propan-2-yl methanesulfonate

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:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (60% dispersion in mineral oil, 9 mg, 0.22 mmol) was added to a solution of 1-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-azetidin-3-ol (Intermediate 166, 50 mg, 0.147 mol) in anhydrous DMF (0.5 mL) at 0 C under nitrogen and the mixture was stirred for 10 min. A solution of propan-2-yl methanesulfonate (26.7 μL, 0.221 mmol) in anhydrous DMF (0.5 mL) was then added and the mixture was stirred at room temperature for 18 h. Further sodium hydride (60% dispersion in mineral oil, 9 mg, 0.22 mmol) and propan-2-yl methanesulfonate (26.7 μL, 0.221 mmol) were then added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc (10 mL) then washed with saturated aq. sodium carbonate (4×5 mL), brine (5 mL) and evaporated under vacuum. The crude residue was purified by flash chromatography (0-2% (7M ammonia in MeOH) in DCM) to afford the title compound as a light yellow glass (22 mg, 39%). the mixture was stirred at room temperature for 18 h the mixture was stirred at room temperature for 4 h then washed with saturated aq. sodium carbonate (4×5 mL), brine (5 mL) evaporated under vacuum The crude residue was purified by flash chromatography (0-2% (7M ammonia in MeOH) in DCM)

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

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

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

Procedure: The product from Example 28A (50 mg, 0.14 mmol) in dioxane (5 mL) was treated with NaH (60%) (7 mg, 0.17 mmol) stirred at rt for 10 min and treated with isopropyl methanesulfonate (78 mg, 0.56 mmol). The reaction was heated at 85° C. for 12 hrs, quenched with H2O, the mixture was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 5.2 mg (9%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (d, J=6.14 Hz, 6H) 1.81 (s, 9H) 3.75-3.83 (m, 1H) 4.12 (s, 3H) 4.92 (s, 2H) 7.10 (d, J=9.21 Hz, 1H) 7.63 (dd, J=9.21, 2.76 Hz, 1H) 8.18 (d, J=2.45 Hz, 1H) 9.28 (s, 1H); MS (DCI/NH4+) m/z 397 (M+H)+. The reaction was heated at 85° C. for 12 hrs quenched with H2O the mixture was extracted with EtOAc (2×) The combined organic layers were dried over MgSO4 filtered concentrated The residue was purified by column chromatography

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

Procedure: The product from Example 28A (50 mg, 0.14 mmol) in dioxane (5 mL) was treated with NaH (60%) (7 mg, 0.17 mmol) stirred at rt for 10 min and treated with isopropyl methanesulfonate (78 mg, 0.56 mmol). The reaction was heated at 85° C. for 12 hrs, quenched with H2O, the mixture was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 5.2 mg (9%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (d, J=6.14 Hz, 6H) 1.81 (s, 9H) 3.75-3.83 (m, 1H) 4.12 (s, 3H) 4.92 (s, 2H) 7.10 (d, J=9.21 Hz, 1H) 7.63 (dd, J=9.21, 2.76 Hz, 1H) 8.18 (d, J=2.45 Hz, 1H) 9.28 (s, 1H); MS (DCI/NH4+) m/z 397 (M+H)+. The reaction was heated at 85° C. for 12 hrs quenched with H2O the mixture was extracted with EtOAc (2×) The combined organic layers were dried over MgSO4 filtered concentrated The residue was purified by column chromatography

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a rapidly stirred solution of 8.28 g (60 mmol) of isopropyl methanesulfonate in 150 mL of THF at -73° C. (internal temp.) was added 25 mL (60 mmol) of 2.4M n-butyllithium dropwise over 20 min. The internal temperature was not allowed to rise above -69° C. throughout the course of the addition. After an additional 15 min., 5.17 g (30 mmol) of freshly distilled diethyl chlorophosphate was added at a rate to keep the solution temperature below -69° C. The reaction mixture was stirred for 0.3 h at -73° C. and for 0.5 h at -40° C. when it was quenched with 125 mL of saturated NH4Cl solution. The reaction mass was warmed to room temperature and the THF removed under reduced pressure. The remainder was partitioned between methylene chloride and water (3×75 mL). The extracts were dried (Na2SO4), concentrated, and purified by flash chromatography (350 g silica gel) eluting with 1:1 methylene chloride/ether to provide 5.20 g (67%) of title compound as a colorless oil. to rise above -69° C. throughout the course of the addition the solution temperature below -69° C was quenched with 125 mL of saturated NH4Cl solution The reaction mass was warmed to room temperature the THF removed under reduced pressure The remainder was partitioned between methylene chloride and water (3×75 mL) The extracts were dried (Na2SO4) concentrated purified by flash chromatography (350 g silica gel) eluting with 1:1 methylene chloride/ether

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a rapidly stirred solution of 8.28 g (60 mmol) of isopropyl methanesulfonate in 150 mL of THF at -73° C. (internal temp.) was added 25 mL (60 mmol) of 2.4M n-butyllithium dropwise over 20 min. The internal temperature was not allowed to rise above -69° C. throughout the course of the addition. After an additional 15 min., 5.17 g (30 mmol) of freshly distilled diethyl chlorophosphate was added at a rate to keep the solution temperature below -69° C. The reaction mixture was stirred for 0.3 h at -73° C. and for 0.5 h at -40° C. when it was quenched with 125 mL of saturated NH4Cl solution. The reaction mass was warmed to room temperature and the THF removed under reduced pressure. The remainder was partitioned between methylene chloride and water (3×75 mL). The extracts were dried (Na2SO4), concentrated, and purified by flash chromatography (350 g silica gel) eluting with 1:1 methylene chloride/ether to provide 5.20 g (67%) of title compound as a colorless oil. to rise above -69° C. throughout the course of the addition the solution temperature below -69° C was quenched with 125 mL of saturated NH4Cl solution The reaction mass was warmed to room temperature the THF removed under reduced pressure The remainder was partitioned between methylene chloride and water (3×75 mL) The extracts were dried (Na2SO4) concentrated purified by flash chromatography (350 g silica gel) eluting with 1:1 methylene chloride/ether

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

Procedure: Sodium hydride (60% dispersion in mineral oil, 9 mg, 0.22 mmol) was added to a solution of 1-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-azetidin-3-ol (Intermediate 166, 50 mg, 0.147 mol) in anhydrous DMF (0.5 mL) at 0 C under nitrogen and the mixture was stirred for 10 min. A solution of propan-2-yl methanesulfonate (26.7 μL, 0.221 mmol) in anhydrous DMF (0.5 mL) was then added and the mixture was stirred at room temperature for 18 h. Further sodium hydride (60% dispersion in mineral oil, 9 mg, 0.22 mmol) and propan-2-yl methanesulfonate (26.7 μL, 0.221 mmol) were then added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc (10 mL) then washed with saturated aq. sodium carbonate (4×5 mL), brine (5 mL) and evaporated under vacuum. The crude residue was purified by flash chromatography (0-2% (7M ammonia in MeOH) in DCM) to afford the title compound as a light yellow glass (22 mg, 39%). the mixture was stirred at room temperature for 18 h the mixture was stirred at room temperature for 4 h then washed with saturated aq. sodium carbonate (4×5 mL), brine (5 mL) evaporated under vacuum The crude residue was purified by flash chromatography (0-2% (7M ammonia in MeOH) in DCM)