Carbetocin preparation method

Abstract

The invention belongs to the technical field of medicinal chemistry and particularly relates to a carbetocin preparation method. The carbetocin preparation method comprises the following steps of: (1) sequentially coupling to an amino resin by adopting an Fmoc sold-phase synthesis process so as to obtain a linear peptide resin A the structural formula of which is shown in the specification, wherein X is C1, Br or I, and Y is C1, Br or I; (2) adding a Na2S solution to the linear peptide resin and carrying out cyclization reaction so as to obtain peptide resin B; and (3) splitting the peptide resin B so as to obtain a carbetocin crude product. The carbetocin preparation method has the advantages that the process problems of expensive raw materials, need of heavy metal reagents and the like caused by using sulfydryl protected amino acids are avoided, the cost is low, no lots of waste liquid is generated, reaction conditions are mild, and the large-scale production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of carbetocin. Background technique [0002] Carbetocin is a synthetic long-acting nonapeptide analog 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 receptor of uterine smooth muscle, causing rhythmic contraction of the uterus, increasing its frequency and increasing uterine tension on the basis of the original contraction. 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 ute...

AI Technical Summary

Problems solved by technology

[0008] Chinese patent CN200910106889.0 discloses a solid-phase method for preparing carbetocin, which uses solid-phase synthesis to sequentially connect amino acids with Fmoc protecting groups to obtain carbetocin precursor peptide-amino resin; Use triphenylphosphine palladium to remove the allyl protecting group of the cysteine ​​side chain, add an organic base, lithium chloride, cyclize, crack, purify, and freeze-dry to obtain refined carbetocin. Reagents for allyl protecting groups are expensive and not conducive to large-scale production

[0009] Chinese patent CN201110151928.6 discloses a preparation method of carbetocin, which uses a novel thiol-protected amino acid Fmoc-Cys ((CH 2 ) 3 COOAll), the reagent price of de-side chain allyl protecting group is also very expensive in this method, is unfavorable for large-scale production

[0010] Chinese patent CN201110001400.0 discloses a method for preparing carbetocin from polypeptide synthesis. This method uses solid-phase synthesis to synthesize linear carbetocin precursor peptide, and then cyclizes it in liquid phase. In this method, Cyclization requires very dilute solvent (10 -4 -10 -5 mol / L), a large amount of waste liquid is produced, and polymers are easily produced at the same time, which has the disadvantages of low cyclization efficiency and complicated follow-up treatment.

[0011] Chinese patent CN102796178A has announced a kind of preparation method of carbetocin, and this method adopts novel thiol-protected amino acid Fmoc-Cys ((CH 2 ) 3 COOCH 2 CH 2 CN) as a raw material, the raw material is expensive, and Fmoc-Cys ((CH 2 ) 3 COOCH 2 CH 2 CN) There are many protective side reactions, which is not conducive to large-scale production

Images