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Intermediate 3: 1-(4-chloro-3,5-difluorophenyl)-2,2,2-trifluoroethanone 5-Bromo-2-fluoro-1 ,3-dichlorobenzene (7.0 g, 28.7 mmol) was stirred at room temperature in THF (50 ml_) under argon and isopropylmagenesium chloride lithium chloride complex (24.3 ml_, 1.3 M in THF, 1.1 eq) was added over 1 min and stirred at RT for 30 min. To this was added piperidine trifluoroacetamide (5.6 ml_, 1.32 eq) over about 1 minute at 0C and the reaction was stirred at room temperature for 2 h. The reaction was quenched with aqueous saturated NH4CI (50 ml_) and extracted with MTBE (2 x 50 ml_). Solvents were removed under reduced pressure and the crude product was purified using 12 g Redi-Sep column, eluting with 0 to 50% ethyl acetate in heptanes, to yield 3.5 g of 1-(4-chloro-3,5-difluorophenyl)-2,2,2- trifluoroethanone. H-NMR (400 MHz, CDCI3) delta ppm 8.06 (dd, 2H, J1 = 6.2 Hz, J2 = 0.9 Hz).
1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroethan-1-one (Intermediate Compound 9) (0328) (0329) 9 (0330) [0164] To a cooled (10 C) solution of 1-bromo-3,5-dichloro-4-fluorobenzene (1.10 kg, 4.51 mol) in THF (9.70 L) was added /-PrMgCI LiCI (3.64 L, 4.74 mol, 1.3 molar) while maintaining the internal temperature at < 20 C. The reaction was stirred for 2 hours with an internal temperature of 18 C, before cooling to - 9 C. Methyl trifluoroacetate (499 ml_, 4.96 mol) was added while maintaining the internal temperature < 10 C. Reaction was warmed to 20 C and stirred for 3 hours before it was quenched with 4 molar HCI (1.50 L). The biphasic mixture was stirred 2 hours before it was diluted with heptane (4 L). The reaction was mixed for 10 min. and the layers allowed to separate. The aqueous layer was removed extracted 1X 2 L EtOAc and the combined organic fractions were washed 1 X 4L 22% aq. NaCI and dried over MgS04 (1.5 kg) for 15 hours. The organic solution was filtered and concentrated in vacuo. The residue was dissolved in toluene (4 L) and concentrated in vacuo. The resultant oil was dissolved in toluene (4 L) and concentrated in vacuo a second time to give 1.06 kg of 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroethan-1-one (89%) that was 91% pure. (0331) [0165] Note that the yields for smaller scale reactions have ranged between 60 - 94% for this experiment. (0332) [0166] 1H NMR (400MHz, CHLOROFORM-d) delta = 8.06 (dd, J=0.8, 6.1 Hz, 2H). (0333) [0167] Note that the hemiacetal hydrate can be detected in the 1H NMR as a doublet at delta = (0334) 7.69.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In toluene; at 110.0℃;Inert atmosphere;
5-bromo-1 ,3-dichloro-2-fluorobenzene (1 .00 equivalents), bis(pinacolato)diboron (1 .30 equivalents), Pd(dppf)Cl2 (0.05 equivalents) and potassium acetate (2.50 equivalents) are stirred under nitrogen atmosphere in toluene at 1 10 C until completion of the reaction (monitoring with GC/MS, usually finished within 4-16 h). Active carbon and Celite (kieselguhr) are added to the reaction mixture and stirred at 100 C for 10 minutes. Subsequently, the mixture is hot filtered and concentrated under reduced pressure. The obtained crude product is purified via column chromatography using a cyclohexane/ dichloromethane mixture (1 :1 ), giving E1 as solid (78 %).
78%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In toluene; at 110.0℃;Inert atmosphere;
5-bromo-1 ,3-dichloro-2-fluorobenzene (1 .00 equivalents), bis(pinacolato)diboron (1 .30 equivalents), Pd(dppf)Cl2 (0.05 equivalents) and potassium acetate (2.50 equivalents) are stirred under nitrogen atmosphere in toluene at 1 10 C until completion of the reaction (monitoring with GC/MS, usually finished within 4-16 h). Active carbon and Celite (also known as diatomaceous earth or kieselgur) are added to the reaction mixture and stirred at 100 C for 10 minutes. Subsequently, the mixture is hot filtered and concentrated under reduced pressure. The obtained crude product is purified via column chromatography using a cyclohexane/ dichloromethane mixture (1 :1 ), giving E1 as solid (78 %). AAV1 (78% yield), wherein 5-bromo-1 ,3-dichloro-2-fluorobenzene (CAS 17318-08-0) and bis(pinacolato)diboran (CAS 73183-34-3) were used as reactants
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