Investigation of a Weak Temperature–Rate Relationship in the Carbamoylation of a Barbituric Acid Pharmaceutical Intermediate

    • Alexander G. O’Brien *†
    • Yangmu Chloe Liu *†
    • Mark J. Hughes
    • John Jin Lim
    • Neil S. Hodnett
    • Nicholas Falco
    • GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States
    • GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom

    The rate of reaction between N,N′-dicyclohexylbarbituric acid 1 and ethyl 2-isocyanatoacetate 2 is invariant with temperature. Positive orders in each reactant and dissociation of triethylammonium salts of 1 and product 3 at elevated temperature indicate that reaction occurs via a catalytic mechanism where changes to the positions of equilibria negate changes in the rate of the turnover-limiting step. A model for the consumption of 1 in a flow reactor accurately predicted the outcome of a laboratory-scale multivariate study.

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