160866-61-5Relevant articles and documents
An Efficient Synthesis of the Novel Dopamine Autoreceptor Antagonist S-(-)-OSU6162, via Palladium Catalyzed Cross-Coupling Reaction.
Sonesson, Clas,Lindborg, Jonas
, p. 9063 - 9066 (1994)
Optically active S-(-)-OSU6162 ((-)-1) has been synthesized in 4 steps with an overall yield of 48 percent.The four steps consists of palladium catalyzed cross-coupling, catalytic hydrogenation, classical resolution with tartaric acid and reductive amination.
The synthesis of OSU 6162: Efficient, large-scale implementation of a Suzuki coupling
Lipton, Michael F.,Mauragis, Michael A.,Maloney, Mark T.,Veley, Michael F.,VanderBor, Dale W.,Newby, John J.,Appell, Robert B.,Daugs, Edward D.
, p. 385 - 392 (2013/09/06)
The synthesis of the chiral, nonracemic 3-aryl piperidine, OSU 6162 (1), a potential CNS agent from Pharmacia Corporation, is presented. The key construction in the described synthesis is a palladium-catalyzed aryl cross-coupling reaction between bromosulfone (4) and pyridyl borane (14). Initially developed conditions for this Suzuki reaction, conducted in tetrahydrofuran/aqneous hydroxide, delivered free base (6) or hydrochloride salt (15a) in reproducible 80% yield. However, by changing the solvent to toluene and the base to carbonate, significant decreases in catalyst requirement were realized, and the methane sulfonate salt (15b) of the coupled product could be obtained in reproducible 92-94% yield on 200-kg input. The success of the Suzuki reaction was critically dependent on a bulk source of the pyridyl borane coupling partner. Cryogenic conditions were developed for its generation via lithium-halogen exchange to generate thermally labile 3-lithiopyridine followed by transmetalation with diethylmethoxy borane. This highly exothermic series of transformations yielded crystalline diethyl-3-pyridyl borane in reproducible 75-80% yield on scales ranging up to 200-kg input. Selective reduction of the biaryl, classical resolution and introduction of the propyl group via the Gribble reductive amination procedure completed the synthesis of OSU 6162 free base. This route was employed to deliver over 35 kg of clinical-quality bulk drug in short order.
