5-氯-1-异吲哚啉酮

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 4′-bromo-5,5-dimethyl-6′,7′-dihydro-5′H-spiro[1,3-dioxane-2,8′-isoquinoline](5.0 g, 16 mmol), 5-chloro-2,3-dihydro-isoindol-1-one (2.7 g, 16 mmol), (+)-(1S,1S)-1,2-diaminocyclohexane (0.576 mL, 4.8 mmol), copper (I) iodide (456 mg, 2.4 mmol) and Cs2CO3 (10.4 g, 32 mmol) in dioxane (80 mL) was heated at 150° C. for 4 hours. After cooling to room temperature, it was diluted with water (50 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to afford a crude product (5.5 g, 86%) as light yellow solid. MS: 399.1 (M+H+). After cooling to room temperature extracted with EtOAc (200 mL×2) The combined organic layers were dried over anhy Na2SO4, filtered concentrated in vacuo

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 25 mL sealed tube, 5-chloro-2,3-dihydro-isoindol-1-one (801 mg, 4.8 mmol), 4-bromo-6,7-dihydro-5H-[2]pyrindin-7-ylamine (intermediate B-18 [C], 937 mg, 4.4 mmol), CuI (200 mg, 1.1 mmol), Cs2CO3 (3.0 g, 9.2 mmol) and (+)-(S,S)-1,2-diaminocyclohexane (0.4 mL, 3.2 mmol) were dissolved in dioxane (16 mL). The resulting reaction mixture was heated at 150° C. for 3 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×125 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to yield the title compound (1.02 g, 80%) as a light yellow solid. MS: 300.2 (M+H+). In a 25 mL sealed tube The resulting reaction mixture extracted with EtOAc (2×125 mL) The organic layer was washed with brine dried over anhydrous Na2SO4 filtered concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient)

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 25 mL sealed tube, 5-chloro-2,3-dihydro-isoindol-1-one (801 mg, 4.8 mmol), 4-bromo-6,7-dihydro-5H-[2]pyrindin-7-ylamine (intermediate B-18 [C], 937 mg, 4.4 mmol), CuI (200 mg, 1.1 mmol), Cs2CO3 (3.0 g, 9.2 mmol) and (+)-(S,S)-1,2-diaminocyclohexane (0.4 mL, 3.2 mmol) were dissolved in dioxane (16 mL). The resulting reaction mixture was heated at 150° C. for 3 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×125 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to yield the title compound (1.02 g, 80%) as a light yellow solid. MS: 300.2 (M+H+). In a 25 mL sealed tube The resulting reaction mixture extracted with EtOAc (2×125 mL) The organic layer was washed with brine dried over anhydrous Na2SO4 filtered concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient)

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 25 mL sealed tube, 5-chloro-2,3-dihydro-isoindol-1-one (801 mg, 4.8 mmol), 4-bromo-6,7-dihydro-5H-[2]pyrindin-7-ylamine (intermediate B-18 [C], 937 mg, 4.4 mmol), CuI (200 mg, 1.1 mmol), Cs2CO3 (3.0 g, 9.2 mmol) and (+)-(S,S)-1,2-diaminocyclohexane (0.4 mL, 3.2 mmol) were dissolved in dioxane (16 mL). The resulting reaction mixture was heated at 150° C. for 3 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×125 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to yield the title compound (1.02 g, 80%) as a light yellow solid. MS: 300.2 (M+H+). In a 25 mL sealed tube The resulting reaction mixture extracted with EtOAc (2×125 mL) The organic layer was washed with brine dried over anhydrous Na2SO4 filtered concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In analogy to the procedures described for the preparation of example 137, 3-bromo-5-[(R)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-pyridine (example 137 [B]) has been reacted with 5-chloro-2,3-dihydro-isoindol-1-one to give 2-{5-[(R)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-pyridin-3-yl}-5-chloro-2,3-dihydro-isoindol-1-one, which was then deprotected with 4M HCl in dioxane to give the title compound as light yellow solid. MS: 330.1 (M+H+).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In analogy to the procedures described for the preparation of example 135, 3-bromo-5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridine (example 135[B]) has been reacted with 5-chloro-2,3-dihydro-isoindol-1-one to give 2-{5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-5-chloro-2,3-dihydro-isoindol-1-one, which was then deprotected with 4M HCl in dioxane to give the title compound as white solid. MS: 344.0 (M+H+).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In analogy to the procedures described for the preparation of example 135, 3-bromo-5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridine (example 135[B]) has been reacted with 5-chloro-2,3-dihydro-isoindol-1-one to give 2-{5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-5-chloro-2,3-dihydro-isoindol-1-one, which was then deprotected with 4M HCl in dioxane to give the title compound as white solid. MS: 344.0 (M+H+).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In analogy to the procedures described for the preparation of example 135, 3-bromo-5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridine (example 135[B]) has been reacted with 5-chloro-2,3-dihydro-isoindol-1-one to give 2-{5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-5-chloro-2,3-dihydro-isoindol-1-one, which was then deprotected with 4M HCl in dioxane to give the title compound as white solid. MS: 344.0 (M+H+).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium bis(trimethylsilyl) amide (2 mL, 2 M in THF, 2 mmol) was added dropwise at 0° C. to a solution of 5-chloro-2,3-dihydro-isoindol-1-one (0.34 g, 2 mmol) in THF (10 mL). After stirring for 10 min, 1-bromomethyl-4-methoxy-benzene (0.52 g, 2.6 mmol) was added dropwise. The resulting reaction mixture was allowed to stir at room temperature for 48 hours before quenching with saturated aqueous ammonium chloride solution. After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the crude product (0.6 g, 100%) as a yellow oil. MS: 288.0 (M+H+). It was used directly in the next step, without further purification. The resulting reaction mixture to stir at room temperature for 48 hours before quenching with saturated aqueous ammonium chloride solution After extraction with EtOAc the organic layer was washed with brine dried over anhy Na2SO4, filtered concentrated in vacuo