5-Bromo-α,α-dimethyl-2-pyridinemethanol

In a 2 L round-bottomed flask was mixed 2, 5-dibromopyridine (54 g, 228 mmol) in toluene (600 ml) to give a colorless solution. The reaction was cooled to -78° C. and n-Butyllithium 2.5M hexanes (100 ml, 251 mmol) was added at a rate that the temperature did not exceed -70° C. The reaction was stirred for 30 minutes and then acetone (20.08 ml, 274 mmol) was added quickly. The reaction was stirred for 30 minutes and then quenched with saturated ammonium chloride. The organic layer was washed with brine, dried over sodium sulfate and solvent removed under reduced pressure. The crude residue was purified by column chromatography 20-50percent ethyl acetate/heptane to give 42.5 g of 2-(5-bromopyridin-2-yl)propan-2-ol in 86percent yield.In a 1 L round-bottomed flask was mixed compound 2-(5-bromopyridin-2-yl)propan-2-ol (10 g, 46.3 mmol) and 4-methyl-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (11.87 g, 50.9 mmol) in dioxane (300 ml). To this was added saturated sodium bicarbonate (150 mL). The reaction mixture was degassed via purging with a stream of nitrogen and then Pd(PPh2, 5-Dibromopyridine (1.04 g, 4.39 mmol) was dissolved in toluene (22 mL) in a 100 mL round-bottomed flask. The mixture was cooled to -78 To a stirred solution of 2, 5-dibromopyridine (2.00 g, 8.44 mmol) in anhydrous toluene (100 mL) at-78 under nitrogen was slowly added a solution of .cents.BuLi (4.05 mL, 10.13 mmol, 2.5M in hexanes). After 2 h at-780C, acetone (806 pl, 10.98 mmol) was added. After stirring for 1 h, the reaction mixture was allowed to warm to 0 and was quenched with a saturated NH4CI. A two-phase system was formed; the organic layer was separated, washed with saturated NH4CI, H20 and brine, dried over anhydrous MgS04, filtered and concentrated. The residue was purified by flash chromatography on silica gel (AcOEt/CH2CI2 : 20/80) to afford the title compound 54 (1.37 g, 6.34 mmol, 75percent yield) as a pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) No.(ppm) : ABX System (No.A = 7. 32, No.B = 7. 82, 8x = 8.58, JAB = 8.4 Hz, JBX = 2. 3 Hz, JAx = 0 Hz, 3H), 4.47 (bs, lH), 1.57 (s, 6H).(Example 159)To a solution of 2, 5-dibromopyridine (4 g, 16.89 mmol) in toluene (60 mL) at -78 °C, n- butyl lithium (2.5M in hexane) (10.13 mL, 25.3 mmol) was added dropwise, and the mixture was stirred for 30 min. Acetone (2 mL, 27.2 mmol) was then added to the reaction mixture, and the mixture was stirred for 30 min at -78 °C. The reaction mixture was allowed to warm to room temperature, aqueous ammonium chloride was added to the mixture, and the mixture was partitioned between ethyl acetate and water. Separated organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography using 20percent ethyl acetate in hexanes to afford the title compound (2.4 g, 63.1percent) as a yellow oil. INTERMEDIATE 502-(5-Bromopyridin-2-vD-propan-2-olTo a suspension of 2, 5-dibromopyridine (1.5 g, 6.35 mmol) in toluene (33 mL) cooled to -78°C was added dropwise n-butyllithium (4.5 mL of a 1.6M solution in hexanes, 7.2 mmol). The mixture was stirred for 20 minutes with cooling before addition of acetone (0.56 mL, 7.6 mmol). It was warmed to r.t., stirred for 40 minutes and then poured into a saturated aqueous solution of ammonium chloride (6 mL). The organic 2-(5-Bromopyridin-2-yl)propan-2-ol General procedure: To a solution of methyl 5-bromopicolinate (2.16 g, 10 mmol) in THF (50 mL) at 0 °C was added a solution of 10 mL of 3.0 M methyl magnesium bromide in diethyl ether (30 mmol) dropwise over 0.5 h. The reaction mixture was stirred at rt for 1 h, quenched with saturated NH[00494] Intermediate 45a: 2-(5-bromo-2-pyridyl)propan-2-oI[00495] To a solution of methyl 5-bromopyridine-2-carboxylate (2.lg, 9.72mmol) in dry THF(48mL) at 0 °C, under nitrogen, was slowly added bromo(methyl)magnesium 2.7M in Et20 (10.8mL, 29.l6mmol). The resulting solution was allowed to warm to room temperature and stirred overnight. The reaction was then quenched by the dropwise addition of sat. aq. NH4CI (2mL) then diluted with sat. aq. NaHCO3 (3OmL). The aqueous layer was extracted with EtOAc (2 x 3OmL). The combined organic extracts were washed with brine (3OmL), dried over Na2504 and concentrated in vacuo.The crude material was purified by flash column chromatography using an eluent of 0-100percent EtOAcin heptane to give 2-(5-bromo-2-pyridyl)propan-2-ol (1 .43g, 6.64mmol, 68percent yield) as a yellow oil.1H NMR (CDCI3, 400MHz) O/ppm: 7.89 (1H, m), 7.83 (1H, dd, J= 8.4Hz, 2.4Hz), 7.33 (1H, dd, J=8.4Hz, 0.8Hz), 4.41 (1 H, br 5), 1 .55 (6H, 5).MS Method 2: RT: 1.31 mi m/z 217.8 [M+H][00521] Intermediate 50a: 2-(5-bromo-2-pyridyl)propan-2-oI[00522] n-Butyllithium (2.47M in heptane, 4mL, 9.88mmol) was added dropwise to a suspension of 5-bromo-2-iodopyridine (2.67g, 9.41 mmol) in Et20 (45mL) at -78 °C under a nitrogen atmosphere, and the orange solution was stirred at -78 °C for 30 minutes. Acetone (1 .O5mL, 14.3mmol) was thenadded dropwise and the reaction mixture was allowed to warm slowly to room temperature overnight. Water (3OmL) was then carefully added and the aqueous layer was extracted with EtOAc (2 x 3OmL). The combined organic extracts were washed with brine (3OmL), dried over Na2504, filtered and concentrated in vacuo. The residue was purified via column chromatography using an eluent of 0-100percent EtOAc in heptane to afford 2-(5-bromo-2-pyridyl)propan-2-ol (1.41g, 6.S2mmol, 69percent yield) as a light yellow oil.1H NMR (CDCI3, 400MHz) O/ppm: 8.59 (1H, dd, J= 2.0Hz, 0.8Hz), 7.84 (1H, dd, J= 8.4Hz, 2.0Hz), 7.33 (1H, dd, J= 8.4Hz, 0.8Hz), 4.44 (1H, brs), 1.55 (6H, 5).MS Method 3: RT: 3.20 mi m/z216.0/218.0 [M+H]Step 3. To a stirred solution of 1-(5-bromopyridin-2-yl)ethan-1-one (1 , 6.2 g, 30.99 mmol) in tetrahydrofuran (100 mL), was added methyl magnesium chloride solution (18.6 mL, 55.78 mmol, 3.0 M in tetrahydrofuran) at 0 C and the reaction mixture was then stirred at room temperature for 12 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The crude product was purified by silica gel column chromatography using 10percent ethyl acetate in hexane to afford the title compound 2-(5-bromopyridin-2-yl)propan-2-ol (2, 5.8 g, 86percent yield) as a yellow oil. Calculated (M+H): 216.0; Found (M+H): 216.1To a solution of 1-(5-bromopyridine-2-yl)ethanone (2.9 g, 14.5 mmol) inanhydrous THF (87 mL) at -78 °C was added methylmagnesium bromide (38.66 mL, 116.0 mmol) (3M in diethyl ether) dropwise. The resulted mixture was stirred at room temperature for overnight. Saturated ammonium chloride solution was added and the mixture stirred for 30 mm, then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (60-120 silicagel, 2-3percent EtOAc/hexane) to gave the product of Step 2 (1.66 g, 53percent yield) as a pale yellow liquid. LCMS retention time: 1.40 mm (Method 8).2-(5-Bromopyridin-2-yl)propan-2-ol (B25.1) (0431) To a mixture of 1-(5-bromopyridin-2-yl)ethanone (400 mg, 2 mmol) in 8 mL THF was added 6 mL CHTo a mixture of 1 -(5- bromopyridin-2-yl)ethanone (400 mg, 2 mmol) in 8 mL THF was added 6 mL CH3MgBr (1 mol/L) at -15 °C under N2 atmosphere. The mixture was stirred for 5 h at 25 °C, quenched with sat. NH4CI (30 mL) and stirred for 1 h, extracted with ethyl actetate (50 mL x 2). The combined organic layers were washed with 50 mL water and 50 mL brine, dried over Na2SO4, concentrated. The residue was purified on silica gel (PE/EA1O:1)to give title compound (180 mg, 42percent) as a colorless oil. 1H-NMR (400 MHz, CDCI3) O ppm 1.54 (5, 6H), 7.31 (dd, 1H), 7.82 (dd, 1H), 8.58 (d, 1H).EXAMPLES 8-17 The general procedures of Examples 1-4 were followed in Examples 8-17 in which 2, 5 dibromopyridine was lithiated and adducts formed with different enolizable ketones. However, the batch reactions in Examples 8-17 were not run in a jacketed flask and the BuLi was added quickly via a manual syringe, instead of a syringe pump. The solution was chilled in a 0 C. ice bath prior to addition. Product distribution was determined by GC/MS (uncorrected) as described above. The percent of 2 adduct reflects the extent of lithiation at the 2 position and the percent of 5 adduct reflects the percent of lithiation at the 5 position. TABLE 3 Reac- 2-Adduct 5-Adducttion (A) (B) Ketone Type Solvent percent percent A:B Example 2-methyl- Batch toluene 75 2 47:1 '8 3- pentanone Example 2-methyl- Flow toluene 60 8 '8:1 '9 3- pentanone Example 3-methyl- Batch toluene 67 2 0:1 10 2- butanone Example 3-methyl- Flow toluene 65 4 18:1 11 2- butanone Example cyclo- Batch luene 33 2 22:1 12 pentanone Example cyclo- Flow toluene 34 3 10:1 13 pentanone Example cyclo- Flow THF 0 64 100percent B 14 pentanone Example cyclo- Batch toluene 54 3 20:1 15 hexanone Example cyclo- Flow toluene 52 3 14:1 16 hexanone Example acetone Batch toluene 34 3 11:1In a 2 L round-bottomed flask was mixed 2, 5-dibromopyridine (54 g, 228 mmol) in toluene (600 ml) to give a colorless solution. The reaction was cooled to -78 C. and n-Butyllithium 2.5M hexanes (100 ml, 251 mmol) was added at a rate that the temperature did not exceed -70 C. The reaction was stirred for 30 minutes and then acetone (20.08 ml, 274 mmol) was added quickly. The reaction was stirred for 30 minutes and then quenched with saturated ammonium chloride. The organic layer was washed with brine, dried over sodium sulfate and solvent removed under reduced pressure. The crude residue was purified by column chromatography 20-50% ethyl acetate/heptane to give 42.5 g of 2, 5-Dibromopyridine (1.04 g, 4.39 mmol) was dissolved in toluene (22 mL) in a 100 mL round-bottomed flask. The mixture was cooled to -78 0C. n-Butyllithium (3.02 mL, 4.83 mmol) was added dropwise. The mixture was stirred 30 min, followed by the addition of acetone (2 mL). The mixture was stirred 40 min and then let warm to rt. The mixture was washed with ammonium chloride (5% aq, 50 mL), water (50 mL) and then brine (50 rnL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by Biotage (16% ethyl acetate in hexanes). Concentration of the desired fractions afforded the product (0.82 g, 3.78 mmol, 86 % yield). MS (ESI) m/z 216.0 [M]+, 218.1 [M+2]+.To a stirred solution of 2, 5-dibromopyridine (2.00 g, 8.44 mmol) in anhydrous toluene (100 mL) at-78 under nitrogen was slowly added a solution of ¢BuLi (4.05 mL, 10.13 mmol, 2.5M in hexanes). After 2 h at-780C, acetone (806 pl, 10.98 mmol) was added. After stirring for 1 h, the reaction mixture was allowed to warm to 0 and was quenched with a saturated NH4CI. A two-phase system was formed; the organic layer was separated, washed with saturated NH4CI, H20 and brine, dried over anhydrous MgS04, filtered and concentrated. The residue was purified by flash chromatography on silica gel (AcOEt/CH2CI2 : 20/80) to afford the title compound 54 (1.37 g, 6.34 mmol, 75% yield) as a pale yellow oily liquid. 1H NMR (400 MHz, CDCl3) No.(ppm) : ABX System (No.A = 7. 32, No.B = 7. 82, 8x = 8.58, JAB = 8.4 Hz, JBX = 2. 3 Hz, JAx = 0 Hz, 3H), 4.47 (bs, lH), 1.57 (s, 6H).(Example 159) 2-(S-{2-Fluoro-5-[3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl]phenyl}pyridin-2-yl)propan-2-ol (Compound No. 2-648) (159a) 2-(5-Bromopyridin-2-yl)propan-2-ol An n-butyllithium solution (1.6 M in hexane, 8.5 mL, 13 mmol) was added to a toluene solution (60 mL) of 2, 5-dibromopyridine (2.6 g, 11 mmol) under a nitrogen atmosphere at -78C. The resulting mixture was stirred at -78C for 30 min, and then acetone (1.2 mL, 16 mmol) was added thereto. The resulting mixture was further stirred for 30 min. The reaction solution was returned to room temperature, and a saturated ammonium chloride aqueous solution was added thereto to terminate the reaction. After extraction with ethyl acetate, the organic layer was washed with water and brine, and then dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (Biotage, eluting solvent; hexane/ethyl acetate) to obtain 1.7 g (yield: 73%) of the title compound as a light yellow oily material. 1H-NMR (500 MHz, CDCl3) delta ppm: 8.58 (1H, d, J = 2.4 Hz), 7.82 (1H, dd, J = 2.4, 8.3 Hz), 7.31 (1H, d, J = 8.3 Hz), 4.42 (1H, s), 1.54 (6H, s). MS(ESI) m/z: 216 (M+H)+To a solution of 2, 5-dibromopyridine (4 g, 16.89 mmol) in toluene (60 mL) at -78 C, n- butyl lithium (2.5M in hexane) (10.13 mL, 25.3 mmol) was added dropwise, and the mixture was stirred for 30 min. Acetone (2 mL, 27.2 mmol) was then added to the reaction mixture, and the mixture was stirred for 30 min at -78 C. The reaction mixture was allowed to warm to room temperature, aqueous ammonium chloride was added to the mixture, and the mixture was partitioned between ethyl acetate and water. Separated organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography using 20% ethyl acetate in hexanes to afford the title compound (2.4 g, 63.1%) as a yellow oil. lH NMR (400 MHz, CDC13): delta 8.58 (d, J= 2.0 Hz, 1H), 7.82 (dd, J; = 2.0 Hz, J2 = 8.4 Hz, 1H), 7.32 (d, J= 8.8 Hz, 1H), 4.4 (s, 1H), 1.56 (s, 3H), 1.53 (s, 3H). ESI-MS m/z = 216 (M+H)+.INTERMEDIATE 502-(5-Bromopyridin-2-vD-propan-2-olTo a suspension of 2, 5-dibromopyridine (1.5 g, 6.35 mmol) in toluene (33 mL) cooled to -78C was added dropwise n-butyllithium (4.5 mL of a 1.6M solution in hexanes, 7.2 mmol). The mixture was stirred for 20 minutes with cooling before addition of acetone (0.56 mL, 7.6 mmol). It was warmed to r.t., stirred for 40 minutes and then poured into a saturated aqueous solution of ammonium chloride (6 mL). The organic 2-(5-Bromopyridin-2-yl)propan-2-ol 2, 5-Dibromopyridine (5 g, 0.021 mol) was dissolved in toluene (100 mL). The mixture was cooled to -78 C. A 2.5 M solution of n-butyllithium in hexane (8.44 mL, 0.021 mol) was added dropwise. The mixture was stirred 30 minutes, followed by the addition of anhydrous acetone (10 mL). The mixture was stirred 45 minutes and then allowed to warm to room temperature for 1 h. The mixture was washed with aqueous ammonium chloride solution (5%, 100 mL) and water (100 mL), then brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0 to 10% ethyl acetate in heptanes) to afford the title compound (2.21 g, 48%) as a yellow oil. deltaH (500 MHz, CDCl3) 8.57 (d, J 2.1 Hz, 1H), 7.81 (dd, J 8.4, 2.3 Hz, 1H), 7.31 (d, J 8.4 Hz, 1H), 4.41 (s, 1H), 1.53 (s, 6H).To a suspension of 2, 5-dibromopyridine [(L.] [OEQ.)] in Tol (0. 1M) at [- 78C] was added dropwise n-BuLi (1.07eq.). The mixture was stirred [AT-78C] for 3h then acetone (1.2eq.) was added. The final mixture was stirred for an extra 2h at [- 78C, ] poured in saturated aqueous [NH4CL] and extracted with Tol (2x). The combined organic extracts were dried over [NA2SO4, ] filtered and concentrated. Flash chromatography (Hex: EtOAc; 4: 1) afforded the title compound as a white solid.To a suspension of 2, 5-dibromopyridine in toluene (12 ml/mmol) cooled to -78 C. was added n-butyllithium 2.5M in hexanes (1.05 eq) and the resulting mixture was stirred in the cold for 2.5 hours. Acetone (2 eq) was added and stirring was continued for 1.5 h. After quenching with saturated aqueous ammonium chloride solution, the mixture was warmed to room temperature and partitioned between ethyl acetate and water. The product from the organic phase was chromatographed on silica gel eluting with 20% ethyl acetate in hexane to afford the STEP 1: 2-(2-HYDROXVPROPAN-2-YL)-5-BROMOPVRIDINE: To A-78C suspension of 2, 5-dibromopyridine in toluene (0.2M) was added n-butyllithium (L. LEQ.) and the reaction mixture stirred at -78C for 30min. Acetone (1. 2eq. ) was then added, the mixture stirred at -78C for 40min, then quenched with saturated NH4CI. The aqueous phase was extracted with ethyl acetate, the organic layer washed once with brine, dried over MGS04, filtered and concentrated. The crude material was purified by flash chromatography on silica gel (20% ethyl acetate in hexanes) to afford 2- (2-hydroxypropan-2-yl)-5-bromopyridine as a yellow oil.Example 46 1-(4-(4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)benzyl)phenyl)-5-methyl-1H-1, 2, 4-triazole-3-carboxamide A microwave vial was charged with methyl-1-(4-(2-(4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl)propan-2-yl)phenyl)-1H-pyrazole-3-carboxamide (Intermediate IX) (60 mg, 0.143 mmol), 2-(5-Bromopyridin-2-yl)propan-2-ol) (31 mg, 0.143 mmol), K3PO4 (91 mg, 0.430 mmol), second generation Xphos Precatalyst (11.29 mg, 0.014 mmol), water (0.5 mL) and THF (2 mL). The mixture was evacuated and degassed with N2 for 5 min, and then heated in the microwave at 100 C. for 1 h. After cooling to RT, the mixture was concentrated in vacuo. The resulting crude material was purified by preparative HPLC to afford 1-(4-(4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)benzyl)phenyl)-5-methyl-1H-1, 2, 4triazole-3-carboxamide (15 mg, 23%): LCMS Rt=1.33 min (condition A), MS (M+1)=428.3. 1H NMR (400 MHz, Methanol-d4) delta 8.70 (dd, J=2.3, 0.9 Hz, 1H), 8.03 (dd, J=8.3, 2.4 Hz, 1H), 7.74 (dd, J=8.3, 0.9 Hz, 1H), 7.68-7.57 (m, 2H), 7.57-7.43 (m, 4H), 7.43-7.30 (m, 2H), 4.14 (s, 2H), 2.52 (s, 3H), 1.57 (s, 6H).To an stirred and cooled (0 C) solution of

Molecular Weight:216.07
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:214.99458
Monoisotopic Mass:214.99458
Topological Polar Surface Area:33.1
Heavy Atom Count:11
Complexity:138
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes