4,6-dichloronicotinaldehyde

Part II -- Synthesis of 4, 6-dichloropyridine-3-carbaldehyde [0231] (4, 6-Dichloropyridin-3-yl)methanol (4.9 g, 28 mmol) was dissolved in CHC1(4, 6-dichloropyridin-3-yl) methanol (4 g, 22.5 mmol) was dissolved in 200 mL of dichloromethane and then manganese dioxide (13.7 g, 157.6 mmol) was added and reacted at room temperature overnight. The manganese dioxide was removed by filtration through celite and the reaction solution was concentrated under reduced pressure to give 4, 6-dichlorotolic aldehyde as a white solid(3.5 g, yield 88.4percent).Step 2, Preparation of intermediate 4, 6-dichlorotolic aldehyde(4, 6-dichloropyridin-3-yl) methanol (4 g, 22.5 mmol) was dissolved in 200 mL of dichloromethane, Manganese dioxide (13.7 g, 157.6 mmol) was then added and allowed to react overnight at room temperature. The manganese dioxide was removed by filtration through celite, and the reaction solution was concentrated under reduced pressure to give 4, 6-dichloronicotinic aldehyde (3.5 g, yield 88.4percent) as a white solid.[01368] To a 2000-nt 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed (4, 6-dichloropyridin-3-yl)methanol (78.4 g, 440.41 mmol, 1.00 equiv), dichioromethane (1000 mL), PCC (284.83 g, 1.32 mol, 3.00 equiv) and Silica gel (235 g). The resulting mixture was stined at room temperature for 4 h and concentrated under vacuum. The residue was applied onto a silica gel colunm eluted with ethyl acetate/petroleum ether (0:1-1:6) to afford 62 g (80percent) of 4, 6-dichloropyridine-3-carbaldehyde as a white solid.To a 2000-mL 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed (4, 6-dichloropyridin-3-yl)methanol (78.4 g, 440.41 mmol, 1.00 equiv), dichloromethane (1000 mL), PCC (284.83 g, 1.32 mol, 3.00 equiv) and Silica gel (235 g). The resulting mixture was stirred at room temperature for 4 h and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (0:1-1 :6) to afford 62 g (80percent) of 4, 6-dichloropyridine-3-carbaldehyde as a white solid.To a solution of (4, 6-dichloropyridin-3-yl)methanol (4.9 g, 1.0 eq) in DCM (150 mL) at 0°C under nitrogen atmosphere, Dess-Martin periodinane (17.5 g, 1.5 eq) was added and stirred at rt for 2 h while monitoring by TLC. After TLC showed completion of starting material, the solution was quenched with water (20 mL) and filtered through Celite® bed. The filtrate was extracted with DCM (150 mL) and the organic layer was washed with saturated NaHC0A solution of oxalyl chloride (2.32 mL, 26.963 mmol) in DCM (30 mL) was cooled down to -78 °C. To this solution was added DMSO (3.83 mL, 53.922 mmol) dropwise under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for another 30 min. To this reaction mixture was added a solution of (4, 6-dichloro-3- pyridyl)methanol (1.6 g, 8.987 mmol) in DCM (10 mL), and then the reaction mixture was stirred for 30 min. Then, to this stirred reaction mixture was added triethylamine (11.2 mL, 80.883 mmol). The reaction mixture was stirred at the same temperature for another 30 min. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was quenched with saturated sodium bicarbonate solution (30 mL). The product was extracted using DCM (2x50 mL). The combined organic layer was again washed with water (3x30 mL) and finally with brine solution (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4, 6-dichloropyridine-3-carbaldehyde (1.53 g) as a light yellow solidTo a solution of 202.1 (lOg, 0.045mmol, l .Oeq) in dichloromethane (lOOmL) at -78°C, diisobutyl aluminium hydride (54mL, 0.054mmol, 1.2eq) was added. Reaction mixture was stirred at -78°C for lh. After completion of reaction, methanol was slowly added to the reaction mixture at -78°C followed by addition of IN HC1 and extracted with dichloromethane. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain 206.1. (7.0g, 87.52 percent). MS(ES): m/z 175.48 [M]+A stirred -60 °C solution of ethyl 4, 6-dichloronicotinate (4.0 g, 18.2 mmol) in DCM (70mL) was treated dropwise with diisobutylaluminum hydride (1 M in toluene) (20.0 mL, 20.0 mmol) over 20 mins (temperature -50 °C to -60 °C during addition), and stirred at -60°C for 3 hours. The reaction was quenched by dropwise addition of 1M HC1 (50 mL) andstirred for 1 hour. Extra DCM (100 mL) was added, the layers separated, and the aqueouslayer was extracted with another portion of DCM (100 mL). The combined organic layerswere washed with brine, dried and evaporated to give a crude solid which was purified byflash silica chromatography, elution gradient 0 to 20percent EtOAc in heptane. Pure fractions were evaporated to dryness to afford 4, 6-dichloronicotinaldehyde (2.55 g, 80percent) as a white crystalline solid. ‘H NMR (500 MHz, DMSO-d6, 27 °C) 8.02 (1H, d), 8.80 (1H, t), 10.25 (1H, s). m/z: ES+ [M+MeOH2]+ 208.To a solution of ethyl 4, 6-dichloronicotinate (500 mg, 2.43 mmol) in DCM at - 78°C, DIBAL-H (2.67 mL, 2.67 mmol) was added dropwise and stirred for 3h at -78°C. The mixture was allowed to warm up to 0°C then water (0.12 mL) was added dropwise to the mixture followed by aq. NaOH (15percent, 0.12 mL). H4, 6-Dichloropyridine-3-carbaldehyde To the solution of methyl 4, β-dichloropyridine-S-carboxylate (20 g, 91.32 mmol) in CH2CI2 (200 ml) at -78 To a solution of methyl 4, 6-dichloronicotinate (370 g, 1.8 mol) in dichloromethane (4500 mL) was added diisobutylaluminum hydride (1.00 M in dichloromethane, 1974 mL) at -70 °C. The reaction was stirred at -70 °C for 30 min, quenched with 2M HCl, and extracted with dichloromethane (2x). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography on silica gel (eluent: 30percent EtOAc in heptane) to give 4, 6-dichloronicotinaldehyde (76.8 g, yield 45percent). LCMS (ESI) [M+H]To a stirred solution of ethyl 4, 6-dichloronicotinate (36.8 g, 1.0 eq) in DCM (250 mL) at -78°C under nitrogen atmosphere, DiBAL-H (1.2 eq, 1M solution in toluene) was added drop wise and stirred at -78°C for 30 min while monitoring by TLC. After TLC showed completion of starting material, the solution was quenched with saturated ammonium chloride solution (50 mL) at -78°C and diluted with DCM (1 L). The layers were separated and the organic layer was washed with brine (200 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The resulting crude material was purified by flash chromatography (Combiflash® - Redisep, 120 g) using EtOAc in hexane as the eluent. The 4, 6-dichloronicotinaldehyde was eluted at 7percent EtOAc in hexane and the (4, 6-dichloropyridin-3-yl)methanol was eluted at 10percent EtOAc in hexane. The aldehyde fractions were concentrated to obtain aldehyde as white solid (9.86 g, 33.5percent). 1H NMR (400 MHz, CDC1