(2-iodo-3-methylphenyl)methanol

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (53 mg, 2.2 mmol) was added to a 0° C. solution of 2-iodo-3-methyl-phenyl-methanol ((Example 5: step a) 492 mg, 2 mmol) in DMF (20 mL). The solution was stirred at 0° C. for 30 min and tert-butyl bromoacetate (0.4 mL, 2.5 mmol) was added. The solution was warmed to rt over 15 min and stirred for 3 h at rt. EtOAc (80 mL) and water (40 mL) were added, the layers were separated, and the organic layer was washed with water (6×20 mL), brine (30 mL), and was dried over sodium sulfate. Concentration of the solution followed by SiO2 flash column chromatography (5–10% EtOAc in hexanes) yielded the title compound (0.571 g, 79%) as an oil. 1H-NMR (CDCl3): δ 7.36 (dd, 1H, J=1.4, 7.4 Hz), 7.30 (t, 1H, 7.4 Hz), 7.24 (dd, 1H, J=1.4, 7.4 Hz), 4.72 (s, 2H), 4.15 (s, 2H), 2.53 (s, 3H), 1.56 (s, 9H). The solution was warmed to rt over 15 min stirred for 3 h at rt the layers were separated the organic layer was washed with water (6×20 mL), brine (30 mL) was dried over sodium sulfate

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

実験手順: n-Butyllithium (2.5M) [4.03 mL] was added to a solution of (2-iodo-3-methyl-phenyl)-methanol (1.00 g, 4.04 mL) [example 213, step a] in ether [20 mL] at −78° C. and stirred for 0.5 hours. Trimethyl borate [1.13 mL, 10.1 mmol) was added and the solution was stirred for 2 hours at room temperature, followed by evaporation. The crude residue was dissolved in ethanol/toluene (1/2) [30 mL] and 2M sodium carbonate [16.2 mL] followed by addition of {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.49 g, 1.01 mmol) [example 27, step c]. The solution was bubbled with argon and then tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.15 mmol) was added. The reaction was refluxed for 3 hours and then cooled to room temperature. Ethyl acetate was added and the crude reaction was washed with brine, dried over magnesium sulfate and evaporated. Column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.40 g, 74%) as a solid. ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.12; found: 532.7. the solution was stirred for 2 hours at room temperature followed by evaporation The crude residue was dissolved in ethanol/toluene (1/2) [30 mL] The solution was bubbled with argon The reaction was refluxed for 3 hours the crude reaction was washed with brine dried over magnesium sulfate evaporated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Thionyl chloride [5 mL] was added to 2-iodo-3-methyl-benzoic acid (2.00 g, 7.63 mmol) at room temperature and heated to 50° C. for 1 hour. The solution was then cooled and evaporated. The crude residue was dissolved in ethyl acetate, washed with brine and dried with magnesium sulfate. The crude product was then dissolved in THF [5 mL] and a 1M solution of lithium aluminum hydride [10.7 mL] was added at room temperature and stirred for 1 hour. Water [0.1 mL] and 15% NaOH [0.1 mL] were added followed by evaporation. Column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.50 g, 26%) as a solid. 1H-NMR (CDCl3): δ 3.20 (t, 2H, J=7.6 Hz), 2.98 (s, 3H), 2.52 (t, 2H, J=7.2 Hz), 2.09 (m, 2H). The solution was then cooled evaporated The crude residue was dissolved in ethyl acetate washed with brine dried with magnesium sulfate The crude product was then dissolved in THF [5 mL] a 1M solution of lithium aluminum hydride [10.7 mL] was added at room temperature Water [0.1 mL] and 15% NaOH [0.1 mL] were added followed by evaporation

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Thionyl chloride [5 mL] was added to 2-iodo-3-methyl-benzoic acid (2.00 g, 7.63 mmol) at room temperature and heated to 50° C. for 1 hour. The solution was then cooled and evaporated. The crude residue was dissolved in ethyl acetate, washed with brine and dried with magnesium sulfate. The crude product was then dissolved in THF [5 mL] and a 1M solution of lithium aluminum hydride [10.7 mL] was added at room temperature and stirred for 1 hour. Water [0.1 mL] and 15% NaOH [0.1 mL] were added followed by evaporation. Column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.50 g, 26%) as a solid. 1H-NMR (CDCl3): δ 3.20 (t, 2H, J=7.6 Hz), 2.98 (s, 3H), 2.52 (t, 2H, J=7.2 Hz), 2.09 (m, 2H). The solution was then cooled evaporated The crude residue was dissolved in ethyl acetate washed with brine dried with magnesium sulfate The crude product was then dissolved in THF [5 mL] a 1M solution of lithium aluminum hydride [10.7 mL] was added at room temperature Water [0.1 mL] and 15% NaOH [0.1 mL] were added followed by evaporation

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2-Iodo-3-methyl-phenyl)-methanol (1608 mg, 6.8 mmol, Example 131: step b) was dissolved into DMF (10 mL). The solution was cooled to 0° C. To this was added sodium hydride in one portion and the reaction continued to stir at 0° C. for 30 minutes. To the cooled solution was added t-butylbromoacetate (1.3 mL, 8.9 mmol) and then the reaction was warmed to RT and then heated to 50° C. for 4 hours. The solvents were removed in vacuo and the resulting residue was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) and the solvent was removed in vacuo resulting in the title compound (1.29 g, 53%) that was used with out further purification. 1H-NMR (CDCl3): δ 7.28–7.13 (m, 3H), 4.63 (s, 2H), 4.07 (s, 2H), 2.44 (s, 3H), 1.47 (s, 9H). the reaction was warmed to RT heated to 50° C. for 4 hours The solvents were removed in vacuo the resulting residue was dissolved into EtOAc washed with brine The combined organic layers were dried (MgSO4) the solvent was removed in vacuo

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Iodo-3-methyl-benzoyl chloride (1360 mg, 4.86 mmol, Example 131: a) was dissolved into THF (2 mL) and cooled to −78° C. To this was slowly added a slurry of lithium aluminum hydride (184.3 mg, 4.86 mmol) that was carefully weighed into a dry flask and cooled to 78° C., before THF (2 mL) was added. The reaction was warmed to RT slowly and stirred for an hour. The reaction was quenched by cooling back to −78° C. and adding 200 μL water, 200 μL 15% NaOH, 600 μL water and then poured over celite and filtered with THF. The title compound was obtained as a yellow solid. 1H-NMR (CDCl3): δ 7.21–7.19 (m, 2H), 7.14–7.11 (m, 1H,), 4.61 (s, 2H), 2.43 (s, 3H). was carefully weighed into a dry flask was added The reaction was warmed to RT slowly The reaction was quenched by cooling back to −78° C. adding 200 μL water, 200 μL 15% NaOH, 600 μL water poured over celite filtered with THF

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Iodo-3-methyl-benzoyl chloride (1360 mg, 4.86 mmol, Example 131: a) was dissolved into THF (2 mL) and cooled to −78° C. To this was slowly added a slurry of lithium aluminum hydride (184.3 mg, 4.86 mmol) that was carefully weighed into a dry flask and cooled to 78° C., before THF (2 mL) was added. The reaction was warmed to RT slowly and stirred for an hour. The reaction was quenched by cooling back to −78° C. and adding 200 μL water, 200 μL 15% NaOH, 600 μL water and then poured over celite and filtered with THF. The title compound was obtained as a yellow solid. 1H-NMR (CDCl3): δ 7.21–7.19 (m, 2H), 7.14–7.11 (m, 1H,), 4.61 (s, 2H), 2.43 (s, 3H). was carefully weighed into a dry flask was added The reaction was warmed to RT slowly The reaction was quenched by cooling back to −78° C. adding 200 μL water, 200 μL 15% NaOH, 600 μL water poured over celite filtered with THF

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

実験手順: Thionyl chloride (6 mL) was added over 1 min to a 0° C. solution of 2-iodo-3-methyl benzoic acid (3.0 g, 11.4 mmol) in DCM (10 mL). The solution was stirred for 24 h at rt and the volatile components were removed in vacuo. A portion of the crude acid chloride (955 mg) was dissolved in THF (15 mL) and NaBH4 (380 mg, 10 mmol) was added. After stirring for 90 min, multiple spots were evident by TLC analysis. The reaction mixture was cooled to −78° C. and solid LiAlH4 (300 mg, 7.91 mmol) was added. The reaction was stirred for 30 min, after which TLC analysis showed one major spot. The reaction was quenched by addition of EtOAc (10 mL) and was slowly poured into a vigorously stirred solution of HCl (1M, 30 mL). EtOAc (70 mL) was added, the layers were separated, and the organic layer was washed with NaHCO3 (3×15 mL), water (15 mL), brine (40 mL), and was dried over sodium sulfate. Removal of the solvent in vacuo yielded the title compound (752 mg, 89%) as a thick oil which was used without further purification. 1H-NMR (CDCl3): δ 7.27 (m, 2H), 7.20 (m, 2H), 4.74 (m, 2H), 2.50 (s, 3H), 2.0 (br s, 1H). the volatile components were removed in vacuo A portion of the crude acid chloride (955 mg) was dissolved in THF (15 mL) After stirring for 90 min The reaction mixture was cooled to −78° C. The reaction was stirred for 30 min The reaction was quenched by addition of EtOAc (10 mL) was slowly poured into a vigorously stirred solution of HCl (1M, 30 mL) EtOAc (70 mL) was added the layers were separated the organic layer was washed with NaHCO3 (3×15 mL), water (15 mL), brine (40 mL) was dried over sodium sulfate Removal of the solvent in vacuo

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

実験手順: Thionyl chloride (6 mL) was added over 1 min to a 0° C. solution of 2-iodo-3-methyl benzoic acid (3.0 g, 11.4 mmol) in DCM (10 mL). The solution was stirred for 24 h at rt and the volatile components were removed in vacuo. A portion of the crude acid chloride (955 mg) was dissolved in THF (15 mL) and NaBH4 (380 mg, 10 mmol) was added. After stirring for 90 min, multiple spots were evident by TLC analysis. The reaction mixture was cooled to −78° C. and solid LiAlH4 (300 mg, 7.91 mmol) was added. The reaction was stirred for 30 min, after which TLC analysis showed one major spot. The reaction was quenched by addition of EtOAc (10 mL) and was slowly poured into a vigorously stirred solution of HCl (1M, 30 mL). EtOAc (70 mL) was added, the layers were separated, and the organic layer was washed with NaHCO3 (3×15 mL), water (15 mL), brine (40 mL), and was dried over sodium sulfate. Removal of the solvent in vacuo yielded the title compound (752 mg, 89%) as a thick oil which was used without further purification. 1H-NMR (CDCl3): δ 7.27 (m, 2H), 7.20 (m, 2H), 4.74 (m, 2H), 2.50 (s, 3H), 2.0 (br s, 1H). the volatile components were removed in vacuo A portion of the crude acid chloride (955 mg) was dissolved in THF (15 mL) After stirring for 90 min The reaction mixture was cooled to −78° C. The reaction was stirred for 30 min The reaction was quenched by addition of EtOAc (10 mL) was slowly poured into a vigorously stirred solution of HCl (1M, 30 mL) EtOAc (70 mL) was added the layers were separated the organic layer was washed with NaHCO3 (3×15 mL), water (15 mL), brine (40 mL) was dried over sodium sulfate Removal of the solvent in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (53 mg, 2.2 mmol) was added to a 0° C. solution of 2-iodo-3-methyl-phenyl-methanol ((Example 5: step a) 492 mg, 2 mmol) in DMF (20 mL). The solution was stirred at 0° C. for 30 min and tert-butyl bromoacetate (0.4 mL, 2.5 mmol) was added. The solution was warmed to rt over 15 min and stirred for 3 h at rt. EtOAc (80 mL) and water (40 mL) were added, the layers were separated, and the organic layer was washed with water (6×20 mL), brine (30 mL), and was dried over sodium sulfate. Concentration of the solution followed by SiO2 flash column chromatography (5–10% EtOAc in hexanes) yielded the title compound (0.571 g, 79%) as an oil. 1H-NMR (CDCl3): δ 7.36 (dd, 1H, J=1.4, 7.4 Hz), 7.30 (t, 1H, 7.4 Hz), 7.24 (dd, 1H, J=1.4, 7.4 Hz), 4.72 (s, 2H), 4.15 (s, 2H), 2.53 (s, 3H), 1.56 (s, 9H). The solution was warmed to rt over 15 min stirred for 3 h at rt the layers were separated the organic layer was washed with water (6×20 mL), brine (30 mL) was dried over sodium sulfate

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (53 mg, 2.2 mmol) was added to a 0° C. solution of 2-iodo-3-methyl-phenyl-methanol ((Example 5: step a) 492 mg, 2 mmol) in DMF (20 mL). The solution was stirred at 0° C. for 30 min and tert-butyl bromoacetate (0.4 mL, 2.5 mmol) was added. The solution was warmed to rt over 15 min and stirred for 3 h at rt. EtOAc (80 mL) and water (40 mL) were added, the layers were separated, and the organic layer was washed with water (6×20 mL), brine (30 mL), and was dried over sodium sulfate. Concentration of the solution followed by SiO2 flash column chromatography (5–10% EtOAc in hexanes) yielded the title compound (0.571 g, 79%) as an oil. 1H-NMR (CDCl3): δ 7.36 (dd, 1H, J=1.4, 7.4 Hz), 7.30 (t, 1H, 7.4 Hz), 7.24 (dd, 1H, J=1.4, 7.4 Hz), 4.72 (s, 2H), 4.15 (s, 2H), 2.53 (s, 3H), 1.56 (s, 9H). The solution was warmed to rt over 15 min stirred for 3 h at rt the layers were separated the organic layer was washed with water (6×20 mL), brine (30 mL) was dried over sodium sulfate

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

実験手順: n-Butyllithium (2.5M) [4.03 mL] was added to a solution of (2-iodo-3-methyl-phenyl)-methanol (1.00 g, 4.04 mL) [example 213, step a] in ether [20 mL] at −78° C. and stirred for 0.5 hours. Trimethyl borate [1.13 mL, 10.1 mmol) was added and the solution was stirred for 2 hours at room temperature, followed by evaporation. The crude residue was dissolved in ethanol/toluene (1/2) [30 mL] and 2M sodium carbonate [16.2 mL]followed by addition of {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.49 g, 1.01 mmol) [example 27, step c]. The solution was bubbled with argon and then tetrakis (triphenylphosphine) palladium (0) (0.18 g, 0.15 mmol) was added. The reaction was refluxed for 3 hours and then cooled to room temperature. Ethyl acetate was added and the crude reaction was washed with brine, dried over magnesium sulfate and evaporated. Column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.40 g, 74%) as a solid. ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.12; found: 532.7. the solution was stirred for 2 hours at room temperature followed by evaporation The crude residue was dissolved in ethanol/toluene (1/2) [30 mL] The solution was bubbled with argon The reaction was refluxed for 3 hours the crude reaction was washed with brine dried over magnesium sulfate evaporated