A kind of synthetic method of carbetocin

Abstract

The invention belongs to the field of preparation methods of polypeptide drugs, and relates to a synthesis method of carbetocin, comprising the following steps: (1) taking Rink Amide-MBHA Resin as a carrier, after swelling treatment, sequentially adding protected Gly, protected Leu, protected Pro, protected Cys, protected Asn, protected Gln, protected Ile and protected Tyr condensation reaction coupled to swelling Rink Amide‑MBHA Resin, dried to obtain peptide resin 1; (2) peptide resin 1 and vinyl acetic acid reaction to obtain peptide resin 2; (3) cleavage of peptide resin 2 to obtain carbetocin intermediate I; (4) carbetocin intermediate I to obtain carbetocin intermediate I after cyclization reaction. The synthesis method has high reaction selectivity, quick reaction, few by-products and impurities, high yield, safety and environmental protection, and simple and easy operation.

Description

technical field [0001] The invention belongs to the field of polypeptide drug preparation methods and relates to a synthesis method of carbetocin. Background technique [0002] Carbetocin, a cyclic polypeptide, is a synthetic long-acting nonapeptide analogue of oxytocin with agonist properties. [0003] The molecular formula of carbetocin is C 45 h 69 N 11 o 12 S, the molecular weight is 998.17, the chemical name is: deamin-2-oxo-methyltyrosine-1-к-oxytocin, and the structure is: [0004] [0005] Carbetocin can be administered as a single intravenous dose immediately following epidural or spinal cesarean delivery to prevent uterine hypotonia and postpartum hemorrhage. 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 th...

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Problems solved by technology

[0006] Chinese patent applications CN 201110001400.0, CN 201410331088.5, CN 201610189424.6, and CN201610728294.9 disclose the synthesis route of carbetocin. The cyclization method of linear chain peptide is realized by the condensation of carboxyl and amino groups to form amide bonds. Such a technical route requires the use of Sulfhydryl-modified special amino acids have high synthesis costs and are not conducive to large-scale commercial production

[0007] Chinese patent applications CN 201310392663.8, CN 201310412014.X, CN 201410076731.4, CN201410461695.3, CN 201510001735.0, CN 201510848044.4, and CN 201610328262.X disclose the synthesis route of carbetocin through linear cysteine ​​ring The sulfhydryl group on the side chain and the halogen at the end of the linear peptide are eliminated by the elimination reaction. This reaction has more by-products and impurities, and the reaction time is longer. The cyclization reaction usually exceeds 20 hours, and the continuity of the process is poor. It is conducive to the development of subsequent purification processes, and the overall yield of the process is low

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