2-Bromo-4'-iodoacetophenone

To a stirring solution ofp-iodoacetophenone 1 (30.0 g, 122 mmol) in dioxane (200 mL) over an ice-bath was added bromine (6.56 mL, 128 mmol) dropwise. The reaction mixture was stirred at room temperature and monitored by LC/MS. After completion (about 1 hour), the solvent was evaporated by rotovap, and the residue was dried under vacuum to give solid 2 (40g, 100percent). [00466] (Based on J. Med. Chent. 2001, 44, 2990-3000) To a solution of Cbz-D-Ala- OH 3 (5.0 g, 22.4 mmol) in NMP (100 mL) was added cesium carbonate (3.72 g, 11.4 mmol). After stirring at RT for 1 h, 2 (7.60 g, 22.4 mmol) was added. The reaction mixture was stirred at room temperature and monitored by LC/MS to form 4. The reaction solution was diluted with xylene (100 mL) and ammonium acetate (9.25g, 120 mmol) and then stirred at 120°C for 4 hours. Up to 50eq of additional ammonium acetate may be needed depending on the reaction progress. The key is to see solid in the flask at all times. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL). The EtOAc solution was washed with saturated sodium bicarbonate solution (200 mL) twice, and dried by sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and stirred for 1 h to give a precipitate, and the solid 5 (4.0g) was filtered off and dried under vacuum. The mother solution was concentrated by rotovap, the residue was purified on Bio-tage to give 5 (Hexane: EtOAc = 1:1 to EtOAc 100percent). The two products were combined and dried under vacuum to give 5 (5.8 g, 58percent).Example 7Experimental Section:7.1 7.22-Bromo-l-(4-iodophenyl)ethanone:[00192] A solution of l-(4-iodophenyl)ethanone (55.9 mmol) in dioxane (160 mL) was cooled to 10 The appropriate carbonyl compound (50 mmol) was dissolved in 50 mL of ethanol and magnetically stirred with an equimolar quantity of thiosemicarbazide for 24 h at room temperature with catalytic amounts of acetic acid. The desired thiosemicarbazone precipitated from reaction mixture, was filtered, crystallized from suitable solvent, and dried. Equimolar quantities of 4-iodo-acetophenone and bromine, both dissolved in chloroform, were stirred for 4 h at room temperature until the presence of HBr disappeared. The solution was evaporated under vacuum and the obtained pale yellow solid was washed with petroleum ether to give α-bromo-4-iodo-acetophenone in good yield (94percent). Equimolar amounts of the prepared thiosemicarbazone (50 mmol) and α-bromo-4-iodo-acetophenone (50 mmol), both suspended in 50 mL of ethanol, were reacted at room temperature under magnetic stirring for 10 h. The precipitate was filtered and purified by chromatography to give compounds 1-25 in high yield.Example 83A Example 32A To a clear dark solution of l-(4-iodophenyl)ethanone (1.046 kg, 4.251 mol, 1 equiv.) in DCM (8 L) was charged (dropwise) bromine (228 ml, 4.45 mol, 1.047 equiv.) over the period of 30 to 45 min at the ambient temperature. The reaction was slightly exothermic (temperature incresed to about 20-25 °C) and released a lot of hydrogen bromide gas as the by-product. The reaction was considered as complete after 3 to 4 hrs as indicated by HPLC (typically ~7percent starting material, -10percent di-bromo by- product, and ~83percent> desired mono-bromo product, all in areapercent> by HPLC). It was then quenched and neutralized by aqueous NaHC0A 1 L round bottom flask, equipped with a mechanical stirrer, addition funnel, thermocouple and a reflux condenser attached to an alligator trap filled with aq. NaOH (2M), was charged with CuBr2 (92.4 g, 0.414 mol) and ethyl acetate (320 mL). 4-Iodoacetophenone (53.4 g, 0.217 mol) was dissolved into chloroform (320 mL) and placed into the addition funnel. The chloroform solution was added to the ethyl acetate solution and the reaction mixture stirred at 70° C. for 6 hours then cooled to 25° C. for 16 hours. The CuBr salt was removed by filtering through Celite. The filtrate was washed with aq. saturated sodium bicarbonate (2.x.200 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and the solvents were removed under reduced pressure to give crude product contaminated with unreacted starting material. The product was purified by recrystallization from dichloromethane/hexane to give pure material as a tan solid (44.5 g, 63percent yield): mp 109-111° C.Example QC-13a To a solution of 4-iodophenyl ethanone (14.76 g, 60.0 mmol) in 150 mL of dichloromethane was added bromine (9.5 g, 59.5 mmol) dropwise. The resulting solution was stirred at room temperature overnight. The solvent was removed under vacuum. The crude product was recrystallized with dichloromethane/hexanes to give Example QC-13a (11.8 g, 60.5percent) as a grey solid. In a 100 mL round bottom flask, 10 mmol of 4-iodoacetophenone and 11 mmol of N-bromosuccinimide (NBS) were added.35mL of ethyl acetate dissolved, Then add 1g of Amberlyst 15 ion exchange resin as catalyst.The reaction was warmed to 40°C and reacted. After TLC tracks the reaction, The reaction solution was filtered to remove Amberlyst 15 ion exchange resin, and the filtrate was spin-dried.Column chromatography (eluent: petroleum ether/ethyl acetate) gave a yellow solid with a yield of 46percent.Add 100mL round bottom flask10 mmol 4-iodoacetophenone and 11 mmol N-bromosuccinimide (NBS), 35mL of ethyl acetate dissolved, Then add 1g of Amberlyst 15 ion exchange resin as catalyst.The reaction was warmed to 40°C and reacted.After TLC tracks the reaction, The reaction solution was filtered to remove Amberlyst 15 ion exchange resin, The filtrate was spin-dry, Column chromatography (eluent: petroleum ether/ethyl acetate) gave a yellow solid, Yield 46percent.EXAMPLE 16; [2-(4-Iodophenyl)-6-methylimidazo [ 1, 2-a] pyridin-3-yl] methanol; 2-Amino-5-methylpyridine (162 mg, 1.5 mmol) and 4-iodophenacyl bromide (325 mg, 1.0 mmol) were mixed in ethanol (2.0 mL) and stirred at 70 C for 1.5 h. The reaction mixture was cooled and the precipitate was collected by filtration and washed with cold ethanol (2 x 2 mL). The precipitate was partitioned between 2 M NaOH (2 mL) and CH2Cl2 (6 mL). The organic phase was collected, washed with water, dried (MgSO4) and concentrated. The residue was dried in vacuo to give the intermediate compound 2-(4-iodophenyl)-6- methylimidazo[ 1 , 2-a]pyridine as a white solid (219 mg).

Molecular Weight:324.94
XLogP3:3
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:2
Exact Mass:323.86467
Monoisotopic Mass:323.86467
Topological Polar Surface Area:17.1
Heavy Atom Count:11
Complexity:141
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes