4-(3-Chloropropyl)morpholine

Pale Yellow Oil

To a solution of 1-bromo-3-chloropropane (10.0 g, 63.5 mmol) in toluene (100 mL) was added morpholine (11.0 mL, 127 mmol). a) A mixture of morpholine (261 ml, 3.00 mol) and 1-bromo-3-chloropropane (148 ml, 1.50 mol) in toluene (900 ml) was stirred for 18 hours at ambient temperature. Additional 1-bromo-3-chloropropane (25 ml, 0.25 mol) was added, the reaction was stirred for a further 1 hour and then filtered to remove the precipitated solid before the filtrate was concentrated in vacuo. Distillation of the crude oil yieldedb) N-(3-chloropropyl)-morpholine (119.3 g, 49 percent yield) as the fraction boiling at 70 - 80 °C / 2.6 mmHg :1H-NMR (DMSO d6): 3.65 (t, 2H), 3.55 (m, 4H), 2.40 (t, 2H), 2.39 (m, 4H), 1.85 (m, 2H) : MS (+ve ESI) : 164 (M+H)+.a) A mixture of morpholine (261 ml, 3.00 mol) and 1-bromo-3-chloropropane (148 ml, 1.50 mol) in toluene (900 ml) was stirred for 18 hours at ambient temperature. Additional 1-bromo-3-chloropropane (25 ml, 0.25 mol) was added, the reaction was stirred for a further 1 hour and then filtered to remove the precipitated solid before the filtrate was concentrated in vacuo. Distillation of the crude oil yielded N-(3-chloropropyl)-morpholine (119.3 g, 49percent yield) as the fraction boiling at 70-80° C./2.6 mmHg:A mixture of morpholine (261 ml, 3.00 mol) and 1-bromo-3-chloropropane (148 ml, 1.50 mol) in toluene (900 ml) was stirred for 18 hours at ambient temperature. Additional 1-bromo-3 -chloropropane (25 ml, 0.25 mol) was added, the reaction was stirred for a further 1 hour and then filtered to remove the precipitated solid before the filtrate was concentrated in vacuo. Distillation of the crude oil yielded N-(3-chloropropyl)-morpholine (119.3 g, 49 percent yield) as the fraction boiling at 70-80 °C / 2.6 mmHg : A solution of [L-CHLORO-3-BROMOPROPANE] in dry tetrahydrofuran (2 mL) was added to a cold suspension of morpholine (200 mg, 2.29 mmol) and sodium carbonate (0.63 g, 4.56 mmol) in dry tetrahydrofuran (8 mL) at [0°C.] The mixture was stirred at [45°C] overnight. The mixture was allowed to cool to rt, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a mixture of ethyl acetate and n-heptane (70: 30), afforded [3-CHLORO-1-MORPHOLIN-4-YL-PROPANE] (156 mg, 42 percent). A solution of 3-chloro-1-morpholin-4-yl-propane (7.6 mg, 0.046 mmol) in [DRY N, N-] [DIMETHYLFORMAMIDE] (0.10 mL) was added to a solution of 118AF99-121 (15 mg, 0.037 mmol) and caesium carbonate (40 mg, 0.123 mmol) in a mixture of dry [N, N-] [DIMETHYLFORMAMIDE] and acetonitrile (1: 2, 0. 30 mL). After addition of sodium iodide (7.0 mg, 0.047 mmol) the mixture was shaken overnight at [60°C.] The mixture was allowed to cool to rt. Acetonitrile was removed by evaporation under reduced pressure and the residue was partitioned between dichloromethane (2 mL) and water (1 mL). The organic layer was evaporated to dryness. Purification of the residue by preparative reversed phase HPLC [(CIS)] afforded the desired compound (6.1 mg, 32 percent). LCMS [M/Z] 527 [[M+H] +.] HPLC tR= 6.2 min.A solution of l-chloro-3-bromopropane in dry tetrahydrofuran (2 mL) was added to a cold suspension of morpholine (200 mg, 2.29 mmol) and sodium carbonate (0.63 g, 4.56 mmol) in dry tetrahydrofuran (8 mL) at 03-Morpholinopropanethiol [0376] To a suspension of l-bromoro-3-chloropropane (30.00 g, 191 mmol) and potassium carbonate (14.00 g, 101 mmol) in dichloromethane (160 ml) was added morpholine (4.00 g, 46 mmol) in portions. Then the mixture was stirred at room temperature overnight. The mixture was filtered and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate) to give 5.60 g of product.

Gefitinib intermediate

Molecular Weight:163.64
XLogP3:0.8
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:163.0763918
Monoisotopic Mass:163.0763918
Topological Polar Surface Area:12.5
Heavy Atom Count:10
Complexity:83.7
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes