Preparation method of polypeptide synthesis carbetocin

Abstract

The invention discloses a preparation method of polypeptide synthesis carbetocin. The technical scheme of the method comprises the steps of taking Rink Amide MBHA (methylbenzene hydrogen amine) resin as an initial raw material; taking Fmoc-protected amino acid as a monomer; sequentially connecting amino acid, wherein Cys adopts Fmoc-Cys (CH2CH2CH2COOR)-OH, and the last amino acid uses Fmoc-Tyr (Me)-OH, and obtaining protected nonapeptide resin; removing the Fmoc azyl protected group of Tyr; cutting straight chain peptide from the resin by peptide cutting reagents such as FTA (fault tree analysis) and the like; precipitating a straight chain peptide rough product by adding diethyl ether; performing ring formation reaction by adding BOP (butyl octyl phthalate) / HOBt (oxhydryl benzotriazole) / DMF (dimethyl formamide); and purifying the preparation type HPLC (high performance liquid chromatography) in a separating way to obtain a target product. After the method is used, the each-step peptide connecting yield is more than 99%, the peptide cutting yield is 96.2%, and the gross yield is as high as more than 35%. The preparation method is convenient to industrial implementation, and has a higher industrial prospect.

Description

technical field [0001] The invention relates to a method for preparing carbetocin, in particular to a method for preparing carbetocin synthesized from polypeptides. Background technique [0002] Chinese name: carbetocin, carbetocin acetate [0003] English name: Carbetocin [0004] CAS number: 37025-55-1 [0005] Molecular formula: C 45 h 69 N 11 o 12 S [0006] Structural formula: [0007] [0008] Carbetocin, a new gynecological drug developed by Canadian Ferring Pharmaceutical Co., Ltd. to prevent and control post-cesarean hemorrhage in women, has been launched in my country recently, providing a new option for preventing and controlling postpartum hemorrhage in pregnant women. [0009] Carbetocin is a newly synthesized nonapeptide long-acting oxytocin receptor agonist, which can be injected intramuscularly or intravenously. The clinical trial jointly completed by Peking Union Medical College Hospital, Peking University First Affiliated Hospital and Beijing Ob...

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Problems solved by technology

[0010] Chinese invention patent No. ZL200910106889.0 discloses a solid-phase method for preparing carbetocin. The amino resin is used as the starting material, and amino acids with Fmoc protection groups are connected in sequence, and the last amino acid is connected with Br-(CH 2 ) 3 COOH, because brominated alkanes are very active, easily react with NH 2 -Nucleophilic reagents such as "nucleophilic substitution reaction of halogenated hydrocarbons" are not easy to occur -COOH and NH 2 -The directional condensation reaction is difficult to popularize and apply

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