7-iodo-2,3-dihydroisoindol-1-one

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

実験手順: In a similar manner to Step 4 of Example 140, a mixture of 7-amino-4-methylisoindolinone and 7-aminoisoindolinone (10/1, 57.4 mg, 0.357 mmol) was dissolved in acetonitrile (4.6 mL), and the solution was treated with potassium iodide (78 mg, 0.47 mmol), copper iodide (90 mg, 0.47 mmol), iodine (120 mg, 0.471 mmol) and tert-butyl nitrate (0.128 mL, 1.07 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=5/1) to obtain a mixture of 7-iodo-4-methylisoindolinone and 7-iodoisoindolinone (44.8 mg, ratio 10/1, yield 50%). followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=5/1) to obtain

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

実験手順: In a similar manner to Step 4 of Example 140, a mixture of 7-amino-4-methylisoindolinone and 7-aminoisoindolinone (10/1, 57.4 mg, 0.357 mmol) was dissolved in acetonitrile (4.6 mL), and the solution was treated with potassium iodide (78 mg, 0.47 mmol), copper iodide (90 mg, 0.47 mmol), iodine (120 mg, 0.471 mmol) and tert-butyl nitrate (0.128 mL, 1.07 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=5/1) to obtain a mixture of 7-iodo-4-methylisoindolinone and 7-iodoisoindolinone (44.8 mg, ratio 10/1, yield 50%). followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=5/1) to obtain

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 7-iodo-2,3-dihydro-1H-isoindole-1-one (0.087 g, 0.25 mmol), Pd(PPh3)4 (0.031 g, 0.025 mmol), sodium cyanide (0.028 g, 0.6 mmol), and CuI (0.006 g, 0.025 mmol) in acetonitrile (4 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate (typically 2:1 hexane-EtOAc) afforded 2-benzyl-1-oxo-2,3-dihydro-1H-isoindole-7-carbonitrile (0.042 g, 68%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.32 (s, 2H), 4.82 (s, 2H), 7.33 (m, 5H), 7.61 (d, 2H), 7.78 (t, 1H).

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 7-iodo-2,3-dihydro-1H-isoindole-1-one (0.087 g, 0.25 mmol), Pd(PPh3)4 (0.031 g, 0.025 mmol), sodium cyanide (0.028 g, 0.6 mmol), and CuI (0.006 g, 0.025 mmol) in acetonitrile (4 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate (typically 2:1 hexane-EtOAc) afforded 2-benzyl-1-oxo-2,3-dihydro-1H-isoindole-7-carbonitrile (0.042 g, 68%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.32 (s, 2H), 4.82 (s, 2H), 7.33 (m, 5H), 7.61 (d, 2H), 7.78 (t, 1H).

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 7-iodo-2,3-dihydro-1H-isoindole-1-one (0.087 g, 0.25 mmol), Pd(PPh3)4 (0.031 g, 0.025 mmol), sodium cyanide (0.028 g, 0.6 mmol), and CuI (0.006 g, 0.025 mmol) in acetonitrile (4 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate (typically 2:1 hexane-EtOAc) afforded 2-benzyl-1-oxo-2,3-dihydro-1H-isoindole-7-carbonitrile (0.042 g, 68%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.32 (s, 2H), 4.82 (s, 2H), 7.33 (m, 5H), 7.61 (d, 2H), 7.78 (t, 1H).

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a nitrogen de-gassed solution of 7-iodoisoindolin-1-one (159) (0.233 g, 0.899 mmol) in dry DMF (6 mL) were added triethylamine (0.501 mL, 3.598 mmol) followed by triphenylphosphine (0.035 g, 0.14 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.063 g, 0.090 mmol), CuI (0.026 g, 0.14 mmol) and finally (trimethylsilyl)acetylene (0.292 mL, 1.63 mmol). The reaction mixture was then heated under microwave irradiation at 100° C. for 30 then 10 minutes. The reaction mixture was concentrated in vacuo, then absorbed onto silica gel and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-46% EtOAc in dichloromethane) to give the title compound (I60) (0.120 g, 49% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 8.47 (s, 1H), 7.60-7.51 (m, 2H), 7.49 (dd, J=6.7, 2.0 Hz, 1H), 4.32 (s, 2H), 1.03 (t, J=7.9 Hz, 9H), 0.66 (q, J=7.9 Hz, 6H). LCMS Method C: rt 6.44 min; m/z 272.2 [M+H]+. 10 minutes The reaction mixture was concentrated in vacuo absorbed onto silica gel purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-46% EtOAc in dichloromethane)

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

実験手順: Methyl 2-iodo-6-methylbenzoate (I58) (2.00 g, 7.245 mmol) and NBS (1.418 g, 7.969 mmol) were stirred in chlorobenzene (50 mL) and benzoyl peroxide (75% w/w, 0.234 g, 0.724 mmol) was added. The reaction was stirred at 90° C. for 18 hours, cooled to room temperature, filtered and the precipitate was washed with cyclohexane (4×10 mL). The combined filtrates were evaporated, and the resulting brown oil was diluted with THF (50 mL). Aqueous ammonia solution (20 mL) was added, and the mixture was stirred vigorously for 17 hours. The mixture was diluted with water (20 mL) and the THF was removed in vacuo. DCM (150 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (2×100 mL), the combined organics were washed with brine (100 mL), dried (MgSO4) and filtered. Silica gel was added and the volatiles were removed in vacuo to give the crude material absorbed onto silica gel. The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% methanol in EtOAc) to give the title compound (I59) (0.757 g, 40% yield) as a beige solid; 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J=7.8, 0.7 Hz, 1H), 7.46 (dd, J=7.5, 0.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.10 (brs, 1H), 4.37 (d, J=0.6 Hz, 2H). LCMS Method C: rt 5.06 min; m/z 260.0 [M+H]+. cooled to room temperature filtered the precipitate was washed with cyclohexane (4×10 mL) The combined filtrates were evaporated the resulting brown oil was diluted with THF (50 mL) Aqueous ammonia solution (20 mL) was added the mixture was stirred vigorously for 17 hours The mixture was diluted with water (20 mL) the THF was removed in vacuo DCM (150 mL) was added the layers were separated the aqueous layer was extracted with DCM (2×100 mL) the combined organics were washed with brine (100 mL) dried (MgSO4) filtered Silica gel was added the volatiles were removed in vacuo to give the crude material absorbed onto silica gel The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a nitrogen de-gassed solution of 7-iodoisoindolin-1-one (I59) (0.233 g, 0.899 mmol) in dry DMF (6 mL) were added triethylamine (0.501 mL, 3.598 mmol) followed by triphenylphosphine (0.035 g, 0.14 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.063 g, 0.090 mmol), CuI (0.026 g, 0.14 mmol) and finally (trimethylsilyl)acetylene (0.292 mL, 1.63 mmol). The reaction mixture was then heated under microwave irradiation at 100° C. for 30 then 10 minutes. The reaction mixture was concentrated in vacuo, then absorbed onto silica gel and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-46% EtOAc in dichloromethane) to give the title compound (I60) (0.120 g, 49% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 8.47 (s, 1H), 7.60-7.51 (m, 2H), 7.49 (dd, J=6.7, 2.0 Hz, 1H), 4.32 (s, 2H), 1.03 (t, J=7.9 Hz, 9H), 0.66 (q, J=7.9 Hz, 6H). LCMS Method C: rt 6.44 min; m/z 272.2 [M+H]+. 10 minutes The reaction mixture was concentrated in vacuo absorbed onto silica gel purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-46% EtOAc in dichloromethane)

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

実験手順: Methyl 2-iodo-6-methylbenzoate (I58) (2.00 g, 7.245 mmol) and NBS (1.418 g, 7.969 mmol) were stirred in chlorobenzene (50 mL) and benzoyl peroxide (75% w/w, 0.234 g, 0.724 mmol) was added. The reaction was stirred at 90° C. for 18 hours, cooled to room temperature, filtered and the precipitate was washed with cyclohexane (4×10 mL). The combined filtrates were evaporated, and the resulting brown oil was diluted with THF (50 mL). Aqueous ammonia solution (20 mL) was added, and the mixture was stirred vigorously for 17 hours. The mixture was diluted with water (20 mL) and the THF was removed in vacuo. DCM (150 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (2×100 mL), the combined organics were washed with brine (100 mL), dried (MgSO4) and filtered. Silica gel was added and the volatiles were removed in vacuo to give the crude material absorbed onto silica gel. The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% methanol in EtOAc) to give the title compound (I59) (0.757 g, 40% yield) as a beige solid; 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J=7.8, 0.7 Hz, 1H), 7.46 (dd, J=7.5, 0.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.10 (br s, 1H), 4.37 (d, J=0.6 Hz, 2H). LCMS Method C: rt 5.06 min; m/z 260.0 [M+H]+. cooled to room temperature filtered the precipitate was washed with cyclohexane (4×10 mL) The combined filtrates were evaporated the resulting brown oil was diluted with THF (50 mL) Aqueous ammonia solution (20 mL) was added the mixture was stirred vigorously for 17 hours The mixture was diluted with water (20 mL) the THF was removed in vacuo DCM (150 mL) was added the layers were separated the aqueous layer was extracted with DCM (2×100 mL) the combined organics were washed with brine (100 mL) dried (MgSO4) filtered Silica gel was added the volatiles were removed in vacuo to give the crude material absorbed onto silica gel The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.

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

実験手順: In a similar manner to Step 4 of Example 140, a mixture of 7-amino-4-methylisoindolinone and 7-aminoisoindolinone (10/1, 57.4 mg, 0.357 mmol) was dissolved in acetonitrile (4.6 mL), and the solution was treated with potassium iodide (78 mg, 0.47 mmol), copper iodide (90 mg, 0.47 mmol), iodine (120 mg, 0.471 mmol) and tert-butyl nitrate (0.128 mL, 1.07 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=5/1) to obtain a mixture of 7-iodo-4-methylisoindolinone and 7-iodoisoindolinone (44.8 mg, ratio 10/1, yield 50%). followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=5/1) to obtain