BMS-776532

An efficient route to two functionalized 2-aryl-5H-chromeno[2,3-b]pyridines (azaxanthenes) is reported.The addition of lithiated 2,6-dichloropyridine to salicylaldehyde followed by cyclization was a key process improvement identified for the formation of the azaxanthene core.Further elaboration of 2-chloro-5H-chromeno[2,3-b]pyridin-5-ol at the 5 position was accomplished via Lewis acid-catalyzed coupling with com. available [(1-methoxy-2-methylprop-1-en-1-yl)oxy]trimethylsilane.A partial classical resolution coupled with a preparative chiral supercritical fluid chromatog. (SFC) separation was used to isolate the desired enantiomer of the azaxanthene carboxylic acid that is a common intermediate for both compounds I (R = Me, Et).Suzuki-Miyaura cross-coupling with appropriately substituted boronic acids, followed by condensation with 2-amino-1,3,4-thiadiazole, provided the target compounds I (R = Me, Et) with an overall yield of approx. 10%.The use of stable, amorphous materials to support clin. comparison of functionalized azaxanthenes I (R = Me, Et) is also discussed.

Preparative chiral supercritical fluid chromatog. (SFC) employing an enantioenriched feedstock obtained via partial classical resolution enabled rapid access to kilogram quantities of a key intermediate common to two glucocorticoid (GC) receptor modulator candidates for which neither chem. nor enzymic resolutions provided the desired chiral purity (>99.0 HPLC area percent).We developed a partial classical resolution of the racemate that afforded 85:15 enantioenriched mixtures with 90% recovery of the desired enantiomer and reduced the SFC processing time by 54%.The SFC method used a 5 cm × 28 cm column packed inhouse with 20 μm Chiralpak AD, a total column flow rate of 150 g/min, a cosolvent composition of 12% methanol, and a column back pressure of 75 bar.The feed processing rate was up to 80 mL/h, which translated to 67 g/day of the enantioenriched mixture or 57 g/day of the desired enantiomer.This combined classical resolution/SFC process was employed to obtain a total of 1.0 kg of the desired enantiomer with an enantiomeric excess greater than 99.5% in 79% isolated yield by running the SFC separation over 23 days, 24 h/day, and 5 days/wk.Stable column pressure drops of 7-11 bar were measured throughout the manufacturing campaign.This separation approach enabled the first large-scale preparation of the two GC compounds and permitted their evaluation in toxicol. and first-in-human studies within a few months of entering development.