4-Chloro-3-fluoro-2-iodobenzenamine

Compound 104[00325]; Compound 103 (1 10.0g, 0.296mol) was added to a 3L four-neck round bottom flask equipped with overhead stirrer, reflux condenser, water bath, 250ml addition funnel, an internal temperature probe and an argon inlet. Ethanol (900ml) was charged to the flask and cooled to 5A mixture of 91C (230 mg, 0.560 mmol), bis(pinacolato)diboron (171 mg, 0.672 mmol), Xphos palladium(II) complex (41.4 mg, 0.056 mmol) and potassium acetate (165 mg, 1.679 mmol) and dioxane (5.6 mL) was stirred at 80C under nitrogen for 1.5 h. It was cooled to rt, To a solution of 4-chloro-3-fluoro-2- iodoaniline (300 mg, 1.105 mmol) in EtOAc (6.9 mL) was added to a solution of HCl (37% wt, 2.3 mL, 27.8 mmol) in water (6.9 mL) at 0C. The resulting mixture was stirred for 10 minutes. To this suspension was added a solution of sodium nitrite (84 mg, 1.216 mmol) in water (0.5 mL) over three minutes. The reaction was stirred for 30 min. A solution of sodium azide (79 mg, 1.216 mmol) in 0.5 mL water was added slowly to the above reaction mixture. The mixture was then stirred in an ice-water bath under nitrogen and allowed to warm to rt overnight. The mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic fractions were washed with brine (30 mL) and dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give the title compound.To a solution of 1008 (3.0 g, 11.07 rnmoi) in DMF (40 ml) was added pyruvic acid (2.4 mL, 33.2 mrnol) and DABCO (3.7 mL, 33.2 nunol). Then the reaction mixture was degassed with argon for 10 miii and Pd(OAc)2 (246 mg) was added. After stirring the reaction mixture at 100C for 3 h, water (15 ml) was added to the reaction mixture and then extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 andconcentrated under reduced pressure, The crude residue was purified h Comhit'Iash column chromatography (hexane/EtOAc, 1:2) to afford 1009 (1.0 g, 43%) as a solid. 'H NMR (300 MHz, DMSO-c4?): d 12.32 (s, IH), 7.31 (q, 2H), 7.12 (s, IH).Compound 104[00325]; Compound 103 (1 10.0g, 0.296mol) was added to a 3L four-neck round bottom flask equipped with overhead stirrer, reflux condenser, water bath, 250ml addition funnel, an internal temperature probe and an argon inlet. Ethanol (900ml) was charged to the flask and cooled to 50C. Hydrochloric acid (37%, 145.9ml) was added dropwise keeping the internal temperature below 150C.[00326] The mixture was warmed to 50-550C for 2h after which time analysis by HPLC method Test 20 (MeOH) indicated complete conversion of starting material (Rt 6.73min) to one product (Rt 5.44min). The reaction was cooled to 50C and a solution of NaOH (80.0g in 1000ml water prepared, 865ml added) was added gradually keeping the temperature below 150C, monitoring the pH until neutral. The mixture was transferred to a one-neck flask and stored at 40C for 15h.[00327] A total of 970ml of distillate was removed by concentration in vacuo at 350C to give a colorless solution with precipitated solids. The slurry was allowed to cool to 40C for Ih after which time the solid was filtered under vacuum and washed with 40C ethanol:water 1 :4 (200ml). After drying at 350C under vacuum for 72h, impure Compound 104 (80g, 99% yield, 95% purity at 254nm) was obtained. To a solution of 1007 (30 g, 80 mmol) in CH2CI2 (30 rnL) was added TFA (10.0mL) at room temperature. After stirring the reaction mixture at room temperature for 16 h, solvent was evaporated and the crude Was washed with hexane (2(1 mL) to afford 1008 (1.0 g, crude) as a solid.