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Synthetic method of glycopeptide

A synthesis method and glycopeptide technology, which is applied in the field of glycopeptide synthesis, can solve the problems of small loading capacity of solid phase carriers, limit the large-scale synthesis of glycopeptides, and low activity, and achieve large-scale synthesis, heterogeneous separation, and high reaction efficiency. high effect

Inactive Publication Date: 2014-07-16
INST OF MICROBIOLOGY - CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the reaction in solid-phase synthesis of glycopeptides is a heterogeneous reaction, which brings some disadvantages
In a heterogeneous reaction system, the activity of the reactants is lower than that in a homogeneous system, and it is often necessary to use a large excess of reagents to complete the reaction; conventional analytical methods such as thin-layer chromatography, nuclear magnetic resonance, and mass spectrometry cannot be used in real time. Monitor the progress of the reaction; the small loading capacity of the solid phase carrier limits the synthesis of a large number of glycopeptides

Method used

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  • Synthetic method of glycopeptide
  • Synthetic method of glycopeptide
  • Synthetic method of glycopeptide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1, the synthesis of ionic liquid

[0041] The reaction equation is as follows:

[0042]

[0043] Synthesis of Compound 1: Under nitrogen protection, 4-hydroxymethylphenol (4.00 g, 32.22 mmol), potassium carbonate (4.67 g, 33.82 mmol) and 1,3-dibromopropane (9.85 ml, 96.44 mmol ) in dry acetone (30 mL) was stirred at reflux for 5 hours. After thin-layer chromatography showed that 4-hydroxymethylphenol was consumed, the reaction solution was filtered and the solvent was evaporated under reduced pressure, and the resulting mixture was separated and purified by column chromatography (ethyl acetate:petroleum ether=1:3→1:2) , to obtain compound 1 (3.28 g, 39.6%) as a white solid.

[0044] The characterization results of compound 1 are as follows: 1 H NMR (500MHz, CDCl 3 )δ7.29(d,J=8.5Hz,2H),6.90(d,J=8.5Hz,2H),4.62(s,2H),4.11(t,2H),3.61(t,2H),2.32( m,2H); 13 C NMR (150MHz, CDCl 3 )δ158.4, 133.5, 128.7, 114.7, 65.5, 65.0, 32.4, 30.1.

[0045] Synthesis of ...

Embodiment 2

[0047] Embodiment 2, the synthesis of glycosylated amino acid building block formula III

[0048] The reaction equation is as follows:

[0049]

[0050] In the above reaction equation, the meanings of the abbreviations used are as follows: Troc: 2,2,2-trichloroethoxycarbonyl; TBSCl: tert-butyldimethylsilyl chloride; TBS: tert-butyldimethylsilyl; Ac : acetyl; Fmoc: 9-fluorenylmethoxycarbonyl; Ser: serine; Allyl: allyl; DMF: N,N-dimethylformamide; DCM: dichloromethane; DBU: 1,8-diazepine Bicycloundec-7-ene.

[0051] "One-pot" synthesis of glycosyl donor 3: compound 2 (12.0 g, 33.84 mmol) was dissolved in pyridine (150 ml) solvent, stirred and cooled to 0 °C, tert-butyldimethylsilyl chloride (6.63 g, 44.00 mmol) was added to the reaction system, and after 30 minutes, it was stirred overnight at room temperature. After thin-layer chromatography showed that compound 5 was consumed, acetic anhydride (35 ml) was added to the reaction system, stirred at room temperature for 6 hour...

Embodiment 3

[0057] Embodiment 3, the glycopeptide shown in synthetic formula II

[0058]

[0059] In the above process, the reaction conditions of each step are as follows: (a) 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 4-dimethylaminopyridine (DMAP), Acetonitrile, nitrogen, room temperature, 7 hours; (b) piperidine, dichloromethane, room temperature, 0.5 hours; (c) benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate salt (HBTU), 1-hydroxybenzotriazole (HOBt), N,N-diisopropylethylamine (DIPEA), acetonitrile, nitrogen, room temperature, 8 hours; (d) trifluoroacetic acid: water = 95: 5 (v / v), dichloromethane, 1 hour.

[0060] In the following preparation, the heterogeneous separation method used is as follows:

[0061] For the purification of ionic liquid-supported compounds. The specific operation process is as follows: the reaction mixture is dissolved in dichloromethane (10 ml / g), 4 times the volume of isopropyl ether is added, and then the solven...

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Abstract

The invention discloses a synthetic method of glycopeptides. The method comprises the following steps: (1) an esterification reaction between Fmoc protected amino acid and an ionic liquid is carried out to obtain an ionic liquid supported unit; (2) the ionic liquid supported unit is connected with any one of monomers selected from 1) glycosylated amino acid; and 2) glycosylated amino acid and at least one Fmoc protected amino acid, and the ionic liquid is removed to obtain the glycopeptide, wherein Fmoc represents 9-fluorenylmethyloxycarbonyl. The invention has the following advantages: as the ionic liquid is a micromolecular soluble carrier with a clear structure, the reaction course can be monitored at real time by routine analysis means such as thin-layer chromatography, nuclear magnetic resonance, mass spectrum and the like; and as the ionic liquid carrier also has high load capacity, is easy to synthesize and has low cost, synthesis of glycopeptide in quantity can be realized.

Description

technical field [0001] The invention relates to a method for synthesizing glycopeptides, belonging to the field of organic chemistry. Background technique [0002] Glycopeptides are structural regions formed by the covalent linkage of oligosaccharides and amino acids or polypeptide chains in glycoproteins and proteoglycans, and are extremely important bioinformation molecules in organisms. Glycopeptides play a very important role in many life phenomena and diseases such as cell division, signal transduction, cell recognition, cancer, immunity, inflammation, and microbial infection. The study of the relationship between the structure and function of glycopeptides plays an important role in revealing its biological functions and the development of glycopeptide drugs. Due to the low content and micro-heterogeneity of glycopeptides in organisms, it is very difficult to separate and purify glycopeptides from biological samples. It is often necessary to synthesize glycopeptides a...

Claims

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Application Information

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IPC IPC(8): C07D233/60C07K9/00C07K1/06
CPCC07D233/60C07K9/001
Inventor 李学兵李长庚张振兴
Owner INST OF MICROBIOLOGY - CHINESE ACAD OF SCI
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