Process Development of a Potent Bradykinin 1 Antagonist

Abstract

As part of Merck's continued research effort on inflammation and pain, a safe synthesis of an orally bioavailable and CNS penetrant bradykinin 1 antagonist was developed and demonstrated on kilogram scale. The key step included a novel regioselective metal-halogen exchange reaction on 1,2-dibromo-5-chloro-3fluorobenzene using isopropyl magnesium chloride to install the 1,2,4-oxadiazole ring structure. Suzuki cross-coupling reaction between a highly functionalized and sterically hindered electrophile and boronic ester generated the biaryl ring system, which was converted to the target molecule (1) using standard chemistry. The safe installation of a 1,2,4-oxadiazole ring proved to be challenging since the original synthetic route relied on the preparation of a highly functionalized benzonitrile using potassium cyanide and resulted in low yields and large amounts of potentially hazardous waste. Overall, a safe and robust synthesis was developed, which occurred in eight linear steps with an overall yield of 28%.

Design, preparation and application of conjugated microporous polymers

“…The Suzuki reaction is an arguably efficient method for aryl–aryl bond formation since initial reports in 1979 . The development of the Suzuki reaction has proceeded, including boronic acid and aryl chloride coupling, boronic acid and aryl bromide coupling, boronic acid and aryl iodide coupling, boronic acid and alkenyl triflate coupling, borane and aryl halide coupling, borane and alkyl halide coupling, boronic ester and aryl halide coupling, boronic ester and alkyl halide coupling, borate complexes, etc.…”

Early Development Scale-Up of a Structurally-Challenging 5-Lipoxygenase Activating Protein (FLAP) Inhibitor

“…Since a rapid exotherm was observed during the HCl quench of Dibal-H, with localized hot spots that led to formation of the amine over-reduction side product, we strongly recommend the reverse quench as a preferred alternative for future scale-up. The amidoxime was then formed from 14 by a safe two-step operation, via chloro-oxime formation using NCS and catalytic acid, followed by ammonia treatment. , After a subsequent recrystallization from toluene/heptane, 22.9 kg (in 2 batches) of amidoxime 15 was isolated in 75% combined yield (98.9% HPLC purity, 97.3 wt %, 99.4% ee) based on the assay of crude 14 . The overall yield from solid 11 -DNP to solid 15 over 8 operations was 59%.…”

Development of Flexible and Scalable Routes to Two Phosphatidinylinositol-3-kinase Delta Inhibitors via a Common Intermediate Approach

“…The solution was cooled to 20 °C, and HCl in IPA (5 M, 17.7 L, 88.5 mol) was added over 30 min. The slurry was aged for 1 h and filtered, and the cake was washed with toluene (77 L) and dried under vacuum at 40 °C to afford 5-bromo-2-methoxypyridin-3-ammonium chloride (23) N -( 5 -B r o m o -2 -m e t h o x y p y r i d i n -3 -y l )methanesulfonamide (24). Compound 23 (18.1 kg, 75.6 mol) was dissolved in a mixture of acetonitrile (40.0 L) and pyridine (18.1 kg, 229 mol), and methanesulfonyl chloride (10.8 kg, 94.3 mol) was added over 20 min.…”

“…While pinacolboronate 29 is commercially available on a small scale, the conditions developed for the synthesis of pyridylboronate 21 also proved to be successful for its preparation starting from 4-bromoindole (31). Despite a predilection for polar aprotic solvents in the literature, toluene 24 proved to be a much more effective solvent than dioxane, reducing both the reaction time and the propensity for palladium black precipitation and reaction stalling.…”