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A method for solid-phase synthesis of vasopressin receptor peptide agonist selepressin

A technology of vasopressin and synthetic method, applied in the field of solid-phase synthesis of Selepressin, which can solve the problems of difficult removal of iodine, many impurities, low yield and purity, etc.

Active Publication Date: 2020-10-30
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that when disulfide bonds are oxidized with iodine, there are more impurities, the yield and purity are not high, and the excess iodine is difficult to remove

Method used

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  • A method for solid-phase synthesis of vasopressin receptor peptide agonist selepressin
  • A method for solid-phase synthesis of vasopressin receptor peptide agonist selepressin
  • A method for solid-phase synthesis of vasopressin receptor peptide agonist selepressin

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The preparation of embodiment 1 polypeptide resin

[0041] Weigh 50 g of Rink Amide resin with a substitution degree of 1.0 mmol / g into a solid-phase reaction column, add 50 mL of DMF, and swell with nitrogen gas for 60 minutes; then deprotect with 50 mL of DBLK for 6 min+8 min, and wash with 100 mL of DMF for 6 times. Weigh 74.3g (250mmol) Fmoc-Gly-OH and 33.8g (250mmol) HOBT and dissolve them with 150mL DMF, add 31.5g (210mmol) DIC under ice-water bath to activate for 3min, then add the mixed solution into the reaction column, and react at room temperature for 2 Hours, use ninhydrin to detect the end of the reaction (if the resin is colorless and transparent, the reaction is terminated; if the resin develops color, the reaction is extended for 1 hour). After the reaction is over, wash the resin with 150mL DMF for 3 times, add 150mL DBLK for deprotection for 6min + 8min, wash the resin with 150mLDMF for 6 times, and detect the color of the resin with ninhydrin. Repeat...

Embodiment 2

[0042] The preparation of embodiment 2 polypeptide resins

[0043]Weigh 50 g of Rink Amide-AM resin with a substitution degree of 1.0 mmol / g into a solid-phase reaction column, add 50 mL of DMF, and swell with nitrogen gas bubbling for 60 minutes; then deprotect with 50 mL of DBLK for 6 min+8 min, and wash with 100 mL of DMF for 6 times. Weigh 74.3g (250mmol) Fmoc-Gly-OH and 33.8g (250mmol) HOBT and dissolve them with 150mL DMF, add 31.5g (210mmol) DIC under ice-water bath to activate for 3min, then add the mixed solution into the reaction column, and react at room temperature for 2 Hours, use ninhydrin to detect the end of the reaction (if the resin is colorless and transparent, the reaction is terminated; if the resin develops color, the reaction is extended for 1 hour). After the reaction is over, wash the resin with 150mL DMF for 3 times, add 150mL DBLK for deprotection for 6min + 8min, wash the resin with 150mLDMF for 6 times, and detect the color of the resin with ninhyd...

Embodiment 3

[0044] The preparation of embodiment 3 polypeptide resins

[0045] Weigh 50 g of MBHA resin with a substitution degree of 1.0 mmol / g into a solid-phase reaction column, add 50 mL of DMF, and swell with nitrogen gas for 60 minutes; then deprotect with 50 mL of DBLK for 6 min + 8 min, and wash 6 times with 100 mL of DMF. Weigh 74.3g (250mmol) Fmoc-Gly-OH and 33.8g (250mmol) HOBT and dissolve them with 150mL DMF, add 31.5g (210mmol) DIC under ice-water bath to activate for 3min, then add the mixed solution into the reaction column, and react at room temperature for 2 Hours, use ninhydrin to detect the end of the reaction (if the resin is colorless and transparent, the reaction is terminated; if the resin develops color, the reaction is extended for 1 hour). After the reaction is over, wash the resin with 150mL DMF for 3 times, add 150mL DBLK for deprotection for 6min + 8min, wash the resin with 150mLDMF for 6 times, and detect the color of the resin with ninhydrin. Repeat the ab...

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Abstract

Provided is a method for solid phase synthesis of a vasopressin receptor peptide agonist selepressin. The method comprises the following steps: 1) sequentially coupling a solid-phase resin with amino acids protected by amino groups to synthesize a polypeptide resin H-Cys(allocam)-Phe-Ile-Hgn(Trt)-Asn(Trt)-Cys(allocam)-Pro-Org(i-Pr)-Gly-resin; 2) under solid phase conditions, removing the protective group allocam of cysteine with a ternary catalytic oxidation system and oxidizing the mercapto group into a disulfide bond; and 3) removing the resin and the protecting groups of side chains of Hgn and Asn from the cleavage broth, and purifying same. The method of the present invention does not use an iodine catalyst, greatly reduces post-processing issues, and has the advantages of simple operation, a simplified process, environmental friendliness, high economic efficiency and being suitable for large-scale production, etc.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to a method for synthesizing Selepressin by a solid-phase method. Background technique [0002] Selepressin, namely FE-202158, is a vasopressin receptor peptide agonist, a polypeptide drug developed by Ferring for the treatment of septic shock, and is currently in clinical phase III. Selepressin is a synthetic nonapeptide compound with an amide at the C-terminal and a pair of disulfide bonds (1-6). The peptide sequence is shown in formula I, Cas: 876296-47-8. [0003] [0004] So far, patent CN1964732B has publicly reported the method of preparing Selepressin: use amino resin, prepare crude peptide by standard Fmoc solid-phase peptide synthesis, then oxidize disulfide bond with iodine in methanol acetate solution in liquid phase, reverse high-efficiency liquid Selepressin refined peptide was obtained by phase purification. The disadvantage of this method is that wh...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04
CPCC07K1/04C07K1/06C07K1/08C07K7/06Y02P20/55
Inventor 陈学明梁思思宓鹏程陶安进袁建成
Owner HYBIO PHARMA
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