Synthesis of a tetraamido macrocycle ligand

Reference Number: N 03-07

Inventors: Deline, James E.; Ott, Michael M.; Klotter, Kevin A.

Owner: NISTAC

USPTO Link: 6127536

Invention Summary

Briefly, the present invention comprises an improved, azide-based synthesis of tetraamido-macrocyclic ligands as exemplified by 5,6-Benzo-3,8,11,13-tetraoxo-2,2,9,9-tetramethyl-12,12-diethyl-1,4,7,10-te traazacyclotridecane, H.sub.4 in which the synthesis is made very amenable to commercial production and in which the overall yield of the macrocycle is remarkably increased from 12% (Collins et al.) to approximately 50-60% starting from 1,2-phenylenediamine. The improvement in methodology and yield results primarily from the modification of two steps in the synthesis compared to the method of the prior art as follows:

First, the 1,2-phenylenediamine starting material and 2-bromoisobutyryl bromide are reacted in tetrahydrofuran (THF) as opposed to the methylene chloride used in the prior art. The use of THF as solvent is an important improvement over the prior art synthesis because the intermediate reaction product, 1,2-bis(2-bromo-2-methylpropan-amido)benzene, is caused to precipitate directly out of the reaction mixture. The product then only requires filtration for its isolation, thus allowing a much more practical, and commercially very viable method of separation and purification to be used. The method of Collins et al., by contrast, requires that the reaction mixture be extracted multiple sequential times with aqueous hydrobromic acid and aqueous sodium carbonate, a process which is very impractical for large scale synthesis. Additionally, the use of THF as solvent results in a product of increased purity compared to the method reported by Collins et al. (in addition to a small improvement in yield). The increase in purity may further facilitate an increase in yields for the subsequent steps.

Second, in the final cyclization step, in which diethylmalonyl dichloride is reacted with 1,2-bis(2-amino-2-methylpropanamido)benzene to form the macrocycle, this reaction is carried out in (refluxing) ethyl acetate as the solvent as opposed to the methylene chloride used in the prior art. This again allows for a much simplified method of isolation of the macrocycle reaction product because pure product is caused to precipitate out as the reaction progresses. The method also reduces the required addition time of the reactants from many hours to thirty minutes or less. Moreover, the reaction conditions employing ethyl acetate remarkably increase the yield of the macrocycle from about 24%, as obtained for this one step in the prior art, to approximately 60-70% with the method of the present invention. It may be that this surprising increase in yield is effected at least in part by the driving force afforded by the precipitation of the product according to Le Chatelier's principle. It may also be that the formed product is less subject to unwanted side reactions once precipitated. It may further be that use of a higher temperature (i.e., refluxing ethyl acetate versus room temperature methylene chloride) in combination with ethyl acetate as solvent results in a more favorable reaction pathway. In any event, no other solvent investigated afforded this multifold increase in yield and ease of isolation of the product.