diisopropyl bicarbamate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: A solution of 110.6 mmol of 3-fluoro-benzylalcohol and 108.8 mmol of triphenylphosphine in 150 ml of tetrahydrofuran was added dropwise, within 50 min under a nitrogen atmosphere at 0° C., to a solution of 100.5 mmol of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester and 100.5 mmol of diisopropyl azodicarboxylate in 200 ml of tetrahydrofuran. The mixture was left to warm to RT and stirring was continued for 18 hours. The mixture was evaporated under reduced pressure. The solid residue was triturated in 400 ml of ether to leave a white solid mainly consisting of the product and triphenylphosphinoxide. After filtration, the solid material was triturated in 100 ml of cold methanol to yield (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid [MS: m/e=344 (M+H)+] together with traces of triphenylphosphine and diisopropyl hydrazodicarboxylate. The mixture was left The mixture was evaporated under reduced pressure The solid residue was triturated in 400 ml of ether to leave a white solid After filtration the solid material was triturated in 100 ml of cold methanol

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

実験手順: A solution of 110.6 mmol of 3-fluoro-benzylalcohol and 108.8 mmol of triphenylphosphine in 150 ml of tetrahydrofuran was added dropwise, within 50 min under a nitrogen atmosphere at 0° C., to a solution of 100.5 mmol of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester and 100.5 mmol of diisopropyl azodicarboxylate in 200 ml of tetrahydrofuran. The mixture was left to warm to RT and stirring was continued for 18 hours. The mixture was evaporated under reduced pressure. The solid residue was triturated in 400 ml of ether to leave a white solid mainly consisting of the product and triphenylphosphinoxide. After filtration, the solid material was triturated in 100 ml of cold methanol to yield (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid [MS: m/e=344 (M+H)+] together with traces of triphenylphosphine and diisopropyl hydrazodicarboxylate. The mixture was left The mixture was evaporated under reduced pressure The solid residue was triturated in 400 ml of ether to leave a white solid After filtration the solid material was triturated in 100 ml of cold methanol

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

実験手順: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.02 g, 0.10 mmol), polystyrene supported-triphenylphosphine (0.12 g, 0.24 mmol, 1.92 mmol/g), diisopropyl hydrazine-1,2-dicarboxylate (0.04 g, 0.19 mmol), and isopropanol (0.01 g, 0.21 mmol) were suspended in THF (1.0 mL). The reaction was allowed to shake at ambient temperature for 48 hours. The reaction mixture was filtered, the eluent was collected and concentrated under reduced pressure. Pd(dppf)Cl2 (0.011 g, 0.015 mmol), N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (0.03 g, 0.08 mmol), sodium carbonate (0.10 mL, 0.20 mmol, 2 M) suspended in THF (1.0 mL) were added. The vial was capped and irradiated in a microwave for 15 minutes at 110° C. Silica supported-DMT (0.055 g, 0.05 mmol, 0.94 mmol/g) was added, the vial was sealed and allowed to stir for 4 hours. The reaction mixture was passed through a syringe filter, the eluent was collected and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0 to 95% ACN/water with 0.1% TFA modifier) to afford N-(3-(1-isopropyl-1H-pyrazol-4-yl)-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine. MS ESI calc'd for C18H19F3N5 [M+H]+ 362. found 362. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.80 (d, J=4.8, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.71 (s, 1H), 7.29 (s, 1H), 7.23 (d, J=4.9, 1H), 7.07 (s, 1H), 4.49 (dt, J=6.6, 13.3, 1H), 2.28 (s, 3H), 1.43 (d, J=6.7, 6H). The reaction mixture was filtered the eluent was collected concentrated under reduced pressure were added The vial was capped irradiated in a microwave for 15 minutes at 110° C Silica supported-DMT (0.055 g, 0.05 mmol, 0.94 mmol/g) was added the vial was sealed The reaction mixture was passed through a syringe filter the eluent was collected concentrated under reduced pressure The residue was purified by reverse phase HPLC (0 to 95% ACN/water with 0.1% TFA modifier)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.02 g, 0.10 mmol), polystyrene supported-triphenylphosphine (0.12 g, 0.24 mmol, 1.92 mmol/g), diisopropyl hydrazine-1,2-dicarboxylate (0.04 g, 0.19 mmol), and isopropanol (0.01 g, 0.21 mmol) were suspended in THF (1.0 mL). The reaction was allowed to shake at ambient temperature for 48 hours. The reaction mixture was filtered, the eluent was collected and concentrated under reduced pressure. Pd(dppf)Cl2 (0.011 g, 0.015 mmol), N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (0.03 g, 0.08 mmol), sodium carbonate (0.10 mL, 0.20 mmol, 2 M) suspended in THF (1.0 mL) were added. The vial was capped and irradiated in a microwave for 15 minutes at 110° C. Silica supported-DMT (0.055 g, 0.05 mmol, 0.94 mmol/g) was added, the vial was sealed and allowed to stir for 4 hours. The reaction mixture was passed through a syringe filter, the eluent was collected and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0 to 95% ACN/water with 0.1% TFA modifier) to afford N-(3-(1-isopropyl-1H-pyrazol-4-yl)-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine. MS ESI calc'd for C18H19F3N5 [M+H]+ 362. found 362. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.80 (d, J=4.8, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.71 (s, 1H), 7.29 (s, 1H), 7.23 (d, J=4.9, 1H), 7.07 (s, 1H), 4.49 (dt, J=6.6, 13.3, 1H), 2.28 (s, 3H), 1.43 (d, J=6.7, 6H). The reaction mixture was filtered the eluent was collected concentrated under reduced pressure were added The vial was capped irradiated in a microwave for 15 minutes at 110° C Silica supported-DMT (0.055 g, 0.05 mmol, 0.94 mmol/g) was added the vial was sealed The reaction mixture was passed through a syringe filter the eluent was collected concentrated under reduced pressure The residue was purified by reverse phase HPLC (0 to 95% ACN/water with 0.1% TFA modifier)

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

実験手順: [1-(tert-Butoxycarbonyl)-2(R)-azetidinyl]methanol (1.42 g, 7.60 mmol) was dried by azeotropic evaporation with toluene (3×10 mL) in a 50 mL round-bottom flask. 3-Bromo-5-hydroxypyridine (1.32 g, 7.60 mmol) and triphenylphosphine (2.20 g, 8.40 mmol, 1.1 equiv.) were added. The flask was capped with a rubber septum, and the atmosphere was exchanged three times with N2 (balloon). Anhydrous THF (25 mL) was added via syringe, and the mixture was stirred in an ice bath until all reagents were dissolved. Diisopropyl azodicarboxylate (DIAD, 1.76 mL, 8.40 mmol, 1.1 equiv.) was added dropwise in several portions over 30 min. The resulting mixture was stirred in the thawing ice bath overnight. After removal of the THF, the residue was purified by CC on SiO2 (25×3.8 cm, EtOAc/hexanes 1:4 to 3:7) to give crude product. A 1H NMR spectrum showed that the material was a mixture with diisopropyl hydrazodicarboxylate (containing approx. 56% of the title compound by mass), which was used directly for the next step. 1H NMR (CDCl3, 400 MHz; signals of the title compound only) δ 8.29 (d, 1H, J=1.8 Hz), 8.28 (d, 1H, J=2.7 Hz), 7.43 (t, 1H, J=2.3 Hz), 4.55-4.47 (m, 1H), 4.33 (br s, 1H), 4.13-4.09 (m, 1H), 3.93-3.85 (m, 2H), 2.40-2.20 (m, 2H), 1.43 (s, 9H). The flask was capped with a rubber septum were dissolved The resulting mixture was stirred in the thawing ice bath overnight After removal of the THF the residue was purified by CC on SiO2 (25×3.8 cm, EtOAc/hexanes 1:4 to 3:7) to give crude product

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

実験手順: A solution of 110.6 mmol of 3-fluoro-benzylalcohol and 108.8 mmol of triphenylphosphine in 150 ml of tetrahydrofuran was added dropwise, within 50 min under a nitrogen atmosphere at 0° C., to a solution of 100.5 mmol of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester and 100.5 mmol of diisopropyl azodicarboxylate in 200 ml of tetrahydrofuran. The mixture was left to warm to RT and stirring was continued for 18 hours. The mixture was evaporated under reduced pressure. The solid residue was triturated in 400 ml of ether to leave a white solid mainly consisting of the product and triphenylphosphinoxide. After filtration, the solid material was triturated in 100 ml of cold methanol to yield (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid [MS: m/e=344 (M+H)+] together with traces of triphenylphosphine and diisopropyl hydrazodicarboxylate. The mixture was left The mixture was evaporated under reduced pressure The solid residue was triturated in 400 ml of ether to leave a white solid After filtration the solid material was triturated in 100 ml of cold methanol

反応条件: temp:0.00; pressure:0.00; stir: