Merrell Dow Pharmaceuticals

Merrell Pharmaceuticals, Inc.

Hoechst Marion Roussel

Richard E Donaldson

James R McCarthy

Donald Paul Matthews

Jeffrey S Sabol

James R McConnell

John F Hoops

Robert Duquid

Robert Duguid

The present invention is directed toward a novel process of preparing 2'-exocyclic vinylfluoride derivatives of cytidine analogues for use as ribonucleotide reductase inhibitors.

Process for the preparation of ribonucleotide reductase inhibitors

The present invention is directed toward a novel process of preparing 2'-exocyclic vinylfluoride derivatives of cytidine analogues for use as ribonucleotide reductase inhibitors. The novel process of the present invention utilizes a cytidine derivative as the required starting material and provides the ribonucleotide reductase inhibitor in a more efficient than the reaction sequence. The process is more efficient than the process disclosed by McCarthy et al. in European Patent Application Publication No. 0 372 268 published Jun. 13, 1990, in that it requires fewer chromatographies and results in an overall yield of greater than 25% for the five steps. The present invention further provides the ribonucleotide reductase inhibitor in a four step reaction sequence and results in an overall yield of greater than 35%.

The present invention is directed toward a novel process of preparing 2'-exocyclic vinylfluoride derivatives of cytidine analogues for use as ribonucleotide reductase inhibitors. The novel process of the present invention utilizes a cytidine derivative as the required starting material and provides the ribonucleotide reductase inhibitor in a more efficient five step reaction sequence. The present invention further provides the ribonucleotide reductase inhibitor in a four step reaction sequence and results in an overall yield of greater than 35%.

The compounds 1-(3,4-methylenedioxyphenyl)-3-(N-benzylamino)butane and methyl 5-[[4-(3,4-methylenedioxyphenyl)-N-benzyl-2-butylamino]acetyl]salicylate are intermediates in the preparation of medroxalol.

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Midland, MI, United States of America

Richard E Donaldson