(2-Chloro-5-iodophenyl)(4-fluorophenyl)methanone

Equipped with a thermometer, constant pressure dropping funnel, drying tube 1000mL flask was added three DCM200mL, VIII (70.62g, 250mmol) , was added 1 ml of DMF and, at room temperature was slowly added dropwise oxalyl chloride (23.4mL g, 275mmol), was added dropwise after the completion of 20 incubated 2h.After adding concentrated to remove the DCM, oxalyl chloride 200mL DCM dissolved chloride.Equipped with a thermometer, constant pressure dropping funnel, 1000mL three 26mL flask with a drying tube was added fluorobenzene, DCM200mL the system temperature was dropped to -5 deg.] C, graded added to the system aluminum trichloride (36.67g, 275mmol) , dropped acid chloride prepared raw reaction incubated 6h completed.System 40mL conc HCl + 400mL poured into ice water to quench the reaction, the DCM. The combined organic phases were washed until neutral sodium bicarbonate, once with saturated brine separation was washed with water, dried, and concentrated to give VII84.23g, yield 93.4percent.Oxalyl chloride (72 g, 0.56 moles) was added to a slurry of formula 5a (100 g, 0.35 moles) and a catalytic amount of N, N-dimethylformamide (5mL) in fluorobenzene (250 mL) over about 60 minutes at 15-25 °C under nitrogen atmosphere. The mixture was stirred at 21-25 °C. After completion of the reaction, the reaction mass was concentrated to remove excess oxalyl chloride. The obtained residue was diluted with fluorobenzene (125 mL) and cooled to 15-25 °C. Aluminum chloride (53.5 g, 0.40 moles) was added to this reaction mixture portion- wise while keeping the reaction mass temperature below 25 °C and maintaining it at same temperature to complete the reaction. After completion of reaction, the reaction mass was quenched into precooled dilute hydrochloric acid (5percent, 1700 mL, 0-5 °C) at 5-25 °C. After stirring for 60 minutes at 20-25 °C, the product was extracted with methylene chloride twice (first with 500 mL, then with 250 mL). The combined organic layers were washed with 10percent aqueous sodium hydroxide solution (250mL), water (500mL), and 10percent aqueous sodium chloride solution (250mL), sequentially. Thereafter, the organic layer was concentrated and the obtained residue was diluted with n-heptane (250mL) and stirred to precipitate formula 7a as a white solid (105 g).5-iodo-2-chlorobenzoic acid (33.895 g, 120 mmol) was added DCM (100 mL) DMF (0.175 g, 0.02 eq), Stir, Slowly add oxalyl chloride (12.3 ^, 1.2 called), After the drop is completed at room temperature reaction 21 , The solvent was removed by concentration under reduced pressure, Add DCM (lOOmL), Fluorobenzene (17.298 g, 1.5 eq) was added, Alcia was added to A1C13 (17.6 g, 1 leq) After adding the reaction at room temperature for 3h, After TLC detection reaction was completed, Ice bath slowly add water (100mL), After stirring, The organic phase was washed with 10percent NaCl (50 mL) The organic phase was concentrated under reduced pressure to give a pale yellow oil, Plus isopropyl alcohol (lOOmL), Add water (lOOmL), Ice bath stirring crystallization 2h, Filter, The filter cake was washed with isopropanol / water (1: 1) mixed solution (20 mL) Dried to give 42.1 g of an off-white solid of compound Vb, Yield: 97.3percent Purity: 99.17percent: Synthesis of the fluoride VIII.1Oxalylchloride (176kg; 1386mol; 1 , 14eq) is added to a mixture of 2-chloro-5-iodo benzoic acid (343kg; 1214mol) (compound IX.1 ), fluorobenzene (858kg) and N, N- dimethylformamide (2kg) within 3 hours at a temperature in the range from about 25 to 30°C (gas formation). After completion of the addition, the reaction mixture is stirred for additional 2 hours at a temperature of about 25 to 30°C. The solvent (291 kg) is distilled off at a temperature between 40 and 45°C (p=200mbar). Then the reaction solution (91 1 kg) is added to aluminiumchloride AICIOxalylchloride (176 kg; 1386 mol; 1.14 eq) is added to a mixture of 2-chloro-5-iodo benzoic acid (343 kg; 1214 mol) (compound IX.1), fluorobenzene (858 kg) and N, N-dimethylformamide (2 kg) within 3 hours at a temperature in the range from about 25 to 30° C. (gas formation). After completion of the addition, the reaction mixture is stirred for additional 2 hours at a temperature of about 25 to 30° C. The solvent (291 kg) is distilled off at a temperature between 40 and 45° C. (p=200 mbar). Then the reaction solution (911 kg) is added to aluminiumchloride AlClOxalylchloride (176 kg; 1386 mol; 1.14 eq) is added to a mixture of 2-chloro-5-iodo benzoic acid (343 kg; 1214 mol) (compound IX.1), fluorobenzene (858 kg) and N, N-dimethylformamide (2 kg) within 3 hours at a temperature in the range from about 25 to 30° C. (gas formation). After completion of the addition, the reaction mixture is stirred for additional 2 hours at a temperature of about 25 to 30° C. The solvent (291 kg) is distilled off at a temperature between 40 and 45° C. (p=200 mbar). Then the reaction solution (911 kg) is added to aluminiumchloride AlCl5-Iodo-2-chlorobenzoic acid (20.0 g, 0.071 mol) was added to a solution of 2.0 M oxalyl chloride in dichloromethane (39 ml, 0.078 mol), stirred for suspension, and then 8 drops of DMF solution was added dropwise. After the reaction was carried out for 3 hours, the solution was clarified and the reaction was almost complete. The solvent was spin-dried on a rotary evaporator, then 15 ml of methylene chloride was added, and the solvent was dried. After spin-drying, add 30 ml of dichloromethane, stir, cool to 0-5 ° C, add fluorobenzene (7. lg, 0.074 mol), add anhydrous aluminum trichloride (9.9 g, 0.074 mol) in batches, control The temperature is not more than 5 °C, after the completion of the addition, stirring is continued at 4 ° C for 1 h, the reaction is almost complete by TLC, the reaction is quenched on ice-water mixture, the organic phase is separated, and the aqueous phase is extracted with dichloromethane. The phase was washed twice with 1 mol/L hydrochloric acid, washed once with water, and washed twice with 1 mol/L NaOH solution.The mixture was washed twice with saturated sodium chloride and dried over anhydrous sodium sulfate. Drain filtration, spin dry solvent to obtain oilAfter column chromatography, 20. 1g (78.6percent) of a white solid was obtained. (9.01 g, 25.0 mmol), acetohydroxamic acid (5.63 g, 75.0 mmol, 3.0 eq.) and anhydrous potassium carbonate ( 17.28 g, 125.0 mmol, 5.0 eq.) was dissolved in 50 mL of DMSO after removal of water. After heating to 80 C for 6 h, the TLC monitoring material has been converted. Stop heating, naturally cool to room temperature, and adjust the pH to 3.0 with 1M diluted hydrochloric acid.Extract with ethyl acetate (100 mL × 3), and combine the organic phases. After washing with saturated brine (50 mL×3), dry over anhydrous sodium sulfate, filter, the solvent is removed by rotary evaporation under reduced pressure. A pale yellow oil is obtained which is crystallized from n-hexane. A large amount of white solid precipitated, suction filtration, The filter cake was dried under vacuum to give a white solid product. Namely, (5-chloro-5-iodophenyl)(4-hydroxyphenyl)methanone 8.55 g (yield 95.4%).General procedure: To a stirred solution of 1 (0.01 mol) in 30 mL of CH2Cl2and 30 mL of CH3CN at 0 °C were added Et3SiH(4.79 mL, 0.03 mol), then BF3·Et2O(2.53 mL, 0.02 mol), and theresulting mixture was warmed to room temperature andstirred for 3'8 h. The mixture was poured into saturatedaqueous NaHCO3 and extracted with CH2Cl2 twice. Thecombined organic layers were washed with brine, dried overMgSO4, and concentrated. The residual solid was crystallizedfrom ethanol to give as white solid.According to this procedure the following compoundswere prepared. 1-chloro-2-(4-fluorobenzyl)-4-iodobenzene (2a)White solid, yield 83percent, m.p. 52'54 °C. 1H NMR (400MHz, DMSO-d6): delta 4.02(s, 2H), 7.10'7.13(m, 2H), 7.22'7.25(m, 3H), 7.60(dd, J = 0.8, 6.8 Hz, 1H), 7.72(d, J = 0.8Hz, 1H). 13C NMR (100 MHz, DMSO-d6): delta 36.94, 92.85, 115.21(d, J = 68 Hz), 130.30(d, J = 24 Hz), 131.32, 133.16, 134.87, 136.82, 139.44, 140.77, 159.80, 161.73.(180 g, 0.5 mol)

Molecular Weight:360.55
XLogP3:4.6
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:359.92142
Monoisotopic Mass:359.92142
Topological Polar Surface Area:17.1
Heavy Atom Count:17
Complexity:279
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes