Improved Synthesis of 10-(2-Alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic Acid Derivatives Bearing Acid-Sensitive Linkers

Abstract

Alkylation of the hydrobromide salts of 1,4,7-tris(methoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane and 1,4,7-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane with appropriate α-bromoacetamides, followed by hydrolysis, provides convenient access to 10-(2-alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid derivatives that contain acid-sensitive functional groups. The utility of the method is demonstrated by improved syntheses of two known 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamides bearing acid-sensitive ω-tritylthio alkyl chains in much greater yields based on cyclen as the starting material.

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GRAPHICAL ABSTRACT

Keywords:

• Cyclen
• DO3A monoamide
• DOTA monoamide
• medical imaging
• synthesis

ACKNOWLEDGMENTS

This work was supported by Grants R01-CA118359, P01-CA017094, and P30-CA023074 from the National Institutes of Health.

Notes

¹ There is some ambiguity in the literature as to whether compounds such as 4 and 5 should be termed “DOTA monoamides” or “DO3A monoamides.” CAS names such compounds as 10-(2-alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid derivatives, which is inconsistent with both of these common usages. We employ “DOTA monoamide” in this article because this usage is consistent with use of the term “DOTA tetraamide” to indicate that all four acetate arms of the DOTA are present as amides.