4-(Benzyloxy)-3-chlorobenzaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-[5-Amino-1-(1,1-diethylethyl)-3-methyl-1H-pyrazol-4-yl]-3-fluoro-2-(methyloxy)phenol (2.2 g, 7.5 mmol.) and 3-chloro-4-[(phenylmethyl)oxy]benzaldehyde (2.23 g, 8.6 mmol.) were taken into acetic acid (25 mL) and the resulting mixture heated to 90° C. over 12 hours. An additional aliquot of benzaldehyde (250 mg) was then added and heating was continued an additional 7 hours. At this time air was bubbled through the solution at a steady rate while maintaining a temperature of 90° C. then the mixture was allowed to cool to room temperature. The acetic acid was removed and the residue partitioned with saturated aquyeous sodium hydrogencarbonate and ethyl acetate. The organic layer was then washed once with brine then dried over anhydrous sodium sulfate, filtered and concentrated to give a residue containing roughly a 1:1 mixture of two cyclization products. The desired cyclization isomer was purified by silica gel flash chromatography using 2:1 hexanes ethyl acetate as eluent to afford 5-{3-chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6-fluoro-1-methyl-7-(methyloxy)-3H-pyrazolo[3,4-c]isoquinolin-8-ol (1.73 g, 44% yield) as a yellow solid after concentration and drying of the pure fractions in vacuo. 1H NMR (400 MHz, CDCl3): 7.66 (dd, 1H), 7.59 (d, 1H), 7.54 (d, 1H), 7.46-7.34 (m, 5H), 7.07 (d, 1H), 6.54 (s, 1H), 5.25 (S, 2H), 4.03 (d, 3H), 2.80 (s, 3H), 1.83 (s, 9H); MS (EI) for C29H27N3O3FCl: 520 (MH+). heating At this time air was bubbled through the solution at a steady rate while maintaining a temperature of 90° C. to cool to room temperature The acetic acid was removed the residue partitioned with saturated aquyeous sodium hydrogencarbonate and ethyl acetate The organic layer was then washed once with brine then dried over anhydrous sodium sulfate filtered concentrated to give a residue containing roughly a 1:1 mixture of two cyclization products The desired cyclization isomer was purified by silica gel flash chromatography

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-[5-Amino-1-(1,1-diethylethyl)-3-methyl-1H-pyrazol-4-yl]-3-fluoro-2-(methyloxy)phenol (2.2 g, 7.5 mmol.) and 3-chloro-4-[(phenylmethyl)oxy]benzaldehyde (2.23 g, 8.6 mmol.) were taken into acetic acid (25 mL) and the resulting mixture heated to 90° C. over 12 hours. An additional aliquot of benzaldehyde (250 mg) was then added and heating was continued an additional 7 hours. At this time air was bubbled through the solution at a steady rate while maintaining a temperature of 90° C. then the mixture was allowed to cool to room temperature. The acetic acid was removed and the residue partitioned with saturated aquyeous sodium hydrogencarbonate and ethyl acetate. The organic layer was then washed once with brine then dried over anhydrous sodium sulfate, filtered and concentrated to give a residue containing roughly a 1:1 mixture of two cyclization products. The desired cyclization isomer was purified by silica gel flash chromatography using 2:1 hexanes ethyl acetate as eluent to afford 5-{3-chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6-fluoro-1-methyl-7-(methyloxy)-3H-pyrazolo[3,4-c]isoquinolin-8-ol (1.73 g, 44% yield) as a yellow solid after concentration and drying of the pure fractions in vacuo. 1H NMR (400 MHz, CDCl3): 7.66 (dd, 1H), 7.59 (d, 1H), 7.54 (d, 1H), 7.46-7.34 (m, 5H), 7.07 (d, 1H), 6.54 (s, 1H), 5.25 (S, 2H), 4.03 (d, 3H), 2.80 (s, 3H), 1.83 (s, 9H); MS (EI) for C29H27N3O3FCl: 520 (MH+). heating At this time air was bubbled through the solution at a steady rate while maintaining a temperature of 90° C. to cool to room temperature The acetic acid was removed the residue partitioned with saturated aquyeous sodium hydrogencarbonate and ethyl acetate The organic layer was then washed once with brine then dried over anhydrous sodium sulfate filtered concentrated to give a residue containing roughly a 1:1 mixture of two cyclization products The desired cyclization isomer was purified by silica gel flash chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-2,5-difluorophenol (0.050 g, 0.178 mmol) and 3-chloro-4-[(phenylmethyl)oxy]benzaldehyde (0.044 g, 0.178 mmol) was added acetic acid (1 mL). The mixture was stirred at 120° C. for 4.5 h and then concentrated in vacuo to afford a residue which was co-evaporated with EtOH (2×) to afford a film which was purified by column chromatography (ether-dichloromethane 1:20) to afford 5-{3-chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6,9-difluoro-1-methyl-3H-pyrazolo[3,4-c]isoquinolin-8-ol as a light brown foam (0.042 g, 0.083 mmol, 47% yield). 1H NMR (400 MHz, CDCl3): 7.63 (t, 1H), 7.55-7.51 (m, 2H), 7.46-7.34 (m, 5H), 7.06 (d, 1H), 6.86 (dd, 1H), 5.25 (s, 2H), 2.81 (d, 3H), 1.84 (s, 9H); MS (EI) for C28H24ClF2N3O2: 508 (MH+). concentrated in vacuo to afford a residue which to afford a film which was purified by column chromatography (ether-dichloromethane 1:20)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-2,5-difluorophenol (0.050 g, 0.178 mmol) and 3-chloro-4-[(phenylmethyl)oxy]benzaldehyde (0.044 g, 0.178 mmol) was added acetic acid (1 mL). The mixture was stirred at 120° C. for 4.5 h and then concentrated in vacuo to afford a residue which was co-evaporated with EtOH (2×) to afford a film which was purified by column chromatography (ether-dichloromethane 1:20) to afford 5-{3-chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6,9-difluoro-1-methyl-3H-pyrazolo[3,4-c]isoquinolin-8-ol as a light brown foam (0.042 g, 0.083 mmol, 47% yield). 1H NMR (400 MHz, CDCl3): 7.63 (t, 1H), 7.55-7.51 (m, 2H), 7.46-7.34 (m, 5H), 7.06 (d, 1H), 6.86 (dd, 1H), 5.25 (s, 2H), 2.81 (d, 3H), 1.84 (s, 9H); MS (EI) for C28H24ClF2N3O2: 508 (MH+). concentrated in vacuo to afford a residue which to afford a film which was purified by column chromatography (ether-dichloromethane 1:20)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of t-BuOK (11.7 g, 96 mmol) in THF (200 mL) was added a solution of TosMIC (9.4 g, 48 mmol) in THF (100 mL) at −78° C. The mixture was stirred for 15 minutes, treated with a solution of 4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 30 mmol) in THF (50 mL) dropwise, and continued to stir for 1.5 hours at −78° C. To the cooled reaction mixture was added methanol (30 mL). The mixture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (300 mL). The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic layers were dried and evaporated under reduced pressure to give crude product, which was purified by column chromatography (petroleum ether/EtOAc 10:1) to afford 2-(4-(benzyloxy)-3-chlorophenyl)acetonitrile (2.7 g, 34%). 1H NMR (400 MHz, CDCl3) δ 7.52-7.32 (m, 6H), 7.15 (dd, J=2.4, 8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 5.26 (s, 2H), 3.73 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 154.0, 136.1, 129.9, 128.7, 128.7, 128.1, 127.2, 127.1, 127.1, 124.0, 123.0, 117.5, 114.4, 70.9, 22.5. to stir for 1.5 hours at −78° C To the cooled reaction mixture The mixture was heated at reflux for 30 minutes Solvent of the reaction mixture was removed to give a crude product, which The aqueous phase was extracted with EtOAc (3×100 mL) The combined organic layers were dried evaporated under reduced pressure to give crude product, which was purified by column chromatography (petroleum ether/EtOAc 10:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-chloro-4-hydroxy-benzaldehyde (5.0 g, 32 mmol) and BnBr (6.6 g, 38 mmol) in CH3CN (100 mL) was added K2CO3 (8.8 g, 64 mmol). The mixture was heated at reflux for 2 hours. The resulting mixture was poured into water (100 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give crude product, which was purified by column (petroleum ether/EtOAc 15:1) to give 4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 95%). 1H NMR (CDCl3, 400 MHz) δ 9.85 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.73 (dd, J=2.0, 8.4 Hz, 1H), 7.47-7.34 (m, 5H), 7.08 (d, J=8.8 Hz, 1H), 4.26 (s, 2H). The mixture was heated at reflux for 2 hours extracted with EtOAc (100 mL×3) The combined organic layers were washed with brine dried over anhydrous Na2SO4 evaporated under vacuum to give crude product, which was purified by column (petroleum ether/EtOAc 15:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-chloro-4-hydroxy-benzaldehyde (5.0 g, 32 mmol) and BnBr (6.6 g, 38 mmol) in CH3CN (100 mL) was added K2CO3 (8.8 g, 64 mmol). The mixture was heated at reflux for 2 hours. The resulting mixture was poured into water (100 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give crude product, which was purified by column (petroleum ether/EtOAc 15:1) to give 4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 95%). 1H NMR (CDCl3, 400 MHz) δ 9.85 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.73 (dd, J=2.0, 8.4 Hz, 1H), 7.47-7.34 (m, 5H), 7.08 (d, J=8.8 Hz, 1H), 4.26 (s, 2H). The mixture was heated at reflux for 2 hours extracted with EtOAc (100 mL×3) The combined organic layers were washed with brine dried over anhydrous Na2SO4 evaporated under vacuum to give crude product, which was purified by column (petroleum ether/EtOAc 15:1)