A dibenzocyclooctyne derivative and application thereof

A technology for benzocyclooctynyl alcohol and compound, which is applied in the field of dibenzocyclooctyne derivatives, can solve the problems of tailing, long reaction time, large polarity and the like, achieves easy separation and purification, small steric hindrance, The effect of high ester solubility

Inactive Publication Date: 2019-06-11
NCPC NEW DRUG RES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the existing cyclic alkynes include cyclooctyne, monoarylcyclooctyne and diarylcyclooctyne, wherein diarylcyclooctyne includes an amino group with a more polar group such as a hydroxyl group or an amino group Dibenzocyclooctyne derivatives of formate or acetamide. During the preparation of such compounds, there are defects such as high polarity, difficulty in product separation and purification, and relatively low reaction conversion due to steric hindrance.
The dibenzocyclooctyne derivatives disclosed in patent US20100297250 (Geert-Jan Boons, etc.) and patent WO2012047663A2 (Geert-Jan Boons, etc.) are a class of carbamates or acetamides substituted by hydroxyl or aminoethoxy groups. Due to the high polarity of the compound, a solvent with a higher boiling point and a higher polarity such as DMF needs to be used in the preparation process, and the reaction time is longer, such as 12hr or overnight reaction, and it is difficult to evaporate the solvent after the product is processed. Due to the existence of polar groups, the tailing phenomenon in the column chromatography process is serious, separation and purification are difficult, and the yield is low, only about 70-80%

Method used

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  • A dibenzocyclooctyne derivative and application thereof
  • A dibenzocyclooctyne derivative and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0037] 5,6-Dihydro-11,12-didehydrodibenzo[a,e]cyclooctene-5-yl laurate ( -1) Preparation

[0038] Preparation of Lauroyl Chloride

[0039] Under ice bath at -10°C, dissolve 1 g (4.99 mmol) of lauric acid in 3 ml of freshly distilled thionyl chloride, add dropwise 1 drop of DMF, stir for 20 minutes, raise the temperature to 80°C, react for 3 hours, distill under reduced pressure, evaporate Thionyl chloride and other low-boiling impurities were removed, and the target fraction was collected to obtain 1.07 g of lauroyl chloride as a colorless oily liquid with a content of 99.0% and a yield of 97.8%.

[0040] Preparation of 5,6-dihydro-11,12-didehydrodibenzo[a,e]cyclooctene-5-ester of laurate (I-1)

[0041] Under ice bath at -5°C, dissolve 0.50g (2.27mmol) of 4-dibenzocyclooctynol (compound C) in 15ml of dichloromethane, add dropwise 0.91ml (11.33mmol) of pyridine, stir for 30min, add dropwise Lauroyl chloride 1.0g (4.53mmol), stirred at room temperature for 3h, the reaction s...

Embodiment 2

[0043] Preparation of 5,6-dihydro-11,12-didehydrodibenzo[a,e]cyclooctene-5-ester of myristic acid (I-2)

[0044] Preparation of myristoyl chloride

[0045] Under ice bath at -5°C, dissolve 1g (4.38mmol) of myristic acid in 5ml of freshly steamed thionyl chloride, add 2 drops of DMF dropwise, stir at room temperature for 20 minutes, raise the temperature to 70°C, react for 4h, and distill under reduced pressure , distilled thionyl chloride and other low-boiling impurities, collected the target fraction, and obtained 1.06 g of myristoyl chloride, a colorless oily liquid, with a content of 98.8% and a yield of 98.1%.

[0046] Preparation of 5,6-dihydro-11,12-didehydrodibenzo[a,e]cyclooctene-5-ester of myristic acid (I-2)

[0047]Under ice bath at 0°C, dissolve 0.47g (2.15mmol) of 4-dibenzocyclooctynol (compound C) in 15ml of tetrahydrofuran, add 0.87ml (10.73mmol) of pyridine dropwise, stir for 20min, and add myristoyl chloride dropwise 1.06g (4.29mmol), stirred at room tempera...

Embodiment 3

[0049] Preparation of 5,6-dihydro-11,12-didehydrodibenzo[a,e]cyclooctene-5-ester of palmitate (I-3)

[0050] Preparation of Palmitoyl Chloride

[0051] Under ice bath at 0°C, dissolve 1.0g (3.90mmol) of palmitic acid in 5ml of freshly distilled thionyl chloride, add 2 drops of DMF dropwise, stir at room temperature for 20 minutes, raise the temperature to 80°C, react for 3h, and distill under reduced pressure. Distill thionyl chloride and other low-boiling impurities, collect target fractions, and obtain palmitic acid 5,6-dihydro-11,12-didehydrodibenzo[a,e]cyclooctene-5-ester (I -3) 1.05g, colorless oily liquid, content 99.2%, yield 98.5%.

[0052] Preparation of 5,6-dihydro-11,12-didehydrodibenzo[a,e]cyclooctene-5-ester of palmitate (I-3)

[0053] Under ice bath at 5°C, dissolve 0.40g (1.82mmol) of 4-dibenzocyclooctynol (Compound C) in 15ml of dichloromethane, add 0.73ml (9.1mmol) of triethylamine dropwise, stir for 20min, drop Add 1.0g (3.64mmol) of palmitoyl chloride, st...

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Abstract

The invention relates to a dibenzocyclooctyne derivative and application thereof. The dibenzocyclooctyne derivative is especially used for carrying out click reaction with azide compounds to prepare stable 1,2,3-triazole compounds, and the latter have a wide range of uses in labeling glycans, proteins and lipids of living cells, glycoprotein enrichment of proteomics, protein and oligonucleotide modification, and tissue reconstruction engineering.

Description

technical field [0001] The present invention relates to a class of dibenzocycloctyne derivatives, in particular to dibenzocycloctyne long-chain fatty acid ester derivatives, a preparation method thereof and its preparation for click reaction with azide compounds to prepare stable Use in 1,2,3-triazole compounds. Background technique [0002] It has been found that cyclooctyne and azide can give stable 1,2,3-triazole compounds in the click cycloaddition reaction without the use of metal catalysts, which is useful in labeling glycans, proteins and lipids in living cells; Glycoprotein enrichment, protein and oligonucleotide modification in proteomics; and tissue reengineering are widely used. The existing "strain-promoted alkyne-azide cycloaddition reaction (SPAAC)" has also entered materials science, such as the assembly, cross-linking and surface modification of dendrimers; the derivation of polymers and nanostructures and surface pattern modification, etc. [0003] Despit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/14C07C69/24C07D249/04
Inventor 董桂敏刘魏胡军平邱召来付安坤安丽亚
Owner NCPC NEW DRUG RES & DEV
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