Preparation method of terlipressin impurity Q

A technology of terlipressin and impurities, which is applied in the field of preparation of terlipressin impurity Q, and can solve the problems of not preparing impurity Q, etc.

Pending Publication Date: 2022-07-01
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, a large number of documents in the prior art report the preparation method of terlipressin, but there is no report about the preparation of impurity Q

Method used

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  • Preparation method of terlipressin impurity Q
  • Preparation method of terlipressin impurity Q
  • Preparation method of terlipressin impurity Q

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1 Synthesis of Polypeptide Fragment One

[0059] Weigh 16.7 g of Rink Amide resin (the substitution degree is 0.60 mmol / g, the scale is 10 mmol), the resin is swollen with DMF for 30 minutes, the resin is drained, and washed twice with DMF. 20% piperidine / DMF solution was added to remove the Fmoc protecting group, the reaction was stirred at room temperature for 10 minutes, the resin was sucked dry, the operation was repeated once, and then washed with DMF for 6 times. In addition, take Fmoc-Gly-OH 8.92g (30mmol), HOBT 4.86g (36mmol) and 60ml DMF, stir to dissolve, add 5.63ml (36mmol) of DIPCDI under ice bath for activation, add it to the resin, react at room temperature for 2 hours, Use the kaiser method to detect whether the reaction is complete. If the resin is colorless and transparent, it means the reaction is complete; if the resin develops color, it means the reaction is not complete, and the above operation needs to be repeated for two shots. This judgm...

Embodiment 2

[0063] Example 2 Synthesis of Polypeptide Fragment II

[0064] Take the peptide resin in Example 1 and add it to the lysis solution (TFA:H 10ml / g) 2 (O:DTDP=90:5:5), stirred and reacted at room temperature for 2 hours, filtered, poured the filtrate into frozen anhydrous ether for precipitation, centrifuged, washed three times with anhydrous ether, and vacuum-dried to obtain polypeptide fragment II 16.9g with a purity of 88.05 %.

Embodiment 3

[0065] Example 3 Synthesis of Polypeptide Fragment II

[0066] Take the peptide resin in Example 1 and add it to the lysis solution (TFA:H 10ml / g) 2 O:DTNP=90:5:5), stirred at room temperature for 2 hours, filtered, poured the filtrate into frozen anhydrous ether for precipitation, centrifuged, washed three times with anhydrous ether, and vacuum-dried to obtain polypeptide fragment II 17.4g with a purity of 86.43 %. chromatogram as image 3 The chromatographic data for typical characteristic peaks are shown in Table 3.

[0067] table 3

[0068]

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Abstract

The invention relates to the technical field of polypeptide synthesis, in particular to a preparation method of a terlipressin impurity Q. The preparation method comprises the following steps: firstly synthesizing a polypeptide fragment I and a polypeptide fragment II which are good in stability, then carrying out disulfide bond exchange on SH of a fourth Cys residue at the C end of the polypeptide fragment I and SNpys or SPyr of the fourth Cys residue at the C end of the polypeptide fragment II through condensation reaction to form a first pair of disulfide bonds, and carrying out iodine oxidation reaction to form a second pair of disulfide bonds while removing an Acm protecting group of the Cys. Experiments show that the terlipressin impurity Q obtained by the preparation method is high in purity and few in impurity, and the purity of a crude product can reach 75% or above.

Description

technical field [0001] The invention relates to the technical field of polypeptide synthesis, in particular to a preparation method of terlipressin impurity Q. Background technique [0002] Terlipressin is a synthetic analog of a hormone secreted by the posterior pituitary gland. It can be hydrolyzed by enzymes in the human body to generate vasopressin, which has a contracting effect on smooth muscle. It is mainly used clinically to treat esophageal varices bleeding. Its peptide sequence is as follows: [0003] [0004] Terlipressin can generate impurities Q during the preparation and storage process, which can affect the safety of the drug. In the process of developing the terlipressin production process, it is necessary to prepare a reference substance of impurity Q for the study of its product quality. [0005] The peptide sequence of impurity Q is as follows: [0006] [0007] At present, a large number of literatures in the prior art report the preparation met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/16C07K1/08C07K1/06C07K1/04C07K1/113C07K1/16
CPCC07K7/16
Inventor 汪伟姜绪邦尹传龙唐洋明余品香
Owner HYBIO PHARMA
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