Multikilogram-scale synthesis at a biphenyl carboxylic acid derivative using a Pd/C-mediated Suzuki coupling approach

Reaction of 4-bromo-3-methylanaine with 4-chlorobutyryl chloride/TEA and su bsequent treatment of the resulting secondary amide intermediate with KOt-B u gives 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one in 65% yield, This proce dure has been optimised (74-76% overall yield) and has been carried out on 41 molar scale. In a variation of this process, we have employed NaOH as th e ring-closing base under phase-transfer conditions, NaOH is added to a mix ture of 4-bromo-3-methylaniline, 4-chlorobutyryl chloride, and catalytic TB AC in THF/ H2O, A further 2 equiv of aqueous NaOH is added, and the mixture is heated at 40-45 degrees C, providing access to cyclised product In an i mproved 86% yield. 1-(4-Bromo-3-methylphenyl)pyrrolidin-2-one is subsequent ly coupled with 4-carboxyphenylboronic acid under standard Suzuki coupling conditions [Pd(PPh3)(4), Na2CO3, DME/H2O] to give 2'-methyl-4'-(2-oxo-1-pyr rolidinyl)biphenyl-4-carboxylic acid in 64% yield, contaminated with 40-80 ppm of residual Pd, In a modification of this process, we have used Pd/C as the catalyst, Reaction in MeOH/ H2O gives an improved yield of the bipheny lcarboxyiic acid with residual Pd levels of <6 ppm, This process has been c arried out on 24 molar scale, The synthesis of the arylpyrrolidinone and su bsequent Suzuki coupling have been combined into a one-pot procedure, provi ding access to 2'-methyl-4'-(2-oxo-1-pyrrolidinyl)biphenyl-4-carboxylic aci d in 82% overall yield from 4-bromo-3-methylaniline.