4-[[4-(chloromethyl)phenyl]methyl]morpholine;hydrochloride

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-tert-Butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (160 g), 4-(4-(chloromethyl)benzyl)morpholine hydrochloride (138 g, 0.87×) and potassium carbonate (165 g, 1.04×) were added to DMF (960 mL, 6×) in a 5 liter jacketed vessel. The mixture was heated to 40 to 50° C. and agitated for 12 to 24 hours. The mixture was cooled to 25 to 35° C., then ethyl acetate (1600 mL, 10×) and water (1600 mL, 10×) were added. The mixture was agitated at 25 to 35° C., settled, and split. Additional ethyl acetate (800 mL, 5×) and water (800 mL, 5×) were added. The mixture was agitated at 25 to 35° C., settled, and split. The combined organic phase was washed four times with water (400 mL, 2.5×). The organic phase was distilled under vacuum below 50° C. to 6× volume. Additional ethyl acetate (2880 mL, 18×) was continuously added, and the distillation was continued to maintain about 6× volume. The temperature was adjusted to 40 to 45° C., then seeds (0.8 g, 0.005×) were added. The mixture was held for about 30 minutes to build seed bed, then heptane (960 mL, 6×) was added over about 1.5 hours. The mixture was cooled to 15 to 25° C. over about 1 to 1.5 hours, agitated at 15 to 25° C. for at least one hour, and held for 16 hours. The solid was filtered, washed with heptane:ethyl acetate (5× total, 2.5× heptane, 2.5× ethyl acetate), and dried under reduced pressure with nitrogen sweep at 35 to 45° C. until LOD≦1%, to give (S)-tert-butyl 5-amino-4-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate as a white solid (215.3 g, 86% yield); MS m/z: 524.3 (M+1); 1H NMR (DMSO-d6, 300 MHz) δ 7.57 (br s, 1H), 7.48-7.43 (m, 3H), 7.34 (d, J=8.1 Hz, 2H), 7.29 (d, J=7.5 Hz, 2H), 7.19 (br s, 1H), 5.21 (s, 2H), 4.71 (dd, J=10.2, 4.2 Hz, 1H), 4.54 (d, J=17.4 Hz, 1H), 4.40 (d, J=17.7 Hz, 1H), 3.56 (dd, J=4.5, 4.5 Hz, 4H), 3.45 (s, 2H), 2.34 (dd, J=4.5, 4.5 Hz, 4H), 2.15-1.99 (m, 4H), 1.32 (s, 9H) ppm; 13C NMR (DMSO-d6, 75 MHz) δ 171.8, 171.3, 167.8, 153.4, 137.7, 135.3, 133.3, 130.2, 129.5, 129.0, 127.6, 115.1, 114.6, 79.7, 69.4, 66.2, 62.1, 53.5, 53.1, 44.8, 31.8, 27.6, 24.8 ppm. The mixture was cooled to 25 to 35° C. The mixture was agitated at 25 to 35° C. split Additional ethyl acetate (800 mL, 5×) and water (800 mL, 5×) were added The mixture was agitated at 25 to 35° C. split The combined organic phase was washed four times with water (400 mL, 2.5×) The organic phase was distilled under vacuum below 50° C. to 6× volume Additional ethyl acetate (2880 mL, 18×) was continuously added the distillation to maintain about 6× volume was adjusted to 40 to 45° C. seeds (0.8 g, 0.005×) were added The mixture was held for about 30 minutes heptane (960 mL, 6×) was added over about 1.5 hours The mixture was cooled to 15 to 25° C. over about 1 to 1.5 hours agitated at 15 to 25° C. for at least one hour held for 16 hours The solid was filtered washed with heptane ethyl acetate (5× total, 2.5× heptane, 2.5× ethyl acetate), and dried under reduced pressure with nitrogen sweep at 35 to 45° C. until LOD≦1%

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-tert-Butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (160 g), 4-(4-(chloromethyl)benzyl)morpholine hydrochloride (138 g, 0.87×) and potassium carbonate (165 g, 1.04×) were added to DMF (960 mL, 6×) in a 5 liter jacketed vessel. The mixture was heated to 40 to 50° C. and agitated for 12 to 24 hours. The mixture was cooled to 25 to 35° C., then ethyl acetate (1600 mL, 10×) and water (1600 mL, 10×) were added. The mixture was agitated at 25 to 35° C., settled, and split. Additional ethyl acetate (800 mL, 5×) and water (800 mL, 5×) were added. The mixture was agitated at 25 to 35° C., settled, and split. The combined organic phase was washed four times with water (400 mL, 2.5×). The organic phase was distilled under vacuum below 50° C. to 6× volume. Additional ethyl acetate (2880 mL, 18×) was continuously added, and the distillation was continued to maintain about 6× volume. The temperature was adjusted to 40 to 45° C., then seeds (0.8 g, 0.005×) were added. The mixture was held for about 30 minutes to build seed bed, then heptane (960 mL, 6×) was added over about 1.5 hours. The mixture was cooled to 15 to 25° C. over about 1 to 1.5 hours, agitated at 15 to 25° C. for at least one hour, and held for 16 hours. The solid was filtered, washed with heptane:ethyl acetate (5× total, 2.5× heptane, 2.5× ethyl acetate), and dried under reduced pressure with nitrogen sweep at 35 to 45° C. until LOD≦1%, to give (S)-tert-butyl 5-amino-4-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate as a white solid (215.3 g, 86% yield); MS m/z: 524.3 (M+1); 1H NMR (DMSO-d6, 300 MHz) δ 7.57 (br s, 1H), 7.48-7.43 (m, 3H), 7.34 (d, J=8.1 Hz, 2H), 7.29 (d, J=7.5 Hz, 2H), 7.19 (br s, 1H), 5.21 (s, 2H), 4.71 (dd, J=10.2, 4.2 Hz, 1H), 4.54 (d, J=17.4 Hz, 1H), 4.40 (d, J=17.7 Hz, 1H), 3.56 (dd, J=4.5, 4.5 Hz, 4H), 3.45 (s, 2H), 2.34 (dd, J=4.5, 4.5 Hz, 4H), 2.15-1.99 (m, 4H), 1.32 (s, 9H) ppm; 13C NMR (DMSO-d6, 75 MHz) δ 171.8, 171.3, 167.8, 153.4, 137.7, 135.3, 133.3, 130.2, 129.5, 129.0, 127.6, 115.1, 114.6, 79.7, 69.4, 66.2, 62.1, 53.5, 53.1, 44.8, 31.8, 27.6, 24.8 ppm. The mixture was cooled to 25 to 35° C. The mixture was agitated at 25 to 35° C. split Additional ethyl acetate (800 mL, 5×) and water (800 mL, 5×) were added The mixture was agitated at 25 to 35° C. split The combined organic phase was washed four times with water (400 mL, 2.5×) The organic phase was distilled under vacuum below 50° C. to 6× volume Additional ethyl acetate (2880 mL, 18×) was continuously added the distillation to maintain about 6× volume was adjusted to 40 to 45° C. seeds (0.8 g, 0.005×) were added The mixture was held for about 30 minutes heptane (960 mL, 6×) was added over about 1.5 hours The mixture was cooled to 15 to 25° C. over about 1 to 1.5 hours agitated at 15 to 25° C. for at least one hour held for 16 hours The solid was filtered washed with heptane ethyl acetate (5× total, 2.5× heptane, 2.5× ethyl acetate), and dried under reduced pressure with nitrogen sweep at 35 to 45° C. until LOD≦1%

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-tert-Butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (160 g), 4-(4-(chloromethyl)benzyl)morpholine hydrochloride (138 g, 0.87×) and potassium carbonate (165 g, 1.04×) were added to DMF (960 mL, 6×) in a 5 liter jacketed vessel. The mixture was heated to 40 to 50° C. and agitated for 12 to 24 hours. The mixture was cooled to 25 to 35° C., then ethyl acetate (1600 mL, 10×) and water (1600 mL, 10×) were added. The mixture was agitated at 25 to 35° C., settled, and split. Additional ethyl acetate (800 mL, 5×) and water (800 mL, 5×) were added. The mixture was agitated at 25 to 35° C., settled, and split. The combined organic phase was washed four times with water (400 mL, 2.5×). The organic phase was distilled under vacuum below 50° C. to 6× volume. Additional ethyl acetate (2880 mL, 18×) was continuously added, and the distillation was continued to maintain about 6× volume. The temperature was adjusted to 40 to 45° C., then seeds (0.8 g, 0.005×) were added. The mixture was held for about 30 minutes to build seed bed, then heptane (960 mL, 6×) was added over about 1.5 hours. The mixture was cooled to 15 to 25° C. over about 1 to 1.5 hours, agitated at 15 to 25° C. for at least one hour, and held for 16 hours. The solid was filtered, washed with heptane:ethyl acetate (5× total, 2.5× heptane, 2.5× ethyl acetate), and dried under reduced pressure with nitrogen sweep at 35 to 45° C. until LOD≦1%, to give (S)-tert-butyl 5-amino-4-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate as a white solid (215.3 g, 86% yield); MS m/z: 524.3 (M+1); 1H NMR (DMSO-d6, 300 MHz) δ 7.57 (br s, 1H), 7.48-7.43 (m, 3H), 7.34 (d, J=8.1 Hz, 2H), 7.29 (d, J=7.5 Hz, 2H), 7.19 (br s, 1H), 5.21 (s, 2H), 4.71 (dd, J=10.2, 4.2 Hz, 1H), 4.54 (d, J=17.4 Hz, 1H), 4.40 (d, J=17.7 Hz, 1H), 3.56 (dd, J=4.5, 4.5 Hz, 4H), 3.45 (s, 2H), 2.34 (dd, J=4.5, 4.5 Hz, 4H), 2.15-1.99 (m, 4H), 1.32 (s, 9H) ppm; 13C NMR (DMSO-d6, 75 MHz) δ 171.8, 171.3, 167.8, 153.4, 137.7, 135.3, 133.3, 130.2, 129.5, 129.0, 127.6, 115.1, 114.6, 79.7, 69.4, 66.2, 62.1, 53.5, 53.1, 44.8, 31.8, 27.6, 24.8 ppm. The mixture was cooled to 25 to 35° C. The mixture was agitated at 25 to 35° C. split Additional ethyl acetate (800 mL, 5×) and water (800 mL, 5×) were added The mixture was agitated at 25 to 35° C. split The combined organic phase was washed four times with water (400 mL, 2.5×) The organic phase was distilled under vacuum below 50° C. to 6× volume Additional ethyl acetate (2880 mL, 18×) was continuously added the distillation to maintain about 6× volume was adjusted to 40 to 45° C. seeds (0.8 g, 0.005×) were added The mixture was held for about 30 minutes heptane (960 mL, 6×) was added over about 1.5 hours The mixture was cooled to 15 to 25° C. over about 1 to 1.5 hours agitated at 15 to 25° C. for at least one hour held for 16 hours The solid was filtered washed with heptane ethyl acetate (5× total, 2.5× heptane, 2.5× ethyl acetate), and dried under reduced pressure with nitrogen sweep at 35 to 45° C. until LOD≦1%