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The use of in situ mid-infrared spectroscopy to support the development of a pharmaceutical manufacturing process is disclosed. Data on this two-stage telescoped reaction from several reaction scales (

4-(4-Iodo-1H-pyrazol-1-yl)piperidine is a key intermediate in the synthesis of Crizotinib. We report a robust three-step synthesis that has successfully delivered multi-kilogram quantities of the key intermediate. The process includes nucleophilic aromatic substitution of 4-chloropyridine with pyrazole, followed by hydrogenation of the pyridine moiety and subsequent iodination of the pyrazole which all required optimization to ensure successful scale-up.

The Pfizer Green Chemistry metrics program is described and exemplified with a case history involving the synthesis of (S,S)-reboxetine succinate. The initial route used a classical resolution approach and generated high levels of waste. This route was replaced by an enantiospecific synthesis which used Sharpless epoxidation chemistry, an enzymatic process to selectively protect a primary alcohol and a new efficient method of chiral morpholine construction as key steps. These improvements reduced the levels of waste produced by the synthesis by more than 90%. Detailed metrics starting from a common starting material (trans-cinnamyl alcohol) for all routes of synthesis are presented.

The development of a synthetic process for (S,S)-reboxetine succinate, a candidate for the treatment of fibromylagia, is disclosed from initial scale-up to deliver material for registrational stability testing through to commercial route evaluation and subsequent nomination. This entailed evaluation of several alternative routes to result in what would have been a commercially attractive process for launch of the compound.