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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