4-methylsulfonylmorpholine

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:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-(methylsulfonyl)morpholine (0.217 g, 1.314 mmol, Preparation #41) in THF (4 mL) at about 0° C. was added n-BuLi (2.5 M in hexanes, 0.53 mL, 1.3 mmol). The reaction mixture was stirred at about 0° C. for about 1 h. The resulting solution was added dropwise to a solution of 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.350 g, 0.876 mmol, Example #35 Step G) in THF (4 mL) at about 0° C. The reaction mixture was maintained at about 4° C. in a refrigerator for about 48 h. The reaction mixture was partitioned between water (5 mL) and DCM (5 mL) The layers were separated and the aqueous solution was extracted with DCM (2×5 mL). The combined organic extracts were concd under reduced pressure. The product was purified by silica gel chromatography eluting with a gradient of 0-2% MeOH/DCM, then by RP-HPLC (Table 1, Method 1) to give 3-ethyl-1-(morpholinosulfonylmethyl)-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.17 g, 34%) as a yellow oil: LC/MS (Table 1, Method b) Rt=2.32 & 2.42 min; MS m/z: 565 (M+H)+. The reaction mixture was maintained at about 4° C. in a refrigerator for about 48 h The reaction mixture was partitioned between water (5 mL) and DCM (5 mL) The layers were separated the aqueous solution was extracted with DCM (2×5 mL) The product was purified by silica gel chromatography eluting with a gradient of 0-2% MeOH/DCM

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of morpholine (2.00 mL, 22.96 mmol) in DCM (40 mL) was added TEA (3.20 mL, 22.96 mmol) at about −20° C., then methanesulfonyl chloride (2.68 mL, 34.4 mmol) was added dropwise at about −20° C. The reaction mixture was stirred at about −20° C. for about 2 h, then warmed to rt. The mixture was partitioned with saturated aqueous NH4Cl (100 mL) and DCM (3×50 mL). The combined organic layers were concentrated and purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc/heptane to give 4-(methylsulfonyl)morpholine (3.95 g, 100%) as a white solid: 1H NMR (DMSO-d6) δ 3.70-3.60 (m, 4H), 3.12-3.04 (m, 4H), 2.89 (s, 3H). warmed to rt The mixture was partitioned with saturated aqueous NH4Cl (100 mL) and DCM (3×50 mL) The combined organic layers were concentrated purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc/heptane