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A technology of carbetocin and synthesis process, which is applied in the field of chemical synthesis of polypeptide drugs, can solve the problems of difficult synthesis, high production cost, and expensive reagents, and achieve good cyclization effect, short process, and environmental protection effects
Inactive Publication Date: 2015-05-06
苏州天马医药集团天吉生物制药有限公司
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Problems solved by technology
[0008] Due to the unique chemical structure of carbetocin, its synthesis is difficult
Currently reported carbetocin synthesis methods have low yields or expensive reagents and high production costs
Method used
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Embodiment 1
[0028] Embodiment 1: a kind of Synthetic process of carbetocin , characterized in that it includes the following steps:
[0029] Step 1. Weigh 588.2g (synthesis scale: 1000mmol) of AM Resin (1.70mmol / g) into the reaction kettle, add about 5L of dichloromethane (DCM) to swell for about 20min. After the swelling time expires, remove the DCM;
[0030]Add the reaction solution that has been activated in an ice bath. This reaction solution consists of 647.6g Rink Amide AM-Linker, 194.6g 1-hydroxybenzotriazole 1-hydroxybenzotriazole (HoBt) ice bath for 2min, and then add 371mLN,N' -Diisopropylcarbodiimide DIC was obtained by activating it in the solution for 5 minutes. After 8 hours of reaction, a sample of ninhydrin was tested and it was negative, indicating that the coupling reaction was complete, and the reaction solution could be removed.
[0031] Add 5LDMF to wash 2 times, remove DMF, add 5L DBLK to deprotect twice, the time is 5min and 15min respectively, wash with 5LDMF onc...
Embodiment 2
[0040] Embodiment 2: a kind of Synthetic process of carbetocin , characterized in that it includes the following steps:
[0041] (1) Weigh 484.8g of AM Resin (synthesis scale 800mmol) (1.65mmol / g) into the reaction column, add 4LDCM to swell for about 20min. After the swelling time expires, remove the DCM, add the reaction solution that has been activated in an ice bath (690.7g Rink Amide-AM Linker, 207.4g HoBt in an ice bath for 2min, then add 238.0mL DIC to activate in the solution for 5min) and wait for 8 hours to react , sampling ninhydrin test, negative, indicating that the coupling reaction is complete, the reaction solution can be taken out, add 4LDMF to wash twice, after taking out DMF, add 4LDBLK (20% piperidine / DMF solution) to deprotect twice, time They are 5min and 15min respectively, wash once with 4LDMF between two deprotection times for about 1min, and drain. After deprotection, wash in the following order: DMF x 1 time, DMF x 1 time, MeOH x 1 time, DCM x 1 ti...
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Abstract
The invention provides a synthesis process of carbetocin. The synthesis process comprises the following steps: performing a coupling reaction on Fmoc-Gly-OH with Rink Amide-AM Resin obtained in the first step to obtain Fmoc-Gly-Rink Amide-AM Resin; performing deprotection (20% piperidine) with DBLK to obtain H-Gly-Rink Amide-AM RFesin, and orderly completing the coupling of the H-Gly-Rink Amide-AM Resin with Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(Me)-OH and tetrachlorobutyric acid until carbetocin linear peptide resin is synthesized; mixing a cracking agent with the carbetocin linear peptide resin obtained in the fourth step to have a cracking reaction, thereby removing the Rink Amide-AM Resin and side chain protecting groups; cyclizing the carbetocin linear crude peptide into a carbetocin crude product, and separating and purifying the carbetocin crude product to obtain the carbetocin. The synthesis process has the advantages that the polymerization side reaction is prevented, the process route is greatly simplified, the production cost is reduced and the synthesis efficiency is improved; in addition, the purity of the finished product is high; in short, the synthesis process is convenient for large-scale production, and meanwhile, advantageous for environmental protection, and has remarkable economic and social benefits.
Description
technical field [0001] The invention relates to the field of chemical synthesis of polypeptide drugs, in particular to a synthesis process of carbetocin. Background technique [0002] Carbetocin is a chemically synthesized long-acting nonapeptide analogue of oxytocin with agonist properties. Like oxytocin, carbetocin binds to the oxytocin receptors of uterine smooth muscle, causing rhythmic contractions of the uterus, increasing its frequency and increasing uterine tension on the basis of the original contractions. After either intravenous or intramuscular injection of carbetocin, the uterus contracts rapidly, reaching a definite intensity within 2 minutes. A single dose of intravenous carbetocin lasts approximately 1 hour for uterine activation and is therefore sufficient to prevent postpartum hemorrhage immediately after delivery. After giving carbetocin postpartum, the frequency and amplitude of contractions are longer than oxytocin. Carbetocin also has good safety. In...
Claims
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