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Method for synthesizing atosiban by solid phase

A technology of atosiban and synthetic method, which is applied in the field of synthesizing active polypeptide raw materials, can solve the problems of increasing the risk of product quality, affecting the production progress, and complicated equipment requirements, so as to reduce the loss of the target product, reduce the production cost, and The effect of process stability

Active Publication Date: 2010-04-21
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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  • Method for synthesizing atosiban by solid phase
  • Method for synthesizing atosiban by solid phase
  • Method for synthesizing atosiban by solid phase

Examples

Experimental program
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Effect test

Embodiment 1

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

[0055] Add 100.00g Rink Amide resin to the reaction column, add DCM 550ml / time for washing 3 times, then add DMF550ml / time for washing 3 times, add 550ml of prepared 30% piperidine / DMF solution into the glass reaction column, stir After reacting for 30 minutes, the reaction solution was extracted, and 550 ml of DMF was added to wash 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 DIPCDI after completely dissolved, stir well and add to the glass reaction column, stir for 24 Hour. After the reaction is completed, remove the reaction solution, wash with DMF 550ml / time for 3 times, then use DCM 550ml / time for 3 times, and finally use methanol 550ml / time for 3 times, drain, pour out, and put it into a vacuum drying oven for drying 12h. Take it out and weigh it, it is 103.19g, and the...

Embodiment 2

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

[0057] Add 103.19g of Fmoc-Gly-resin to the reaction column, add DCM 550ml / time for washing 3 times, then add DMF550ml / time for washing 3 times. Add 550ml of prepared 30% piperidine / DMF solution into the glass reaction column, stir for 30min, remove the reaction solution, add 550ml of DMF / time for washing 6 times, use 5% ninhydrin ethanol solution to detect the deprotection effect . Weigh 108.34g of Fmoc-Orn(Boc)-OH and 32.21g of HOBT, add DMF and stir to dissolve, after complete dissolution, add 37ml of 1mmol / ml DIPCDI in DMF, and stir evenly. Add the prepared amino acid coupling solution into the reaction column, and stir for 90 minutes to react. The reaction solution was removed, washed 6 times with 550 ml of DMF each time, and the coupling effect was detected with 5% ninhydrin ethanol solution for sampling.

Embodiment 3

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

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

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Abstract

The invention relates to a method for synthesizing atosiban by a solid phase, which comprises the following steps: 1) de-Fmoc-protecting Rink Amide resin serving as a carrier to obtain H2N-Rink Amide resin; 2) connecting carboxyl of Fmoc-Gly-OH and amino of the resin by using HOBT and DIPCI as condensation reagents to obtain Fmoc-Gly (resin); 3) solid-phase synthesizing sequence residue amino acid in turn by adopting Fmoc strategy; 4) performing solid-phase cyclization by using iodine; 5) then cutting the sequence residue amino acid by using pyrolysis reagents (trifluoroacetic acid / thioanisole / 1, 2-dimercaptoethane / water), and settling the sequence residue amino acid by diethyl ether to obtain raw atosiban peptide; and 6) treating the raw product through HPLC preparation and separation to obtain a pure atosiban product.

Description

Technical field: [0001] The invention relates to a method for synthesizing active polypeptide raw materials, in particular to a method for solid-phase synthesis of atosiban. Background technique: [0002] Atosiban (atosiban), its chemical name is: 1-(3-mercaptopropanol acid)-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 antagonist of oxytocin on receptors in the uterus, decidua, and fetal membrane. Its acetate is used clinically to treat premature labor . Atosiban Acetate Injection (AtosibanAcetate Injection) was developed by Ferring AB and was first launched in Austria on March 23, 2000. The trade name is: [0006] Related literature reports that the synthesis method of atosiban is to prepare amino acid resin through Boc-protected glycine (Gly) and chloromethyl resin, and then obtain peptide resin through cyclic ...

Claims

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Application Information

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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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