4-BROMO-2-CHLOROBENZOIC ACID METHYL ESTER

A. At 0°C, thionyl chloride (3.57 g, 30 mmol) was added dropwise into a solution of 4-bromo-2-chlorobenzoic acid (4.71 g, 20 mmol) in methanol (100 mL) slowly. The ice-salt bath used was removed after that dropping and then the reaction mixture was heated to reflux for 3 hours. TLC and LCMS indicated that starting materials reacted completely. The solvent and excess thionyl chloride were removed by rotary evaporation to give a crude product. Then the crude product was dissolved in dichloromethane (100 mL), washed successively with saturated sodium bicarbonate solution (100 mLx2) and saturated brine (100 mL), dried with anhydrous sodium sulfate and filtered. A yellow solid product (4.79 g, 96percent yield) was obtained by rotary evaporation. The molecular ion peak shown by liquid chromatography-mass spectrometry was: MS (ESI): m/z 248.9.8/250.8/252.8 [M+H][0410] To a solution of 4-bromo-2-chlorobenzoic acid (5g, 21.2 mmol) in 50 mL of methanol was added thionyl chloride (1.4 mL, 19.8 mmol) drop-wise. The reaction was heated to 6OA 250 mL round bottom flask equipped with a stir bar and condenser was charged with 4-bromo-2-chlorobenzoic acid (14 g, 59.5 mmol). The solid material was taken up in methanol (82 ml) and the suspension was treated with sulfuric acid (3.17 ml, 59.5 mmol). The mixture was heated to 70 °C with stirring overnight (~18 hours) and then cooled to room temperature and fitted with an ice bath. The solution was neutralized with IN aqueous sodium hydroxide solution and the mixture was transferred to a separatory funnel and extracted with diethyl ether (2 x 300 mL). The organics were dried over sodium sulfate, filtered, and concentrated to a residue in vacuo, to afford the title product as a light orange solid (13.86 g, 93percent). MS(ES)+ m/e 249.1 [M+H]A. methyl 4-bromo-2-chlorobenzoate [001079] To a mixture of 4-bromo-2-chlorobenzoic acid (6.11 g, 25.94 mmol) in methanol (60 mL) cooled to 0°C was added SOCl4-Bromo-2-chlorobenzoic acid (COMBI-BLOCK; CA-4187; 1 000 mg; 4.25 rmrmol; 1 eq.) was dissolved in MeOH (20 mL). The resulting solution was cooled down to 0°C and thionyl chloride (1.23 mL; 16.99 mmol; 4 eq.) was added dropwise. After addition, the reaction mixture was stirred at RT. As the reaction was complete, solvents were evaporated. The crude mixture was dissolved in EtOAc and washed with NaHCOThionyl chloride (1.23 ml_, 17.0 mmol) was added dropwise into a solution of 4-bromo-2- chlorobenzoic acid (Combi-Blocks CA-4187, 1.0 g, 4.25 mmol) in MeOH (20 ml.) at 04-Bromo-2-chlorobenzoic acid (1.00 g, 4.25 mmol) was added to a solution of acetyl chloride (1.70 mL, 23.9 mmol) in methanol (30 mL). The mixture was allowed to stir at rt for 3 days, and was then concentrated in vacuo. This gave 0.84 g (80percent) of the title compound. A solution of compound 4-bromo-2-chlorobenzoic acid (50 g, 212 mmol, 1.0 eq) in SOCb (500 mL) was heated to 100 °C for 4h and then concentrated to dryness. The residue was dissolved in cold methanol (500 mL), and stirred for 15min. The crude material was purified by silical gel column chromatography to afford 174 (PE: ethyl acetate=30: 1) (5.3g, 64percent). Ή NMR (400 MHz, CDCb) ppm: 7.73 (d, J= 8.4 Hz, 1 H), 7.64 (d, J= 1.6 Hz, 1 H), 7.46 (dd, J= 8.4 Hz, 1.6 Hz, 1 H), 3.93 (s, 3H).Synthesis of methyl 4-bromo-2-chlorobenzoate (45): 4-Bromo-2-chlorobenzoic acid (44; 5.59 g, 23.8 mmol) was dissolved in 100 mL of MeOH. SOd2 (5.66 g, 47.6 mmol) was added slowly at 0 °C. The mixture was then stirred at 70 °C for 4 h. After cooling down to room temperature, the mixture was poured into ice water, extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2504 and concentrated to give 3.9 g of methyl 4-bromo-2-chlorobenzoate (45) as white solid. Yield (47percent). LCMS: m/z 249.0 [M+H], tR = 1.79 min

Molecular Weight:249.49
XLogP3:4.1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:247.92397
Monoisotopic Mass:247.92397
Topological Polar Surface Area:26.3
Heavy Atom Count:12
Complexity:174
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes