Preparing method for cetrorelix

A technology of cetrorelix and resin complexes, which is applied in peptide preparation methods, chemical instruments and methods, organic chemistry, etc., can solve the problems of many side reactions during synthesis and acidolysis, and tedious preparation of cetrorelix, etc. To achieve the effect of reducing difficulty

Inactive Publication Date: 2018-07-10
JIANGSU GENSCRIPT BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to provide a simple and efficient preparation method of cetrorelix, which solves the problems of cumbersome preparation of cetrorelix and many side reactions during synthesis and acidolysis

Method used

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  • Preparing method for cetrorelix

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Effect test

Embodiment 1

[0087] The invention is further illustrated by the following examples, which should not be construed as limiting the invention. Embodiment 1: Preparation of Cetrorelix

[0088] (1) Preparation of Fmoc-D-Ala-resin complex

[0089] Add 1g of HMBA resin (1.0mmol / g) into the reactor with filter device, inject 10ml of DMF, let stand for 1h, and filter.

[0090] Take 4mmol Fmoc-D-Ala-OH, 4mmol DIC, 4mmol HOBt and 0.2mmol DMAP, dissolve in 10ml DMF and filter, then add the obtained filtrate into the reactor and react at 30°C for 10h. After the reaction, filter. Then 10ml of DMF was added, the resin was washed three times and filtered.

[0091] (2) Preparation of protected cetrorelix-resin complex

[0092] Add 10ml of PIP / DMF solution with a volume ratio of 1:4 into the reactor, and react at 30°C for 30min. After the reaction is complete, filter. Then add 10ml DMF to wash the resin three times and filter.

[0093] Take 4mmol Fmoc-Pro-OH, 4mmol DIC, 4mmol HOBt, dissolve in 10ml ...

Embodiment 2

[0102] Embodiment 2: Preparation of Cetrorelix

[0103] (1) Preparation of Fmoc-D-Ala-resin complex

[0104] Add 1 g of Pam resin (1.0 mmol / g) into the reactor with a filter device, inject 10 ml of DMF, let stand for 1 h, and filter.

[0105] Take 3mmol Fmoc-D-Ala-OH, 3mmol DIC, 3mmol HOBt and 0.1mmol DMAP, dissolve in 10ml DMF and filter, then add the obtained filtrate into the reactor and react at 20°C for 3h. After the reaction, filter. Then 10ml of DMF was added, the resin was washed three times and filtered.

[0106] (2) Preparation of protected cetrorelix-resin complex

[0107] Add 10ml of PIP / DMF solution with a volume ratio of 1:3 into the reactor, and react at 20°C for 10min. After the reaction is complete, filter. Then add 10ml DMF to wash the resin three times and filter.

[0108] Take 3mmol Fmoc-Pro-OH, 3mmol HBTU, 3mmol HOBt and 6mmol DIEA, dissolve in 10ml DMF, add the resulting solution into the reactor, and react at 20°C for 1h. After the reaction, filte...

Embodiment 3

[0116] Embodiment 3: Preparation of Cetrorelix

[0117] (1) Preparation of Fmoc-D-Ala-resin complex

[0118] Add 1 g of methylol resin (1.0 mmol / g) into a reactor with a filter device, inject 10 ml of DMF, let stand for 1 h, and filter.

[0119] Take 7mmol Fmoc-D-Ala-OH, 7mmol DIC, 7mmol HOBt and 0.5mmol DMAP, dissolve in 10ml DMF and filter, then add the obtained filtrate into the reactor and react at 60°C for 20h. After the reaction, filter. Then 10ml of DMF was added, the resin was washed three times and filtered.

[0120] (2) Preparation of protected cetrorelix-resin complex

[0121] Add 10ml of PIP / DMF solution with a volume ratio of 1:1 into the reactor, and react at 60°C for 60min. After the reaction is complete, filter. Then add 10ml DMF to wash the resin three times and filter.

[0122] Take 6mmol Fmoc-Pro-OH, 6mmol PyBop, 6mmol HOBt and 12mmol DIEA, dissolve in 10ml DMF, add the resulting solution into the reactor, and react at 60°C for 4h. After the reaction,...

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Abstract

The invention discloses a preparing method for cetrorelix. The preparing method for the cetrorelix includes the following steps that (1) resin is used as a carrier, the resin and the C-terminus aminoacid of the cetrorelix are esterified, and an amino acid-resin compound is prepared; (2) a protective cetrorelix-resin compound is prepared with the Fmoc strategy solid-phase polypeptide synthesis method; (3) a side-chain protecting group is removed with TFA, and a de-protection cetrorelix-resin compound is prepared; (4) a cetrorelix crude product is obtained with the ammonia analytical method; (5) the cetrorelix crude product is purified with the high performance liquid chromatography, and a cetrorelix competitive product is obtained. The preparing method is suitable for simply, convenientlyand efficiently preparing the cetrorelix; the problems that an existing method is numerous in side reaction, low in yield and high in cost are solved.

Description

Technical field: [0001] The invention belongs to the field of polypeptide chemistry, in particular to a solid-phase preparation method of cetrorelix. Background technique: [0002] Cetrorelix is ​​an LHRH antagonist developed by Germany's Asta Medica, which can control the stimulation of the ovary, prevent premature discharge of immature follicles, and help conception. A large number of studies have shown that cetrorelix has a good curative effect on ovarian cancer, prostate cancer, uterine fibroids, endometriosis and other diseases, and can prevent and improve benign prostatic hypertrophy and ovarian hyperstimulation syndrome. The structure of cetrorelix is ​​a decapeptide: AC-D-2-Nal-D-4-Cl-Phe-D-3-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala- NH2; its structural formula is as follows: [0003] [0004] Cetrorelix is ​​prepared by chemical synthesis. [0005] Patent CN 101863960 B adopts the Wang resin and Boc strategy to synthesize cetrorelix, but there is a problem: using T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/06C07K1/04
CPCY02P20/55C07K7/23
Inventor 王卫国章方良刘文玉
Owner JIANGSU GENSCRIPT BIOTECH CO LTD
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