4-(2-氨乙基)硫代吗啉-1,1-二氧化物

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1) in 1,4-dioxane (4 mL) was added tris(dibenzylideneacetone) dipalladium (0) (40 mg, 0.04 mmol), 1,1′-bis(diphenyphosphino)ferrocene (25 mg, 0.04 mmol), sodium tert-butoxide (77 mg, 0.80 mmol) and 2-(1,1-dioxidothio-morpholin-4-yl)ethanamine (107 mg, 0.60 mmol). The resulting mixture was evacuated and refilled with nitrogen, sealed and heated at 120° C. overnight. After being cooled to room temperature, the mixture was filtered and washed with ethyl acetate, the organic layers were combined and concentrated in vacuo, the residue was purified by flash chromatography (eluenting with 2% methanol in dichloromethane) to afford 67 mg of the title compound as a light solid (yield was 40%). MS obsd. (ESI+) [(M+H)+] 515, 1H NMR (400 MHz, CDCl3) 8.05 (d, J=7.6 Hz, 1 H), 7.66 (d, J=7.2 Hz, 1 H), 7.53-7.48 (m, 2 H), 7.37-7.28 (m, 2 H), 7.21 (s, 1 H), 5.88 (s, 1 H), 5.26 (m, 1 H), 5.12 (s, 1 H), 4.6 (brs, 1 H), 3.56 (m, 1 H), 3.33 (m, 2 H), 3.14 (m, 8 H), 2.99 (t, J=4.8 Hz, 2 H), 2.46 (s, 3 H), 2.0 (d, J=4.5 Hz, 2 H). The resulting mixture was evacuated refilled with nitrogen sealed After being cooled to room temperature the mixture was filtered washed with ethyl acetate concentrated in vacuo the residue was purified by flash chromatography (eluenting with 2% methanol in dichloromethane)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1) in 1,4-dioxane (4 mL) was added tris(dibenzylideneacetone) dipalladium (0) (40 mg, 0.04 mmol), 1,1′-bis(diphenyphosphino)ferrocene (25 mg, 0.04 mmol), sodium tert-butoxide (77 mg, 0.80 mmol) and 2-(1,1-dioxidothio-morpholin-4-yl)ethanamine (107 mg, 0.60 mmol). The resulting mixture was evacuated and refilled with nitrogen, sealed and heated at 120° C. overnight. After being cooled to room temperature, the mixture was filtered and washed with ethyl acetate, the organic layers were combined and concentrated in vacuo, the residue was purified by flash chromatography (eluenting with 2% methanol in dichloromethane) to afford 67 mg of the title compound as a light solid (yield was 40%). MS obsd. (ESI+) [(M+H)+] 515, 1H NMR (400 MHz, CDCl3) 8.05 (d, J=7.6 Hz, 1 H), 7.66 (d, J=7.2 Hz, 1 H), 7.53-7.48 (m, 2 H), 7.37-7.28 (m, 2 H), 7.21 (s, 1 H), 5.88 (s, 1 H), 5.26 (m, 1 H), 5.12 (s, 1 H), 4.6 (brs, 1 H), 3.56 (m, 1 H), 3.33 (m, 2 H), 3.14 (m, 8 H), 2.99 (t, J=4.8 Hz, 2 H), 2.46 (s, 3 H), 2.0 (d, J=4.5 Hz, 2 H). The resulting mixture was evacuated refilled with nitrogen sealed After being cooled to room temperature the mixture was filtered washed with ethyl acetate concentrated in vacuo the residue was purified by flash chromatography (eluenting with 2% methanol in dichloromethane)

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

实验步骤: A mixture of 4-(2-aminoethyl)thiomorpholine 1,1-dioxide (2.00 g, 11.2 mmol) and triethylamine (1.42 g, 14.0 mmol) in DCM (100 mL) was cooled in an ice bath and treated slowly with 2-nitrobenzene-1-sulfonyl chloride (2.49 g, 11.2 mmol). The mixture was removed from the ice bath and stirred at rt for 18 h. The resulting mixture was washed with water (2×50 mL) and the combined aqueous washes were extracted with DCM (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a yellow solid. Purification by silica gel chromatography (linear gradient 100% DCM to 100:1 DCM:MeOH) gave the title compound as a pale yellow solid (3.47 g, 85% yield). LCMS: m/z 364 (M+H+), retention time 0.98 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.71 (t, J=5.49 Hz, 2H) 2.96 (br. s., 4H) 3.05 (br. s., 4H) 3.20 (q, J=5.49 Hz, 2H) 5.93 (br. s., 1H) 7.73-7.84 (m, 2H) 7.84-7.93 (m, 1H) 8.11-8.23 (m, 1H). was cooled in an ice bath The mixture was removed from the ice bath The resulting mixture was washed with water (2×50 mL) the combined aqueous washes were extracted with DCM (50 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo to a yellow solid Purification by silica gel chromatography (linear gradient 100% DCM to 100:1 DCM:MeOH)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1) in 1,4-dioxane (4 mL) was added tris(dibenzylideneacetone) dipalladium (0) (40 mg, 0.04 mmol), 1,1′-bis(diphenyphosphino)ferrocene (25 mg, 0.04 mmol), sodium tert-butoxide (77 mg, 0.80 mmol) and 2-(1,1-dioxidothio-morpholin-4-yl)ethanamine (107 mg, 0.60 mmol). The resulting mixture was evacuated and refilled with nitrogen, sealed and heated at 120° C. overnight. After being cooled to room temperature, the mixture was filtered and washed with ethyl acetate, the organic layers were combined and concentrated in vacuo, the residue was purified by flash chromatography (eluenting with 2% methanol in dichloromethane) to afford 67 mg of the title compound as a light solid (yield was 40%). MS obsd. (ESI+) [(M+H)+] 515, 1H NMR (400 MHz, CDCl3) 8.05 (d, J=7.6 Hz, 1 H), 7.66 (d, J=7.2 Hz, 1 H), 7.53-7.48 (m, 2 H), 7.37-7.28 (m, 2 H), 7.21 (s, 1 H), 5.88 (s, 1 H), 5.26 (m, 1 H), 5.12 (s, 1 H), 4.6 (brs, 1 H), 3.56 (m, 1 H), 3.33 (m, 2 H), 3.14 (m, 8 H), 2.99 (t, J=4.8 Hz, 2 H), 2.46 (s, 3 H), 2.0 (d, J=4.5 Hz, 2 H). The resulting mixture was evacuated refilled with nitrogen sealed After being cooled to room temperature the mixture was filtered washed with ethyl acetate concentrated in vacuo the residue was purified by flash chromatography (eluenting with 2% methanol in dichloromethane)