4-Chloro-3-iodobenzoic acid

4-chloro-3-iodobenzoic acid A solution of 3-amino-4-chlorobenzoic acid (8.6 g, 50 mmol) in 2:1 3M HCl/acetone (150 mL) at -3° C. was treated dropwise with sodium nitrite (3.8 g, 55 mmol) in water (30 mL), stirred for 30 minutes, treated with potassium iodide (14.5 g, 87.5 mmol) in water (50 mL), stirred for 15 minutes at 0° C. and at room temperature for 2 hours, and treated with water (500 mL) and excess NaHCO3 to provide a solid. The solid was collected by filtration and recrystallized from 20percent methanol/water to provide the desired product. MS (DCI/NH3) m/z 282 (M+H)+; 1H NMR (300 MHz, DMSO-d6) delta 13.35 (br s, 1H), 8.4 (d, 1H), 7.95 (dd, 1H), 7.7 (d, 1H).*4-Chloro-3-iodobenzoyl chloride was prepared by dissolving In a 5-L round-bottom flask equipped with a magnetic stirring bar and a gas scrubber, To an oven dried 50 mL round bottom flask was added 20 mL of dry methylene chloride (DCM), 2.35 g of 4-Chloro-3-iodo benzoic acid, and 3 drops of dimethyl formamide (DMF) to this solution was added drop wise by addition funnel 7.0 mL of 2.0M oxalyl chloride (CO2Cl2). The resultant mixture was stirred for 6 hours at room temperature. The solution was rotary evaporated to leave the neat acid chloride weighing 2.41 g (> 98percent yield). To this residue was added 20 mL of acetonitrile (ACN), 1.33 mL of diisopropyl ethyl amine, 1.25 mL (8.4 mmol, 0.45g) of 2-Methoxy-5-amino pyridine. The resultant solution was stirred for 15 hours and heated to reflux then quenched by the addition of 10 mL of brine and 10 mL of EtOAc. The product was taken up in 20 mL of EtOAc and washed with brine (1 x 15 mL), 1 M NaOH (2 x 25 mL), water (1 x 15 mL) and dried over MgSO4. The solution was rotary evaporated to leave a purplish waxy solid weighing 2.84 g (91.2percent crude yield). The solids were dissolved into 25 mL of warm methanol (MeOH) and left sealed for 24 hours. White- violet powder was recovered. This process repeated again to yield 1.96g (63.0percent) fluffy light violet solid. TLC was single spot rf 0.58 in 1 :1 Hexane/Ethyl Acetate. 1H NMR 400 MHz DMSO-d6: deltaH 9.01 (IH, br s), 8.24-6.77 (7H, m), 3.65 (3H, s); MS (ES+) m/z 389 (M+H); HPLC (214 nm), rt 4.22 min, 99.4percent.The 4-chloro-3-iodo-benzoyl chloride used as a starting material was prepared as follows: EPO Example 50: 4-Chloro-3-(9H-pyrimido[4, 5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]- benzamideStep 1: 4-Chloro-3-iodo-N-[3-(trifluoromethyl)phenyl]benzamide4-Chloro-3-iodobenzoic acid (1.00 g, 0.00354 mol) was slurried in DCM (9 mL) and was cooled at 0 0C. To the mixture was added DMF (27 muL, 0.00035 mol) followed by oxalyl chloride (0.449 mL, 0.00531 mol). The resulting mixture was stirred at 0 0C for 30 minutes and then was warmed to 20 0C and was stirred for 60 minutes, by which time solution had occurred. LCMS of a sample quenched in methanol showed clean formation of the methyl ester (M+H 297/299, 3:1). The reaction mixture was concentrated to remove the excess oxalyl chloride providing acid chloride as a yellow solid acid. To the product was added DCM (1OmL), 3-(trifluoromethyl)benzenamine (0.484 mL, 0.00389 mol), then DIPEA (0.925 mL, 0.00531 mol). After 16 h, LCMS showed clean conversion to the expected M+H 426/428 (3:1). The reaction was quenched into 10percent citric acid, and the resulting mixture was extracted with DCM. The organic layer was washed with water, then 3-(4-Chloro-3-iodo-phenyl)-5-methanesulfonyl-4, 5, 6, 7-tetrahydro-1H-pyrazolo[4, 3-c]pyridine. To a solution of the above piperidone (10 g, 56 mmol) and p-toluenesulfonic acid (40 mg) in benzene (60 mL) was added morpholine (4.9 mL, 56 mmol). The reaction mixture was heated in a flask equipped with a condenser and a Dean-Stark trap at 90° C. for 16 h. The reaction mixture was cooled and concentrated to give the desired enamine as a beige solid, which was used without further purification. The enamine was dissolved in CH2Cl2 (40 mL), treated with TEA (9.4 mL, 67.2 mmol), and cooled to 0° C. To this solution was added 4-chloro-3-iodobenzoyl chloride* (16.9 g, 56 mmol). The reaction mixture was allowed to warm to rt, stirred for 14 h, and then concentrated. The resulting red oil was diluted with EtOH (56 mL) and treated with hydrazine (5.34 mL, 170 mmol) at 0° C. The resulting slurry was allowed to warm to rt and stirred for 16 h. EtOAc (120 mL) was added, and after 2 h the resulting precipitate was filtered and washed with additional EtOAc to afford the desired product as a white solid (8.80 g, 36percent). HPLC: Rt=6.08. MS (ESI): mass calcd. for C13H13ClIN3O2S, 437.7; m/z found, 438.1 [M+H]+. 1H NMR (DMSO-d6): 8.05 (d, J=1.9, 1H), 7.51 (d, J=8.3, 1H), 7.43 (dd, J=8.4, 1.9, 2H), 4.30 (s, 2H), 3.36 (t, J=5.8, 2H), 3.30 (br s, 1H), 2.86 (s, 3H), 2.69 (t, J=5.6, 2H).*Prepared by dissolving General procedure: To a solution of 3-iodo-4-methylbenzoic acid 5'1 (262mg, 1.0mmol) in dry DCM (10mL) at 0°C was added oxalyl chloride (0.13mL, 1.5mmol) and 3 drops of dry DMF. The resulting reaction mixture was stirred at room temperature for 3h, and then the solvent was removed under reduced pressure. The crude product was used directly for the next step without further purification.Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA.TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA...2-chloro-3, 5-dinitrobenzoic acid; 2-chloro-3-fluorobenzoic acid; 2-chloro-4-fluorobenzoic acid; 2-chloro-6-fluoro-3-methylbenzoic acid; Compound 33b (7.2 g, 35.4 mmol) was added in a dropwise fashion to a solution of 33a (2 g, 7.1 mmol) in toluene (100 mL) at 85 C under argon. After 1 hr at 85 C, the reaction mixture was cooled to rt, and quenched with water (20 mL). The organic layer was separated, washed with saturated NaHC03 and brine. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel (EtO Ac/Hexanes 0 ~ 30%) to afford the product as colorless oil (1.8 g, 80%): 'HNMR (300MHZ, CDCl3) 8.33 (d, 1H, J = 1.8 Hz), 8.04 (dd, 1H, J = 1.8 & 8.4 Hz), 7.46 (d, 1H, J = 8.1 Hz), 4.35 (q, 2H, J = 6.9 Hz), 1.59 (s, 9H), 1.31 (t, 3H, J = 6.9 Hz).

Molecular Weight:282.46
XLogP3:2.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:281.89445
Monoisotopic Mass:281.89445
Topological Polar Surface Area:37.3
Heavy Atom Count:11
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes