Carbamate linkage

Scheme 2 Drug-PEG conjugate via a benzyl carbamate linkage and its thiolytic cleavage...

CDI-activated hydroxyls also may undergo a side reaction to form active carbonates. This occurs when an imidazolyl carbamate reacts with another hydroxyl group before the second hydroxyl has had a chance to get activated with CDI. Particularly with adjacent hydroxyls on the same molecule, this can be a problem if a defined reactive species is desired. Any carbonates formed, however, are still reactive toward amines to create carbamate linkages. 

Figure 3.13 CDI reacts with hydroxyl groups to form an active imidazole carbamate intermediate. In the pres ence of amine-containing compounds, a carbamate linkage is created with loss of imidazole.

Figure 4.11 DSC can react with hydroxyl groups to create a succinimidyl carbonate intermediate that is highly reactive toward nucleophiles. In the presence of an amine-containing molecule, the active species can form stable carbamate linkages.

Figure 9.38 The acetyl azide group of this Cascade Blue derivative has dual functions. It can react with amine groups to form amide bonds, or it can be converted to an isocyanate at high temperatures to couple with hydroxyl functional groups, creating a carbamate linkage.

Figure 25.5 An SC-mPEG can be used to modify amine-containing molecules to form stable carbamate linkages.

Figure 25.8 N,N -carbonyldiimidazole (CDI) may be used to activate the terminal hydroxyl of mPEG to an imidazole carbamate. Reaction of this intermediate with an amine-containing compound results in the formation of a stable carbamate linkage.

Unfortunately, the presence of the benzylic alcohol moiety at the focal point of the dendrimer, along with the catalyst (used in the urethane formation) led to the formation of undesired side products, presumably due to carbamate interchange. These side reactions were avoided by switching to monomer 19, methyl-3,5-dihydroxybenzoate. While the carbamate linkages of dendrons 53 and 54 were too unstable under the alkylation conditions required to afford larger dendrons, the merits of the concept was adequately demonstrated for this accelerated synthesis of [G-3] dendrons. 

Figure 5 Conjugation of PLGA to doxorubicin via a noncleavable carbamate linkage (adapted with permission from the publisher [24]).

Pliotolytic. Bussacchini et al. (1985) studied the photolysis (7, = 254 nm) of phenmedipham in ethanol, ethanol/water, and hexane as solvents. In their proposed free radical mechanism, homolysis of the carbon-oxygen bond of the carbamate linkage gave the following photoproducts 3-(hydroxylphenyl)carbamic acid methyl ester, m-toluidine, 2-hydroxy-4-aminomethyl benzoate, 3-hydroxy-5-aminomethyl benzoate, 2-amino-4-hydroxymethyl benzoate, and 2-amino-6-hydroxymethyl benzoate. 

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