5-Bromopyridine-2-carbaldehyde

Light yellow Cryst

This compound was prepared according to general procedure C bytreating 2, 5-dibromopyridine (237 mg, 1 mmol) with DMF (115 μL, 1.5 mmol). The crude product was purified by flash chromatography(hexane/ethyl acetate 10:1) to give the product 27b as an off-brownsolid (149 mg, 80percent); Rf (hexane/ethyl acetate 8:1): 0.45; 1H NMR(400 MHz, CDCl3): δ 10.03 (1H, s), 8.85 (1H, dd, J=0.8, 2.0 Hz), 8.02(1H, ddd, J=0.8, 2.0, 8.0 Hz), 7.85 (1H, dd, J=0.8, 8.0 Hz); 13C NMR(100 MHz, CDCl3): δ 192.4, 151.7, 151.3, 140.0, 126.3, 122.8. Thespectroscopic data matched that reported in the literature.Example 41; 2-({3-[S-(2-FluorophenyExample 5 -- Synthesis of Compound 109 A solution of 2, 5-dibromopyridine 8 (25 g, 105.5 mmol) in toluene (1.24 L) was cooled to -78 °C before being treated dropwise with a 2.5 M solution of n-butyl lithium (n-BuLi) in hexane (50.6 mL, 126.6 mmol) at -78 °C. The resulting reaction mixture was stirred at -78 °C for 1 hr before being treated with anhydrous DMF (11.6 g, 12.2 mL, 158.0mmol) at-78 °C. The reaction mixture was stirred at -78 °C for an additional 1 hr before being gradually warmed to room temperature for 6 hr. When TLC and HPLC showed that the reaction was complete, the reaction mixture was quenched with H2O (200 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic extracts were then washed with H2O (2 x 200 mL) and saturated aqueous NaCl (100 mL) and dried over magnesium sulfate (MgS04). The solvents were then removed in vacuo, and the residual pale-yellow oil was purified by flash column chromatography (0-15percent EtOAc-hexane gradient elution) to afford the desired 5-bromo-pyridine-2-carbaldehyde 9 (10.2 g, 52percent yield ) as pale-yellow solids.Following general procedure of Wang et al. [35], a solution of BuLi (2.5 M in hexanes, 10.0 ml, 25.3 mmol) was slowly added to a solution of 2, 5-dibromopyridine (5.0 g, 21 mmol) in dry toluene (250 ml) at −78 °C and the mixture was stirred for 5 h. Next, dry DMF (2.15 ml, 27.6 mmol) was added. After stirring for 1 h at −78 °C, the solution was warmed up to −10 °C and the reaction was quenched with saturated NHSynthesis of Compound 1038A solution of 2, 5-Dibromo-pyridine (22.2 g, 93.7 mmol, 1.0 equiv.) in toluene (1.2 L) was treated with nBuLi (70.25 ml, 112.4 mmol, 1.2 equiv.) dropwise at -78° C. The resulting solution was stirred at -78° C. for about 30 minutes, and DMF (11 ml, 141 mmol, 1.5 equiv.) was added. The reaction solution was warmed up gradually to RT and then stirred overnight. When TLC and MS showed the reaction was complete, the reaction mixture was concentrated in vacuo, and the residue was directly purified by column chromatography (SiOTo a stirred solution of 5-bromopicolinonitrile (0.5 g, 2.732 mmol, 1.0 eq) in tetrahydrofuran (10 mL) at -78 °C DIBAL (4 mL, 4.98 mmol, 1.5 eq) was added and reaction mixture was stirred for 4 h at -78 °C. The reaction mixture was monitored by TLC, and quenched with 2N HCI (2 mL) and extracted with dichloromethane (10 mL), dried over sodium sulphate and evaporated to provide fairly pure 5-bromopicolinaldehyde (0.3 g, ~ 60 percent) which was used to the next stage without further purification.Example V; Preparation of [1-(6-difluoromethylpyridin-3-yl)ethyl](methyl)-oxido-λExample V; Preparation of [1-(6-difluoromethylpyridin-3-yl)ethyl](methyl)-oxido-λTo a solution of 2-iodo-5-bromopyridine (18.4 g, 65 mmol) in THF (100 mL) at -15° C. was added isopropylmagnesium chloride (2M, 35 mL, 70 mmol) dropwise at a rate such that the temperature of the reaction did not exceed 0° C. The reaction was stirred at -15° C. for 1 h, then DMF (7.5 mL, 97 mmol) was added dropwise at a rate such that the temperature of the reaction did not exceed 0° C. The reaction was stirred for 30 min, then warmed to room temperature for an additional 1 h. The reaction was cooled back down to 0° C. and 2 N HCl (80 mL) was added dropwise, maintaining the temperature below 20° C. After stirring for 30 min, 2 N NaOH was added until pH 7 was reached. The organic layer was then separated and the aqueous layer extracted with CHTo a solution of 2-iodo-5-bromopyridine (18.4 g, 65 mmol) in THF (100 mL) at −15° C. was added isopropylmagnesium chloride (2M, 35 mL, 70 mmol) dropwise at a rate such that the temperature of the reaction did not exceed 0° C. The reaction was stirred at −15° C. for 1 h, then DMF (7.5 mL, 97 mmol) was added dropwise at a rate such that the temperature of the reaction did not exceed 0° C. The reaction was stirred for 30 min, then warmed to room temperature for an additional 1 h. The reaction was cooled back down to 0° C. and 2 N HCl (80 mL) was added dropwise, maintaining the temperature below 20° C. After stirring for 30 min, 2 N NaOH was added until pH 7 was reached. The organic layer was then separated and the aqueous layer extracted with CHA solution of isopropylmagnesium chloride Grignard reagent (26.52g, 257.84mmol) in tetrahydrofuran wasslowly added dropwise to a solution of 5-bromo-2-iodopyridine (61g, 214.87mmol) in tetrahydrofuran (700mL) at -20°Cunder nitrogen, the solution was stirred at -20°C for 3 hours and warmed to 0°C. N, N-dimethylformamide (18.85g, 257.84mmol) was added dropwise in batches at 0°C. The reaction solution was warmed to 20°C after the addition, andfurther stirred for 6 hours. When TLC showed the completion of the reaction, the reaction solution was added withsaturated ammonium chloride (100mL) to quench the reaction, and the aqueous layer was extracted with ethyl acetate(140mL 3 3), the organic layers were combined and washed with brine (100mL 3 2) and dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give the title compound (44g) which was used directly in the next stepwithout further purification 1H NMR (400MHz, CHLOROFORM-d) ppm 10.04 (s, 1H), 8.85 (d, J=1.8 Hz, 1H), 8.03 (dd, J=1.8, 8.3 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H).

Molecular Weight:186.01
XLogP3:1.3
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:184.94763
Monoisotopic Mass:184.94763
Topological Polar Surface Area:30
Heavy Atom Count:9
Complexity:107
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes