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Clegg I.M.,Pfizer | Pearce J.,Chemical Research and Development | Content S.P.,Chemical Research and Development
Applied Spectroscopy | Year: 2012

The application of in situ Raman spectroscopy at small scale (maximum 80 mL) during the development of a manufacturing process is disclosed. The reaction was run in aqueous solution between ambient and 100 °C. Raman spectroscopy has proven to be a viable method to track the reaction. Three distinct phases could be followed: dissolution of the starting material, production of a reactive intermediate, and then subsequent conversion of that intermediate to form product. The bjective of the work was to confirm the presence of a reactive intermediate and this could only be carried out via in situ spectroscopy as the intermediate was known to be unstable. Toward the end, the reaction passes though several neutralization points and these are consistent with changes in the pectra. Comparison of data obtained at an illumination wavelength of 998 nm with that obtained at 785 nm is also disclosed. The data obtained at shorter wavelength was contaminated by reasonably strong uorescence, whereas the data obtained at 998 nm was free of fluorescence. An unexpected observation from this work was that the reaction time was much shorter than expected and this work was key in showing that a reduction in batch cycle time was possible during commercial manufacture. © 2012 Society for Applied Spectroscopy. Source

Gu J.,Pfizer | Storz T.,Chemical Research and Development | Vyverberg F.,Chemical Research and Development | Wu C.,Kilolab Facilities | And 2 more authors.
Organic Process Research and Development | Year: 2011

A practical, robust, and high-yielding three-step-one-pot procedure for the diastereoselective synthesis of (±)-2-exo-norbornyl carboxylic acid starting from norbornylene has been found and demonstrated on multikilogram scale, setting a new benchmark for low-pressure hydroformylation of cyclic, bridged olefins. The newly found, nonhygroscopic crystalline sodium salt of this acid provides a practical isolation point. © 2011 American Chemical Society. Source

Peng Z.,Pfizer | Ragan J.A.,Pfizer | Colon-Cruz R.,Pfizer | Conway B.G.,Pfizer | And 14 more authors.
Organic Process Research and Development | Year: 2014

This paper describes an improved sequence for the conversion of an oxazolidinone (3) to a β-keto lactone (5). The primary drivers behind this change were the modest and variable yields observed in the intramolecular cyclization to generate the β-keto lactone. Changing the cyclization substrate from oxazolidinone to alkyl ester offered a significantly improved cyclization, as well as improvements in the alkyne hydrogenation. Selection of the optimal substrates for methanolysis and intermediate salt formation are also described. © 2013 American Chemical Society. Source

Dunetz J.R.,Chemical Research and Development | Berliner M.A.,Chemical Research and Development | Xiang Y.,Analytical Research and Development | Houck T.L.,Chemical Research and Development | And 12 more authors.
Organic Process Research and Development | Year: 2012

This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone a-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively nonnucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator. © 2012 American Chemical Society. Source

Brenek S.J.,Chemical Research and Development | Caron S.,Chemical Research and Development | Chisowa E.,Chemical Research and Development | Chisowa E.,Pfizer | And 17 more authors.
Organic Process Research and Development | Year: 2012

The research, development, and scale-up of the broad-spectrum antibacterial candidate sulopenem are presented. An enabled medicinal chemistry synthesis of this active pharmaceutical ingredient was utilized for Phase 1 and early Phase 2 manufacture but was not conducive to larger scale. The limitations associated with the first-generation synthesis were partially addressed in an improved second-generation synthesis of the target molecule where the penem ring is constructed via a modified Eschenmoser sulfide contraction sequence. Other highlights of the second-generation process include an improved synthesis of an important trithiocarbonate intermediate and a superior process for Pd-catalyzed deallylation of the penultimate ester to obtain low levels of residual palladium. © 2012 American Chemical Society. Source

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