6-Bromo-2-methyl[1,2,4]triazolo[1,5-a]pyridine

To compound 13 (7.01 g) in acetic anhydride (9 mL), concentrated hydrochloric acid (1 mL) was added and heated at reflux for 14 hours. The reaction mixture was neutralized with aqueous NaHCOTo (1, 2-diamino-5-bromopyridin-1-indole) 2, 4, 6-trimethylbenzenesulfonate (13.47 g, 34.69 mmol) in Ac2O (70 mL)Add in suspensionp-Toluenesulfonic acid hydrate (1.37 g, 7.21 mmol).The reaction mixture is placed in a sealed tubeAnd heated to 100 C for 24 hours.After the reaction, The reaction was quenched with water (30 mL)EtOAc.The residue obtained was diluted with water (50 mL).Adjust to pH=10 with saturated aqueous sodium carbonate solution.It was then extracted with EtOAc (200 mL x 3).The combined organic phases were dried over anhydrous sodium sulfate.Filter and concentrate under reduced pressure.The residue obtained was purified by silica gel column chromatography (EtOAc / EtOAcThe crude product was obtained as a yellow solid (3.90 g).The crude product was dissolved in DCM (50 mL).Then, triethyloxonium tetrafluoroboric acid (22.0 mL, 22 mmol, 1.0 M) was added thereto.The resulting mixture was stirred at room temperature overnight.After the reaction is over, filter, The filter cake was rinsed with DCM (50 mL).The resulting filtrate was washed with aq. sat. Na2CO3 (5.Dry over anhydrous sodium sulfate, Filter and concentrate under reduced pressure.The title compound was obtained as a yellow solid (0.85 g, yield 12%).To a suspension of 6-bromo-2-methyl-[l, 2, 4]triazolo[1, 5-a]pyridine (0.84 g, 4.00 mmol) in anhydrous l, 4-dioxane (20 mL) were added Pd2(dba)3 (0.36 g, 0.40 mmol), BINAP (0.49 g, 0.79 mmol), diphenylmethanimine (1.45 g, 8.02 mmol) and t-BuONa (0.77 g, 8.01 mmol). The mixture was degassed and refilled with N2 for several times and heated to 105 C and stirred overnight. The mixture was concentrated in vacuo and the residue was purified by silica chromatography (EtOAc/PE (v/v) = 1/2 to 1/1 to EtOAc 100%) to afford the title compound as brown liquid (0.34 g, yield 27%).MS (ESI, pos. ion) m/z: 313.0 [M+H]+;1H NMR (400 MHz, CDCl3) d (ppm): 7.97-7.92 (m, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.47-7.37 (m, 3H), 7.36-7.28 (m, 3H), 7.14 (dd, J= 7.4, 1.7 Hz, 2H), 6.99 (dd, J = 9.3, 1.8 Hz, 1H), 2.53 (s, 3H).To To a suspension of (l, 2-diamino-5-bromopyridin-l-ium)2, 4, 6- trimethylbenzenesulfonate (13.47 g, 34.69 mmol) in Ac20 (70 mL) was added 4- methylbenzenesulfonic acid hydrate (1.37 g, 7.21 mmol). The mixture was placed in a sealed tube and heated to 110 C and stirred for 24 h. The mixture was quenched with water (30 mL), then concentrated in vacuo. The residue was diluted with water (50 mL), and the resulting mixture was adjusted to pH = 10 with saturated Na2C03 aqueous solution and then extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v) = 1/10 to 1/5) to afford the crude product as a yellow solid (3.90 g). The crude product was dissolved in DCM (50 mL), then tri ethyl ox onium tetrafluorob orate (22.0 mL, 22 mmol, 1.0 M) was added to the resulting solution. The resulting mixture was stirred at room temperature overnight, then filtered and the filter cake was washed with DCM (50 mL). The filtrate was washed with saturated Na'CO, aqueous solution (50.0 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo to afford the title compound as a yellow solid (0.85 g, yield 12%).MS (ESI, pos. ion) m/z: 212.0 [M+H]+.To a solution of To boronic acid ester compound having acetamide side chain (15, 1.902 g), and 6-bromo-2-methyltriazolopyridine compound (14, 1.162 g) in dioxane (40 mL) and water (10 mL), Na2CO3 (1.85 g) and Pd(Ph3P)4 (588 mg) were added and the solution was stirred at 90 to 100 C. for 1 hour. Then, the solvent was removed under reduced pressure. The residue was dissolved in ethanol, and 1.246 g of colorless compound 16 precipitated. The mother liquid was purified by column chromatography (chloroform-methanol (9:1)). 223 mg of colorless compound 16 was precipitated from ethanol. Total: 1.469 g (76%).Compound 16: 1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) 2.04 (s, 3H), 2.62 (s, 3H), 3.60-3.72 (m, 2H), 3.87 (dd, 9, 7, 1H), 4.14 (dd, 9, 9, 1H), 4.81-4.90 (m, 1H), 7.34 (dd, 8.5, 2, 1H), 7.49 (dd, 8.5, 8.5, 1H), 7.62 (dd, 13, 2, 1H), 7.66-7.75 (m, 2H), 8.69 (d, 1, 1H);LRMS m/z 383 (M+, 44), 339 (18), 311 (7), 280 (19), 255 (56), 242 (27), 158 (26), 85 (26), 73 (20), 56 (52), 43 (100).To compound 13 (7.01 g) in acetic anhydride (9 mL), concentrated hydrochloric acid (1 mL) was added and heated at reflux for 14 hours. The reaction mixture was neutralized with aqueous NaHCO3, and extracted with methanol-chloroform (1:9). After washing with water and dryness, solvent was removed. The residue was recrystallized from ethanol to afford 2.985 g of compound 14 as colorless needle-like crystal. The mother liquid from the recrystallization was purified by column chromatography (hexane-ethyl acetate (1:1)) to afford 401 mg of compound 14. Total: 3.385 g (92%).Compound 14: as colorless needle-like crystal mp: 154.5-155 C. (Hexane-CHCl3);1H-NMR (300 MHz, CDCl3) 2.60 (s, 3H), 7.54 (d, 1, 2H), 8.64 (dd, 1, 1, 1H);LRMS m/z 211, 213 (M+, 96, 100), 170, 172 (13, 12), 156, 158 (10, 7), 143, 145 (10, 6), 64 (58), 42 (18).EXAMPLE 5(S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-l-(4-(2-methyl-[l, 2, 4]triazolo[l, 5-a]pyridin-6-yl)phenyl)ethyl)-l, 3-oxazinan-2-oneTo a solution of 6-bromo-2-methyl-[l, 2, 4]triazolo[l, 5-a]pyridine (9.5 mg, 0.045 mmol) in DME (3 mL) was added Pd(PPh3)4 (5.2 mg, 0.0045 mmol) under N2. After being stirred at room temperature for 1 hour, the mixture was added a solution of (2^-6- (2-hydroxy-2-methylpropyl)-6-isopropyl-3-(f5>;l-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)phenyl)ethyl)-l, 3-oxazinan-2-one (20 mg, 0.045 mmol) in ethanol (1.5 mL) and saturated NaHCO3 solution(l mL). The mixture was heated to reflux for 2 hours under N2. The reaction mixture was treated with ethyl acetate (10 mL) and water (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC to give f5^-6-(2-hydroxy- 2-methylpropyl)-6-isopropyl-3-(5y)- 1 -(4-(2-methyl-[ 1 , 2, 4]triazolo[ 1 , 5-a]pyridin-6-yl) phenyl)ethyl)-l, 3-oxazinan-2-one (6.00 mg, 30%). LC-MS Method 2 tR = 0.99 min, m/z = 451. 1H NMR (CD3OD): 0.90 (d, 3H), 1.00 (d, 3H), 1.33 (d, 6H), 1.65 (d, 3H), 1.78 (d, IH), 1.93 (m, 2H), 2.17 (m, IH), 2.28 (m, IH), 2.58 (s, 3H), 2.84 (m, IH), 3.39 (m, IH), 5.73 (q, IH), 7.52 (d, 2H), 7.76 (m, 3H), 8.01 (d, IH), 8.99 (s, IH). (S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-l-(4-(4, 4, 5, 5-tetramethyl- l, 3, 2-dioxaborolan-2-yl)phenyl)ethyl)-l, 3-oxazinan-2-one was prepared as described in WO 2009/134400 Example 17.

Molecular Weight:212.05
XLogP3:1.8
Hydrogen Bond Acceptor Count:2
Exact Mass:210.97451
Monoisotopic Mass:210.97451
Topological Polar Surface Area:30.2
Heavy Atom Count:11
Complexity:153
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes