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Synthesis of degarelix by solid phase segment method

A technology of solid-phase synthesis and degarelix, applied in peptide preparation methods, chemical instruments and methods, organic chemistry, etc., can solve problems such as high price, shedding, and increased cost of large-scale production

Active Publication Date: 2013-10-16
HAINAN SHUANGCHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 5-10% TFA / DCM is used to remove the protecting group Trt of amino acid residue 4Aph (Trt), which will cause part of the protecting group Boc of the third amino acid residue Lys (ipr, Boc) to fall off, so that the exposed amino group It will react with L-4,5-dihydroorotic acid to generate new impurities; in addition, Pd(Ph 3 P) 4 / phenylsilane / DCM, Pd(Ph 3 P) 4 The price is relatively expensive, which will increase the cost of large-scale production

Method used

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  • Synthesis of degarelix by solid phase segment method
  • Synthesis of degarelix by solid phase segment method
  • Synthesis of degarelix by solid phase segment method

Examples

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preparation example Construction

[0042] Partial structural formulas involved in the preparation method provided by the invention are shown in the following table:

[0043]

[0044] As used herein, "solid phase synthesis" or "solid phase peptide synthesis (solid phase peptide synthesis)" is a peptide synthesis technique well known in the art, including but not limited to the following methods: covalently synthesize an amino-protected amino acid Linked (bonded) on a solid-phase support; in the presence of a deprotecting agent, the protective group of the amino group is removed, so that the first amino acid is connected to the solid-phase support; then the amino group is blocked (protected) by the second amino acid The carboxyl group is activated, and the second amino acid activated by the carboxyl group reacts (condenses) with the amino group of the first amino acid that has been attached to the solid-phase support to form a peptide bond, thus forming a protective group on the solid-phase support. Dipeptide:...

Embodiment 1

[0108] Synthesis of Fmoc-D-Ala-AM resin

[0109] Add Rink Amide-AM resin (5mmol, substitution degree 0.5mmol / g) into the solid phase reactor, add 100ml DMF to swell for 30min, and wash twice with DMF. Add 100ml of 20% PIP / DMF solution to remove Fmoc protection for 10 minutes, drain, then add 100ml of 20% PIP / DMF solution to remove Fmoc protection for 20 minutes, wash with DMF for 3 times, DCM for 2 times, and DMF for 3 times. 4.67g Fmoc-D-Ala-OH (15.0mmol, 3.0eq.) and 3.04g HOBt (22.5mmol, 4.5eq.) were dissolved in 80ml DMF, and 4.7ml DIC (30.0mmol, 6.0eq.) was added at 0-5°C .), pre-activated for 2-5 minutes, added to the solid-phase reactor, and reacted with nitrogen gas for 2-3 hours, and the ninhydrin test was negative. Drained, washed 3 times with DMF and 3 times with DCM, and dried to obtain Fmoc-D-Ala-AM resin, the degree of substitution was 0.42mmol / g.

Embodiment 2

[0111] Synthesis of Fmoc-D-Ala-MBHA Resin

[0112] Add Rink Amide-MBHA resin (5mmol, substitution degree 0.8mmol / g) into the solid phase reactor, add 100ml DMF to swell for 30min, and wash twice with DMF. Add 100ml of 20% PIP / DMF solution to remove Fmoc protection for 10 minutes, drain, then add 100ml of 20% PIP / DMF solution to remove Fmoc protection for 20 minutes, wash 3 times with DMF, 2 times with DCM, and 2 times with DMF. Dissolve 4.67g Fmoc-D-Ala-OH and 3.04g HOBt in 80ml DMF, add 4.7ml DIC at 0-5°C, pre-activate for 2-5min, add it to a solid-phase reactor, react with nitrogen gas for 2-3h, ninhydrin The ketone test was negative. Drained, washed 3 times with DMF and 3 times with DCM, and dried to obtain Fmoc-D-Ala-MBHA resin, the degree of substitution was 0.58mmol / g.

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Abstract

The invention discloses synthesis of degarelix by a solid phase segment method, wherein Fmoc-amino acid is connected with resin so that Fmoc-amino acid-resin can be obtained; a solid phase synthesis method is adopted, and the steps of orderly connecting amino acid from the end C to the end N and removing the Fmoc group are carried out, so that Fmoc protected polypeptide resin can be obtained; the method comprises the following steps of: (1) forming polypeptide resin as shown in formula III and polypeptide resin as shown in formula IV, respectively; (2) mixing the polypeptide resin as shown in formula III with 1-5% of trifluoroacetic acid (TFA), connecting L-4,5-dihydroorotate to the side chain amino of the polypeptide resin after the protecting group of the sixth amino acid residue at the end C is removed, and then removing the Fmoc group to obtain polypeptide resin as shown in formula V; removing the Fmoc group of the polypeptide resin as shown in formula IV and acetylating the polypeptide resin, thereby obtaining polypeptide resin as shown in formula VI, and then cutting to obtain segments as shown in formula VII; (3) coupling the polypeptide resin as shown in the formula V with the segments as shown in the formula VII, thereby obtaining the polypeptide resin as shown in formula II; (4) separating polypeptide on the polypeptide resin as shown in the formula II from the resin, thereby obtaining degarelix as shown in formula I.

Description

technical field [0001] The invention relates to the field of polypeptide solid-phase synthesis, in particular to the synthesis of degarelix by a solid-phase fragment method. Background technique [0002] Degarelix is ​​a GnRH antagonist, a new drug for the treatment of advanced prostate cancer developed by Ferring, and its trade name is Firmagon. Degarelix has a rapid onset of action, suppresses gonadotropins, testosterone, and prostate-specific antigen, lowers testosterone levels at least as well as leuprolide depot injection (Lupron Depot), and lowers testosterone levels Statistically significantly faster. [0003] Degarelix is ​​a synthetic decapeptide, most of which are D-type unnatural amino acids, and its peptide sequence structure is [0004] Ac-D-2Nal-D-Phe(4Cl)-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(ipr)-Pro-D-Ala-NH 2 , the chemical structural formula is as follows: [0005] [0006] The side chain amino protecting group L-Hor (L-hydrogenated orotic acid) ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04
CPCY02P20/55
Inventor 云晓吴四清袁剑琳张巍陈超
Owner HAINAN SHUANGCHENG PHARMA
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