1-bromo-3-fluoro-5-methoxybenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (40 mg, 0.063 mmol) and 1-bromo-3-fluoro-5-methoxybenzene (15.62 mg, 0.076 mmol) in anhydrous dioxane (0.4 ml) was purged with N2 and then chloro[tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (6.5 mg, 0.013 mmol) and tripotassium phosphate (0.191 ml, 0.191 mmol) were added under N2 flow. The mixture was heated to 60° C. overnight. Then the crude mixture was extracted with DCM. The combined organic extracts were washed with water and evaporated under reduced pressure. 1 mL of 1:1 CH2Cl2 and TFA was added to the resulting residue and the solution was stirred for 2 h. Then the solvent was evaporated under reduced pressure to give an amber residue. The residue was diluted with 1.5 ml DMSO, filtered and purified by mass directed reverse phase column chromatography eluting with acetonitrile/water+0.1% TFA to give the title product. LC-MS: calculated for C25H21ClFN3O5, 497.12, observed m/e: 498.11 (M+H)+ (RT 1.03/2.00 min) Then the crude mixture was extracted with DCM The combined organic extracts were washed with water evaporated under reduced pressure 1 mL of 1:1 CH2Cl2 and TFA was added to the resulting residue Then the solvent was evaporated under reduced pressure to give an amber residue filtered purified by mass eluting with acetonitrile/water+0.1% TFA

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 1-bromo-3-fluoro-5-methoxybenzene (5 g), (4-methoxyphenyl)methanethiol (3.76 g), and toluene (100 mL) were added Pd2(dba)3 (0.447 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.564 g) and DIPEA (8.52 mL). The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (6.20 g). extracted with EtOAc The organic layer was separated washed successively with water and brine dried over MgSO4 concentrated in vacuo The residue was purified by silica gel column chromatography (EtOAc/hexane)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1-bromo-3-fluoro-5-methoxybenzene (15 g, 73.16 mmol), tris(2-methylphenyl)phosphane (1.781 g, 5.85 mmol) and ethyl acrylate (11.90 mL, 109.74 mmol) in TEA (135 mL) was added palladium(II) acetate (0.329 g, 1.46 mmol) at room temperature under nitrogen atmosphere, and the mixture was stirred at 90° C. for 2 days. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give ethyl (E)-3-(3-fluoro-5-methoxyphenyl)acrylate (14.2 g, 63.3 mmol, 87%) as a colorless oil. The solvent was evaporated under reduced pressure the residue was diluted with water the mixture was extracted with ethyl acetate The organic layer was washed with water and brine dried over magnesium sulfate the solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol) in DMF (20 mL) at 65° C. was slowly added a solution of 4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). After stirring for 30 minutes, a solution of 3-bromo-5-fluoroanisole (2.05 g, 10 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirred at 65° C. for 24 h. The reaction mixture was allowed to cool to ambient temperature then was poured into water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were loaded onto a SCX-2 cartridge, which was then washed with acetonitrile then eluted with 2N ammonia in methanol. Concentration of the basic methanolic fractions in vacuo gave the title compound (1.5 g, 50%). 1H NMR (CDCl3, 400 MHz): 6.65 (dd, J=2.2, 1.6 Hz, 1H), 6.63 (dd, J=2.3, 1.6 Hz, 1H), 6.37 (dd, J=2.3, 2.1 Hz, 1H), 4.29-4.21 (m, 1H), 3.75 (s, 3H), 2.70-2.61 (m, 2H), 2.31-2.21 (m, 5H), 2.01-1.93 (m, 2H), 1.86-1.75 (m, 2H). LCMS (Method B): RT=2.1 min, M+H+=300. the reaction mixture was stirred at 65° C. for 24 h extracted with ethyl acetate (2×100 mL) was then washed with acetonitrile then eluted with 2N ammonia in methanol

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1-bromo-3-fluoro-5-methoxybenzene (3.0 g, 0.015 mol) in dry CH2Cl2 (80 mL) under an inert atmosphere and cooled to −30° C. was added 1 M BBr3 (4.27 mL, 0.045 mol) in 21 mL of CH2Cl2 dropwise while maintaining temperature at −30° C. The reaction was stirred for 3 h at 0-5° C. and then the reaction mixture was quenched with aqueous saturated NaHCO3. Water was added and the mixture was extracted with CH2CO2 three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (2.54 g, 91%). the reaction mixture was quenched with aqueous saturated NaHCO3 Water was added the mixture was extracted with CH2CO2 three times The organic layer was washed with brine dried over Na2SO4 evaporated to dryness

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1-bromo-3,5-difluorobenzene (10 g, 0.052 mol) in dry DMF (300 mL) cooled to 0-5° C. was added sodium methoxide (5.60 g, 0.1036 mol) and the reaction mixture was stirred at RT for 24 h. The reaction mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (7.5 g, 71%). The reaction mixture was extracted with ethyl acetate three times The organic layer was washed with brine dried over Na2SO4 evaporated to dryness

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-methyl 2-amino-3-(3-fluoro-5-hydroxyphenyl)propanoate was purchased from NetChem (USA). (3-bromo-5-fluoroanisole (9-1) was purchased from Accela ChemBio Co., Ltd., (Shanghai, China) and can also be purchased from Amfinecom Inc (USA) or Apollo Scientific Ltd. (UK)). DL-5-fluoro-meta-tyrosine (9) and methyl 2-amino-3-(3-fluoro-5-hydroxyphenyl)propanoate (10)) were synthesised as follows.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol) in DMF (20 mL) at 65° C. was slowly added a solution of 4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). After stirring for 30 minutes, a solution of 3-bromo-5-fluoroanisole (2.05 g, 10 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirred at 65° C. for 24 h. The reaction mixture was allowed to cool to ambient temperature then was poured into water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were loaded onto a SCX-2 cartridge, which was then washed with acetonitrile then eluted with 2N ammonia in methanol. Concentration of the basic methanolic fractions in vacuo gave the title compound (1.5 g, 50%). 1H NMR (CDCl3, 400 MHz): 6.65 (dd, J=2.2, 1.6 Hz, 1H), 6.63 (dd, J=2.3, 1.6 Hz, 1H), 6.37 (dd, J=2.3, 2.1 Hz, 1H), 4.29-4.21 (m, 1H), 3.75 (s, 3H), 2.70-2.61 (m, 2H), 2.31-2.21 (m, 5H), 2.01-1.93 (m, 2H), 1.86-1.75 (m, 2H). LCMS (Method B): RT=2.1 min, M+H+=300. the reaction mixture was stirred at 65° C. for 24 h extracted with ethyl acetate (2×100 mL) was then washed with acetonitrile then eluted with 2N ammonia in methanol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A RBF was charged with 1-bromo-3-fluoro-5-methoxybenzene (2.104 g, 10.26 mmol), (3-chlorophenyl)boronic acid (1.765 g, 11.29 mmol), potassium carbonate (4.25 g, 30.8 mmol), and Pd(Ph3P)4 (0.593 g, 0.513 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (25.7 ml) and water (8.55 ml) were added. A reflux condenser was attached, and the flask was lowered into a 90° C. heating bath for 45 min. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 25-g silica gel column, 0-5% EtOAc/Heptane) to give 3′-chloro-3-fluoro-5-methoxy-1,1′-biphenyl (2.47 g, 10.44 mmol, 102% yield) as a clear oil containing about 10 wt % impurities. The flask was flushed with Ar (g) 1,4-dioxane (25.7 ml) and water (8.55 ml) were added A reflux condenser was attached was lowered into a 90° C. heating bath for 45 min diluted with water extracted with EtOAc (2×) The combined organic extracts were dried over sodium sulfate filtered concentrated The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 25-g silica gel column, 0-5% EtOAc/Heptane)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (40 mg, 0.063 mmol) and 1-bromo-3-fluoro-5-methoxybenzene (15.62 mg, 0.076 mmol) in anhydrous dioxane (0.4 ml) was purged with N2 and then chloro[tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (6.5 mg, 0.013 mmol) and tripotassium phosphate (0.191 ml, 0.191 mmol) were added under N2 flow. The mixture was heated to 60° C. overnight. Then the crude mixture was extracted with DCM. The combined organic extracts were washed with water and evaporated under reduced pressure. 1 mL of 1:1 CH2Cl2 and TFA was added to the resulting residue and the solution was stirred for 2 h. Then the solvent was evaporated under reduced pressure to give an amber residue. The residue was diluted with 1.5 ml DMSO, filtered and purified by mass directed reverse phase column chromatography eluting with acetonitrile/water+0.1% TFA to give the title product. LC-MS: calculated for C25H21ClFN3O5, 497.12, observed m/e: 498.11 (M+H)+ (RT 1.03/2.00 min) Then the crude mixture was extracted with DCM The combined organic extracts were washed with water evaporated under reduced pressure 1 mL of 1:1 CH2Cl2 and TFA was added to the resulting residue Then the solvent was evaporated under reduced pressure to give an amber residue filtered purified by mass eluting with acetonitrile/water+0.1% TFA