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Stage #1: With aluminum (III) chloride In dichloromethane at 0℃; for 1 h; Stage #2: at -80℃; for 16 h;
AlCl3 (16.89 g, 126.7 mmol) was dissolved in DCM (130 mL), and AcCl (9 mL, 126.7 mmol) was added thereto at 0°C. The mixture was stirred for 1 hour. (4-bromo-2,6-difluoro-phenyl)-trimethyl-silane (27.48 g, 105.59 mmol) obtainedin Step B was dissolved in DCM(70 mL) and slowly added thereto at -80°C. The mixture was stirred for 16 hours. Aftertermination of the reaction, the reaction solution was diluted with ammonium chloride aqueous solution at 0°C andextracted with Et2O. The organic layer was dried with anhydrous magnesiumsulfate and purified by column chromatography(eluent, EtOAc/Hex = 1/10) to obtain the title compound (19.89 g, 74 percent).NMR: 1H-NMR (CDCl3) δ 7.16(2H, m), 2.58(3H, s)
A mixture of l-(4-bromo-2,6-difluorophenyl)ethanone (prepared according to the method described in PCT Patent Publication WO 2004/72070; 4.56 g, 19.4 mmol) and N,N-dimethylacetamide dimethyl acetal (6.94 g, 58.2 mmol) in toluene (45 mL) was refluxed for 16 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes to yield the title compound (4.78 g). in NMR delta 7.79 (br s, 1H), 7.11 (m, 2H), 5.31 (br s, 1H), 3.12 (br s, 3H), 2.89 (s, 3H).
1-Bromo-3,5-difluorobenzene (100 g) was dissolved in THF (600 mL) and cooled to -78C. LDA (300 mL, 2N in heptane/ THF/ethylbenzene) was added over 20 mm and the mixture stirred for 1 h. This mixture was added via transfer canula to acetic anhydride (250 mL, cooled to -78C) within 30 mins. Then the mixture was warmed to -30C, THF was removed in vacuum and dichloromethane (300 mL) was added. The mixture was basified with saturated sodium bicarbonate solution and extracted 3x with dichloromethane (300 mL). The organic phase was washed with sat. ammonia chloride solution and sat. brine, dried and concentrated at 100 mbar/ 50C in vacuum. The residue was fractional destilled in vacuum at 30 to 10 mbar/ 70-100C to yield 57.8 g and 74.7 g (content 80%) desired product.Analysis: HPLC-MS: R1 = 0.974 mm (Z018_504), M+H = 235
(R)-4-{(R)-1-[2,3-dimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazol-4-yloxy]ethyl}-1-[(S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one[ No CAS ]
With hydrazine hydrate; In tetrahydrofuran; at 20℃;
To 1-(4-Bromo-2,6-difluoro-phenyl)ethanone (22.05 g) dissolved in THF (80 mL) was added hydrazine hydrate (10 mL) at ambient temperature and the mixture was stirred over night. Water (50 mL) and 2-Me-THF (70 mL) were added and the organic phase was dried and concentrated in vacuum. The crude product was dissolved in acetonitrile (70 mL) at 80C and cooled to room temperature for 2 days. The precipitate was filtered and washed with acetonitrile and dried under vacuum for 45 mm at 45C to provide 15.6 g white needles.Analysis: HPLC-MS: R1 = 0.58 mm (X01 1_503), M+H = 229/231
4-bromo-2,6-difluoro-N-methoxy-N-methylbenzamide[ No CAS ]
[ 75-16-1 ]
[ 746630-34-2 ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; diethyl ether; at 0 - 20℃; for 18h;
A mixture of 4-bromo-2,6-difluorobenzoic acid (5.0 g, 21 mmol), HATU (9.63 g, 25.3 mmol), N,O-dimethylhydroxylamine hydrochloride (2.06 g, 21.1 mmol), and DIPEA (5.45 g, 42.2 mmol) in DMF (30 mL) was stirred at rt for 16 h. After this time, a saturated aqueous NH4Cl solution was added, and the resulting mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:EtOAc=2:1) to give the title compound as colorless gum.
AlCl3 (16.89 g, 126.7 mmol) was dissolved in DCM (130 mL), and AcCl (9 mL, 126.7 mmol) was added thereto at 0C. The mixture was stirred for 1 hour. (4-bromo-2,6-difluoro-phenyl)-trimethyl-silane (27.48 g, 105.59 mmol) obtainedin Step B was dissolved in DCM(70 mL) and slowly added thereto at -80C. The mixture was stirred for 16 hours. Aftertermination of the reaction, the reaction solution was diluted with ammonium chloride aqueous solution at 0C andextracted with Et2O. The organic layer was dried with anhydrous magnesiumsulfate and purified by column chromatography(eluent, EtOAc/Hex = 1/10) to obtain the title compound (19.89 g, 74 %).NMR: 1H-NMR (CDCl3) delta 7.16(2H, m), 2.58(3H, s)
(2E,4E)-5-(4-bromo-2,6-difluorophenyl)hexa-2,4-dienoic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
(E)-4-diethoxyphosphorylbut-2-enoic acid ethyl ester (75 %) (9.21 g, 36.806 mmol) obtained in Step A wasdissolved in THF (70 mL), and LiHMDS (37 mL, 36.80 mmol) was slowly added thereto at -78C. The mixture was stirredfor 30 minutes and cooled to - 78C. <strong>[746630-34-2]1-(4-bromo-2,6-difluoro-phenyl)ethanone</strong> (7.16 g, 28.31 mmol) obtained in Step Cwas dissolved in THF(25 mL) and slowly added thereto. The mixture was stirred at room temperature for 16 hours. Thereaction solution was diluted with ammonium chloride aqueous solution at 0C and extracted with Et2O. The organiclayer was dried with anhydrous magnesiumsulfate and purified by column chromatography (eluent, EtOAc/Hex = 1/20)to obtain the title compound (7.95 g, 84 %).NMR: 1H-NMR (CDCl3) delta 7.67(1H, m), 7.12(2H, m), 6.26 (1H, d), 5.96(1H, d), 4.23(2H, q), 2.20(3H, m), 1.31(3H, t)
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In tetrahydrofuran; water; at 80℃; for 48h;Inert atmosphere;
General procedure: To a two-neck flask were added 4-(9H-9-Carbazole)phenylboronic acid (1.52 g, 5.3 mmol), 4-bromo-2,6-difluorobenzylaldehyde (0.77 g, 3.5 mmol), THF (20.0 mL), and aqueous potassium carbonate solution (12.5 mL, 2.0 M). The mixture was degassed by the freeze-pump-thaw cycle two times. Pd(PPh3)2Cl2 (280.4 mg, 0.4 mmol) was added and degassed by freeze-pump-thaw once again. Then the bright yellow solution was slowly heated to 80 C under nitrogen atmosphere and kept for 48 h and then extracted with DCM and water. The organic layers were combined and dried with anhydrous Na2SO4. Finally, the crude product was concentrated under reduced pressure and further purified by silica gel column chromatography (PE/DCM = 1/4-1/2) to furnish the desired product Cz-24 (1.25 g, 93.0%).
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