Solid-phase fragment synthesis method for carbetocin

Abstract

The invention relates to a solid-phase fragment synthesis method for carbetocin. The method comprises the following steps: 1) with solid-phase synthetic resin as a carrier, successively connecting the solid-phase synthetic resin with proline, cysteine, asparagine (Asn), glutamine, isoleucine and tyrosine all having protected amino groups and side chains; 2) removing the mercapto protection group of cysteine; 3) carrying out coupling with bromo-butyric acid under an alkaline condition; 4) after removal of a terminal amino protection group, coupling a terminal amino group with a carboxyl group at the side chain of cysteine so as to form a ring; 5) subjecting cyclic seven-peptide fragment resin to cracking; 6) with the solid-phase synthetic resin as a carrier, successively connecting the solid-phase synthetic resin to glycine and leucine with protected amino groups; 7) connecting a cyclic seven-peptide fragment obtained in the step 5) to dipeptide resin; and 8) carrying out cracking so as to obtain carbetocin. According to the invention, sites located between Pro to Leu are selected; and carbetocin prepared by using the preparation method has high purity.

Description

technical field [0001] The invention relates to a preparation method of cyclic peptide, in particular to a solid-phase synthesis method of 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. [0003] The clinical and pharmacological properties of carbetocin are similar to those of naturally occurring oxytocin. Like oxytocin, carbetocin binds to the oxytocin receptors of uterine smooth muscle, causing rhythmic contractions of the uterus, increasing its frequency and increasing uterine tension on the basis of the original contractions. Oxytocin receptor levels in the uterus are low in the non-pregnant state, increase during pregnancy, and peak at parturition. Carbetocin therefore has no effect on the non-pregnant uter...

AI Technical Summary

Problems solved by technology

Choose between Cys-Pro (such as 201410076731.4), then Cys is the initial connecting amino acid of the fragment, because Fmoc-Cys(Mmt)-OH is prone to racemization when coupled with Wang resin, the Cys enantiomeric impurities are significantly increased Large (see comparative example 1), and the Cys enantiomer impurity has a great influence on the purification, which will greatly reduce the yield of refined peptide

Select the site between Leu-Gly (such as 201310412014.X), then a single glycine as a fragment will cause a large reaction steric hindrance during coupling and docking, and the lack of glycine impurities in the product will increase, which will bring inconvenience to purification

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