(1 S, 2S)-2-(4-Bromo-phenyl)-cyclopropanecarboxylic acid

(1 S, 2S)-2-(4-Bromo-phenyl)-cyclopropanecarboxylic acid

To a stirred solution of (trans)-2-(4-bromophenyl)cyclopropanecarboxylic acid (6.52 g, 27.04 mmol), which can be prepared in accordance with the process set forth on page 82 of WO 2009/024823, in 400 ml of EtOH was added a solution of (R)-(+)-1 -(1 -Naphthyl)ethylamine (4.63g, 4.37 ml_, 27.04 mmol), in 1 00 ml of EtOH followed by 25 ml of H₂0. This was stirred at rt for about 4 h. The solid was collected by filtration and washed with 40 ml of cold EtOH/H₂0 (20/1 ) providing 3.18 grams of salt as a white solid (58 % recovery) equivalent to 1 .86 g of free acid. This was taken up in 2 N NaOH and extracted 5Xs with EtOAc. The aq. phase was placed on a rotary evaporator to remove the remaining EtOAc. The resulting clear solution was transferred to an erlenmeyer flask, cooled in an ice bath, and cone. HCI was added dropwise while stirring to pH 4. The resulting solid was collected by filtration providing 1 .63 g of Intermediate R. The product was analyzed by chiral SFC (UV detection) using isocratic method (mobile phase: 25% MeOH with 0.1 % DMEA, supercritical C0₂) on ChiralPak AD-H, 10 x 250 mm, 5 μιη particle size, giving an enantiomeric purity of >95%, Rt 3.88 min (isomer 1 ) and 4.79 min (isomer 2). 

¹ H NM R (400 MHz, CDCI₃) δ ppm 1 .37 (ddd, J=8.20, 6.64, 4.69 Hz, 1 H), 1 .67 (ddd, J=9.28, 5.08, 4.79 Hz, 1 H), 1 .87 (ddd, J=8.50, 4.69, 4.39 Hz, 1 H), 2.48-2.63 (m, 1 H), 6.87-7.06 (m, 2H), 7.37-7.46 (m, 2H).

http://www.google.com/patents/EP2536701A1?cl=en











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