5-FLUORO-2-METHYLBENZOXAZOLE

2. 5-Fluoro-2-methylbenzoxazole; 2-Amino-4-fluorophenol (1.01g, 7.95mmol, 1.0eq), triethyl orthoacetate (1.60ml, 8.7mmol, 1.1eq) and bismuth (III) trifluoromethanesulfonate (50mg) were mixed and stirred at ambient temperature for 30mins. The resulting solution was then diluted with dichloromethane and purified by silica flash chromatography (dichloromethane) to give the title compound as a clear liquid, 1.045g (87percent). The liquid transformed to a crystalline solid at temperatures below 5°C. MS (MALDI-TOF): MH(a) 5-Fluoro-2-methylbenzo[d]oxazole (2665) To a solution of 2-amino-4-fluorophenol (2.72 g) and triethyl orthoacetate (7.89 ml) in ethanol (100 ml) was added ytterbium(lll) trifluoromethanesulfonate (310 mg, 0.500 mmol). The reaction was heated at reflux for 2 hours whereupon LCMS indicated complete conversion. The resulting dark solution was cooled, concentrated to a dark residue, then purified directly on a pre-packed silica column (SF40-150g), using a gradient of 0-100percent ethyl acetate in hexanes to afford the titled compound(1 .65 g) as an orange oil, which was used without further purification. LCMS m/z 151 .9 [M+H]. [0398] To a stirred mixture of Comp-50c (0.2 g, 1.32 mmol) in THF (20 mL) was added solution of i-BuOK (2 mL, 1 M in THF) at 0 C. Comp-8b(0.26 g, 1.32 mmol) was added portion wise and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with H20 (5 mL) and extracted with EtOAc (50 mL X 2). The organic layer was washed with brine, separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 10-20% EtOAc in hexane) to afford (E)-2-(2-(2, 5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)- 5-fluorobenzo|d]oxazole (47, 0.04 g, 10%) as a yellow solid. (0698) [0399] HPLC purity : 99.79% (0699) [0400] MS(ESI) m/e [M+H]+ Rt %: 333.0/2.32/95.5% (0700) [0401] 1H NMR (400 MHz, CD() delta 1.99 - 2.04 (m, 3 H), 2.12 - 2.17 (m, 3 H), 6.21 - 6.30 (m, 1 H), 6.57 - 6.64 (m, 1 H), 6.92 - 7.00 (m, 1 H), 7.16 - 7.22 (m, 2 H), 7.33 - 7.40 (m, 1 H), 7.41 - 7.53 (m, 3 H) 7.61 - 7.90 (m, 2 H).[0589] Compound 82: To a stirred solution of Comp-82b (0.1 g, 0.66 mmol) in mixture of THF (5 mL) and ffiuOH (1 mL) was added r-BuOK (0.2 g, 1.98 mmol) and the reaction mixture was stirred for 10 min. Comp-50c(0.1 g, 0.66 mmol) was added portion wise and the reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with H20 (5 mL) and extracted with EtOAc (10 mL X 2). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude. The crude obtained was purified by prep HPLC to afford (E)-2-(2-(l-cyclopentyl-2, 5- dimethyl-lH-pyrrol-3-yl)vinyl)-5-fluorobenzo[d]oxazole (82; 0.08 g, 40%) as white solid. (1026) [0590] HPLC Purity: 99.8% (1027) [0591] MS (ESI) m/e [M+H]+ Rt %: 325.2/2.47/99.4% (1028) [0592] 1H NMR (400 MHz, DMSO- d6) delta 1.62- 1.64 (m, 2 H), 1.82- 1.84 (m, 4 H), 1.98 - 2.08 (m, 2 H), 2.24 (s, 3 H), 2.36 (s, 3 H), 4.54 - 4.67 (m, 1 H), 6.26 (s, 1 H), 6.50 (d, J=15.65 Hz, 1 H), 7.10 - 7.19 (m, 1 H), 7.46 (dd, J=8.80, 2.45 Hz, 1 H), 7.62 - 7.64 (m, 1 H), 7.67 (d, J=15.65 Hz, 1 H).[0614] To a stirred solution of Comp-50c (0.073 g, 0.48 mmol) in mixture of THF (5 mL) and tBuOH (0.5 mL) was added t-BuOK (0.16 g, 1.46 mmol) at 0 C. Comp-80b (0.1 g, 0.48 mmol) was added portion wise and the reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with H20 (5 mL) and extracted with EtOAc (10 mL X 2). The organic layer was washed with brine, separated, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 100- 200 mesh, 2-5% EtOAc in hexane) to afford (E)-2-(2-(l-cyclohexyl-2, 5-dimethyl-lH-pyrrol- 3-yl)vinyl)-5-fluorobenzo[d]oxazole (104, 0.08 g, 51%) as a yellow solid. (1076) [0615] HPLC Purity: 99.4% (1077) [0616] MS (ESI) m/e [M+H]+/ Rt'%: 339.15/2.56/99.8% (1078) [0617] 1H NMR (400 MHz, DMSO-d6) delta 1.17 - 1.27 (m, 2 H), 1.35 - 1.45 (m, 2 H), 1.62 - 1.69 (m, 1 H), 1.73 - 1.96 (m, 6 H), 2.22 - 2.27 (m, 3 H), 2.35 - 2.39 (m, 3 H), 6.20 - 6.25 (m, 1 H), 6.46 - 6.53 (m, 1 H), 7.09 - 7.16 (m, 1 H), 7.41 - 7.48 (m, 1 H), 7.60 - 7.66 (m, 1 H), 7.66 - 7.70 (m, 1 H).[0436] Compound 50: To a solution of Comp-50c (3.95 g, 26.15 mmol) in THF:iBuOH (50 mL 4: 1 ) was added t-BuOK (8.78 g, 78.47 mmol) and the reaction mixture was stirred for 10 min. Comp-3b (5.18 g, 23.54 mmol) was added portion wise and the reaction mixture was stirred at room temperature for 16h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with H20 and extracted with EtOAc. The organic layer was washed with brine, separated, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 2-3% MeOH in ethyl acetate) to afford (E)-2-(2-(2, 5-dimethyl-l-(l- me1hylpiperidin-4-yl)-lH-pyrrol-3-y])viny])-5-fluorobenzo[d]oxazole (50; 1.8 g, 20%) as yellow solid. (0756) [0437] HPLC Purity: 98.7%. (0757) [0438] MS (ESI) m/e |M+H|+/ Rt/%: 354.20/1.42/98.2%. (0758) [0439] 1H NMR (400 MHz, DMSO-c delta 1.69-1.72 (m, 2 H) 1.98 - 2.07 (m, 2 H) 2.11 - 2.17 (m, 2H) 2.20 (s, 3 H) 2.27 (s, 3H) 2.38 (s, 3 H) 2.88 (d, J=11.25 Hz, 2 H) 3.92-3.98 (m, 1 H) 6.26 (s, 1 H) 6.51 (d, J=15.65 Hz, 1 H) 7.11-7.16 (m, 1 H) 7.46 (dd, J=9.05, 2.69 Hz, 1 H) 7.62 - 7.71 (m, 2 H).[0552] To a stirred solution of Comp-48e (0.27 g, 1.32 mmol) and Comp-50c (0.2 g, 1.32 mmol) in THF:t-BuOH (5 mL 4:1) was added f-BuOK (0.15 g, 1.32 mmol) at 0 C and the reaction mixture was stirred at RT for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was poured on crushed ice and extracted with EtOAc (30 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 30-40% EtOAc in hexane) to afford (E)-5-fluoro-2-(2-(5-methyl-l-(l-methylpiperidin-4-yl)-lH-pyrazol-4- yl)vinyl)benzo[d]oxazole (78, 0.07 g, 15%) as pale yellow solid. (0972) [0553] HPLC purity : 99.89% (0973) [0554] MS (ESI) m/e [M+H]+/Rt %: 341.15/1.22/99.6% (0974) [0555] 1H NMR (400 MHz, DMSO-d6) delta 1.80 (d, .7=11.25 Hz, 2 H), 2.01 - 2.07 (m, 2 H), 2.08 - 2.17 (m, 2 H), 2.25 (s, 3H), 2.42 (s, 3 H), 2.91 (d, J=8.80 Hz, 2 H), 4.12 - 4.23 (m, 1 H), 6.91 (d, J=16.14 Hz, 1 H), 7.17-7.23 (m, 1 H), 7.54 (dd, J=9.05, 2.69 Hz, 1 H), 7.64 (d, J=16.14 Hz, 1 H), 7.69 (dd, J=8.80, 4.40 Hz, 1 H), 8.05 (s, 1 H).

Molecular Weight:151.14
XLogP3:2.3
Hydrogen Bond Acceptor Count:3
Exact Mass:151.043341977
Monoisotopic Mass:151.043341977
Topological Polar Surface Area:26
Heavy Atom Count:11
Complexity:153
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes