Process Development and Pilot Plant Synthesis of Methyl 2-Bromo-6-chlorobenzoate

Abstract

A scalable process for a pilot plant synthesis of methyl 2-bromo-6-chlorobenzoate (1) is described. The strategy employed for the synthesis hinged on the esterification of the sterically encumbered parent acid produced through an o-lithiation/ carboxylation approach. Vigilant temperature control was paramount for the success of this synthetic pathway. Initiation of an exothermic benzyne decomposition pathway during the o-lithiation step occurred at -70 °C. In the pilot plant, cooling via the jacket service was suitable to provide batch temperatures of -75 °C. However, control of reaction heat required liquid nitrogen injection into the process vessel simultaneously with the exothermic reagent charges. Esterification of the carboxylic acid was accomplished with potassium carbonate/methyl iodide, and subsequent crystallization resulted in 79% overall yield of the title compound from inexpensive starting materials.

Pro und kontra Strömungsreaktoren in der Synthese

“… Temperaturprofil der in Schema gezeigten Reaktion (Δ H rxn =155 kJ mol −1 ) in Teflon‐, Edelstahl‐ und Silicium‐Strömungsreaktoren mit Innendurchmesser 1 mm 69…”

Selective Metalation of 4,6-Dibromoresorcinol Dimethyl Ether with LiTMP

“…Hickey and co-workers studied the metalation of 3-bromochlorobenzene on an industrial scale and also found that benzyne formation could be minimized by careful control of reaction temperature. 8 Although the product was not what we had expected, the metalation was regioselective. We next examined the reaction of the anion of 1 with representative electrophiles.…”

Sporolide B: synthetic studies

“…21 After treatment of the resultant carboxylic acids with trimethylsilyldiazomethane, a mixture of isomeric esters 30a and 30b (1:3) was obtained. Although the mixture proved difficult to separate, the subsequent palladium-catalyzed Suzuki coupling 22 with vinylboronic anhydride effectively resolved the isomers, furnishing only the styrene derived from 30b and returning 30a .…”