The mild combination of T3P (n-propanephosphonic acid anhydride) and pyridine has been developed for low-epimerization amide bond formation and implemented for the synthesis of a key intermediate to a glucokinase activator. This robust method is general for the coupling of various racemization-prone acid substrates and amines, including relatively non-nucleophilic anilines, and provides amides in high yields with very low epimerization. With easy reaction setup and product isolation, this protocol offers several practical and experimental benefits.

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Detector response is not always equivalent between detectors or instrument types. Factors that impact detector response include molecular structure and detection wavelength. In liquid chromatography (LC), ultraviolet (UV) is often the primary detector; however, without determination of UV response factors for each analyte, chromatographic results are reported on an area percent rather than a weight percent. In extreme cases, response factors can differ by several orders of magnitude for structurally dissimilar compounds, making the uncalibrated data useless for quantitative applications. While impurity reference standards are normally used to calculate UV relative response factors (RRFs), reference standards of reaction mixture components are typically not available during route scouting or in the early stages of process development. Here, we describe an approach to establish RRFs from a single experiment using both online nuclear magnetic resonance (NMR) and LC. NMR is used as a mass detector from which a UV response factor can be determined to correct the high performance liquid chromatography (HPLC) data. Online reaction monitoring using simultaneous NMR and HPLC provides a platform to expedite the development and understanding of pharmaceutical reaction processes. Ultimately, the knowledge provided by a structurally information rich technique such as NMR can be correlated with more prevalent and mobile instrumentation [e.g., LC, mid-infrared spectrometers (MIR)] for additional routine process understanding and optimization.

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Recently, ultrahigh pressure liquid chromatography (UHPLC) has been shown to overcome the pressure limitations that small particles impose on conventional pumping systems. High speed separations in UHPLC produce peak widths that range between 100 to 1000 ms, of which many are too narrow to be monitored by scanning mass spectrometers. The only mass spectrometer that is fast enough for such separations is the time‐of‐flight mass spectrometer (TOFMS). State‐of‐the‐art TOFMS instruments for liquid chromatography can record and store complete mass spectra at rates as high as 100 spectra s−1. In this study, high speed separations with high resolution were demonstrated using 13–15 cm×29–100 μm i.d. capillaries packed with 1.5 μm nonporous octadecylsilane‐ and isohexylsilane‐modified silica particles utilizing a home‐built UHPLC system. The UHPLC system was successfully coupled to TOFMS via a liquid‐sheath electrospray interface. Separations of selected combinatorial chemistry samples, pharmaceutical compounds, and herbicides were completed in less than 100 s using UHPLC/TOFMS. Total column efficiencies ranged from 20,000–30,000 plates. The fundamental and practical aspects of UHPLC/TOFMS are discussed. Results are compared with those obtained from typical capillary LC. © 2000 John Wiley & Sons, Inc. J Micro Sep 12: 462–469, 2000

N-Aryl pyrazoles were prepared from anilines in a three step telescoped approach. An aniline was diazotized to give the diazonium fluoroborate, followed by reduction with tin(II) chloride to give the corresponding hydrazine, which in turn reacted with a ketoenamine to give the N-aryl pyrazole. The deprotection of the methyl ether was accomplished with PhBCl 2 to give the final product. The continuous flow methodology was used to minimize accumulation of the highly energetic and potentially explosive diazonium salt and hydrazine intermediates to enable the safe scale-up of N-aryl pyrazoles. The heterogeneous reaction mixture was successfully handled in both lab scale and production scale. A continuous extraction was employed to remove organic impurities from the diazotization step, which eliminated the need for chromatography in the purification of the final N-aryl pyrazole.

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