Development of a Practical Synthesis of Functionalized Azaxanthene-Derived Nonsteroidal Glucocorticoid Receptor Modulators

Abstract

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 commercially available ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane. A partial classical resolution coupled with a preparative chiral supercritical fluid chromatography (SFC) separation was used to isolate the desired enantiomer of the azaxanthene carboxylic acid that is a common intermediate for both compounds 1 and 2. Suzuki−Miyaura cross-coupling with appropriately substituted boronic acids, followed by condensation with 2-amino-1,3,4-thiadiazole, provided the target compounds with an overall yield of approximately 10%. The use of stable, amorphous materials to support clinical comparison of functionalized azaxanthenes 1 and 2 is also discussed.

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

“…However, there are several examples of acid preactivation to form the O -acylisourea. ,,,,,,,,,,, If an additive such as HOBt, HOAt, or HOPO is employed, the preactivation step can eventually afford the activated ester. In one example, HOAt ester formation could be monitored by HPLC Acid preactivation was carried out in the −5 to 25 °C range, and preactivation times varied from 15 min to 18 h. None of the articles provided details on the need for acid preactivation versus the more common all-in protocol. Amide coupling conditions: If acid preactivation is required, the next step is the addition of the amine coupling partner and the base if the amine is supplied as a salt.…”

“…A final brine wash can be incorporated prior to telescoping into the next step or solvent distillation for product isolation. For typical workup examples, see refs , , , , , and . A water-immiscible solvent such as EtOAc, IPAc, or MTBE can be added prior to workup to favor the phase cut. ,, Water washes can be sufficient to remove EDCI- and HOBt-related byproducts Extractive workup with water, aqueous NaHCO 3 , and aqueous citric acid …”

“…In many examples, an “all-in” protocol was followed in which EDCI was added last to a mixture of the acid, amine, additive (if required), and base (normally to freebase the amine if it was supplied as a salt). However, there are several examples of acid preactivation to form the O -acylisourea. ,,,,,,,,,,, …”

Large‐scale chiral supercritical fluid chromatography of a key intermediate in the synthesis of two S1P1 final active pharmaceutical ingredients

“…Chiral resolution of these compounds in large quantities has been achieved by several techniques including chiral chromatography (SFC and normal phase), crystallization, and the combination of these two . Among these techniques, SFC has been demonstrated to be the most general and powerful technique in discovery and pre‐clinical development due to its high throughputs, reduce solvent consumption and readiness to scale up from method development . In the cases where final compounds are not amenable to SFC, usually because of poor solubility and/or low resolution, SFC purification of intermediates or precursors has been explored as a successful alternate to the final APIs .…”

A Partial Classical Resolution/Preparative Chiral Supercritical Fluid Chromatography Method for the Rapid Preparation of the Pivotal Intermediate in the Synthesis of Two Nonsteroidal Glucocorticoid Receptor Modulators

“…The clinical campaign required the delivery of 1 kg of the desired enantiomer 8a with a chiral purity of ≥99.0 analytical HPLC area percent (AP) under an aggressive timeline. In the original discovery chemistry route for the preparation of the two GC candidates 1 and 2 (Scheme 1), 12 preparative chiral SFC was employed in the antepenultimate step to isolate gram quantities of 8a. For this chiral separation, solubility measurements followed by chiral screening on analytical HPLC for a potential SMB process did not yield any promising hits.…”