1-(1-Ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Step 3[00251j To an oven-dried vial was charged a solution of isopropyl magnesium /lithium chloride solution (1.0 M in THF) (6.32 ml, 8.22 mmol) at room temperature, andto this solution was added 4-bromo-1-(1-ethoxyethyl)-1H-pyrazole (1.00 g, 4.56 mmol)dropwise and the resulting mixture was stirred at room temperature for 16 h. Theresulting solution was then cooled to -20 °C and 2-methoxy-4, 4, 5, 5-tetramethyl-1, 3, 2- dioxaborolane (1.73 1 g, 10.95 mmol) was added via syringe and the resulting mixture was allowed to warm to rt. After 2h at room temperature, the reaction was quenched by addition of aq. sat. ammonium chloride (15 mL) causing a white precipitate to form.After diluting with additional water (20 mL), the mixture was extracted with hexanes (140 mL x 2) and the combined extracts were washed with aq. sat. sodium bicarbonate, brine, then dried over sodium sulfate, filtered and concentrated to afford 1.20 g (99percent) of the product as a colorless oilStep 3 To an oven dried vial was charged a solution of isopropylmagnesium chloride - lithium chloride complex (1.0 M in THF) (6.32 ml, 8.22 mmol) at rt, and 4-bromo-l-(l- ethoxyethyl)-lH-pyrazole from Step 2 (1.00 g, 4.56 mmol) was added dropwise and the resulting mixture was stirred at rt overnight. The solution obtained was then cooled to -20 °C and 2-methoxy-4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (1.731 g, 10.95 mmol) was added dropwise via syringe. After the addition was complete, the reaction was allowed to slowly warm to rt and stir at rt for 2 h. The reaction was quenched at this time by the addition of aq. sat. NHA solution of isopropylmagnesium chloride-lithium chloride complex (1.0 M in THF) (6.32 ml, 8.22 mmol) was charged to the dried flask under rt, And 4-bromo-1- (1-ethoxyethyl) -1H-pyrazole (1.00 g, 4.56 mmol) from step 2 was added dropwise and the resulting mixture was stirred overnight at rt. The resulting solution was then cooled to -20 ° C and 2-methoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane was added dropwise via syringe (1.731 g, 10.95 mmol). After the addition was complete, the reaction was slowly warmed to rt and stirred at rt for 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (15 mL) to form a white precipitate. Water (20 mL) was added and the mixture was extracted with hexane (140 mL x 2). The combined extracts were washed with saturated aqueous sodium bicarbonate, brine, then dried over anhydrous sodium sulfate, filtered and concentrated to afford 1.20 g (99percent) of the desired product as a colorless oil.1-(Ethoxyethyl)-4-(4, 4, 5, 5-tetramethyl[1, 3, 2]dioxaborolan-2-yl)-1H-pyrazole (19).; To a 100 ml solution of iPrMgCl.LiCl (50 mmol, 1.8 equiv) was added 4-bromo-1-(ethoxyethyl)-1H-pyrazole (22, 6.15 g, 28 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 12 hrs and then cooled to -20° C. Methoxy pinacolborate (23, 10.6 g, 67 mmol, 2.4 equiv) was then added to the reaction mixture. The resulting mixture was stirred at 0-10° C. for 1 h. Aqueous NH1-(Ethoxyethyl)-4-(4, 4, 5, 5-tetramethyl[1, 3, 2]dioxaborolan-2-yl)-1H-pyrazole (24) [0165] To a 100 ml solution of iPrMgCl.LiCl (50 mmol, 1.8 equiv) in THF was added 4-bromo-1-(ethoxyethyl)-1H-pyrazole (6.15 g, 28 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 12 h and then cooled to −20° C. Methoxy pinacolborate (10.6 g, 67 mmol, 2.4 equiv) was then added to the reaction mixture at −20° C. The resulting mixture was stirred at 0-10° C. for 1 h. Aqueous NH1-(1-ethoxyethyl)-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (11-II)To a solution of compound 11-II-a (600 mg, 2.73 mmol) in dioxane (15 mL) was added KOAc (800 mg, 8.2 mmol), bis(pinacolato)diboran (1.39 g, 5.4 mmol) and Pd(dppf)Cl1-(1-ethoxyethyl)-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (5-II) 1-(Ethoxyethyl)-4-(4, 4, 5, 5-tetramethyl[1, 3, 2]dioxaborolan-2-yl)-1H-pyrazole (19). A 22 L 4-neck flask equipped with a mechanical stirrer, thermowell, addition funnel, and N1-(Ethoxyethyl)-4-(4, 4, 5, 5-tetramethyl[1, 3, 2]dioxaborolan-2-yl)-1H-pyrazole (19).; A 22 L 4-neck flask equipped with a mechanical stirrer, thermowell, addition funnel, condenser and NGeneral procedure: To a solutionof 5-bromo-3-(1-(2-chloro-5-fluorophenyl)ethoxy)pyridin-2-amine (100 mg, 0.29mmol) and 4, 4, 5, 5-tetramethyl-2-phenyl-1, 3, 2-dioxaborolane (71 mg, 0.35 mmol)in toluene was added freshly prepared aqueous solution of Cs2CO3(332 mg, 1.02 mmol) in water, followed by the addition of 1, 1?-bis(diphenylphosphino)ferrocenepalladium dichloride (21.30 mg, 0.03 mmol). The mixture was degassed andcharged with nitrogen three times and then heated in a 80 oil bath for 12 h. Aftercooling down the mixture to room temperature, the solution was concentrated invacuum. The crude product was purified by column chromatography on silica geleluted with dichloromethane/ methanol (200:1, v/v) to give product as a whitesolid (70 mg, 70.38% yield).Potassium carbonate (16.1 g, 0.116 mol) and water (30 mL) were added at room temperature to a suspension of 6 (10.0 g, 0.029 mol) and 1-(1-ethoxyethyl)-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)- 1H-pyrazole (7.42 g, 0.029 mol) in 1, 4-dioxane (100 mL). The two-phase mixture was degassed with nitrogen for ~30 min, and tetrakis(triphenylphosphine)palladium(0) (0.60 g, 0.52 mmol) was added. The mixture was heated to 80C and stirred at that temperature for 10-12 h (TLC). The mixture was then cooled to room temperature and filtered, the aqueous layer was separated from the filtrate, and the organic layer was mixed with ethyl acetate (100 mL), washed with water (2 ×100 ml), and concentrated under reduced pressure. The oily residue was treated with diisopropyl ether (100 mL), the mixture was stirred for 2 h at room temperature, and the precipitate was filtered off, washed with (i-Pr)2O (20 mL), and dried. Yield 10.0 g (77%), yellow solid. 1 H NMR spectrum (500 MHz, CDCl3), delta, ppm: 1.20 t (3H, J = 4.5 Hz), 1.42 t (3H, J = 7.5 Hz), 1.76 d (3H, J = 6.0 Hz), 3.08 q (2H, J = 7.5 Hz), 3.46 s (2H), 3.42-3.44 m (1H), 3.52- 3.55 m (1H), 4.31 d (2H, J = 10.0 Hz), 4.72 d (2H, J = 9.0 Hz), 5.61 q (1H, J = 6.0 Hz), 6.86 d (1H, J = 3.5 Hz), 7.25 d (1H, J = 4.0 Hz), 8.25 s (1H), 8.40 s (1H), 8.76 s (1H). 13C NMR spectrum (500 MHz, CDCl3), deltaC, ppm: 151.87, 151.54, 150.53, 138.74, 127.08, 124.87, 121.75, 115.45, 114.49, 101.36, 87.97, 64.33, 58.60, 52.20, 46.59, 27.16, 22.1, 14.72, 7.73. Mass spectrum: m/z 420.136 [M + H]+ .The tetrakis (triphenylphosphine) palladium was added Compound A-1 (45g, 0.158mol), 1- (1- ethoxyethyl) -4-pyrazolyl-boronic acid pinacol (63g, 0.237mol) and potassium carbonate (43.6 Frequency g, 0.316mol) in n-butanol mixed solution (200mL) and water (200mL), the four replaced with argon, the reaction solution was stirred at 100 deg.] C overnight and cooled to room temperature, filtered, dried, and concentrated, petroleum ether and ethyl acetate (v / v = 2/1) as eluent flash column to give a yellow oil a-2 (31g, 0.1288mol, yield: 81.5%) through.To a RBF was added 2, 4-dichloro-7H-pyrrolo[2, 3-d]pyrimidine (540 mg, 2.87 mmol),

Molecular Weight:266.15
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:266.1801728
Monoisotopic Mass:266.1801728
Topological Polar Surface Area:45.5
Heavy Atom Count:19
Complexity:309
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes