1-(2-BROMOETHYL)-4-FLUOROBENZENE

4-[4-[l-(3-Bromo-phenyl)-eihoxy]-2-(^yrido[23-d]pyrimidin-4-ylarnino)-phenylsulfanyl]-phenol; Example 168a; 1 -( 1 -Bromo-ethyl)-4-fluoro-benzene; [0612] To a solution of l-(3-Bromo-phenyl)-ethanol (7.0 g, 34.0 mmol) in dichloromethane (40 mL) was added drop wise phosphorus tribromide (77 g, 34.0 mmol) .The mixture was stirred at room temperature for 16 h. The reaction was poured onto ice/water. The aqueous phase was made basic with sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic phase was washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (7.8 g, 80 percent).(±)4(14romoethyI)41uorobenzene.A mixture of 1-ethyi-4-fluorohenzene (0248g, 2mmol), NBS (0.35g. 2mmol) and benzoyl peroxide (0. 14g, 0.6mmoi) were dissolved in 20 mL Cd4, The mixture was stirred at 0 °C for 5 hours and then the reaction was cone. in vacuo and resulting oil was purified via silica gel chromatography (PE-EtOAC 5: 1) to give the title compound (330 mg, 80percent) as a yellow oil. LCMS 202 (M ± Hj.1-(4-fluorophenyl)ethanol (1 equiv., 25 g) was taken up in dichloromethane (150 mL), and PBr3 (0.7 equiv., 12 mL) was added dropwise at 4° C. over a period of 20 min.A solution of 1-(4-fluorophenyl)ethanol (0.455 mL, 3.57 mmol) and phosphoms tribromide (0.673 mL, 7.13 mmol) in CHC13 (10 mL) was heated at 70 °C for 3 d. The reaction mixture was quenched in ice water and diluted in ethyl acetate. The organic layer was separated and washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated in vacuo to get the crudematerial. The cmde product was purified on a silica gel column with Hexanes/CH2C1(2/1) to afford 1-(1-bromoethyl)-4-fluorobenzene (154 mg, 0.758mo1, 21.3 percent) as acolourless oil. ‘H NMR (400 MHz, CHLOROFORM-d) ö 7.49 - 7.40 (m, 2H), 7.09 - 7.00(m, 2H), 5.23 (q, J=7.0 Hz, 1H), 2.06 (d, J=6.8 Hz, 3H).To a solution of ethyl 2-(4-(2H-tetrazol-5-yl)phenylsulfonamido)acetate (1.2 g, 0.0047 mol, Intermediate 51 ) and To a solution of N-(2-hydroxyethyl)-4-(2H-tetrazol-5-yl)benzenesulfonamide (300 mg, 0.001 1 mol, intermediate 17) and /V, /V-diisopropylethylamine (0.38 mL, 0.0022 mol, commercial source: Finar) in acetonitrile (6 mL), 1 -(1 -bromoethyl)-4-fluorobenzene (271 mg, 0.0013 mol, Intermediate 142) was added at 26°C. The reaction mixture was heated to 85°C and stirred for 16 h at the same temperature. Upon completion, the reaction mixture was cooled to 26°C, dissolved in ethyl acetate (10 mL) and washed with water (30 mL) and brine (40 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The crude was purified by column chromatography (silicagel 100-200 mesh), eluted with 1.5percent methanol in dichloromethane. The pure fractions were collected and concentrated under reduced pressure to afford (4-(2-(1 -(5-fluoropyridin-2-yl)ethyl)-2H-tetrazol-5-yl)-N-(2- hydroxyethyl)benzenesulfonamide (1 10 mg, 26percent) as an off white solid.The obtained racemic compound was submitted to chiral prep-SFC for the separation of isomers.SFC prep Conditions:Column: Chiralpak IG (30x250mm), 5mupercentC02: 55percent: percentco-solvent: 45percent (100percent methanol)Flow: 90g/mm, Back pressure: 90bar, UV: 254nm, Stack time: 5.5mnLoading: 8.6 mg, Solubility: MeOH, No. of inj: 20Instrument model: Make/model: SFC-200-002The two pure fractions were dried under lyophilization to afford:Isomer 1 : (43 mg, 10percent) as a brown gummy solid and as a single unknown enantiomer.1H NMR (400 MHz, DMSO-de) delta 8.24 (d, J=8.1 Hz, 2H), 7.96 (d, J=8.3 Hz, 2H), 7.52-7.49 (m, 2H), 7.26-7-21 (m, 2H), 6.44-6.39 (m, 1 H), 3.38-3.35 (m, 2H), 2.85-2.82 (m, 2H), 2.02 (d, J=7 Hz, 3H). MS m/z [M+H]+= 392.05, chiral purity: eepercent = 99.53percent. Isomer 2: (49 mg, 1 1 percent) as a brown gummy solid and as a single unknown enantiomer.1H NMR (400 MHz, DMSO-d6) delta 8.25 (d, J=8.3 Hz, 2H), 7.97 (d, J=8.3 Hz, 2H), 7.76-7.73 (m, 1 H), 7.52-7.49 (m, 2H), 7.26-7-21 (m, 2H), 6.44-6.39 (m, 1 H), 4.67-4.64 (m, 1 H), 3.39-3.34 (m, 2H), 2.86-2.81 (m, 2H), 2.03-2.01 (m, 3H). MS m/z [M+H]+= 392.02, chiral purity: eepercent = 99.80percent