RESUMO
The synthesis of a key intermediate in the preparation of oral antidiabetic drug Saxagliptin is discussed with an emphasis on the challenges posed by the cyclopropanation of a dihydropyrrole. Kinetic studies on the cyclopropanation show an induction period that is consistent with a change in the structure of the carbenoid reagent during the course of the reaction. This mechanistic transition is associated with an underlying Schlenk equilibrium that favors the formation of monoalkylzinc carbenoid IZnCH2I relative to dialkylzinc carbenoid Zn(CH2I)2, which is responsible for the initiation of the cyclopropanation. The factors influencing reaction rates and diastereoselectivities are discussed with the aid of DFT computational studies. The rate accelerations observed in the presence of Brønsted acid-type additives correlate with the minimization of the undesired induction period and offer insights for the development of a robust process.
Assuntos
Ciclopropanos/química , Pirróis/química , Zinco/química , Ciclização , Cinética , Teoria Quântica , EstereoisomerismoRESUMO
Kinetic and computational studies on the amidation of esters with mixtures of formamide and sodium methoxide are described. Rate studies are consistent with a fast deprotonation of formamide followed by two reversible acyl transfers affected by solvent participation. MP2 calculations suggest that the first acyl transfer between the ester and sodium formamide is rate-determining. The transition structures leading to the formation and collapse of the first tetrahedral intermediate are calculated to be isoenergetic.
Assuntos
Formamidas/química , Metanol/química , Sódio/química , Ésteres , Íons/química , Cinética , Modelos Moleculares , SolventesAssuntos
Indústria Farmacêutica , Preparações Farmacêuticas/síntese química , Tecnologia Farmacêutica , Indústria Farmacêutica/instrumentação , Indústria Farmacêutica/métodos , Indústria Farmacêutica/tendências , Tecnologia Farmacêutica/instrumentação , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/tendênciasRESUMO
For over two decades, reaction engineering tools and techniques such as reaction calorimetry, inline spectroscopy and, to a more limited extent, reaction modeling, have been employed within the pharmaceutical industry to ensure safe and robust scale-up of organic reactions. Although each of these techniques has had a significant impact on the landscape of process development, an effective integrated approach is now being realized that combines calorimetry and spectroscopy with predictive modeling tools. This paper reviews some recent advances in the use of these reaction engineering tools in process development within the pharmaceutical industry and discusses their potential impact on the effective application of the integrated approach.
