Serendipitous discovery of a pH-dependant atropisomer bond rotation: toward a write-protectable chiral molecular switch?
Owing to slow rotation of a sterically constrained dimethylamide substituent, two slowly interconverting enantiomers of a preclinical candidate for pharmaceutical development, 1, (6-(3-Chloro-4-fluoro-benzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-[2,6]naphthyridine-1-carboxylic acid dimethylamide) are observed by chiral chromatography. Isolation of pure enantiomer by preparative chiral chromatography followed by enantiopurity analysis over time allowed for a study of the kinetics of enantiomer interconversion under a variety of conditions. Relatively slow racemization was observed in alcohol solvents, with a half life on the order of 5-10 h. A dramatic influence of aqueous buffer pH on racemization was noted, with higher pH leading to rapid racemization within a few minutes, and lower pH leading to essentially no racemization for periods up to a week. A hypothesis explaining this unusual effect of pH on carboxamide bond rotation is offered, and some suggestions for potential utility of such a system are considered.
Welch
Christopher J
CJ
Merck Research Laboratories, Inc., Department of Process Research, Rahway, NJ 07065, USA.
Biba
Mirlinda
M
Pye
Philip
P
Angelaud
Remy
R
Egbertson
Melissa
M
D000577:Amides / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D002942:Circular Dichroism; D004123:Dimethylamines / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D009287:Naphthyridines / Q000737:chemistry*; D009904:Optical Rotation; D013056:Spectrophotometry, Ultraviolet
C538972:(6-(3-chloro-4-fluoro-benzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-(2,6)naphthyridine-1-carboxylic acid dimethylamide); D000577:Amides; D004123:Dimethylamines; D009287:Naphthyridines