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Preparation method of [pyr1]-apelin-13

A boc-pyr-oh, fmoc-pro-oh technology, applied in the field of preparation of [Pyr1]-apelin-13, can solve the problems of only milligram scale and low yield, etc., and achieve low cost and high yield , the effect of high purity

Active Publication Date: 2021-09-21
KUNMING JIDA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Patent CN1283228A uses Boc-protected amino acids for solid-phase synthesis, the coupling reagent uses NMP-HOBt, uses hydrogen fluoride (HF) in the cracking process, and then precipitates with ether. The use of acid leads to the cleavage of resin peptides, and the use of highly corrosive and highly toxic reagent hydrogen fluoride (HF), the yield is also low, and the preparation scale is only in milligrams

Method used

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  • Preparation method of [pyr1]-apelin-13
  • Preparation method of [pyr1]-apelin-13
  • Preparation method of [pyr1]-apelin-13

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1 ([pyr1] -Apelin-13 protective peptide resin preparation)

[0055] The 60 g of a phenanthrine resin (H-PHE-2-CTC-RESIN) was added to a 2L polypeptide synthesis reaction bottle was added to a 2L polypeptide synthesis reaction bottle, and a DMF 480 ml of swelling resin was added for 30 minutes, and the solvent was discharged. Another 1L reaction vessel was taken, and FmoC-PRO-OH 65 g, DMF 480 ml was stirred and cooled to -5 to 5 ° C, and HOBT 29.2 g and DIC 24 g were added, and the temperature of -5 to 5 ° C was activated for 1 hour. The resulting mixture was added to the reaction bottle, and the mixture was stirred at room temperature to react with swellable resin for 1 to 2 hours, and the reaction endpoint was detected by ninluetrel. The reaction solution was filtered off, and the DMF was filtered three times with 480 ml / times. The addition of DBLK 480 ml deprotection reaction for 15 minutes, filtered off the solvent, and washed 6 times with DMF 480 ml / times to...

Embodiment 2

[0057] Example 2 ([Pyr1] -Apelin-13 protective peptide resin preparation)

[0058] 60 g of a phenylanine resin (H-PHE-2-ctc-resin) of 0.73 mmol / g was added to a 2L polypeptide synthesis reaction bottle, and a DMF 480 ml of swelling resin was added for 30 minutes, and the solvent was discharged. Another 1L reaction vessel was taken, FMOC-PRO-OH 59.1 g, DMF 480 ml was stirred and cooled to -5 ~ 5 ° C, and HOBT 23.6 g and DIC 22.0 g, and the temperature of -5 to 5 ° C activation reaction was allowed for 1 hour. The resulting mixture was added to the reaction bottle, and the mixture was stirred with a resin of swelling for 1 to 2 hours, and the reaction endpoint was detected by ninluol. The reaction solution was filtered off, and the DMF was filtered three times with 480 ml / times. The addition of DBLK 480ml deprotection reaction for 15 minutes, filtered off the solvent, and washed 6 times with DMF at 480 mL / times to give 2 peptide resins.

[0059] FMOC-MET-OH, FMOC-PRO-OH, FMOC-...

Embodiment 3

[0060] Example 3 ([pyr1] -Apelin-13 protective peptide resin preparation)

[0061] The 60 g of a phenantine resin (H-PHE-2-CTC-RESIN) was added to a 2L polypeptide synthesis reaction bottle was added to a 2L polypeptide synthesis reaction bottle, and the solvent was added to the solvent. Another 1L reaction container was taken, and FmOc-PRO-OH 50.2 g, DMF 480 ml was stirred and cooled to -5 to 5 ° C, and HOBT 20.1 g and DIC 18.7 g was added, and the temperature of 5 to 5 ° C was allowed for 1 hour. The resulting mixed solution was added to the reaction bottle, and the mixture was stirred at room temperature to react to a resin of swelling for 1 to 2 hours, and the reaction endpoint was detected by ninluol. The reaction solution was filtered off, and the DMF was filtered three times with 480 ml / times. The addition of DBLK 480ml deprotection reaction for 15 minutes, filtered off the solvent, and washed 6 times with DMF at 480 mL / times to give 2 peptide resins.

[0062] FMOC-MET-...

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Abstract

The present invention relates to the preparation method of [Pyr1]-apelin-13, comprising: step (1), the phenylalanine resin is placed in the reaction bottle for swelling treatment; step (2), adding to the reaction bottle containing The mixed solution of the raw material amino acid Fmoc-Pro-OH of the group, coupling agent and DMF carries out the coupling reaction, then deprotects and removes the protecting group Fmoc; step (3), uses Fmoc-Met-OH, Fmoc-Pro in sequence -OH, Fmoc-Gly-OH, Fmoc-Lys(Boc)-OH, Fmoc-His(Trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Leu-OH, Fmoc-Arg(Pbf)-OH , Fmoc-Pro-OH, Fmoc-Arg(Pbf)-OH and Boc-Pyr-OH carry out step (2) respectively, do not remove Boc after the Boc-Pyr-OH coupling is completed, and obtain a side chain protecting group [Pyr1]-apelin-13 protected peptide resin; step (4), cleavage to obtain [Pyr1]-apelin-13 crude peptide; step (5), purification to obtain [Pyr1]-apelin-13. The preparation method is safe, environment-friendly, high in yield and high in purity.

Description

Technical field [0001] The present invention belongs to the field of pharmaceutical technology, and is related to the preparation method of [pyr1] -apelin-13. Background technique [0002] Apelin (Apaliopene) is Tatemoto et al. For the first time in 1998, the endogenous APJ natural ligand extracted from the secretion of stern secretions in 1998, is a new discovery of important biology The action of cardiovascular active polypeptide, with angiotensin II (Angiotensin II, Ang II) has 31% homology, belonging to the new component of renin-angiotensis system, ras, with expansion of blood vessels , Positive muscle strength, reducing anti-autotransin release, reduces blood pressure, adjusting pituitary hormone release, adjusting biological rhythm and inhibits human immunodeficiency virus invasion, etc.. [0003] Apelin represents a prodere having 77 residues, which is processed into Apelin peptides, such as Apelin-36 (thirty peptide), Apelin-17 (seventeeptide), Apelin-16 (split peptide) ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/47C07K1/06C07K1/04
CPCC07K14/47Y02P20/55
Inventor 张朴永袁兵占申长念张云刘小龙王立江
Owner KUNMING JIDA PHARMA
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