(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine

3-[(1R)-1-(2, 6-dichloro-3-fluorophenyl)ethoxy]-2-nitropyridine 3-Hydroxy-2-nitropyridine (175 mg, 1.21 mmol) and triphenylphosphine (440 mg, 1.65 mmol) were added sequentially to a stirred solution of (1S)-1-(2, 6-dichloro-3-fluorophenyl)ethanol (229.8 mg, 1.1 mmol) in THF (10 mL) under a nitrogen atmosphere. The reaction mixture was maintained at room temperature for 1 h and then diisopropyl azo-dicarboxylate (0.34 mL, i.65 mmol) was added at 0°C. The mixture was stirred for an additional 12 h. The reaction mixture was evaporated under vacuum to give an oil. The residue was purified by flash chromatography (eluting with 20->25percent EtOAc in hexanes) to give the title compound as a white solid (321.5 mg; 0.97 mmol; 88.3percent yield); MS (APCI) (M+H)The (S) - 1 - (2, 6-dichloro-3-fluoro phenyl) ethanol (42.80g, 204 . 7mmol), 3-hydroxy-2-nitro-pyridine (28.97g, 206 . 8mmol), triphenylphosphine (61.22g, 233 . 4mmol) in 300 ml toluene in, N300 g of TM2, 205 g of SM2 and 540 g of triphenylphosphine were dissolved in 2 L of THF and 361 g of DEAD was added dropwise at 0 ° C. After completion of the dropwise addition, the mixture was stirred at room temperature for two hours, and the reaction was complete by TLC (PE / EA = 3: 1).The ethyl acetate layer was dried and concentrated to 2 ° C to 0 ° C to precipitate a large amount of solid which was collected by filtration and the filtrate was concentrated to a final concentration of ethyl acetate. 1L. After cooling, the solid was separated. The solids were collected by filtration twice, washed with PE / EA = 5: 1 and filtered to remove solids (about 500 g), and the filtrate was evaporated to remove the solvent.Column chromatography gave 400 g of TM3 (pale yellow solid, eluent PE / EA = 7: 1) in 80percent yield.Step 1: (S)-1-(2, 6-dichloro-3-fluorophenyl)ethanol (20.9 g, 0.10 mol) was dissolved in anhydrous tetrahydrofuran (200 mL), and then 3-hydroxy-2-nitropyridine (16.0 g, 0.11 mol) and triphenylphosphine (40.0 g, 0.15 mol) were subsequently added under a nitrogen atmosphere. (S)-1-(2, 6-dichloro-3-fluorophenyl)ethanol (20.9 g, 0.10 mol) was dissolved in 200 mL anhydrous tetrahydofuran, to which 3-hydroxy-2-nitropyridine (16.0 g, 0.11 mol) and triphenylphosphine (40.0 g, 0.15 mol) were sequentially added under a nitrogen atmosphere, and the reaction solution was stirred at room temperature for 1 hour, cooled to 0° C. and diisopropyl azodicarboxylate (40 mL, 0.15 mol) was added dropwise. 1.82 kg of compound (CZT-2), 1.23 kg 3-hydroxy-2-nitropyridinewith2.60 kg of triphenylphosphine dissolvedIn 15.0 liters of dry toluene, Nitrogen protection, Cool to -20 degrees.In 3 hours slowly joined2.04 kg DIAD 2.62 litersToluene solution, Keep the system temperature between -20 degrees and -10 degrees, After the addition was complete, the temperature was raised to 25 ° C for 2 hours.Add 0.16 liters of water to quench the reaction, Cooled to -5 degrees, filter, The filtrate was concentrated under reduced pressure.Recrystallization from 7.5 liters of absolute ethanol, To obtain 2.50 kg of compound (CZT-3) in a yield of 85percentStep 1) (R)-3-(l-(2.6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine [0168] To a solution of (R)-l-(2, 6-dichloro-3-fluorophenyl)ethanol (10 g, 47.84 mmol) in THF (150 mL) was added NaH (2.3 g, 57.41 mmol, 60percent dispersion in mineral oil) in portions at 0°C in 30 min. The mixture was stirred at rt for 2 h, followed by the dropwise addition of a solution of 3-fluoro-2-nitropyridine (8.2 g, 57.41 mmol) in THF (80 mL) at 0°C over 20 min. The reaction was stirredat rtfor 3 h, then quenched with iced water (10 mL) and concentrated in vacuo. The residue was diluted with EtOAc (150 mL) and HTo a solution of (R)-1-(2, 6-dichloro-3-fluorophenyl)ethanol (10 g, 47.81 mmol, Zhenjiang Radiant Pharma, Ltd. China) in THF (150 mL) was added NaH (1.40 g, 57.42 mmol) in portions at 0°C in 30 minutes. The mixture was then stirred at room temperature for 2h. A solution of 3-fluoro-2-nitropyridine(8.2 g, 57.43 mmol, Shanghai Link Chem, Ltd. China) in THF (80 mL) was added to the reaction dropwise over 20 mm at 0°C. The reaction was then warmed up to rt and stirred further for 3 h. The reaction was quenched with 1 0mL of iced water, and the resulted solution was concentrated in vacuo. The residue was diluted with 150 mL of water, and the resulted aqueous mixture was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with saturated NaHCO3 (400 mL), brine (400 mL), dried over Na2504 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc = 6/1 to 4/1) to provide the title compound as a white solid (13.4 g, 84.8percent). LC-MS (ESI, pos. ion) m/z: 331 [M + H]+.To a solution of (R)-l-(2, 6-dichloro-3-fluorophenyl)ethanol (10 g, 47.84 mmol) in THF (150 mL) was added NaH (2.3 g, 57.41 mmol, 60percent dispersion in mineral oil) in portions at 0 °C over 30 min. The mixture was stirred at rt for 2 h, followed by the addition of a solution of 3-fluoro-2-nitropyridine (8.2 g, 57.41 mmol) in THF (80 mL) at 0 °C over 20 min. The reaction was stirred at rt for 3 h, then quenched with iced water (10 mL) and concentrated in vacuo. The residue was diluted with HThe (R)-1-(2, 6-dichloro-3-fluoro phenyl) ethanol (10g, 47.81mmol) dissolved in tetrahydrofuran (10 ml) in, cooling to 0 °C, in 30 minutes, the batch by adding sodium hydride (1.4g, 57 . 42mmol). Stirring the mixture at room temperature for 2 hours, to cool again to 0 °C, in 20 minutes, adding dropwisely the reaction system 3-fluoro-2-nitro-pyridine (8.2g, 57 . 43mmol) tetrahydrofuran (80 ml) solution. Restored to the room temperature, to continue stirring 3 hours. the response finishes, ice water (10 ml) quenching the reaction, and concentrated under reduced pressure. Residue water (150 ml) is diluted, and using ethyl acetate (150mLx3) extraction. Combined organic phase with saturated NaHCO (R) -1- (2, 6-dichloro-3-fluorophenyl) ethanol (10 g, 47.84 mmol)Was dissolved in tetrahydrofuran (150 mL)The solution was cooled to 0 ° C, Within 30 minutes, To this was added sodium hydride (2.3 g, 57.41 mmol, 60percent dispersion in mineral oil).The mixture was stirred at room temperature for 2 hours, Again cooled to 0 ° C, And in 20 minutes, To this was added 3-fluoro-2-nitropyridine (8.2 g, 57.41 mmol)In tetrahydrofuran (80 mL).The reaction solution was stirred at room temperature for 3 hours, Add ice water (10 mL) and concentrate under reduced pressure.The residue was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 3).The combined organic phases were washed successively with saturated sodium bicarbonate solution (400 mL)Brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4/1)The title compound was obtained as a white solid (13.4 g, 84.6percent).3-Hydroxy-2-nitropyridine (175 mg, 1.21 mmol) and triphenylphosphine (440 mg, 1.65 mmol) were added sequentially to a stirred solution of (1S)-1-(2, 6-dichloro-3-fluorophenyl)ethanol (229.8 mg, 1.1 mmol) in THF (10 mL) under a nitrogen atmosphere. The reaction mixture was maintained at room temperature for 1 h and then diisopropyl azo-dicarboxylate (0.34 mL, 1.65 mmol) was added at 0°C. The mixture was stirred for an additional 12 h. The reaction mixture was evaporated under vacuum to give an oil. The residue was purified by flash chromatography (eluting with 20->25percent EtOAc in hexanes) to give the title compound as a white solid (321.5 mg; 0.97 mmol; 88.3percent yield); MS (APCI) (M+H)The compound of formula (III) (25 g, 0.087 mol) was added to the reaction flask, 2-nitro-3-hydroxypyridine (XII) (14 g, 0.1 mol) was added, DIPEA (33.7 g, 0.26 mol) and2-MeTHF (300 mL).The reaction was heated at reflux for 4 h. TLC indicated the reaction of the starting material was complete. The reaction solution was cooled to room temperature, filtered and the cake was used2-MeTHF (20 mL).The filtrate was washed successively with 1N HCl, 5percent NaHCO3 and saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 26.5 g of a yellow solid in a yield of 92.1percent

Molecular Weight:331.12
XLogP3:4.2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:329.9974257
Monoisotopic Mass:329.9974257
Topological Polar Surface Area:67.9
Heavy Atom Count:21
Complexity:372
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes