2-FLUORO-5-HYDROXYPYRIDINE

White fine crystalline powder

8e. A three neck 3-L flask equipped with an overhead stirred was charged with 6- fluoropyridin-3-ylboronic acid (105 g, 745 mmol) and 1L of THF. The mixture was cooled to 0 C and NaOH 6N (373 mL, 2235 mmol) was added. To the resulting mixture was added hydrogen peroxide 30% (126 mL, 4098 mmol), dropwise via an addition funnel over the course of 30 minutes. After stirring at 0 C for 2 hours the mixture was removed from the ice bath and maintained at RT for 30 minutes. The reaction was acidified to pH 7 with 6 N HC1 (ca. 300 mL) and diluted with 500 mL of ether. The aqueous layer was extracted with ether (2 x 1 L) and the combined organic layers were washed with water (1.5 L) then brine before being dried over sodium sulfate. Filtration and concentration provided a white solid that was dried on high vac overnight to provide 6-fluoropyridin-3-ol.Example 35. Polyphosphoric acid, 140 CSynthesis of 7-Bromo-3-methoxy-5H-chromeno[2, 3-b]pyridin-5-one; Step 1 : A three neck 3-L RBF equipped with an overhead stirred was charged with 6- fluoropyridin-3-ylboronic acid (105 g, 745 mmol) and 1L of THF. The mixture was cooled to 0 C and NaOH 6N (373 mL, 2235 mmol) was added. To the resulting mixture was added hydrogen peroxide 30% (126 mL, 4098 mmol), dropwise via an addition funnel over the course of 30 minutes. After stirring at 0 C for 2 hours the mixture was removed from the ice bath and maintained at RT for 30 minutes. The reaction was acidified to pH 7 with 6 N HC1 (ca. 300 mL) and diluted with 500 mL of ether. The aqueous layer was extracted with ether (2 x 1 L) and the combined organic layers were washed with water (1.5 L) then brine before being dried over sodium sulfate. Filtration and concentration provided a white solid that was dried on high vac overnight to provide 6-fluoropyridin-3 -ol.Example 35. Polyphosphoric acid, 140 CSynthesis of 7-Bromo-3-methoxy-5H-chromeno[2, 3-b]pyridin-5-oneStep 1 : A three neck 3-L RBF equipped with an overhead stirred was charged with 6- fluoropyridin-3-ylboronic acid (105 g, 745 mmol) and 1L of THF. The mixture was cooled to 0 C and NaOH 6N (373 mL, 2235 mmol) was added. To the resulting mixture was added hydrogen peroxide 30% (126 mL, 4098 mmol), dropwise via an addition funnel over the course of 30 minutes. After stirring at 0 C for 2 hours the mixture was removed from the ice bath and maintained at RT for 30 minutes. The reaction was acidified to pH 7 with 6 N HC1 (ca. 300 mL) and diluted with 500 mL of ether. The aqueous layer was extracted with ether (2 x 1 L) and the combined organic layers were washed with water (1.5 L) then brine before being dried over sodium sulfate. Filtration and concentration provided a white solid that was dried on high vac overnight to provide 6-fluoropyridin-3 -ol.A three neck 3-L RBF equipped with an overhead stirred was charged with 6- fluoropyridin-3-ylboronic acid (105 g, 745 mmol) and 1L of THF. The mixture was cooled to 0 C and NaOH 6N (373 mL, 2235 mmol) was added. To the resulting mixture was added hydrogen peroxide 30% (126 mL, 4098 mmol), dropwise via an addition funnel over the course of 30 minutes. After stirring at 0 C for 2 hours the mixture was removed from the ice bath and maintained at RT for 30 minutes. The reaction was acidified to pH 7 with 6 N HC1 (ca. 300 mL) and diluted with 500 mL of ether. The aqueous layer was extracted with ether (2 x 1 L) and the combined organic layers were washed with water (1.5 L) then brine before being dried over sodium sulfate. Filtration and concentration provided a white solid that was dried on high vac overnight to provide6-fluoropyridin-3 -ol.A 1 dram vial was charged with tert-butyl ((lR, 4R, 7R)-2-(2-(6-bromo-l- (0705) (cy clopropylmethyl)-lH-indol-2-yl)-7-methoxy-l -methyl- l H-benzo[d]imidazole-5- carbonyl)-2-azabicyclo[2.2. l]heptan-7-yi)carbamate (0.037 g, 0.040 mmol), 2-fiuoro-5- hydroxypyridine (5.42 mg, 0.048 mmol), cesium carbonate (0.020 g, 0.060 mmol) and Rockphos Pd G3 (3.35 mg, 3.99 pmol) in dioxane (1 mL). The vial was capped and the reaction mixture was made anaerobic by a pump / backfill with nitrogen cycle (5X). The reaction was set to stir at 90 C overnight. After cooling, the mixture was diluted with EtOAc, dried (MgS04), filtered, and concentrated. The resulting residue was dissolved in dichloromethane (1 mL) and treated with TFA (0.5 ml, 6.49 mmol). Mixture was stirred at rt for 90 min before it was concentrated. The residue was dissolved in DMF, filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C l 8, 19 x 200 mm, 5-mth particles; Mobile Phase A: 5;95 acetonitrile: water with 10-mM ammonium acetate: Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 26-66% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The purified material was then diluted with DMF, treated with Si-Pyridine and shaken for a minimum of 2 h. The resulting mixture was filtered and concentrated via centrifugal evaporation to give ((IR, 4R, 7RV7-amino~2~ (0706) azabicycJo[2.2.1]heptan-2-yl)(2-(l-(cyclopropyJmethyl)-6-((6-fluoropyridin-3-yl)oxy)- lH-indol-2-yl)-7-m ethoxy- l-methyl-lH-benzo[d]imidazol-5-yl)methanone (4.1 mg): fit NMR (500 MHz, DM 80-dr, ) d 8.03 (br s, 1H), 7.72 (br d, J=8.5 Hz, 1H), 7.68 (br t, .7=6.0 Hz, i l l ). 7 44 (br s, 1 1 1 ), 7.34 (s, 1 1 1), 7.21 (br dd, .7=8.7, 2.9 Hz, i l l ). 7 06 (s, i l l ). 6 95 - 6.90 (m, 2H), 4.37 (br d, .7=6.4 Hz, 21 1). 4.10 (s, 31 1). 3.98 (s, 31 1 ). 3.75 (br s, 1H), 3.66 - 3.48 (m, 1H), 3.17 (s, 1H), 3.08 - 2.99 (m, 1H), 2.21 (br s, 1H), 2.04 - 1.91 (m, 2H), 1.74 (br t, ./ 9.5 Hz, 1H), 1.48 - 1 40 (m, 1 H), 1.23 (s, 2H), 1.04 - 0.94 (m, 1H), 0.26 (br d, , 7=7.9 Hz, 2H), -0.02 (br s, 2H); LC/MS (M+H) = 581.3; Retention Time = 1.75 min (Method 1).

Molecular Weight:113.09
XLogP3:0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:113.027691913
Monoisotopic Mass:113.027691913
Topological Polar Surface Area:33.1
Heavy Atom Count:8
Complexity:78.8
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes