Method for synthesizing carbetocin through liquid-phase synthetic method

Abstract

The invention discloses a method for synthesizingcarbetocin, comprising the following steps: first, respectively synthesizing an intermediate I: 4-Bromobutyryl-Tyr(me)-Ilw-OH, an intermediate II: H-Gln(trt)-Asn(trt)-Cys(trt)-ome, and an intermediate III: H-Pro-Leu-Gly-NH2, putting the intermediate I, II and III in a solvent, condensing a noncyclized product IV in the presence of condensing agent, finally adding a catalyst to cyclize in alkaline condition to obtain carbetocin. According to the invention, the yield of carbetocin is more than 85 %, the product purity is more than 80 %, the impurities are easy to remove, and the method has remarkable advantages.

Description

technical field [0001] The invention relates to a synthesis method of polypeptide medicine, in particular to a synthesis method of carbetocin. Background technique [0002] Postpartum hemorrhage is the leading cause of illness and death among pregnant women in the world, causing 125,000 pregnant women to die and 20 million women to suffer from illness every year. (Xu Ling et al., "Journal of Practical Medicine", Volume 23, No. 18, 2007, 2940-2941). In recent years, with the increase of cesarean section rate, surgical complications have been paid more and more attention, and the postpartum hemorrhage rate of cesarean section is as high as 19.8% (Gao Suyun et al., "World Journal of Integrated Traditional Chinese and Western Medicine", 2009, Volume 4, No. 9, 665~666). [0003] The main cause of postpartum hemorrhage is uterine atony, accounting for 70% to 80% (Xu Ling et al., "Journal of Practical Medicine", Vol. 23, No. 18, 2007, 2940-2941). The key to reducing morbidity an...

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Problems solved by technology

[0016] 1. It takes a long time for synthesis: Although the rate of solid phase synthesis of peptides has been greatly improved, compared with other synthesis methods (such as biosynthesis), the chain synthesis rate is still very slow. It takes 20 to 120 minutes, and the average synthesis of a nonapeptide takes more than 5 hours

[0017] 2. The efficiency and purity of the synthesis are low and the cost is high: even for the solid-phase synthesis of small peptides with less than 30 amino acids, the synthesis of peptides rich in disulfide bonds and basic amino acid residues is still relatively difficult, and a considerable part of the peptides cannot be successfully synthesized

As the number of amino acids increases, the synthesis efficiency gradually decreases, the content of non-target peptides gradually increases, the purity of target peptides gradually decreases, and subsequent purification becomes more difficult

The raw materials such as resins and protected amino acids for synthetic peptides are expensive, resulting in high cost of peptide synthesis, which cannot fully meet the requirements for commercial production of drugs

[0018] 3. The toxicity of synthetic reagents is high: the reagents for peptide synthesis are very toxic, such as DCM, DMF, piperidine and other organic chemical reagents, which need to be reported to the Environmental Protection Agency for disposal after they become waste liquids

[0022] It can be seen that the carbetocin synthesized by the solid-phase synthesis method has low purity and a long time, and the follow-up purification process is difficult, the yield is low, and the cost is high. This area urgently needs to develop a simple and easy carbetocin with high yield and short time. Synthetic method of betocin

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