Method for synthesizing carbetocin through liquid-phase synthetic method

A technology of carbetocin and a synthesis method, which is applied to the synthesis field of polypeptide drugs, can solve the problems of high toxicity, difficult purification, low efficiency and purity, etc., and achieves the effects of large differences in amino acids, easy separation and purification, and high product purity.

Inactive Publication Date: 2012-05-30
HANGZHOU HEJIN TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 su

Method used

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  • Method for synthesizing carbetocin through liquid-phase synthetic method
  • Method for synthesizing carbetocin through liquid-phase synthetic method
  • Method for synthesizing carbetocin through liquid-phase synthetic method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Synthesis of embodiment one 4-Bromobutyryl-Tyr(me)-Ile-OH

[0084] Add 1.48g Boc-Tyr(me)-OH (5mmol) and an appropriate amount of DMF that can basically dissolve under magnetic stirring in turn into a 250ml round bottom flask, and take another 0.91g H-Ile.ome.Hcl (5mmol) and 0.68 Add gHOBT (5mmol) to a small amount of DMF, then add 2 times the number of moles of NMM and add it to the flask together, continue to adjust the pH to 7 to 8, add 1.03g DCC (5mmol) to stir the reaction, and track and monitor the completion of the reaction by TLC. After 12 hours, the stirring was stopped, and TLC detected that the reaction was incomplete, adding BOP to continue the reaction for 2 hours, and standing at room temperature. Suction filtration (filter insoluble matter DCU), the filtrate is extracted with ethyl acetate and water with a separatory funnel, the upper layer is the product, and the lower layer is extracted twice with ethyl acetate, the ethyl acetate layers are combined, was...

Embodiment 2

[0085] Example 2 Synthesis of H-Gln(trt)-Asn(trt)-Cys(trt)-ome

[0086] Dissolve 3g of Fmoc-Asn(trt)-OH (5mmol) in 10ml of dichloromethane, add 7ml of diethylamine to react for 2 hours, spot the plate after 2 hours, and directly concentrate to obtain 1.8g of solid after the reaction is complete, with a yield of 98%. An appropriate amount of DMF that can be basically dissolved under magnetic stirring, another 3g Fmoc-Gln(trt)-OH (5mmol) and 0.68g HOBT (5mmol) were added to a small amount of DMF, and then N-methylmorpholine (NMM) was added to adjust the pH From 7 to 8, 1.03 g of DCC (5 mmol) was added to stir the reaction, and TLC was followed to monitor the completion of the reaction. After 12 hours, the stirring was stopped, and TLC detected that the reaction was incomplete, adding BOP to continue the reaction for 2 hours, and standing at room temperature. Suction filtration (filter insoluble matter DCU), the filtrate is extracted with ethyl acetate and water with a separator...

Embodiment 3

[0087] Example 3 Synthesis of H-Pro-Leu-Gly-NH2

[0088] Add 1.1g Boc-Pro-OH (5mmol) and an appropriate amount of DMF that can basically dissolve under magnetic stirring in turn in a 250ml round bottom flask, and take another equimolar 0.91g H-Leu.ome.Hcl (5mmol) and 0.68g Add HOBT (5mmol) to a small amount of DMF, then add 2 times the number of moles of N-methylmorpholine (NMM) and add it to the flask together, continue to adjust the pH to 7 to 8, add 1.03gDCC (5mmol) to stir the reaction, TLC tracking monitoring The completion status of the reaction. After 12 hours, the stirring was stopped, and TLC detected that the reaction was incomplete, adding BOP to continue the reaction for 2 hours, and standing at room temperature. Suction filtration (filter insoluble matter DCU), the filtrate is extracted with ethyl acetate and water with a separatory funnel, the upper layer is the product, and the lower layer is extracted twice with ethyl acetate, the ethyl acetate layers are comb...

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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...

Claims

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Application Information

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IPC IPC(8): C07K7/50
Inventor 汪家权倪明敏胡浩汪剑华虹林彬彬程贵青
Owner HANGZHOU HEJIN TECH
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