Method of synthesizing carbetocin

A technology of carbetocin and condensation reagents, which is applied in the field of pharmaceutical synthesis, can solve the problems of high production cost, complicated preparation process, and high single impurity, and achieve the effects of reduced content, high total yield, and improved purity

Active Publication Date: 2016-11-09
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method overcomes the problem that the tetraphenylphosphine palladium catalyst becomes invalid due to poisoning, Fmoc-Cys ((CH 2 ) 3 COOAll) has a complex preparation process and high production costs. Secondly, a large amount of heavy metal salts will be introduced in the process of de-All protection, which increases the difficulty of purification, resulting in a high maximum single impurity of 0.2%, and a purity of only 99.4%. Unfavorable factors such as long de-All protection time and incomplete de-All protection will affect the quality and yield of the product
[0012] Chinese patent CN102796178A discloses a solid-phase synthesis method of carbetocin, which changes the protection (CH 2 ) 3 COOH carboxyl protecting group Alloc is HOCH 2 CH 2 CN, although the cost of the deprotecting agent is reduced, which is beneficial to large-scale production, but the improper selection of the protecting group causes the final total yield of carbetocin in the patented method to be only 51%, and the simple heterogeneity is also high, with a purity of 99.3%
[0013] At present, the highest level of purity of carbetocin does not exceed 99.5%, and the lowest content of a single impurity is only 0.2%. The technical level limits the quality of carbetocin products in my country and it is difficult to have a more obvious improvement. At present There is an urgent need to improve the existing process in order to improve the overall quality of the product

Method used

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  • Method of synthesizing carbetocin
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  • Method of synthesizing carbetocin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: Synthesis of Peptide Resin 1

[0054] Take 0.15mol Fmoc-Gly and 0.15mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15mol DIC, slowly add them to the protected amino acid DMF solution under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid solution ,spare.

[0055] Take 0.05mol of MOBHA resin (substitution value about 0.6mmol / g), swell with DMF for 25 minutes, wash and filter, add activated Fmoc-Gly solution, stir and react at room temperature for 3 hours, remove the reaction solution, wash with DMF for 3 times, DCM was washed 3 times, and the washing time was 3 minutes each time to obtain Fmoc-Gly-MBHA resin, that is, peptide resin 1. Before the next coupling reaction, use 20% PIP / DMF solution to remove Fmoc protection for 25 minutes, wash and filter to obtain Gly - MOBHA resin.

Embodiment 2

[0056] Example 2: Synthesis of Peptide Resin 1

[0057] Take 0.15mol Boc-Gly and 0.15mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15mol DIC, slowly add it to the protected amino acid DMF solution under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid solution ,spare.

[0058] Take 0.05mol of MOBHA resin (substitution value about 0.6mmol / g), swell with DMF for 25 minutes, wash and filter, add activated Fmoc-Gly solution, stir and react at room temperature for 3 hours, remove the reaction solution, wash with DMF for 3 times, DCM was washed 3 times, and the washing time was 3 min each time to obtain Boc-Gly-MOBHA resin, that is, peptide resin 1. Before the next coupling reaction, 30% TFA / DCM solution was used to remove Boc protection for 30 minutes, and DIEA / DCM The solution was neutralized, washed and filtered with DMF and DCM to obtain Gly-MOBHA resin.

Embodiment 3

[0059] Example 3: Synthesis of Peptide Resin 2

[0060] Take 0.15mol Fmoc-Leu and 0.15mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15mol DIC, slowly add them to the protected amino acid DMF solution under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid solution .

[0061]Add the above-mentioned activated protected amino acid solution to the Gly-MOBHA resin prepared in Example 1, stir and react at room temperature for 3 hours, remove the reaction solution, wash 3 times with DMF, and wash 3 times with DCM, each washing time is 3min, Then use 20% PIP / DMF solution to remove Fmoc protection for 25 minutes, wash and filter to complete the access of Leu.

[0062] Access Fmoc-Pro in the same way, Fmoc-Cys ((CH 2 ) 3 COOtBu), Fmoc-Asn (Trt), Fmoc-Gln (Trt), Fmoc-Ile and Fmoc-Tyr (OMe), Fmoc was removed using 20% ​​PIP / DMF solution, washed and filtered to obtain peptide resin 2, Tyr (OMe )-...

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Abstract

The present invention relates the field of synthesis of medicine and discloses a method of synthesizing carbetocin. According to the method, group tBu is selected to be protected to replace Alloc and HOCH2CH2CN used in the prior art so as to protect (CH2)3COOH, and new amino acid resin, deprotection agent, acid-splitting agent and the like are utilized to complete the whole synthetic process, and at the premise of ensuring total yield, the purity of carbetocin is improved and the content of single impurites is significantly reduced.

Description

technical field [0001] The invention relates to the field of medicine synthesis, in particular to a method for synthesizing carbetocin. Background technique [0002] Carbetocin (Carbetocin) is a synthetic long-acting oxytocin 8-peptide analog with agonist properties developed by Ferring Pharmaceutical Co., Ltd. of Denmark. Its clinical and pharmacological properties are similar to those of naturally occurring oxytocin. 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. Oxytocin receptor levels in the uterus are low in the non-pregnant state, increase during pregnancy, and peak at parturition. Carbetocin therefore has no effect on the non-pregnant uterus, but has potent uterotonic effects on the pregnant and newborn uterus. [0003] After either intravenous or intramuscular injection of carbetocin, t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/16C07K1/08C07K1/06C07K1/04
CPCC07K7/16Y02P20/55
Inventor 黄璜郭德文曾德志文永均
Owner CHENGDU SHENGNUO BIOPHARM
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