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/aqueous 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 lithiumhalogen 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.

The Swern oxidation has been widely exploited for the oxidation of alcohols to their respective carbonyl compounds. The cryogenic operating conditions (<-60 °C) employed for the Swern oxidation, however, limit its utility for scale-up operations. Process development efforts on the Swern oxidation have demonstrated that an in-line reactor system can be used for the successful formation of the alkoxysulfonium salt precursor of the carbonyl compound. Two reagent streams, consisting of the alcohol/dimethylsulfoxide/ methylene chloride and the oxalyl chloride, are loaded at ambient temperature to an in-line reactor, allowing the temperature to rise to 40 °C. The alkoxysulfonium chloride intermediate is discharged directly into triethylamine to complete the reaction. Residence times of 0.1-1.4 s in the in-line reactor were demonstrated to produce successful results in 750-gal pilot-plant equipment.

The synthesis of (S)-N-Boc-bis(4-fluorophenyl)alanine, an intermediate in the synthesis of denagliptin, is described from the synthesis of a 12 g proof of principle sample to a >900 kg cGMP manufacturing campaign. The chiral centre was established by the asymmetric hydrogenation of the sterically crowded precursor, ethyl 2-acetamido-3,3-bis(4-fluorophenyl)acrylate. The ability to isolate the various intermediates in a physical form that would readily allow filtration, washing, and ultimately purification underpinned the successful manufacturing campaign.

The salt (I) reacts with cyclopentadiene (II) in the presence of NaH to form the tricyclus (III).

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