2-AMINO-3-FLUOROBENZONITRILE

A mixture [OF 2, 3-DIFLUOROBENZONITRILE] (19.0 g, 137 mmol) and ethanol (200 ml) pre-saturated with ammonia gas was heated at [140°C] in an autoclave for 8 h (terminal pressure 200 psi). The mixture was allowed to cool to ambient temperature and evaporated to dryness. The residue was dissolved in water (400 ml) and extracted with diethyl ether (2 x 300 ml). The combined organics were washed with water (300 [ML)] and brine (250 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. Trituration with isohexane (150 ml) afforded 2-amino-3-fluorobenzonitrile (9.8 g, 50percent) as an off-white solid: 8H (360 MHz, [CDCL3)] 4.47 (2H, s), 6.65- 6.71 [(1H, ] m), 7.14-7. 20 (2H, m). 2-Amino-3-fluorobenzonitrile (9.8 g, 71.9 mmol) was bromo- deaminated as described in to afford 2-bromo-3- fluorobenzonitrile as a pale brown solid: 8H (360 MHz, [CDCL3)] 7.62-7. 68 [(1H, ] m), 7.74-7. 85 [(1H, ] ddd, [J9, ] 9, 1), 7.74-7. 85 [(1H, ] ddd, [J8, 1, ] 1). 2-Bromo-3-fluorobenzonitrile (2.50 g, 12.5 mmol) was coupled to 2- (2-fluoro-5-nitrophenyl) -4, 4, 5, [5-TETRAMETHYL- [1, ] 3, 2] dioxaborolane as described in to give 6, 2'-difluoro-5'-nitrobiphenyl-2-carbonitrile as a black solid: [8H] (400 MHz, CDCl3) 7.40-7. 44 [(1H, ] m), 7.47-7. 52 [(1H, ] m), 7.59-7. 67 (2H, m), 8.37-8. 44 (2H, m). 6, [2APOS;-DIFLUORO-5APOS;-NITROBIPHENYL-2-CARBONITRILE] [(3. 25] g, 12.5 mmol) was reduced using the procedure described in to give 5'-amino-6, 2'- difluorobiphenyl-2-carbonitrile as a brown oil: aH (360 MHz, [CDCL3)] 3.74 [(2H, ] s), 6.68 [(1H, ] m), 6.73-6. 77 (1H, m), 7.02 [(1H, ] dd, J 9, 9), 7.37-7. 49 (2H, m), 7.56-7. 65 [(1H, ] m). 5'-Amino-6, [2APOS;-DIFLUOROBIPHENYL-2-CARBONITRILE] was bromo- deaminated as described in to furnish 5'-bromo-6, 2'- difluorobiphenyl-2-carbonitrile as a pale brown solid: [No.H ] (360 MHz, [CDCL3)] 7.13 [(1H, ] dd, [J9, ] 9), 7.37-7. 49 (2H, ddd, [J9, ] 9, 1), 7.57-7. 62 (4H, m). 2- (8-Fluoroimidazo [1, 2-a] pyridin-7-yl) propan-2-ol (97 mg, 0.5 mmol) was coupled with 5'-bromo-6, 2'-difluorobiphenyl-2-carbonitrile (177 mg, 0.6 mmol), as described in Example 6, affording the title imidazopyridine as a white amorphous solid (90 mg, 44percent): 8H (360 MHz, [CD13)] 1.73 (6H, d, J 0. 6), 2.05-2. 08 [(1H, ] m), 7. 19 [(1H, ] t, [J7.] 0), 7.38-7. 68 (6H, m), 7. 71 [(1H, ] s), 8.22 [(1H, ] d, J 7.0) ; [M/Z] (ES+) 408 (100percent, [[MH] +).]A mixture of 2, 3-difluorobenzonitrile (19. 0 g, 137 mmol) and ethanol (200 ml) pre-saturated with ammonia gas was heated at 140°C in an autoclave for 8 h (terminal pressure 200 psi). The mixture was allowed to cool to ambient temperature and evaporated to dryness. The residue was dissolved in water (400 ml) and extracted with diethyl ether (2 x 300 ml). The combined organics were washed with water (300 ml) and brine (250 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. Trituration with isohexane (150 ml) afforded 2-amino-3-fluorobenzonitrile (9.8 g, 50percent) as an off-white solid: 1H NMR (360 MHz, CDCl3) 8 4.47 (2H, s), 6.65-6. 71 (1H, m), 7.14-7. 20 (2H, m).2-amino-3-fluorobenzonitrileTo a round-bottomed flask was added (Z)-7-fluoro-3-(hydroxyimino)indolin-2-one (3.12 g, 17.32 mmol) in dimethyl formamide (150 mL) to give a brown/amber solution. The solution was heated to 180° C., which produced a steady reflux. Internal temperature was monitored to be 152° C. The reaction was heated at that temperature for 3 hours and then stirred at room temperature overnight. The reaction was diluted with water (125 mL), saturated aqueous sodium bicarbonate (125 mL) and ethyl acetate (250 mL), shaken and separated. The aqueous layers were extracted 2 more times with ethyl acetate. The organics were combined and back extracted once with an equal volume of water. The organics were then dried over magnesium sulfate, filtered and evacuated. The residue was purified via flash column eluting with methylene chloride to afford 2-amino-3-fluorobenzonitrile as a green tinted white solid (2.36 g, 17.34 mmol, 78percent). To 100 mL of the round bottom flask was added 1 g (about 7.35 mmol) of [00604] To a mixture of 188-1 (400 mg, 2.94 mmol, 1 eq), 188-la (1.20 g, 4.41 mmol, 0.648 mL, 1.5 eq) and Cs2C03 (2.87 g, 8.82 mmol, 3 eq) in dioxane (10 mL) were added Xantphos (510.1 mg, 0.882 mmol, 0.3 eq) and Pd(OAc)2 (66 mg, 0.294 mmol, 0.1 eq) in one portion under N2. The mixture was stirred at 100 C for 16 hours. The crude LCMS showed no desired product was detected but TLC (Petroleum ether: ethyl acetate = 10: 1, Rf = 0.15, UV 254 nm) indicated compound 188-1 remained and one major new spot had formed. The reaction mixture was quenched with water (35 mL), and extracted with EtOAc (30 mL*3). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give the 188-2 (239 mg, 0.853 mmol, 29.0% yield). 1HNMR (400 MHz, DMSO-i_) 9.01 (s, 1H), 7.69 - 7.76 (m, 2H), 7.53 (d, J= 8.53Hz, 2H), 7.40 (td, J= 8.09, 4.89 Hz, 1H), 6.87 (d, J= 8.03Hz, 2H).

Molecular Weight:136.13
XLogP3:1.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:136.04367633
Monoisotopic Mass:136.04367633
Topological Polar Surface Area:49.8
Heavy Atom Count:10
Complexity:160
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes