner HAINAN ZHONGHE PHARM CO LTD
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