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Solid phase preparation method of carbetocin

A technology of carbetocin and solid-phase synthesis, which is applied in the field of solid-phase synthesis of polypeptides, and achieves the effects of high yield, wide application prospects, and less input of raw materials

Active Publication Date: 2009-10-14
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] In the methods described in these patents, carbetocin is cyclized in the liquid phase. This method requires the reaction raw materials to react in a very dilute solution. A large amount of solvent is required in large-scale production, and a large amount of waste liquid is generated immediately.

Method used

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Experimental program
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Effect test

Embodiment 1

[0043] Embodiment 1: the preparation of Fmoc-Gly-amino resin

[0044] Add 14.2g of amino resin, with a substitution degree of 0.7mmol / g, into the solid-phase reaction column, add DCM to swell the resin for 30 minutes, and place 5.95g of Fmoc-Gly-OH, 7.6g of HATU, and 2.97g of HOAt in an ice bath. Dissolve in DMF, add to the above resin and react for 10 minutes, then add 2.4ml TMP, and react at room temperature for 45 minutes. After washing with DMF for 3 times, washing with DCM for 3 times, shrinking with methanol for 3+5+8min to obtain Fmoc-Gly-amino resin, the detection degree of substitution is 0.6mmol / g. The so-called "3+5+8min" means shrinking with methanol three times for 3min, 5min and 8min respectively.

Embodiment 2

[0045] Embodiment 2: the preparation of Fmoc-Gly-amino resin

[0046] Add 14.2g of Rink Amide amino resin, with a substitution degree of 0.2mmol / g, into the solid-phase reaction column. After adding DCM to swell the resin for 30 minutes, mix 1.7g of Fmoc-Gly-OH, 2.2g of HATU, and 0.85g of HOAt on ice Dissolve in DMF in a bath, add to the above resin and react for 10 minutes, then add 5-15ml DIPEA to improve the reaction efficiency, and react at room temperature for 45 minutes. After washing with DMF for 3 times, washing with DCM for 3 times, shrinking with methanol for 3+5+8min to obtain Fmoc-Gly-amino resin, the detection degree of substitution is 0.13mmol / g. The so-called "3+5+8min" means shrinking with methanol three times for 3min, 5min and 8min respectively.

Embodiment 3

[0047] Embodiment 3: carbetocin precursor peptide I-amino resin (BrCH 2 CH 2 CH 2 Preparation of COOTyr(Me)-Ile-Gln(Trt)-Asn(Trt)-Cys(Alloc)-Pro-Leu-Gly-CO-aminoresin)

[0048] Weigh 1 mmol of Fmoc-Gly-amino resin into the reactor, swell with DCM for 0.5 h, then use 20% DBLK for 10 min to remove Fmoc protection, and connect Fmoc-Leu-OH after washing. Dissolve 1.78g Fmoc-Leu-OH, 0.49g HOBt, and 0.61ml DIC in DCM (a small amount of DMF can be added to aid dissolution), activate in an ice-water bath for 7 minutes, add to a solid-phase reactor, and react at room temperature for 1-2 hours. The end point of the reaction was determined by the ninhydrin method. Repeat the above steps, and use the amino acids of the Fmoc protecting group to sequentially complete the remaining connections to obtain the carbetocin precursor peptide I-amino resin. The structure is: BrCH 2 CH 2 CH 2 COOTyr(Me)-Ile-Gln(Trt)-Asn(Trt)-Cys(Alloc)-Pro-Leu-Gly-CO-aminoresin.

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Abstract

The invention discloses a solid phase synthesis method of carbetocin. The technical proposal comprises the following steps of: obtaining Fmoc-Gly-amino resin by reaction of Fmoc-Gly-OH and amino resin with the substitutability being 0.2 mmol / g-0.9 mmol / g; sequentially connecting amino acids with Fmoc protecting groups by the solid phase synthesis method to obtain carbetocin precursor peptide I-amino resin; stripping off cysteine side chain protecting groups to obtain carbetocin precursor peptide II-amino resin; adding organic alkali and lithium chloride in solvent for cyclization to obtain carbetocin-amino resin; cracking to obtain carbetocin crude peptide; and purifying and freeze-drying to obtain the carbetocin. The method adopts the amino resin to synthesize carbetocin by the solid phase cyclization technology. The process is characterized by simple operation, easy post-treatment, high yield, low cost, and the like, and has considerable economical and practical value and broad application prospect.

Description

technical field [0001] The invention relates to a method for solid-phase synthesis of polypeptides, in particular to a method for synthesizing carbetocin. Background technique [0002] Carbetocin is a synthetic long-acting nonapeptide analogue of oxytocin with agonist properties. A single dose intravenously may be administered immediately after cesarean section under epidural or spinal anesthesia to prevent uterine hypotonia and postpartum hemorrhage. The clinical trial jointly completed by Peking Union Medical College Hospital, Peking University First Affiliated Hospital and Beijing Obstetrics and Gynecology Hospital showed that compared with the traditional continuous infusion of oxytocin to control bleeding after elective cesarean section, the drug has less bleeding after 24 hours. There was no significant difference in blood loss, and there was no significant difference in total intraoperative and postoperative blood loss; there was no significant difference between the...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04C07K1/113A61P15/04
CPCY02P20/55
Inventor 潘俊锋李红玲马亚平袁建成
Owner HYBIO PHARMA
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