63740-75-0Relevant articles and documents
Ultrafast chiral separations for high throughput enantiopurity analysis
Barhate, Chandan L.,Joyce, Leo A.,Makarov, Alexey A.,Zawatzky, Kerstin,Bernardoni, Frank,Schafer, Wes A.,Armstrong, Daniel W.,Welch, Christopher J.,Regalado, Erik L.
supporting information, p. 509 - 512 (2017/01/13)
Recent developments in fast chromatographic enantioseparations now make high throughput analysis of enantiopurity on the order of a few seconds achievable. Nevertheless, routine chromatographic determinations of enantiopurity to support stereochemical investigations in pharmaceutical research and development, synthetic chemistry and bioanalysis are still typically performed on the 5-20 min timescale, with many practitioners believing that sub-minute enantioseparations are not representative of the molecules encountered in day to day research. In this study we develop ultrafast chromatographic enantioseparations for a variety of pharmaceutically-related drugs and intermediates, showing that sub-minute resolutions are now possible in the vast majority of cases by both supercritical fluid chromatography (SFC) and reversed phase liquid chromatography (RP-LC). Examples are provided illustrating how such methods can be routinely developed and used for ultrafast high throughput analysis to support enantioselective synthesis investigations.
Ion mobility spectrometry-mass spectrometry analysis for the site of aromatic hydroxy
Shimizu, Atsushi,Chiba, Masato
, p. 1295 - 1299 (2013/07/26)
Hydroxylated metabolites often retain the pharmacological activity of parent compound, and the position of hydroxylation determines the formation of chemically reactive intermediates, such as quinones and analogs, from para- and/or ortho-hydroxylation of phenols or arylamines. Therefore, the identification of exact position of hydroxylation is often required at the early development stage of new drug candidates. In many cases, liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides identical MS/MS spectra among isomeric hydroxylated metabolites, and therefore, it alone cannot unequivocally identify the exact position(s) of hydroxylation. Ion mobility spectrometry (IMS), integrated with LC-MS/MS, recently showed the capability of separating isomeric species based on differences in their drift times from IMS, which are linearly proportional to the collision cross-section (CCS) reflecting physical size and shape. In the present study, a chemical derivatization of isomeric hydroxylated metabolites with 2-fluoro-N-methyl pyridinium p-toluenesulfonate was found to confer distinct theoretical CCS value on each isomer by forming corresponding N-methyl pyridine (NMP) derivative. The regression lines established by the comparison between theoretical CCS values and observed drift times from IMS for each set of parent compound (labetalol, ezetimibe, atorvastatin, and warfarin) and its MS/MS product ions accurately and selectively projected the actual drift times of NMP derivatives of corresponding aromatic or isomeric hydroxylated metabolites. The established method was used for the accurate assignment of predominant formation of 2-hydroxylated metabolite from imipramine in NADPH- fortified human liver microsomes. The present application expands the versatility of LC-IMS-MS technique to the structure identification of isomeric hydroxylated metabolites at the early stage for drug development.
Analogs of 3-(1-Phenyl-3-oxobutyl)-4-hydroxycoumarin (Warfarin) Prepared from Substituted Salicylic Acids
Obaseki, Andrew O.,Steffen, James E.,Porter, William R.
, p. 529 - 533 (2007/10/02)
Some derivatives of salicylic acid containing substituents meta to the carboxyl group were used to prepare analogs of the anticoagulant drug warfarin, 3-(1-phenyl-3-oxobutyl)-4-hydroxycoumarin, containing substituents in either the 6- or 8-position of the coumarin ring.When the substituent was the hydroxyl group, the resulting products are previously identified metabolites of warfarin.The substituted salicylic acid is first acetylated with acetic anhydride, then either converted to the acid chloride and condensed with diethyl malonate in the presence of sodium hydroxide or converted to the mixed anhydride with formic acid and condensed with ethoxymagnesium diethyl malonate to yield, in either case, the corresponding 3-carbethoxy-4-hydroxycoumarin substituted in the 6- or 8-position of the coumarin ring.These compounds readily condense with benzalacetone to form the corresponding substituted warfarin in the presence of 5 mole percent tertiary amine catalyst.This method offers an improved route for the synthesis or 8-hydroxywarfarin.
