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a) N-(4-bromo-5-chloro-2-fluorophenyl)-2-[(35)-l-(cyclopropylcarbonyl)-3- pyrrolidinyl]acetyl}hydrazinecarboxamideTo a round bottom flask was added triphosgene (2.66 mmol) and dichloromethane (20 mL) under nitrogen, and the solution was cooled to -78 C. In a separate vial, 4- bromo-5-chloro-2-fluoroaniline (6.83 mmol) was dissolved in dichloromethane (20 mL) and Hunig's base (17.1 mmol) was added. This solution was slowly added to the cooled solution and then the reaction was allowed to warm to room temperature. After 10 min, analysis by LCMS indicated desired intermediate formation. The reaction was cooled again to -78 C and 2-[(35)-l-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (3.98 mmol) in dichloromethane (5 mL) was added slowly. The reaction was allowed to warm to room temperature and stirred for 30 min. Analysis by LCMS indicated desired product formation. The reaction was poured into a separatory funnel and partitioned with saturated aq sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3x) and the combined organic layers were dried over Na2S04, filtered, and concentrated to an oil. The residue was purified by silica gel chromatography (0-15%isopropanol/ethyl acetate). The desired fractions were combined and concentrated to afford the title product as an oil (1.12 g, 60%). MS(ES)+ m/e 461.1, 463.0 [M+H]+.
With N-Bromosuccinimide; In acetonitrile; at 25℃; for 1h;
4-Bromo-5-chloro-2-fluoroaniline To a mixture of 5-chloro-2-fluoroaniline (1 equiv.) in acetonitrile (0.5 M) was added N-bromosuccinimide (1 equiv.) at 25 C. The mixture was stirred at 25 C. for 1 h. The mixture was concentrated to a residue, the residue was purified via silica gel chromatography to give 4-bromo-5-chloro-2-fluoroaniline (91%) as a yellow oil. 1H NMR (400 MHz, CDCl3) delta ppm: 7.23 (d, J=10.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 3.92-2.64 (br, 2H).
With N-chloro-succinimide; In acetonitrile; at 90℃; for 0.5h;
4-Bromo-2,3-dichloro-6-fluoroaniline To a mixture of <strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (1 equiv.) in acetonitrile (0.36 M) was added NCS (1 equiv.) portion-wise at 90 C. over 30 min. The mixture was stirred at 90 C. for 1 h. The residue was purified by chromatography to give 4-bromo-2,3-dichloro-6-fluoroaniline (76%) as a brown solid. 1H NMR (400 MHz, CDCl3) delta ppm: 7.35 (d, J=10.5 Hz, 1H).
With hydrogenchloride; iron; In ethanol; water; at 0℃; for 0.5h;
To a stirred solution of 99 (23 g, 90.39 mmol) in EtOH (90 mL) and cone HC1 (90 mL) cooled to 0 C was added Fe powder (47.52 g, 848.5 mmol) in small portions over 30 min. After addition was complete, the reaction mixture was stirred at RT for another 30 min. The solvent was distilled off under reduced pressure. Water was added to the resulting residue and the mixture neutralized with NaHC03 and diluted with EtOAc. The resulting biphasic reaction mixture was filtered through Celite and washed with EtOAc. The phases of the filtrate were separated and the organic layer was washed with water and brine solution, dried over Na2S04 and concentrated to afford 100 (18 g, 88.75 %) as a yellow solid.
Copper(I) cyanide (3.99 g, 44.55 mmol) was added to a mixture of <strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (5.0 g, 22.28 mmol) in DMF (30 mL) at room temperature, and the mixture was stirred at 150C for 5 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was filtered. The organic layer was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 4-amino-2-chloro-5-fluorobenzonitrile (2.81 g, 16.47 mmol, 74.0%) as a grayish white solid. 1H NMR (300 MHz, CDCl3):delta 4.34(2H,brs), 6.82(1H,d,J=7.6 Hz), 7.21-7.29(1H,m).
51.2%
In N,N-dimethyl-formamide; at 140℃; for 10h;
To a stirred solution of 100 (18 g, 80.19 mmol) in DMF (100 mL) was added cuprous cyanide (1 1.49 g, 128.2 mmol) and the resulting mixture was heated to 140 C for 10 h. The reaction mixture was cooled to RT and and DMF was evaporated under reduced pressure. The resulting residue was partitioned between DCM and water and the resulting biphasic mixture was filtered. The phases of the filtrate were separated and the organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The crude compound was purified by column chromatography (4% EtOAc/hexane) to afford 101 (7 g, 51.20%) as a white solid.
5-chloro-2-fluoro-4-(1-isobutyl-1H-pyrazol-4-yl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67 mg
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere; Irradiation;
<strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (100mg, 0.446mmol),Isobutyl-1H-pyrazole-4-boronic acid pinacol ester(223 mg, 0.891 mmol),Pd (dppf) Cl2 (163 mg, 0.223 mmol)And potassium carbonate (123 mg, 0.890 mmol) were stirred in 1,4-dioxane / water (10 mL / 2 mL)Under nitrogen atmosphere, the temperature was raised to 110 C for 1 hour under microwave irradiation.Cool to room temperature,add water,Dichloromethane extraction,dry,Purification by column chromatography gave 5-chloro-2-fluoro-4- (1-isobutyl-1H-pyrazol-4-yl) aniline(67.0 mg).
Chemistry
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120K+ Compounds
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