Merck + Co., Inc.

Karl Hansen

Paul N Devine

Robert M Wenslow

Yuan Cheng

Ian W Davies

Philippe Rabbat

Christopher M Lindemann

Russell R Ferlita

Alex Minhua Chen

Robert M Wenslow, Jr

Ivan Lee

Vicky K Vydra

Philippe M Rabbat

Louis Matty, Jr

Stephen Howard Cypes

Evangelia Spartalis

Stephen Cypes

Alex M Chen

Joseph D Armstrong

The dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine is a potent inhibitor of dipeptidyl peptidase-IV and is useful for the prevention and/or treatment of non-insulin dependent diabetes mellitus, also referred to as type 2 diabetes. The invention also relates to a crystalline monohydrate of the dihydrogenphosphate salt as well as a process for its preparation, pharmaceutical compositions containing this novel form and methods of use for the treatment of diabetes, obesity, and high blood pressure.

Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor

Enantiomerically enriched hydroxychromanones are obtained by the AlCl -catalyzed intramolecular Friedel-Crafts acylation of the corresponding 3-phenoxy-2-alkylcarbonyloxy-propionic acid followed by cleavage of the carboxylate in the presence of an alkali metal peroxide or hydroperoxide. Enantiomerically enriched cis-aminochromanols can then be prepared by treating the hydroxychromanones with a hydroxylamine and hydrogenating the resulting oxime. The cis-aminochromanols can be employed as intermediates in the production of HIV protease inhibitors which are useful for treating HIV infection and AIDS.

Process for preparing hydroxychomanones and cis-aminochromanols

cis-aminochromanols are obtained in high yield and with high selectivity over their trans counterparts by hydrogenating the corresponding oximes in the presence of a catalyst and an acid selected from HBr, HCl, and organic sulfonic acid. The cis-aminochromanols can be employed as intermediates in the production of HIV protease inhibitors which are useful for treating HIV infection and AIDS.

Process for preparing cis- aminochromanols

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Atlantic Highlands, NJ, United States of America

Karl Hansen