Solid-phase synthesis method of carbetocin

Abstract

The invention provides a solid-phase synthesis method of carbetocin, and the method comprises the following steps of: sequentially coupling amino acid containing Fmoc (fluorenylmethoxycarbonyl) protecting group by Rink Amide AM Resin to obtain Fmoc-Cys(CH2CH2CH2COOCH2CH2CN)-Pro-Leu-Gly-Rink Amide AM Resin; then sequentially coupling the remaining Fmoc-amino acid, removing the protecting group, and cyclizing to obtain carbetocin-Amide AM Resin; and cracking, purifying and freeze-drying to obtain the carbetocin. The carbetocin is subjected to solid-phase cyclization synthesis by using a novel mercapto protecting group and a false solid-phase dilution principle. The solid-phase synthesis method is simple to operate, low in cost and environmentally-friendly, and meanwhile can be used for greatly improving the purity and the yield as a solid-phase cyclization technology is used at the same time.

Description

technical field [0001] The invention relates to the technical field of carbetocin synthesis, in particular to a solid-phase synthesis method of carbetocin. Background technique [0002] Carbetocin is a synthetic long-acting oxytocin nonapeptide cyclic peptide analogue with agonist properties. Its clinical and pharmacological properties are similar to natural oxytocin, and it binds to oxytocin receptors in uterine smooth muscle , cause the rhythmic contraction of the uterus, on the basis of the original contraction, increase its frequency and increase the tension of the uterus, which can prevent the lack of tension of the uterus, postpartum hemorrhage and promote the involution of the uterus. Regardless of intravenous injection or intramuscular injection, it can rapidly contract the uterus to meet certain requirements within 2 minutes, and the active effect on the uterus after a single dose of intravenous administration can last for 1 hour, which is enough to prevent postpart...

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Problems solved by technology

[0008] The application number CN200910106889.0 discloses a solid-phase method for preparing carbetocin, which uses solid-phase synthesis to sequentially link amino acids with Fmoc protecting groups to obtain carbetocin precursor peptide-amino resin; Triphenylphosphine palladium removes the allyl protecting group of cysteine ​​side chain, adds organic base, lithium chloride, cyclization, cracking, purification, and freeze-drying to obtain refined carbetocin. In this method, the side chain is removed Allyl protecting group reagents are expensive and not conducive to large-scale production

The preparation method of carbetocin disclosed in the application number CN201110151928.6 adopts a novel thiol-protected amino acid Fmoc-Cys ((CH 2 ) 3 COOAll), the side chain allyl protecting group reagent price is also very expensive in this method, is unfavorable for large-scale production

Application number CN201110001400.0 discloses a preparation method for synthesizing carbetocin. The method uses a solid phase to form a linear carbetocin precursor peptide and liquid phase cyclization. The cyclization of this method needs to be carried out in a 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, resulting in low cyclization efficiency and complicated post-treatment.

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