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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: 2019-04-05
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
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Effect test

Embodiment 1

[0054] Example 1 (preparation of [Pyr1]-apelin-13 protected peptide resin)

[0055] Add 60 g of phenylalanine resin (H-Phe-2-CTC-resin) with a degree of substitution of 0.90 mmol / g into a 2L polypeptide synthesis reaction flask, add 480 mL of DMF to swell the resin for 30 minutes, and drain off the solvent. Take another 1L reaction vessel, add Fmoc-Pro-OH 65g, DMF 480mL, stir and cool down to -5~5°C, add HOBt 29.2g and DIC 24g, keep the temperature at -5~5°C for activation reaction for 1 hour. Add the obtained mixed liquid into the above-mentioned reaction bottle, stir at room temperature to make it react with the swollen resin for 1-2 hours, and the end point of the reaction is determined by the ninhydrin method. The reaction solution was filtered off and washed three times with DMF at 480 mL / time. Add 480 mL of DBLK for deprotection reaction for 15 minutes, filter off the solvent, and wash 6 times with 480 mL of DMF each time to obtain 2-peptide resin.

[0056] Use Fmoc-Me...

Embodiment 2

[0057] Embodiment 2 (preparation of [Pyr1]-apelin-13 protected peptide resin)

[0058] Add 60 g of phenylalanine resin (H-Phe-2-CTC-resin) with a substitution degree of 0.73 mmol / g into a 2L polypeptide synthesis reaction flask, add 480 mL of DMF to swell the resin for 30 minutes, and drain the solvent. Take another 1L reaction vessel, add 59.1g of Fmoc-Pro-OH and 480ml of DMF, stir and cool down to -5~5°C, add 23.6g of HOBt and 22.0g of DIC, and keep the temperature at -5~5°C to activate the reaction for 1 hour. Add the obtained mixed solution into the above-mentioned reaction bottle, stir at room temperature to make it react with the swollen resin for 1-2 hours, and the reaction end point shall be determined by the ninhydrin method. The reaction solution was filtered off and washed three times with DMF at 480 mL / time. Add 480 mL of DBLK for deprotection reaction for 15 minutes, filter off the solvent, and wash 6 times with 480 mL / time of DMF to obtain 2-peptide resin.

[0...

Embodiment 3

[0060] Example 3 (preparation of [Pyr1]-apelin-13 protected peptide resin)

[0061] Add 60 g of phenylalanine resin (H-Phe-2-CTC-resin) with a degree of substitution of 0.62 mmol / g into a 2L polypeptide synthesis reaction flask, add 480 mL of DMF to swell the resin for 30 minutes, and drain off the solvent. Take another 1L reaction vessel, add Fmoc-Pro-OH 50.2g, DMF 480mL, stir and cool down to -5~5°C, add HOBt 20.1g and DIC 18.7g, keep the temperature at -5~5°C for 1 hour to activate the reaction. Add the obtained mixed solution into the above-mentioned reaction bottle, stir at room temperature to make it react with the swollen resin for 1-2 hours, and the end point of the reaction is determined by the ninhydrin method. The reaction solution was filtered off and washed three times with DMF at 480 mL / time. Add 480 mL of DBLK for deprotection reaction for 15 minutes, filter off the solvent, and wash 6 times with 480 mL / time of DMF to obtain 2-peptide resin.

[0062] Use Fmoc-...

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Abstract

The invention relates to a preparation method of [Pyr1]-apelin-13. The method comprises the following steps: step (1), placing phenylalanine resin in a reaction flask for swelling treatment; step (2),adding a mixed solution containing raw material amino acid Fmoc-Pro-OH with a protecting group, a coupling agent and DMF into the reaction flask for a coupling reaction, and then performing deprotection to remove the protecting group Fmoc; step (3), respectively performing the step (2) by successively using Fmoc-Met-OH, Fmoc-Pro-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, and not removing Boc after coupling of Boc-Pyr-OH is completed to obtain [Pyr1]-apelin-13 protecting peptide resin witha side chain protecting group; step (4) cracking to obtain [Pyr1]-apelin-13 crude peptide; and step (5) purifying to obtain [Pyr1]-apelin-13. The preparation method is safe and environmentally friendly, and is high in yield and high in purity.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to a preparation method of [Pyr1]-apelin-13. Background technique [0002] Apelin (Apelin peptide) is the endogenous APJ natural ligand extracted and purified from the secretion of bovine stomach for the first time by Tatemoto et al. in 1998 through the reverse pharmacological method. Cardiovascular active polypeptide, which has 31% homology with angiotensin II (Ang II), belongs to the new component of renin-angiotensin system (RAS), and has the function of dilating blood vessels , positive muscle strength, reducing the release of antidiuretic hormone, lowering blood pressure, regulating the release of pituitary hormones, adjusting biological rhythms and inhibiting the invasion of human immunodeficiency virus and other biological effects. [0003] Apelin denotes a preprotein with 77 residues that is processed into biologically active forms of apelin peptides, such as apeli...

Claims

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Application Information

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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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