4-(2-iodoethyl)morpholine

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: 500 mg (0.980 mmol) of the compound from example 82A were dissolved in 10 ml of DMF, 414 mg (1.270 mmol) of cesium carbonate and 259 mg (1.08 mmol) of 4-(2-iodoethyl)morpholine were added and the mixture was stirred at RT for 18 h, at 40° C. for 18 h and at 100° C. for 8 h. After cooling, water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The purification was effected by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 102 mg (17% of theory) of the title compound were obtained. After cooling the mixture was extracted with ethyl acetate The combined organic phases were dried over sodium sulfate concentrated on a rotary evaporator The purification

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 7-nitro-1,2,3,4-tetrahydroquinoline (D1) (246 mg, 1.38 mmol) in DMF (2.7 ml) was added potassium carbonate (574 mg, 4.15 mmol) followed by a solution of 4-(2-iodoethyl)morpholine (500 mg, 2.07 mmol) in DMF (2 ml) and the reaction heated to 70° C. After cooling to ambient temperature the reaction mixture was diluted with water and extracted with EtOAc which was washed with water, dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by silica SPE chromatography. Elution with 80% EtOAc/petroleum ether gave the title compound as an orange gum (29 mg). 1H NMR (250 MHz, CDCl3) δ (ppm): 7.39 (m, 2H), 7.00 (d, 1H), 3.73 (m, 4H), 3.47 (m, 2H), 3.38 (m, 2H), 2.79 (t, 2H), 2.49-2.59 (m, 6H), 1.96 (m, 2H). After cooling to ambient temperature the reaction mixture extracted with EtOAc which was washed with water dried over MgSO4 concentrated in vacuo to give the crude product which was purified by silica SPE chromatography Elution with 80% EtOAc/petroleum ether

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: Methyl 4-bromo-3-hydroxybenzoate (143 mg) and 4-(2-iodoethyl)morpholine.HCI (189 mg) were combined in DMF (10 ml). Sodium hydride (55 mg, 60% dispersion in mineral oil) was added and the reaction heated at 80° C. under nitrogen for 5 hours. The reaction was quenched with water (10 ml) and the solvent evaporated under vacuum. Ethyl acetate/chloroform (1:1, 30 ml) and water (30 ml) were added to the residue resulting in precipitation of a solid, which was filtered off and washed with ether. The solid was partitioned between ethyl acetate/chloroform (1:1, 2×50 ml) and aqueous sodium hydrogen carbonate solution (1 M, 50 ml). The organic layers were combined, dried over a hydrophobic filter and evaporated to give methyl 4-bromo-3-{[2-(4-morpholinyl)ethyl]oxy}benzoate as a yellow gel (103 mg). The reaction was quenched with water (10 ml) the solvent evaporated under vacuum Ethyl acetate/chloroform (1:1, 30 ml) and water (30 ml) were added to the residue resulting in precipitation of a solid, which was filtered off washed with ether The solid was partitioned between ethyl acetate/chloroform (1:1, 2×50 ml) and aqueous sodium hydrogen carbonate solution (1 M, 50 ml) dried over a hydrophobic filter evaporated

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

実験手順: A mixture of 1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (100 mg, 0.23 mmol) from Step 1 of this Example, 4-(2-iodoethyl)morpholine (111 mg, 0.46 mmol) from Step 2 of this Example, Cs2CO3 (250 mg, 0.69 mmol), and NMP (2 mL) was stirred at rt for 3 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with a gradient of 33% DCM in THF to 100% THF, to afford (3aR,7aR)-2,2-dimethyl-3-(6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)octahydrobenzo[d]oxazole (84 mg, 67%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.90 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 7.29 (s, 1H), 7.14-7.19 (m, 2H), 6.90 (m, 1H), 5.35 (s, 2H), 4.11-4.17 (m, 2H), 3.70-3.75 (m, 4H), 3.65 (m, 1H), 3.08 (m, 1H), 2.76-2.84 (m, 3H), 2.57-2.60 (m, 4H), 2.17 (m, 1H), 1.82-1.92 (m, 2H), 1.78 (s, 3H), 1.46 (s, 3H), 1.33-1.39 (m, 4H); LCMS (ESI) m/z 548 (M+H)+. washed with brine The organic layer was separated dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by silica gel flash chromatography eluting with a gradient of 33% DCM in THF to 100% THF

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-[5-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (100 mg, 0.24 mmol), 4-(2-iodo-ethyl)-morpholine (90 mg, 0.37 mmol), N,N-diisopropylethylamine (63 mg, 0.49 mmol) and silver triflate (75 mg (0.29 mmol) in 1,4-dioxane (5 ml) was heated at 85° C. under nitrogen for 16 hours. Purification of the mixture by silica gel chromatography, eluted with a gradient of MeOH in CHCl3 led to 3-{5-[(2,4-dimethoxy-benzyl)-(2-morpholin-4-yl-ethyl)-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one as a yellow solid (40 mg, 31%). Purification of the mixture by silica gel chromatography eluted with a gradient of MeOH in CHCl3

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

実験手順: A mixture of 4-(2-chloro-ethyl)-morpholine hydrochloride (5 g, 26.9 mmole), and sodium iodide (20 g, 134.4 mmole) in acetone (50 ml) was refluxed for 16 hours. After cooled to room temperature, the reaction was partitioned between CHCl3 and brine. The aqueous layer was extracted with CHCl3 (2×25 ml). The combined organic layers were washed with brine, and dried over anhydrous Mg2SO4. Removal of the solvent gave 4-(2-iodo-ethyl)-morpholine as a pale yellowish oil (3.84 g, 59%). was refluxed for 16 hours the reaction was partitioned between CHCl3 and brine The aqueous layer was extracted with CHCl3 (2×25 ml) The combined organic layers were washed with brine dried over anhydrous Mg2SO4 Removal of the solvent

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

実験手順: To 5-methoxy-2-methyl-1H-indole (5.00 g; 31.0 mmol) in 30 mL of dry THF at 0° C. was added dropwise MeMgBr (3.0M in Et2O; 11.4 mL; 34.2 mmol). The solution was stirred 30 min at r.t. after which ZnCl2 (0.5M in THF; 64 mL; 32 mmol) was added. The mixture was stirred at r.t., after 1 h, N-(2-iodoethyl)morpholine (14.41 g; 51.5 mmol) was added. The final mixture was stirred at r.t. overnight. The mixture was poored in saturated NaHCO3 (100 mL), extracted with EtOAc (2×100 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, concentrated and flash chromatographed (Silica gel; EtOAc/Ace O to 10%) to yield 587 mg (7%) of the title compound. was added extracted with EtOAc (2×100 mL) The organic phase was washed with brine (100 mL) dried over Na2SO4 filtered concentrated flash chromatographed (Silica gel; EtOAc/Ace O to 10%)

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

実験手順: 500 mg (0.980 mmol) of the compound from example 82A were dissolved in 10 ml of DMF, 414 mg (1.270 mmol) of cesium carbonate and 259 mg (1.08 mmol) of 4-(2-iodoethyl)morpholine were added and the mixture was stirred at RT for 18 h, at 40° C. for 18 h and at 100° C. for 8 h. After cooling, water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The purification was effected by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 102 mg (17% of theory) of the title compound were obtained. After cooling the mixture was extracted with ethyl acetate The combined organic phases were dried over sodium sulfate concentrated on a rotary evaporator The purification

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 7-nitro-1,2,3,4-tetrahydroquinoline (D1) (246 mg, 1.38 mmol) in DMF (2.7 ml) was added potassium carbonate (574 mg, 4.15 mmol) followed by a solution of 4-(2-iodoethyl)morpholine (500 mg, 2.07 mmol) in DMF (2 ml) and the reaction heated to 70° C. After cooling to ambient temperature the reaction mixture was diluted with water and extracted with EtOAc which was washed with water, dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by silica SPE chromatography. Elution with 80% EtOAc/petroleum ether gave the title compound as an orange gum (29 mg). 1H NMR (250 MHz, CDCl3) δ (ppm): 7.39 (m, 2H), 7.00 (d, 1H), 3.73 (m, 4H), 3.47 (m, 2H), 3.38 (m, 2H), 2.79 (t, 2H), 2.49-2.59 (m, 6H), 1.96 (m, 2H). After cooling to ambient temperature the reaction mixture extracted with EtOAc which was washed with water dried over MgSO4 concentrated in vacuo to give the crude product which was purified by silica SPE chromatography Elution with 80% EtOAc/petroleum ether