1 research outputs found
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, CuBr<sub>2</sub>, 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