A Mechanistic Insight into a Simple C−N Bond Formation via S_N2 Displacement: A Synergistic Kinetics and Design of Experiment Approach

Abstract

A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes was recently identified as new highly potent and selective dopamine (DA) D 3 receptor antagonists. This class of molecules deserved the Chemical Development special attention to quantify the reliability and robustness of the pivotal S N 2 displacement step between the 1,2,4-triazol-3-yl-halide derivative (4) and variously substituted azabicyclo[3.1.0]hexanes (5). To reach this goal we applied the classical Design of Experiment (DoE) approach, simultaneously trying to build up a descriptive kinetic model of the chemistry. The synergistic use of these two techniques allowed us to select new, higher-yielding and more robust reaction conditions and, at the same time, to identify their Design Space.

Automation Technologies to Enable Data-Rich Experimentation: Beyond Design of Experiments for Process Modeling in Late-Stage Process Development

“…Using numerical techniques to guide the optimization procedure offers significant efficiency gains over iterative, experimental approaches alone. Optimization of experimental factors through response surface modeling is not uncommon; − however, the unique ability to include time in the optimization via the DRSM model expands the optimization problem set to include time-dependent responses, such as productivity, cycle time, and stability.…”

Design of Experiments (DoE) and Process Optimization. A Review of Recent Publications

“…A GSK development team 62 The results from the DoE study showed an adequate fit to the data and demonstrated that the high setting for all four factors, which corresponded to the previously existing reaction conditions, led to the highest yield within the design space. In other words, the DoE suggested no improved conditions.…”

“…A GSK development team developed a robust S N 2 displacement step in the synthesis of analogues of dopamine D 3 receptor antagonist SB-277011. The reaction between chloropropylthiotriazole 118 and amine-HCl salt 119 to provide 120 was plagued by the formation of impurity 121 arising from intramolecular cyclization of 118 (Scheme ).…”

Synthesis of Methyl 3-Hydroxyisoxazole-5-Carboxylate Via Bromination of Dimethyl Fumarate under Photoflow Conditions and Its Safe Homologation into 3-(3-Methoxyisoxazol-5-yl) Propanoic Acid

“…During our investigations, we observed that the nucleophilic displacement of the chloride atom by Meldrum’s acid ( 12 ) was slow, even when heating to reflux in MeCN. To promote this displacement, addition of a catalytic amount of potassium iodide accelerated the conversion rate, and full conversion into 10 was reached after 6 h at 50 °C. Nevertheless, the main drawback of using Meldrum’s acid ( 12 ) or malonate derivatives in this reaction was the formation of 10–20% a/a of overalkylated side product 13 .…”