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Method for synthesizing carbetocin in fragment mode

A technology of carbetocin and fragments, which is applied in the field of synthesis of crude carbetocin, can solve the problems of large air resistance of resin amino acids, difficult production operation, and long time consumption, so as to reduce the use of TFA and facilitate industrial production. Effect of improved connection efficiency

Active Publication Date: 2022-03-11
山东辰龙药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Such a reaction process is carried out in a liquid phase system, but it is not easy to operate in production, and the process is relatively complicated
[0007] Patents CN103833831A and CN106854235A are all methods of solid-phase synthesis of carbetocin by fragment method, and the formation of resin amino acid steric resistance is relatively large, and the degree of substitution of amino acid is not high
In the cyclization process, 4-bromobutyric acid or 4-chlorobutyric acid is used for cyclization, and the reaction efficiency is low and time-consuming
The amount of TFA is large, resulting in a large amount of trifluoroacetic acid, cumbersome production operations, and indirectly affecting process impurities

Method used

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  • Method for synthesizing carbetocin in fragment mode
  • Method for synthesizing carbetocin in fragment mode

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0046] Embodiment of the present invention: the method for synthesizing carbetocin in fragment mode, comprises the following steps:

[0047] Step (1): Synthesis of fragment Ⅰ [Fmoc-Pro-Leu-Gly-NH2-Rink Amide-AM]:

[0048] The amino resin with Fmoc protection, after de-Fmoc protection, is sequentially synthesized with the pretreated activated amino acids Fmoc-Gly-OH, Fmoc-Leu-OH and Fmoc-Pro-OH with Fmoc protection groups by solid phase synthesis Fragment Ⅰ [Fmoc-Pro-Leu-Gly-NH2-Rink Amide-AM]:

[0049] Specifically, the Fmoc-protected amino resin is added to DCM for swelling, and the swollen resin obtained after filtration is added to a deprotection solution to remove the Fmoc group, and after washing with a washing solution, the amino acid with Fmoc protection activated by pretreatment is sequentially connected by solid-phase synthesis Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH;

[0050] Pretreatment activation refers to mixing Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH and condensin...

Embodiment 1

[0072] Example 1: Step (1): Synthesis of Fragment I [Fmoc-Pro-Leu-Gly-NH2-Rink Amide-AM]:

[0073] The amino resin with Fmoc protection, after de-Fmoc protection, is sequentially synthesized with the pretreated activated amino acids Fmoc-Gly-OH, Fmoc-Leu-OH and Fmoc-Pro-OH with Fmoc protection groups by solid phase synthesis Fragment Ⅰ [Fmoc-Pro-Leu-Gly-NH2-Rink Amide-AM]:

[0074] Specifically, the Fmoc-protected amino resin is added to DCM for swelling, and the swollen resin obtained after filtration is added to a deprotection solution to remove the Fmoc group, and after washing with a washing solution, the amino acid with Fmoc protection activated by pretreatment is sequentially connected by solid-phase synthesis Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH;

[0075] Pretreatment activation refers to mixing Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH and condensing agent respectively, dissolving them in DMF, and activating them for use.

[0076] Further, the deprotection solution is a...

Embodiment 2

[0095] Example 2: Step (1): Synthesis of Fragment I [Fmoc-Pro-Leu-Gly-NH2-Rink Amide-AM]:

[0096] The amino resin with Fmoc protection, after de-Fmoc protection, is sequentially synthesized with the pretreated activated amino acids Fmoc-Gly-OH, Fmoc-Leu-OH and Fmoc-Pro-OH with Fmoc protection groups by solid phase synthesis Fragment Ⅰ [Fmoc-Pro-Leu-Gly-NH2-Rink Amide-AM]:

[0097] Specifically, the Fmoc-protected amino resin is added to DCM for swelling, and the swollen resin obtained after filtration is added to a deprotection solution to remove the Fmoc group, and after washing with a washing solution, the amino acid with Fmoc protection activated by pretreatment is sequentially connected by solid-phase synthesis Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH;

[0098] Pretreatment activation refers to mixing Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH and condensing agent respectively, dissolving them in DMF, and activating them for use.

[0099] Further, the deprotection solution is a...

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Abstract

The invention discloses a method for synthesizing carbetocin in a fragment manner, comprising the following steps: (1) Synthesis of Fragment I [Fmoc-Pro-Leu-Gly-NH2-Rink Amide-AM]; (2) Fragment II [C4H6O-Tyr(Me)-Ile-Gln(Trt)-Asn(Trt)-Cys-CTC resin] synthesis; (3) Fragment Ⅲ [C4H6O-Tyr(Me)-Ile-Gln(Trt)-Asn( Synthesis of Trt)-Cys-OH]: the beneficial effect of the present invention is: the Cys amino acid is transformed into a structural unit of self-containing thioether and protected butyric acid, solving the problems of low efficiency and long time in the cyclization step; reducing Compared with the existing fragment synthesis method, the degree of substitution of resin amino acids has been increased by nearly 50%, the connection efficiency has been increased by 30%, and the cost has been greatly reduced; the solid-phase synthesis of carbetocin has been reduced. In the step of prime, the Boc protecting group in Tyr and the butyric acid protecting group in Cys are simultaneously removed through one-step acid hydrolysis, which reduces the use of TFA and is beneficial to industrial production.

Description

Technical field: [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a new method for synthesizing crude carbetocin with low cost, high purity and suitability for industrialization. Background technique: [0002] Carbetocin is a synthetic long-acting cyclic nonapeptide analogue of oxytocin with agonist properties, and 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] The molecular formula of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/16C07K1/08C07K1/06C07K1/04
CPCC07K7/16Y02P20/55
Inventor 徐发往李兴臣梁祺李浩师艳秋
Owner 山东辰龙药业有限公司