4-chloro-1-isocyanato-2-methylbenzene

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

実験手順: To a solution of isoindoline (238 mg, 2.0 mmol) in dry 1,4-dioxane (10 mL) was added 4-chloro-2-methylphenyl isocyanate (335 mg, 2.0 mmol) under argon at room temperature. The reaction mixture was then stirred at RT overnight. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization from ethanol to give the title compound (540 mg, 94%) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 2.24 (s, 2H), 4.76 (s, 4H), 7.20 (dd, J=2.5, 8.5 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.30-7.32 (m, 2H), 7.34-7.37 (m, 2H), 7.42 (d, J=8.5 Hz, 1H), 7.84 (s, 1H); 13C NMR (DMSO-d6): δ 17.7, 51.9, 122.8, 125.6, 126.8, 127.3, 128.1, 129.5, 134.7, 136.8, 154.2; MS (MH+, 287); EA calc'd for C16H15ClN2O: C, 67.02; H, 5.27; N, 9.77. Found C, 66.82; H, 5.41; N, 9.92. The solvent was evaporated under reduced pressure the residue was purified by recrystallization from ethanol

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

実験手順: TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 4-chloro-1-isocyanato-2-methyl-benzene (0.17 mgl, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(4-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (380 mg, 90%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.6 min (99%); mp. 256-258° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 1H, CH—H), 2.19 (s, 3H, CH3), 2.31-2.47 (m, 1H, CH—H), 2.63 (br. s., 1H, CHH), 2.82-3.00 (m, 1H, CuI), 4.27-4.51 (m, 4H, CH2, CHH), 5.11 (dd, J=5.2, 13.3 Hz, 1H, CHN), 7.09-7.24 (m, 3H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 7.87 (d, J=3.4 Hz, 1H, Ar), 7.90 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 17.61, 22.49, 31.20, 42.83, 47.12, 51.58, 121.64, 121.98, 122.99, 125.36, 125.77, 126.97, 129.04, 129.46, 130.36, 137.14, 142.42, 144.58, 155.22, 167.92, 170.99, 172.85; LCMS MH=441. Anal Calcd for: C22H21ClN4O4+0.2H2O: C, 59.45; H, 4.85; N, 12.60; Cl, 7.98. found: C, 59.21; H, 4.71; N, 12.46; Cl, 8.21. the mixture was stirred for 10 minutes The solid was isolated by filtration the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL)

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloro-1-isocyanato-2-methyl-benzene (93.3 mg, 0.56 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin-3-yl)-methanone (150 mg, 0.51 mmol) in pyridine (5 mL). The mixture was heated to 45° C. for 12 h. The reaction mixture was concentrated in vacuo and the resulting yellow solid was triturated with CH2Cl2, filtered, and washed with CH2Cl2. Purification by flash column chromatography [(10% NH4OH/MeOH)/ethyl acetate 2:98] afforded the title compound as a white solid (197 mg, 83%). MS: 464.1 (MH+); HPLC Rf: 5.55 min. (HPLC method 4). The reaction mixture was concentrated in vacuo the resulting yellow solid was triturated with CH2Cl2 filtered washed with CH2Cl2 Purification by flash column chromatography [(10% NH4OH/MeOH)/ethyl acetate 2:98]

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloro-1-isocyanato-2-methyl-benzene (93.3 mg, 0.56 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin-3-yl)-methanone (150 mg, 0.51 mmol) in pyridine (5 mL). The mixture was heated to 45° C. for 12 h. The reaction mixture was concentrated in vacuo and the resulting yellow solid was triturated with CH2Cl2, filtered, and washed with CH2Cl2. Purification by flash column chromatography [(10% NH4OH/MeOH)/ethyl acetate 2:98] afforded the title compound as a white solid (197 mg, 83%). MS: 464.1 (MH+); HPLC Rf: 5.55 min. (HPLC method 4). The reaction mixture was concentrated in vacuo the resulting yellow solid was triturated with CH2Cl2 filtered washed with CH2Cl2 Purification by flash column chromatography [(10% NH4OH/MeOH)/ethyl acetate 2:98]

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

実験手順: To a solution of isoindoline (238 mg, 2.0 mmol) in dry 1,4-dioxane (10 mL) was added 4-chloro-2-methylphenyl isocyanate (335 mg, 2.0 mmol) under argon at room temperature. The reaction mixture was then stirred at RT overnight. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization from ethanol to give the title compound (540 mg, 94%) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 2.24 (s, 2H), 4.76 (s, 4H), 7.20 (dd, J=2.5, 8.5 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.30-7.32 (m, 2H), 7.34-7.37 (m, 2H), 7.42 (d, J=8.5 Hz, 1H), 7.84 (s, 1H); 13C NMR (DMSO-d6): δ 17.7, 51.9, 122.8, 125.6, 126.8, 127.3, 128.1, 129.5, 134.7, 136.8, 154.2; MS (MH+, 287); EA calc'd for C16H15ClN2O: C, 67.02; H, 5.27; N, 9.77. Found C, 66.82; H, 5.41; N, 9.92. The solvent was evaporated under reduced pressure the residue was purified by recrystallization from ethanol

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

実験手順: To a solution of isoindoline (238 mg, 2.0 mmol) in dry 1,4-dioxane (10 mL) was added 4-chloro-2-methylphenyl isocyanate (335 mg, 2.0 mmol) under argon at room temperature. The reaction mixture was then stirred at RT overnight. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization from ethanol to give the title compound (540 mg, 94%) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 2.24 (s, 2H), 4.76 (s, 4H), 7.20 (dd, J=2.5, 8.5 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.30-7.32 (m, 2H), 7.34-7.37 (m, 2H), 7.42 (d, J=8.5 Hz, 1H), 7.84 (s, 1H); 13C NMR (DMSO-d6): δ 17.7, 51.9, 122.8, 125.6, 126.8, 127.3, 128.1, 129.5, 134.7, 136.8, 154.2; MS (MH+, 287); EA calc'd for C16H15ClN2O: C, 67.02; H, 5.27; N, 9.77. Found C, 66.82; H, 5.41; N, 9.92. The solvent was evaporated under reduced pressure the residue was purified by recrystallization from ethanol

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

実験手順: TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 4-chloro-1-isocyanato-2-methyl-benzene (0.17 mgl, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(4-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (380 mg, 90%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.6 min (99%); mp. 256-258° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 1H, CH—H), 2.19 (s, 3H, CH3), 2.31-2.47 (m, 1H, CH—H), 2.63 (br. s., 1H, CHH), 2.82-3.00 (m, 1H, CuI), 4.27-4.51 (m, 4H, CH2, CHH), 5.11 (dd, J=5.2, 13.3 Hz, 1H, CHN), 7.09-7.24 (m, 3H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 7.87 (d, J=3.4 Hz, 1H, Ar), 7.90 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 17.61, 22.49, 31.20, 42.83, 47.12, 51.58, 121.64, 121.98, 122.99, 125.36, 125.77, 126.97, 129.04, 129.46, 130.36, 137.14, 142.42, 144.58, 155.22, 167.92, 170.99, 172.85; LCMS MH=441. Anal Calcd for: C22H21ClN4O4+0.2H2O: C, 59.45; H, 4.85; N, 12.60; Cl, 7.98. found: C, 59.21; H, 4.71; N, 12.46; Cl, 8.21. the mixture was stirred for 10 minutes The solid was isolated by filtration the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL)

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

実験手順: TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 4-chloro-1-isocyanato-2-methyl-benzene (0.17 mgl, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(4-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (380 mg, 90%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.6 min (99%); mp. 256-258° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 1H, CH—H), 2.19 (s, 3H, CH3), 2.31-2.47 (m, 1H, CH—H), 2.63 (br. s., 1H, CHH), 2.82-3.00 (m, 1H, CuI), 4.27-4.51 (m, 4H, CH2, CHH), 5.11 (dd, J=5.2, 13.3 Hz, 1H, CHN), 7.09-7.24 (m, 3H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 7.87 (d, J=3.4 Hz, 1H, Ar), 7.90 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 17.61, 22.49, 31.20, 42.83, 47.12, 51.58, 121.64, 121.98, 122.99, 125.36, 125.77, 126.97, 129.04, 129.46, 130.36, 137.14, 142.42, 144.58, 155.22, 167.92, 170.99, 172.85; LCMS MH=441. Anal Calcd for: C22H21ClN4O4+0.2H2O: C, 59.45; H, 4.85; N, 12.60; Cl, 7.98. found: C, 59.21; H, 4.71; N, 12.46; Cl, 8.21. the mixture was stirred for 10 minutes The solid was isolated by filtration the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL)

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

実験手順: TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 4-chloro-1-isocyanato-2-methyl-benzene (0.17 mgl, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(4-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (380 mg, 90%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN 0.1% H3PO4 in H2O: tR=3.6 min (99%); mp. 256-258° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 1H, CHH), 2.19 (s, 3H, CH3), 2.31-2.47 (m, 1H, CHH), 2.63 (br. s., 1H, CHH), 2.82-3.00 (m, 1H, CHH), 4.27-4.51 (m, 4H, CH2, CH2), 5.11 (dd, J=5.2, 13.3 Hz, 1H, CHN), 7.09-7.24 (m, 3H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 7.87 (d, J=3.4 Hz, 1H, Ar), 7.90 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 17.61, 22.49, 31.20, 42.83, 47.12, 51.58, 121.64, 121.98, 122.99, 125.36, 125.77, 126.97, 129.04, 129.46, 130.36, 137.14, 142.42, 144.58, 155.22, 167.92, 170.99, 172.85; LCMS MH=441. Anal Calcd for: C22H21ClN4O4+0.2H2O: C, 59.45; H, 4.85; N, 12.60; Cl, 7.98. found: C, 59.21; H, 4.71; N, 12.46; Cl, 8.21. the mixture was stirred for 10 minutes The solid was isolated by filtration the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL)

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

実験手順: TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 4-chloro-1-isocyanato-2-methyl-benzene (0.17 mgl, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(4-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (380 mg, 90%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN 0.1% H3PO4 in H2O: tR=3.6 min (99%); mp. 256-258° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 1H, CHH), 2.19 (s, 3H, CH3), 2.31-2.47 (m, 1H, CHH), 2.63 (br. s., 1H, CHH), 2.82-3.00 (m, 1H, CHH), 4.27-4.51 (m, 4H, CH2, CH2), 5.11 (dd, J=5.2, 13.3 Hz, 1H, CHN), 7.09-7.24 (m, 3H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 7.87 (d, J=3.4 Hz, 1H, Ar), 7.90 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 17.61, 22.49, 31.20, 42.83, 47.12, 51.58, 121.64, 121.98, 122.99, 125.36, 125.77, 126.97, 129.04, 129.46, 130.36, 137.14, 142.42, 144.58, 155.22, 167.92, 170.99, 172.85; LCMS MH=441. Anal Calcd for: C22H21ClN4O4+0.2H2O: C, 59.45; H, 4.85; N, 12.60; Cl, 7.98. found: C, 59.21; H, 4.71; N, 12.46; Cl, 8.21. the mixture was stirred for 10 minutes The solid was isolated by filtration the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL)

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

実験手順: Starting with 150 mg (0.34 mmol) of the iminophosphorane from Example 3A, 60 mg (0.36 mmol) of 4-chloro-2-methylphenyl isocyanate and 67 mg (0.34 mmol) of N-(3-chlorophenyl)piperazine, the general procedure [E] and chromatographic purification (method 2) give 97 mg (46% of theory) of product. the general procedure [E] and chromatographic purification (method 2) give 97 mg (46% of theory) of product

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

実験手順: Starting with 150 mg (0.34 mmol) of the iminophosphorane from Example 3A, 60 mg (0.36 mmol) of 4-chloro-2-methylphenyl isocyanate and 67 mg (0.34 mmol) of N-(3-chlorophenyl)piperazine, the general procedure [E] and chromatographic purification (method 2) give 97 mg (46% of theory) of product. the general procedure [E] and chromatographic purification (method 2) give 97 mg (46% of theory) of product