morpholine-4-sulfonyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: With intensive cooling, 32.7 ml of sulfuryl chloride are added at approximately 0° C. to 23.5 ml of morpholine. The suspension is then carefully heated to 60° C., causing the onset of hydrogen chloride evolution. After 5 h at 60° C., the evolution of hydrogen chloride is complete. The cooled brown reaction mixture is poured onto ice, and the precipitating oil is extracted with ether, washed with water, 5% sodium hydrogen carbonate solution and water and dried with sodium sulfate. The organic phases are concentrated by evaporation and distilled at elevated temperature and reduced pressure (90° C.; 1 mbar) to yield the title compound: 1H-NMR (200 MHz, DMSO-d6): 3.80 and 3.29 (2t, 5 Hz, per 4 H). The cooled brown reaction mixture is poured onto ice the precipitating oil is extracted with ether washed with water, 5% sodium hydrogen carbonate solution and water dried with sodium sulfate The organic phases are concentrated by evaporation distilled at elevated temperature and reduced pressure (90° C.; 1 mbar)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: With intensive cooling, 32.7 ml of sulfuryl chloride are added at approximately 0° C. to 23.5 ml of morpholine. The suspension is then carefully heated to 60° C., causing the onset of hydrogen chloride evolution. After 5 h at 60° C., the evolution of hydrogen chloride is complete. The cooled brown reaction mixture is poured onto ice, and the precipitating oil is extracted with ether, washed with water, 5% sodium hydrogen carbonate solution and water and dried with sodium sulfate. The organic phases are concentrated by evaporation and distilled at elevated temperature and reduced pressure (90° C.; 1 mbar) to yield the title compound: 1H-NMR (200 MHz, DMSO-d6): 3.80 and 3.29 (2t, 5 Hz, per 4 H). The cooled brown reaction mixture is poured onto ice the precipitating oil is extracted with ether washed with water, 5% sodium hydrogen carbonate solution and water dried with sodium sulfate The organic phases are concentrated by evaporation distilled at elevated temperature and reduced pressure (90° C.; 1 mbar)

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

Procedure: Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (150 mg, 0.383 mmol) and 4-morpholinesulfonyl chloride (142 mg, 0.766 mmol) the title compound of Step A was obtained as a yellow foam (96 mg, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78-10.01 (m, 1H), 8.34 (d, J=5.5 Hz, 1H), 7.58 (td, J=7.4, 2.4 Hz, 1H), 7.17-7.41 (m, 2H), 6.57-6.68 (m, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.42-3.63 (m, 8H), 2.91-3.11 (m, 4H).

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

Procedure: To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (1.5 g, 4.5 mmol) in pyridine (15 mL) was added morpholine-4-sulfonyl chloride (1.26 g, 6.8 mmol). The reaction was stirred at rt for 12 h. Then the reaction was washed with water (50 mL), and extracted with DCM (2×50 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:EtOAc 60:1) to afford the title compound of Step A (297 mg, 13.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=5.3 Hz, 1H), 7.27-7.36 (m, 2H), 7.21-7.26 (m, 2H), 6.98 (d, J=5.3 Hz, 1H), 3.58-3.64 (m, 4H), 3.22-3.33 (m, 1H), 3.14-3.21 (m, 4H), 1.40 (d, J=7.0 Hz, 6H). MS (ES+): 480 [M+H]+. Then the reaction was washed with water (50 mL) extracted with DCM (2×50 mL) The organic layer was washed with brine dried over anhydrous NaSO4 filtrated concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:EtOAc 60:1)

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

Procedure: A solution of 4.6 g of sulfuryl chloride in acetonitrile was treated dropwise with 996 mg of morpholine at ambient temperature under an atmosphere of nitrogen. After complete addition, the mixture was refluxed for 16 h, cooled to room temperature, and concentrated in vacuo to yield the title product as a red oil. TLC: Rf=0.65 CH2Cl2. (1H)-NMR (CDCl3) consistent with structure. After complete addition the mixture was refluxed for 16 h concentrated in vacuo