2-FLUORO-5-NITROPHENYLBORONIC ACID PINACOL ESTER

A mixture [OF 2-BROMO-1-FLUORO-4-NITROBENZENE] (prepared according to the procedure of Groweiss in Org. Proc. Res. [DEU., ] 2000, 4 [(1), ] 30-33) (66 g, 300 mmol), [KOAC] (58. 9 g, 600 mmol), bis (pinacolato) diboron (83. [8] g, 330 mmol) and dichloro [[L, ] [1APOS;-BIS] (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (7. 35 g, 9 mmol) in 1, 4-dioxane (900 ml containing 18 ml DMSO) was degassed with nitrogen for 1 h then heated at [90°C] for 14 h. The reaction was cooled to ambient temperature, filtered, the filter- cake washed with [ETAO] and the filtrate concentrated in vacuo. The residue was stirred with 2 N aqueous [NAOH] solution (11) for 45 min and then filtered. The filtrate was extracted with Et20 (2 x 750 ml) and the organics discarded. The aqueous component was cooled to [0°C] then treated with 36percent hydrochloric acid (ca. 175 ml) added dropwise over 15 min until pH 5. The resulting precipitate was allowed to stand at [0°C] for 2 h then filtered and washed with ice-cold water. The sand-coloured solid was dried under vacuum (300 mmHg) over phosphorus pentoxide to afford 2- (2-fluoro-5-nitrophenyl)-4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolane (76.1 g, 95percent) : 8H (400 MHz, CDC13) 1.38 (12H, s), 7.17 [(1H, ] dd, [J 9] and 9), 8.32 [(1H, ] ddd, J 9, 5 and 3), 8.64 [(1H, ] dd, J 5 and 3). A slurry of 3-bromopyridine (19 g, 120 mmol), [2-(2-FLUORO-5-] nitrophenyl) -4, 4, 5, [5-TETRAMETHYL- [1, ] 3, 2] dioxaborolane (40 g, 150 mmol) and KF (23 g, 396 mmol) in THF (600 ml) and water (30 ml) was degassed with nitrogen for 10 min, then treated with tris [(DIBENZYLIDENEACETONE)-] dipalladium [(0)] (2.2 g, 2.4 mmol) followed by tri-tert-butylphosphine (0.2 M solution in 1, 4-dioxane ; 2.4 ml, 0.48 mmol), and the reaction was stirred mechanically at ambient temperature for 30 min. The mixture was then heated at [50°C] for 1 h before being cooled to ambient temperature. The reaction was poured into ice-cold 0.5 N aqueous [NAOH] solution and stirred for 1 h. The solid product was collected by filtration, washed with water, allowed to dry under suction, then washed with isohexane and dried to give 3- (2-fluoro-5-nitrophenyl) pyridine as a grey solid (26.2 g, contaminated with [DIBENZYLIDENEACETONE)] : [8H] (400 MHz, CDCl3) 7.37 (1H, t, J 9), 7.45 [(1H, ] ddd, J 8, 5 and 1), 7.89-7. 93 [(1H, ] m), 8. [28-8.] 33 [(1H, ] m), 8.40 [(1H, ] dd, J 7 and 3), 8.71 [(1H, ] d, J 4), 8.84 [(1H, ] s). A suspension [OF 3- (2-FLUORO-5-NITROPHENYL)] pyridine (26 g, 119 mmol) in EtOH (200 ml) and EtOAc [(200] ml) was treated with [PTO2] (1.35 g, 6 mmol) then exposed to 50 psi hydrogen until uptake ceased (circa 3 hours). The reaction was filtered through glass-microfibre filter paper and concentrated to gave [3-(2-FLUORO-5-AMINOPHENYL)] pyridine (22.4 g) as a dark oil which solidified on standing: [8H] (360 MHz, [CDCL3)] 3.65 (2H, s), 6.65- 6.72 (2H, m), 6.99 [(1H, ] dd, J 9 and 9), 7.33-7. 37 [(1H, ] m), 7.84-7. 86 [(1H, ] m), 8.58 [(1H, ] d, [J4), 8. 76 (1H, ] m). A solution [OF 3-(2-FLUORO-5-AMINOPHENYL) PYRIDINE] (22.4 g, 119 mmol) in 1, 4-dioxane (40 ml) was treated with [A] solution of 48percent aqueous hydrobromic acid (500 ml). The resulting suspension was cooled to 0°C before being treated dropwise over 20 min with an aqueous solution of [NAN02] (9.5 g, 137 mmol) in water (30 ml) keeping the internal temperature [LT;5°C.] After stirring at [0°C] for 2 h, a cooled [(0°C)] solution of CuBr (25.6 g, 179 mmol) in 48percent aqueous hydrobromic acid (150 ml) was added to the reaction which was then stirred at [0°C] for [10] min before heating at [50°C] for 20 min. The reaction was cooled to ambient temperature, diluted with ice-cold water (500 ml), then treated with ice- cold aqueous [33percent] ammonium hydroxide solution until pH 8-9 (ca. 750 [ML).] After stirring for 20 min the product was extracted into EtOAc (600 ml), the organics were washed with water, brine (300 ml), dried over anhydrous [NAS04, ] filtered and pre-adsorbed onto silica. Purification by column chromatography [silica ; 20-50percent EtOAc/isohexane (containing 1percent [MEOH] and 1percent triethylamine) ] gave [3- (5-BROMO-2-FLUOROPHENYL)] pyridine as a white solid (22 g, 73percent for sequence): [SN] (360 MHz, [CDCL3)] 7.09 [(1H, ] dd, [J] 9 and 1), 7.37-7. 40 [(1H, ] m), 7.46-7. 51 [(1H, ] m), 7.56-7. 59 [(1H, ] m), 7.83-7. 86 [(1H, ] m), 8. 63-8.65 [(1H, ] m), 8. 77-8. 79 [(1H, ] m). 3- (5-Bromo-2-fluorophenyl) pyridine (21 g, 83 [MMOL), ] [KOAC] (16.4 g, 167 mmol) and bis (pinacolato) diboron (23.3 g, 92 mmol) were dissolved in 1, 4-dioxane (250 ml) and DMSO (5 ml) and the mixture degassed with nitrogen for 1 h. Dichloro [[1, ] [1APOS;-BIS] (diphenylphosphino) ferrocene]- palladium (II) dichloromethane adduct (2 g, 2.5 mmol) was added and the mixture heated at [90°C] for 18 h. The mixture was cooled to ambient temperature, filtered and the filter cake washed with [ET20.] The filtrate was evaporated to dryness and the residue stirred with ice-cold 2 N aqueous [NAOH] solution (500 ml) for 20 min. The aqueous mixture was filtered and the filtrate washed with [ET20] (2 x 300 ml). The organics were discarded and the aqueous phase cooled to 0°C before adjusting the pH to [8] by addition of [36percent] hydrochloric acid. This gave a gummy solid, which was extracted into Et20 (500 ml). The solid product at the [WATER-ET20] interface was collected by filtration and dried to afford 4-fluoro-3-(pyridin- 3-yl) boronic acid as a buff-coloured solid (3.7 g): aH (400 MHz, DMSO) 7.32 [(1H, ] dd, J 11 and [8), ] 7.53 [(1H, ] dd, J 8 and 5), 7.85-7. 90 [(1H, ] m), 7.97-8. 02 (2H, m), 8. 21 (2H, s), 8.61 [(1H, ] d, J4), 8.78 [(1H, ] s). A mixture of lithium diisopropylamide (2 M in [HEPTANE/THF/] ethylbenzene, stabilised with 0. 5percent [W/W] LiBr; 1.9 ml, 3.8 mmol) and THF [(3] ml) was cooled to-78°C and a solution [OF 2-CHLORO-3-FLUOROPYRIDINE] (500 mg, 3.8 mmol) in THF (3 ml) was added dropwise over 1 min. After 2 h, acetone (pre-dried twice over activated 4 Å molecular sieves) was added dropwise and the mixture allowed to warm to ambient temperature, then quenched with saturated aqueous [NH4C1] solution (10 ml) and extracted with EtOAc (50 ml). The organic phase was dried over anhydrous [MGS04] and concentrated in uacuo. The crude material was purified by column chromatography (silica; 10-20percent EtOAc/isohexane) to afford 2- (2-chloro-3- fluoropyridin-4-yl) propan-2-ol (687 mg, 95percent): [SN] (360 MHz, CDCl3) 1.66 (6H, s), 7.53 [(1H, ] m), 8.16 [(1H, ] m) ; m/z (ES+) 190 (100percent, [[MH] +).] [2- (2-CHLORO-3-FLUOROPYRIDIN-4-YL)] propan-2-ol (687 mg, 3.6 mmol) was converted to [2- (8-FLUOROIMIDAZO [1, ] 2-a] pyridin-7-yl) propan-2-ol (240 mg, 34percent) as described in aH (360 MHz, [CDC13)] 1.71 (6H, s), 7.14 (1H, t, J 6.8), 7.58-7.61 (2H, m), 7.91 (1H, d, J 7.1); m/z (ES+) 195 (100percent, [MH]+). 2-(8-Fluoroimidazo[1, 2-a]pyridin-7-yl)propan-2-ol(1.00 g, 5.2 mmol) was brominated as described in Example 1, affording [2- (3-BROMO-8-] fluoroimidazo [l, 2-a] pyridin-7-yl) propan-2-ol (637 mg, [45percent)] : [8H] (360 MHz, CDCl3) 1.72 (6H, s), 7.32 [(1H, ] t, [J 6.] 9), 7. 59 [(1H, ] s), 7.89 [(1H, ] d, [J 7.] 3) [; M/Z] (ES+) 275 (100percent, [MH] +), 273 (100). [HUNIGAPOS;S] base (0.44 ml, 3.8 mmol) and triethylsilyl [TRIFLUOROMETHANE-] sulfonate (0.57 ml, 2.6 mmol) were added sequentially to a cold [(-78°C), ] stirred solution of 2- (3-bromo-8-fluoroimidazo [1, 2-a] pyridin-7-yl) propan-2- ol (637 mg, 2.3 mmol) in [CH2CL2] (13 ml) and the solution warmed to ambient temperature. The mixture was partitioned between CH2Cl2 (50 ml) and water (50 [ML)] and the organic phase dried over anhydrous [MGS04, ] filtered through a short plug of silica (eluent CH2C12) and concentrated to afford 3-bromo-8-fluoro-7- [[2- (TRIETHYLSILYLOXY)] prop-2-yl] imidazo [[L, ] 2- pyridine (906 mg, quant. ) : [8N] (360 MHz, [CDC1S)] 0.70 (6H, q, [J 7.] 8), 0.99 (9H, t, [J 7.] 8), 1.71 (6H, s), 7.32 [(1H, ] t, [J6.] 9), 7.59 [(1H, ] s), 7. 88 [(1H, ] d, J 7.3). [3-BROMO-8-FLUORO-7- [2-(TRIETHYLSILYLOXY) PROP-2-YL] IMIDAZO [1, ] 2- pyridine was coupled with 4-fluoro-3- (pyridin-3-yl) phenylboronic acid as described in and then deprotected by treatment with an ethanolic solution of 37percent hydrochloric acid (5 drops in 2 ml of ethanol). After 18 h, the solution was concentrated [II] vacuo and purified by column chromatography on silica, to afford the title compound as a white amorphous solid: [8H] (360 MHz, [CD13)] 1.74 (6H, s), 7.20 [(1H, ] t, [J 7.] 0), 7.26-7. 44 (2H, m), 7.54-7. 62 (2H, m), 7.71 [(1H, ] s), 7.90-7. 93 (2H, m), 8. 05 [(1H, ] d, [J 7.] 3), 8.65-8. 66 [(1H, ] m), 8.85 [(1H, ] s); [M/Z] [(ES+)] 366 (100percent, [MH] +).

Molecular Weight:267.06
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:267.1078163
Monoisotopic Mass:267.1078163
Topological Polar Surface Area:64.3
Heavy Atom Count:19
Complexity:355
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes