2-BENZYLOXY-5-BROMOPYRIDINE

To a solution of 5-bromopyridin-2 (1E-ONE (100 mmol, 17. 4 g, 1. 0 eq.) in benzene (170 mL) was added silver (I) carbonate (67. 0 mmol, 18. 5 g, 0. 67 eq.). The flask was wrapped with aluminum foil and then benzyl bromide (120 mmol, 20. 5 g, 1. 2 eq.) was added via syringe in a steady stream. The mixture was heated to 50 °C and stirred in the dark for approximately 24 hours. LC/MS of the reaction mixture indicates two peaks both with M+H = 265 corresponding to the desired molecular weight. On the basis of relative polarities, the more polar peak was thought to be the N-alkylated product and consisted of approximately 20 percent of the total. The reaction mixture was allowed to cool to room temperature and the silver salt was removed by filtration of the mixture through a pad of celite. The filter cake was washed with benzene and the organic layer was washed twice with 2percent sodium bicarbonate and twice with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified on a Biotage Sp4 65i over a gradient of 5-95percent hexanes in ethyl acetate to afford the title compound as a golden oil (25. 1 g, 95percent). LRMS : 265 (M+H) +. H NMR (DMSO-D6, 400 MHz) ; 8. 29 (1 H, s) 7. 72 (1 H, D, J=8. 5 Hz) 7. 31-7. 43 (5 H, m) 6. 54 (1 H, d, J=8. 5Hz) 5. 34 (2 H, s)To a solution of 5-bromopyridin-2(1 H)-one (1.28 g, 7.36 mmol) and Ag2CO3 (3 g, 11.04 mmol) in toluene (50 mL) was added (bromomethyl)benzene (1.25 g, 7.36 mmol) dropwiseand the reaction mixture was stirred at 100 °C over night. The reaction mixture was filteredthrough a short pad of silica gel and washed with DCM. The filtrate was concentrated to yield the title compound as light yellow oil (1 .8 g, 95percent).To a solution of 5-bromopyridin-2(1H)-one (1.28 g, 7.36 mmol) and AgTo a solution of 1 (1.4 g, 8 mmol) in dry THF (80 mL) was added benzyl bromide (1.14 mL, 9.6 mmol) and AgA mixture of 2, 5-dibromopyridine (20 g, 84.4 MMOL), DIBENZO-18-CROWN-6 (1.5 g, 4. 2mmol), benzyl alcohol (11. 9 g, 11.4 mL, 109.8 mmol), potassium hydroxyde (11. 4 g, 202.6 mmol) and toluene (200 mL) was atirred at reflux with a Dean-Stark apparatus for 1.5 hours. After removal of solvent in reduced pressure, the residue was diluted with water, and extracted with chloroform. The separated organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica-gel, (hexane: ethyl acetate, 98: 2) followed by recrystallization from hexane, to give 2- (BENZYLOXY)-5- bromopyridine (20.6 g, 92percent) as a colorless solid.A mixture of 2, 5-dibromopyridine (20.0 g, 84.4 mmol), dibenzo-18-crown-6 (1.5 g, 4.2 mmol), benzyl alcohol (11.9 g, 11.4 mL, 109.8 mmol) and KOH (11.4 g, 202.6 mmol) in toluene (200 mL) was refluxed with Dean-Stark for 1.5 hours. After removal of solvent under reduced pressure, the residue was diluted with water, and extracted with chloroform. The separated organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica-gel, (hexane:ethyl acetate, 98:2) followed by recrystallization from hexane, to give 2-benzyloxy-5-bromopyridine (20.6 g, 92 percent) as a colorless solid. Manufacturing Example 12-1-1 2-Benzyloxy-5-bromopyridine; To a solution of phenyl-methanol (20.5 g, 190 mmol) in N, N-dimethylformamide (200 mL) was added sodium hydride (7.6 g, 190 mmol) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2, 5-Dibromopyridine was then added thereto on the ice bath (0° C.), and stirred for 60 minutes at room temperature. The reaction mixture was partitioned into is water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:20 then 1:10) to obtain the title compound (15.1 g, 90percent).To a solution of phenyl-methanol (20.5 g, 190 mmol) in N, N-dimethylformamide (200 mL) was added sodium hydride (7.6 g, 190 mmol) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2, 5-Dibromopyridine was then added thereto on the ice bath (0° C.), and stirred for 60 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:20 then 1:10) to obtain the title compound (15.1 g, 90percent). A suspension of 2, 5-dibromopyridine (2.0 g, 8.4 mmol), dibenzo-18-crown-6 (0.14 g, . 05 equiv), benzyl alcohol (1.1 mL, 1.3 equiv), and potassium hydroxide [(1. 1] g, 2.4 equiv) in toluene (30 mL) were heated at reflux for 3 h in an apparatus fitted with a Dean-Stark trap. The suspension was cooled, concentrated, suspended in water, and extracted into methylene chloride. The combined organic phases were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.9 g (85percent) which was used without purification. Mass spec.: 264.25 (MH) [+.]To a solution of sodium hydride (1.04 g, 26.0 mmol, 1.3 equiv)In N, N-dimethylformamide (30 ml) was added benzyl alcohol (2.59 g, 24.0 mmol, 1.2 equiv)The mixture was stirred at 0 ° C for 1 hour, Followed by the addition of 2, 5-dibromopyridine (4.74 g, 20 mmol, 1.0 equiv)The reaction solution was allowed to react overnight at room temperature.The reaction was diluted with ethyl acetate (300 mL), washed with half-saturated brine (300 mL x 4) and the organic phase was dried over anhydrous sodium sulfate. The filtrate was chromatographed three times with petroleum ether and the residue was purified by column chromatography (Eluent: petroleum ether: ethyl acetate = 200: 1) to give 2- (benzyloxy) -5-bromopyridine (3.76 g, yield: 71.2percent).Example 117; Preparation of 5-(2-(benzyloxy)pyridin-5-yl)-3-(3-(4-(1, 1, 1, 3, 3, 3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy)benzyl)-5-methylimidazolidine-2, 4-dione; 117-a) Preparation of 5-(2-(benzyloxy)pyridin-5-yl)-5-methylimidazolidine-2, 4-dione; 117-a-1) Preparation of 5-bromo-2-(benzyloxy)pyridine; 2-Hydroxy-5-bromopyridine (1.00 g, 5.75 mmol) was dissolved in N, N'-dimethylformamide (23 mL), and the resultant mixture was added with sodium hydride (purity 50percent) (253 mg, 6.32 mmol) under an argon atmosphere under ice-cold conditions. Five minutes later, the resultant mixture was added with benzyl bromide (6.82 mL, 6.90 mmol) at the same temperature, and stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated in vacuo, and purified using silica-gel column chromatography (n-hexane/ethyl acetate=1/1). 5-Bromo-2-(benzyloxy)pyridine (1.51 g, yield 99percent) was obtained as a pale yellow solid.General procedure: To a solution of substituted 2-oxo-1, 2-dihydropyridines (3.36 mmol), zinc oxide (0.30 g, 3.70 mmol), zinc chloride (0.50 g, 3.70 mmol), N, N-diisopropylethylamine (0.48 g, 3.70 mmol), 1, 4-dioxane (15 mL)was added benzyl chloride (0.58 g, 4.04 mmol) under argon atmosphere. The mixture was heated in 110 °C oil bath with rapid stirring for the indicated time. The reactor was cooled to room temperature, and the insoluble residue was filtered off through celite, and the cake was wash with ethyl acetate(30 mL). The filtrate was washed with water (10 mL 2), once with brine (10 mL), dried overmagnesium sulfate, filtered, and concentrated in vacuo to afford crude product. The product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 1:20) to yield thecorresponding compounds.

Molecular Weight:264.12
XLogP3:3.3
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:262.99458
Monoisotopic Mass:262.99458
Topological Polar Surface Area:22.1
Heavy Atom Count:15
Complexity:183
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes