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Synthesis method of desmopressin acetate dimer impurity

A technology for desmopressin and its synthesis method, which is applied in the field of synthesis of desmopressin acetate dimer impurities, can solve the problems of no specificity, low yield, cumbersome liquid phase synthesis, etc., and achieve cost saving , improved yield and purity, and the effect of avoiding linear peptide oxidation

Pending Publication Date: 2022-03-04
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method is not specific and the yield is very low, and the liquid phase synthesis is cumbersome, and the linear peptide needs to be prepared first
Therefore, when it is necessary to synthesize a large amount of this impurity to prepare a standard product, it is necessary to repeat the synthesis many times, exposing its significant defects

Method used

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  • Synthesis method of desmopressin acetate dimer impurity
  • Synthesis method of desmopressin acetate dimer impurity
  • Synthesis method of desmopressin acetate dimer impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Such as figure 1 As shown, it is a synthetic route diagram of (1-6) cross dimer or (1-1,6-6) parallel dimer impurity in Example 1 of the present invention, and the specific synthetic route includes the following steps:

[0063] Peptide Resin Synthesis:

[0064] Weigh 11.9 g of RinkAmide resin (substitution degree is 0.42 mmol / g, 5 mmol), and sequentially couple Fmoc-Gly-OH, Fmoc-D-Arg(Pbf)-OH, Fmoc-Pro-OH, Fmoc-Cys(mmt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Phe-OH, Fmoc-Tyr(tBu)-OH, Mpr(mmt)-OH. Finally, DMF was washed 3 times, DCM was washed 3 times, and methanol was shrunk to obtain 24.1 g of peptide resin. The obtained 16g peptide resin was treated with TFA:EDT:H 2 O=95:2.5:2.5 system was cleaved to obtain 1.2 g of linear peptides.

[0065] Synthesis of dimers:

[0066] Take 8g of peptide resin, add DCM to swell for 5 minutes, drain, then add DCM to swell for 5 minutes; repeat 2 times, drain, then add 120mL of 5% trifluoroacetic acid-DCM solution, react f...

Embodiment 2

[0069] Such as figure 2 As shown, it is a synthetic route diagram of (1-1,6-6) dimer impurities in Example 2 of the present invention, and the specific synthetic route includes the following steps:

[0070] Peptide Resin Synthesis:

[0071] Weigh 11.9g of RinkResin resin (the degree of substitution is 0.42mmol / g, 5mmol), remove Fmoc and couple Fmoc-Gly-OH, Fmoc-D-Arg(Pbf)-OH, Fmoc in sequence according to the side chain of Fmoc solid phase synthesis -Pro-OH, FmocH-Cys(Acm)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Phe-OH, Fmoc-Tyr(tBu)-OH, Mpr(mmt )-OH. Finally, DMF was washed 3 times, DCM was washed 3 times, and methanol was shrunk to obtain 23.2 g of peptide resin. 16 g of the obtained peptide resin was cracked to prepare 1.0 g of linear peptide.

[0072] With 1-3 times the iodine, Acm is oxidized and removed to form another pair of disulfide bonds. Then use 10 times the TFA:TIS:H of the resin 2 Cleavage at O=95:3:2 to obtain (1-1, 1-6) dimer impurity peptide resin...

Embodiment 3

[0076] Such as image 3 As shown, it is a synthetic route diagram of (1-6) misplaced dimer impurities in Example 3 of the present invention, and the specific synthetic route includes the following steps:

[0077] Peptide Resin Synthesis:

[0078] Weigh 11.9g of RinkResin resin (the degree of substitution is 0.42mmol / g, 5mmol), remove Fmoc and couple Fmoc-Gly-OH, Fmoc-D-Arg(Pbf)-OH, Fmoc in sequence according to the side chain of Fmoc solid phase synthesis -Pro-OH, FmocH-Cys(mmt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Phe-OH, Fmoc-Tyr(tBu)-OH, Mpr(Acm )-OH. Finally, DMF was washed 3 times, DCM was washed 3 times, and methanol was shrunk to obtain 25.1 g of peptide resin. 18 g of the obtained peptide resin were cracked to prepare 1.3 g of linear peptides.

[0079] Synthesis of dimers:

[0080]Take 7g of peptide resin, add DCM to swell for 5 minutes, drain, then add DCM to swell for 5 minutes; repeat 2 times, drain, then add 120mL of 5% trifluoroacetic acid-DCM solutio...

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Abstract

The invention belongs to the technical field of chemical pharmacy, and discloses a synthesis method of a desmopressin acetate dimer impurity. Comprising the following steps: 1, synthesizing peptide resin of desmopressin by adopting a solid-phase synthesis method; 2, carrying out a mixed reaction on the peptide resin synthesized in the step 1 by using a removal agent, and selectively removing a side chain protecting group; 3, activating sulfydryl of the resin obtained in the step 2 by adopting an activating agent; step 4, adding linear peptide for reaction, draining, washing and then condensing; and 5, cracking the resin obtained in the step 4 by using a cracking solution to obtain a dimer impurity which is one or two of (1-6) cross dimer impurities and (1-1, 6-6) parallel dimer impurities. According to the present invention, the synthesis steps are simplified, the certain reaction specificity and selectivity are provided, the positioning synthesis of the impurity is achieved, the yield is increased, the purity of the obtained dimer impurity is high, and the impurity further provides conditions for the research of desmopressin.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, in particular to a method for synthesizing desmopressin acetate dimer impurities. Background technique [0002] The peptide sequence structure of desmopressin is: Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-NH 2 (where Mpa and Cys form a ring through a disulfide bond). The dimer impurity of desmopressin is one of its main impurities, and there is no specific literature on its synthesis. The dimer impurity of desmopressin is extremely important for the study of desmopressin, therefore, the synthesis of this impurity is of great significance to the quality and impurity research of desmopressin, and can be used for the production of desmopressin Qualitative and quantitative analysis of impurities in desmopressin provides guarantee for the drug safety of desmopressin. There is no relevant document disclosing this impurity in the prior art. The general method used is: first synthesize linear p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00C07K1/04C07K1/06C07K1/08
CPCC07K7/16C07K2319/00Y02P20/55
Inventor 袁慧星陈蕾尹传龙唐洋明余品香
Owner HYBIO PHARMA
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