Method for synthesizing cyclopeptide drug carbetocin

Abstract

The invention discloses a method for synthesizing a cyclopeptide drug carbetocin. The method comprises the following steps that (1) carbetocin main chain resin is prepared with Y-Tyr(Me)-Ile-Gln(X)-Asn(X)-OH, Fmoc-Cys((CH2)3COOtBu)-OH, Fmoc-Pro-OH, Fmoc-Leu-OH and Fmoc-Gly-OH as starting raw materials by adopting a polypeptide solid-phase synthesis method; (2) the main chain resin is subjected topyrolysis to obtain a crude product of a carbetocin main chain, and a crude product of the carbetocin is obtained through one-step liquid-phase condensation cyclization. The method is a process combining solid-phase synthesis and liquid-phase synthesis, the operation is convenient, and the synthesis steps of the process are greatly shortened; through a fragment synthesis method, the total yield ofthe carbetocin is greatly increased, the product purity of the carbetocin is greatly improved, the occurrence of side reactions and the types of by-products are reduced, and the industrial scale-up synthesis is facilitated.

Description

technical field [0001] The invention relates to the field of medicine manufacture, in particular to a method for synthesizing cyclic peptide drug carbetocin. Background technique [0002] Carbetocin English name: Carbetocin, the amino acid sequence is as follows: [0003] Carbetocin sequence: Cyclo[CH 2 CH 2 CH 2 CO-Tye(Me)-Ile-Gln-Asn-Cys]-Pro-Leu-Gly-NH 2 [0004] The molecular structural formula is as follows, it is a cyclic peptide containing a 20-membered macrocycle: [0005] [0006] Carbetocin is used to prevent uterine atony and postpartum hemorrhage. In addition to massaging the uterus, it is mainly used to contract the uterus. Oxytocin, ergometrine, and prostaglandin preparations are commonly used in uterotonic agents, and each drug has its advantages and disadvantages. Oxytocin is the most widely used, with the advantages of quick onset, safety, and small side effects. The disadvantage is that the action time is short, with a half-life of 1 to 6 minutes....

AI Technical Summary

Problems solved by technology

[0009] In the existing preparation process of carbetocin, the patent document CN102260326A describes a preparation method of carbetocin, wherein when Fmoc-Cys ((CH2)3COOAll) is used as the starting material, four three There will be positive palladium poisoning during phenylphosphine palladium and phenylsilane (the actual amount of palladium is much higher than that reported in the literature), the actual yield is difficult to achieve the desired effect, and heavy metals will remain in the product

And the amount of condensing agent and amino acid used in this method is 3 equivalents, consumes high reagent cost, and effective yield is low

CN106478779A records another preparation method of carbetocin, the yield of crude product is more than 90%, but the actual purification yield is only 30-40%

Used LiOH, NaHCO3 and DMAP raw material in the synthetic method of ES2115543 record, can cause many impurity thus, reduce the purity of product and use effect

Adopted Cys (Alloc) raw material in the synthetic method of CN200910106889, and carry out cyclization with lithium chloride as cyclization reagent, obtain carbetocin after acidolysis, there is the problem of catalyst poisoning in this method, Cys (Alloc) in removing After Alloc protection -SH is exposed, it is very easy to poison the tetrakistriphenylphosphine palladium catalyst, which seriously affects the efficiency of the deprotection reaction

Images