An Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-Dichlorobenzoyl Chloride: Application to the Synthesis of Lamotrigine

2,3-Dichlorobenzoyl cyanide is a key intermediate in the synthesis of Lamotrigine. An assessment of various catalytic systems for the cyanation of 2,3-dichlorobenzoyl chloride with cyanide salts is described. High-throughput experimentation identified many conditions for effecting the requisite chemistry, including amine bases and phase-transfer catalysts, as well as catalyst-free conditions utilizing acetonitrile as a polar cosolvent. A novel catalyst, CuBr₂, was identified by consideration of the possible oxidation of Cu­(I) during high-throughput screening experimentation. CuCN was found to be the best cyanide source for achieving clean conversion; however, the solubility of CuCN was the major factor limiting reaction rate under many conditions. Improving CuCN solubility by using acetonitrile as solvent enhanced the reaction rate even in the absence of the catalysts tested but significantly complicated isolation of the product. With no acetonitrile cosolvent, phase-transfer catalysts such as tetrabutyl­ammonium bromide (TBABr) are effective; however, use of TBABr led to inconsistent reaction profiles from run-to-run, due to an unexpected clumping of the CuCN solid. Switching to cetyl­trimethyl­ammonium bromide (CTAB) alleviated this clumping behavior, leading to consistent reactivity. This CTAB-catalyzed process was scaled up, giving 560 kg of 2,3-dichloro­benzoyl cyanide in 77% isolated yield

A Combined High-Throughput Screening and Reaction Profiling Approach toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of Salbutamol

A combined high-throughput screening and reaction profiling approach to the telescoping of two reductions in the synthesis of Salbutamol is described. Optimization studies revealed the beneficial effect of mildly acidic conditions, and the use of water as a cosolvent. Persistent formation of deoxygenated impurities using a Pd/C catalyst led to the initiation of reaction profiling studies, which revealed that the ketone intermediate formed after rapid debenzylation is the sole source of deoxygenated impurities, indicating that more rapid ketone hydrogenation should minimize this deoxygenation. A dual catalyst approach based on these insights has been developed, with both Pd/Pt and Ru/Pt catalyst systems as more selective than Pd-only systems. Based on reaction profiles that indicate the deoxygenation side reaction is first-order in the concentration of debenzylated ketone intermediate, Pt catalysts for rapid and selective ketone hydrogenation were paired with Pd and Ru catalysts known to perform selective debenzylation. Optimization of these dual catalyst processes led to conditions that were demonstrated on 20 g scale to prepare Salbutamol in 49% isolated yield after recrystallization