| 96% |
at 0℃; for 3 h; |
3-bromo-6-fluoro-2-methylbenzoic acid
To a 0° C. solution of 2-fluoro-6-methyl-benzoic acid (1.48 g, 9.60 mmol) in conc. H2SO4 (40 mL) was added NBS (1.79 g, 10.1 mmol).
The mixture was stirred at 0° C. for 3 hours.
The reaction mixture was poured into ice water (200 mL), and extracted with ether (2*200 mL).
The organic layers were combined, dried over sodium sulfate, and concentrated under vacuum to give the title compound (Compound QQ, 2.15 g, 96percent yield) as a solid. 1H NMR (400 MHz, chloroform-d) δ 7.64 (dd, J=8.84, 5.31 Hz, 1H), 6.92 (t, J=8.84 Hz, 1H), 2.54 (s, 3H); MS 231.0 [M+H]. |
| 90% |
With nitric acid; silver nitrate In water; acetic acid at 20℃; for 1.75 h; |
To a stirred solution of 2-fluoro-6-methyl-benzoic acid (1 g, 6.4 mmol, 1.0 eq) in acetic acid (32 mL) was added nitric acid (3.27 mL), water (3 mL) and bromine (0.36 mL). A solution of silver nitrate (1.43 g, 8.4 mmol 1.3 eq) in water (10 mL) was then added dropwise over a period of 15 min. After the addition was completed, stirring was continued a further 1.5h at room temperature. The reaction was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried ( a2S04), filtered and evaporated in vacuo to afford a crude product, which was triturated with hexane to give the title compound as a yellow solid (1.35 g, 90 percent).LC-MS: m/z 232.9 [M-H]~ 'H NMR (400 MHz, CDC13) δ 7.72 (dd, J = 8.9, 5.4 Hz, 1H), 7.15 (app t, J = 8.9 Hz, 1H), 2.34 (s, 3H). |
| 4 g |
With bromine; nitric acid; silver nitrate; acetic acid In water at 15 - 20℃; for 4 h; Cooling with ice |
Compound 187 A solution of 2-fluoro-6-methylbenzoic acid (10 g, 0.0649 mol) in HO Ac (300 mL) was stirred on a water-bath containing a bit of ice. At ~ 15°C, HN03 (65percent, 32.7 mL) was added dropwise. After addition, H20 (30 mL) was added slowly. After addition, Br2 (3.7 mL) was added dropwise. A solution of silver nitrate (14.33 g, 0.0844 mol) in H20 (100 mL) was added dropwise over a period of 30 minutes. After addition, the reaction mixture was stirred at room temperature for 3 hours 30 minutes. The reaction mixture was poured into H20 (850 mL), and EtOAc (300 mL) was added. The mixture was stirred vigorously for 5 minutes. Both upper liquid layers were decanted from a residue. The separated water layer was combined with the residue, and extracted with EtOAc. Both upper liquid layers were decanted from the residue. The separated water layer was combined with the residue, and extracted again with EtOAc. The organic layers were combined, washed with satured NaCl and dried with Na2S04, filtered off, evaporated, and co-evaporated with toluene. The obtained solid residue was stirred in a small amount of diisopropylether, filtered off, washed with diisopropylether, resulting in 3-bromo-6-fluoro-2-methyl-benzoic acid (4 g).The filtrate was evaporated. The residue was stirred in heptane, filtered off, washed with heptanes (3x), and dried at 50°C in vacuo, resulting in a mixture of bromo-6-fluoro-2-methyl-benzoic acid and 2- fluoro-6-methylbenzoic acid (12 g, 1/0.4 ratio). 3-bromo-6-fluoro-2-methyl-benzoic acid (4 g, 0.0172 mol) was added portionwise to stirring chlorosulfonic acid (25 mL). The resulting solution was stirred at 115°C for 2 hours, left standing at room temperature overnight and next stirred at 115°C for 3 hours more. The reaction mixture was allowed to reach room temperature, and added dropwise to a stirring mixture of crushed ice (150 g) and H20 (50 mL). The product was extracted with EtOAc (2 x). The combined organic layers were washed with brine, dried with Na2S04, filtered off, and evaporated, resulting in a crude mixture containing 5-bromo-3-chlorosulfonyl-2- fluoro-6-methyl-benzoic acid (4.4 g) (Na2C03, 1.407 g, 0.0133 mol) was dissolved in water (25 mL). A solution of (S)-3-aminotetrahydrofuran (2.312 g, 0.0265 mol) in THF (20 mL) was added, and the reaction mixture was cooled to 0°C on an ice-bath. A solution of crude 5-bromo-3-chlorosulfonyl-2-fluoro-6-methyl-benzoic acid (4.4 g) in THF (30 mL) was added dropwise at 0°C. After addition, the reaction mixture was stirred at 0°C for 1 hour, and at room temperature for 2 hours. The mixture was concentrated till ~ 35 mL remained, then left standing for 70 hours. The solid was filtered off and washed with H20 (2x). The filtrate was washed with Et20. The separated waterlayer was acidified with IN HC1 (30 mL), and the product was extracted with 2-MeTHF. The separated waterlayer was acidified further till pH ~ 2 and extracted with 2-MeTHF. The organic layer was washed with brine, dried with Na2S04 and filtered, resulting in crude 5-bromo-2-fluoro-6-methyl-3-[[(3S)-tetrahydrofuran-3- yl]sulfamoyl]benzoic acid (6.5 g). To a stirring solution of crude 5-bromo-2-fluoro-6- methyl-3-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]benzoic acid (1.3 g) in CH3CN (30 mL ) under N2-atm triethylamine (1.42 mL, 0.0102 mol ), 3,4-difluoroaniline (0.446 mL, 4.42 mmol ) and HATU (1.55 g, 4.08 mmol ) were successively added. The reaction mixture was stirred at room temperature for 16 hours. The volatiles were evaporated and the obtained residue was purified by silica gel chromatography (heptane-EtOAc 100/0 to 0/100 ], resulting in compound 187 (0.45 g).An impure fraction was further purified by Preparative HPLC (Stationary phase: RP XBridge Prep CI 8 OBD- 10μιη,30χ150ιηιη), Mobile phase: 0.25percent NH4HC03 solution in water, CH3CN), resulting in more compound 187 (0.048 g) Method F; Rt: 1.06 min. m/z: 491.0 (M-H)~ Exact mass:492.0. 1H NMR (400 MHz, DMSO-dg) δ ppm 1.66 - 1.76 (m, 1 H), 1.94 - 2.05 (m, 1 H), 2.41 (s, 3 H), 3.43 (dd, J=8.9, 4.5 Hz, 1 H), 3.58 - 3.65 (m, 1 H), 3.68 (dd, J=8.9, 6.3 Hz, 1 H), 3.71 - 3.78 (m, 1 H), 3.83 - 3.92 (m, 1 H), 7.36 - 7.42 (m, 1 H), 7.43 - 7.52 (m, 1 H), 7.85 (ddd, J=12.8, 7.5, 2.4 Hz, 1 H), 8.02 (d, J=6.8 Hz, 1 H), 8.55 (s, 1 H), 11.09 (s, 1 H) |
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