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A dipeptide mimetic based on azabicyclo[x,y,0]alkanone skeleton and its preparation method

A peptidomimetic, azabicycle technology, applied in the field of dipeptide mimetic and its preparation, can solve the problems of low yield, long route of alkanone amino acid derivatives, etc., achieve high solubility, easy substrate expansion, synthesis operation easy effect

Active Publication Date: 2021-12-07
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The currently reported synthetic methods of azabicyclo[X.Y.0]alkanone amino acid derivatives have the disadvantages of long routes and low yields

Method used

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  • A dipeptide mimetic based on azabicyclo[x,y,0]alkanone skeleton and its preparation method
  • A dipeptide mimetic based on azabicyclo[x,y,0]alkanone skeleton and its preparation method
  • A dipeptide mimetic based on azabicyclo[x,y,0]alkanone skeleton and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] The structure and preparation method of (3S, 8aR)-5-oxo-1,2,3,5,8,8a-hexahydroindolezine-3-carboxylate are as follows:

[0018]

[0019] The raw material (2S, 5R)-1-acryloyl-5-allylpyrrolidine-2-carboxylic acid methyl ester (16.67g, 74.66mmol, 1.0eq) was dissolved in anhydrous toluene (400ml), nitrogen protection, A catalytic amount of Grubbs second-generation catalyst was added, and the reaction was refluxed for 24 hours. After the completion of the reaction was monitored by TLC, the reaction solution was concentrated and separated by silica gel column chromatography (PE:EA=2:1) ​​to obtain a colorless oil (12.40 g, yield 85.1%). 1 H NMR (300MHz, CDCl 3 ):δ6.13(m,1H),5.35(m,1H), 3.94(m,1H),3.42(m,1H),3.18(s,3H),2.07(m,1H),1.82-1.49( m,4H),1.26(m,1H); ESI-MS m / z calc'd for C 16 h 17 NO 3 [M+Na]+294.1, found 294.3.

Embodiment 2

[0021] The structure and preparation method of (3S, 8aR)-6-bromo-5-oxo-1,2,3,5,8,8a-hexahydroindolezine-3-carboxylate are as follows:

[0022]

[0023] Starting material (3S,8aR)-5-Oxo-1,2,3,5,8,8a-Indolinazine-3-carboxylic acid methyl ester (3.09 g, 15.83 mmol, 1.0 eq) was dissolved in DCM (100ml), slowly added liquid bromine (3.04g, 18.99mmol, 1.2eq) in DCM solution (0.5M) dropwise at 0°C, and reacted at room temperature for 3h. After the completion of the reaction monitored by TLC, the reaction solution was moved to an ice bath, and DIPEA (4.09g, 31.66mmol, 2.0eq) was slowly added dropwise, and reacted overnight at room temperature. After the completion of the reaction was monitored by TLC, the reaction solution was concentrated and separated by silica gel column chromatography (PE:EA=2:1) ​​to obtain a white solid (3.53 g, yield 81.3%). 1 H NMR (300MHz, CDCl 3 ):δ6.96(m,1H),4.56(m,1H),3.91(m,1H),3.73(s,3H),2.60-1.80(m,6H); 13 C NMR (75MHz, CDCl 3 ): δ171.8, 158.2, 1...

Embodiment 3

[0025] Structure of (3S,8aR)-6-(((tert-butoxycarbonyl)amino)-5-methyl-1,2,3,5,8,8a-hexahydroindolazine-3-carboxylate methyl ester And preparation method is as follows:

[0026]

[0027] Starting material (3S,8aR)-6-bromo-5-oxo-1,2,3,5,8,8a-hexahydroindolezine-3-carboxylic acid methyl ester (0.10 g, 0.36 mmol, 1.0 eq ) in a sealed tube, then added tert-butyl carbamate (127mg, 1.08mmol, 3eq), tris(dibenzylideneacetone) dipalladium (17mg, 5%eq.), 4,5-bis-diphenyl Phosphine-9,9-dimethylxanthene (21mg, 10%eq.), cesium carbonate (0.18g, 0.56mmol, 1.5eq), dissolved in toluene (4mL), reacted at 110°C under nitrogen protection 24h. The reaction was monitored by TLC and then cooled to room temperature. The reaction solution was diluted with water and extracted three times with EA. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (PE:EA=2:1) ​​to obtain...

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Abstract

The invention discloses a dipeptide mimic based on an azabicyclo[X,Y,0]alkanone skeleton and a preparation method thereof. The dipeptide mimic has the following structure: wherein, n=1-4; R 1 is amino, alkylamino, substituted alkylamino, nitrogen-substituted or unsubstituted alkylamide, nitrogen-substituted or unsubstituted arylamide, nitrogen-substituted or unsubstituted heteroarylamide, Nitrogen-substituted or unsubstituted alkoxyamide, hydroxyl, substituted alkoxy, substituted alkyl, substituted aryl or substituted heterocyclic aryl; X is O or NR 3 ; 2 and R 3 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the substituents all refer to alkyl, cycloalkyl , aryl or heterocyclic aryl, and a preparation method of the dipeptide mimetic is provided. The dipeptide mimetic of the present invention has good metabolic stability, high bioavailability, and strong membrane penetration ability, and the preparation method has a short route and relatively high efficiency. High and versatile.

Description

technical field [0001] The invention relates to a dipeptide mimetic and a preparation method thereof, in particular to a dipeptide mimetic based on an azabicyclo[X,Y,0]alkanone skeleton and a preparation method thereof. Background technique [0002] In the past few decades, peptides have received more and more attention in the development of new drugs due to their wide range of pharmacological activities. Many of the polypeptides are important signaling molecules, which can bind to various receptors on the cell membrane and in the cells to produce corresponding physiological functions. Many of them can also be used in the study of protein-protein interactions, so polypeptides can be used as many new drug development lead compound in . Peptides have inherent inherent defects, such as poor metabolic stability, low bioavailability, poor membrane permeability, etc., and the solubility of many peptides is not ideal. Therefore, different methods are used to modify the structure o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D487/04
CPCC07D471/04C07D487/04
Inventor 孙海鹰席婉琳杜蕾
Owner CHINA PHARM UNIV
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