ORGN 149 |
| We have been developing MRI contrast agents that possess a macrocyclic gadolinium chelate. During a multi-gram asymmetric synthesis of (R)-DOTAGA(t-Bu)4 [2-(R)-(4,7,10-tris-t-butylcarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic acid, 1-t-butyl ester] (4), a precursor of the chelate moiety, alkylation of 2 with cyclen (1,4,7,10-tetraazacyclododecane) was recognized as a crucial step. Monoalkylated cyclen 3 was initially prepared from bromide 2a (R=Br) following a published procedure [Bioorg. Med. Chem. Lett., 10 (2000), 2133.], as a mixture of (R)- and (S)-isomers. In order to synthesize optically enriched materials, a class of sulfonates was studied. Triflate 2b (R=OTf) was first examined. As expected, minimal racemization was observed. However, there were a number of scale-up drawbacks: a) the stability of the triflate was unknown, b) the inability to ascertain the actual amount of the triflate being added to cyclen was an obstacle to the development of a robust alkylation reaction, c) the reaction at -40ºC was not desirable. We then investigated mesylate chemistry: 1) mesylate 2c (R=OMs) was very stable, even at elevated temperature (up to 55ºC), 2) it can be isolated by aqueous work-up, 3) impurity profiles of 3 were improved dramatically, 4) the process was scalable, and 5) the chiral integrity was maintained. The process utilizing the mesylate was successfully applied to the kilogram-scale synthesis of 4.
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Asymmetric Reactions and Syntheses, Physical Organic Chemistry, Combinatorial Chemistry, Total Synthesis
8:00 PM-10:00 PM, Sunday, 26 March 2006 Georgia World Congress Center -- Ex. Hall B4, Poster
Division of Organic Chemistry |
