9-methyl-3,9-diazabicyclo[4.2.1]nonane

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: To a solution of 9-methyl-3,9-diazabicyclo[4.2.1]nonane (0.56 g) in 1,4-dioxane (10 ml) was added sulfamide (0.37 g) and the reaction mixture was then heated at reflux in 1,4-dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with 7N NH3/MeOH (200 ml). The eluent was then reduced in vacuo to yield 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g) as a yellow solid. A mixture of 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.31 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 5 step i), 0.25 g) in 1,4-dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield 0.35 g the reaction mixture was then heated The reaction mixture was purified eluting with 7N NH3/MeOH (200 ml)

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

Procedure: 9-Methyl-3,9-diazabicyclo[4.2.1]nonane (prepared as described in U.S. Pat. No. 2,999,091) and 2-chloro-5-iodopyridine were coupled according the procedure of Example 15C to provide the title compound (78% yield). 1H NMR (free base, CDCl3, 300 MHz) δ 1.23-1.48 (m, 2H), 1.65-1.76 (m, 1H), 1.91-2.27 (m, 3H), 2.44 (s, 3H), 3.18-3.35 (m, 3H), 3.48-3.54 (m, 2H), 3.65 (br d, J=13.5 Hz, 1H), 6.98 (dd, J=3, 8.25 Hz, 1H), 7.06 (d, J=8.25 Hz, 1H), 7.87 (d, J=3 Hz, 1H); MS (DCI/NH3) m/z 252 (M+H)+, 269 (M+NH4)+; Anal. Calcd. for C13H18ClN3.C7H8O3S: C, 56.66; H, 6.18; N, 9.91. Found: C, 56.76; H, 6.15; N, 9.77.

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

Procedure: The title comound was prepared in 44.7% yield according to example 8 by reacting 6,7-difluoro-1-vinyl-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid with 9-methyl-3,9-diazabicyclo[4.2.1]nonane, m.p. 214°-215° C. The title comound was prepared in 44.7% yield

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

Procedure: The title comound was prepared in 44.7% yield according to example 8 by reacting 6,7-difluoro-1-vinyl-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid with 9-methyl-3,9-diazabicyclo[4.2.1]nonane, m.p. 214°-215° C. The title comound was prepared in 44.7% yield

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

Procedure: To a solution of 9-methyl-3,9-diazabicyclo[4.2.1]nonane (0.56 g) in 1,4-dioxane (10 ml) was added sulfamide (0.37 g) and the reaction mixture was then heated at reflux in 1,4-dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with 7N NH3/MeOH (200 ml). The eluent was then reduced in vacuo to yield 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g) as a yellow solid. A mixture of 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.31 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 5 step i), 0.25 g) in 1,4-dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield 0.35 g the reaction mixture was then heated The reaction mixture was purified eluting with 7N NH3/MeOH (200 ml)

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

Procedure: To a solution of 9-methyl-3,9-diazabicyclo[4.2.1]nonane (0.56 g) in 1,4-dioxane (10 ml) was added sulfamide (0.37 g) and the reaction mixture was then heated at reflux in 1,4-dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with 7N NH3/MeOH (200 ml). The eluent was then reduced in vacuo to yield 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g) as a yellow solid. A mixture of 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.31 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 5 step i), 0.25 g) in 1,4-dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield 0.35 g the reaction mixture was then heated The reaction mixture was purified eluting with 7N NH3/MeOH (200 ml)

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

Procedure: Neat LAH (0.5 g, 13.17 mmol) was added in small portions to a stirred solution of 9-methyl-3,9-diazabicyclo[4.2.1]nonan-4-one (1.0 g, 6.48 mmol) in THF (40 ml) and the mixture was heated at reflux under nitrogen for 3-4 h. Reaction mixture was cooled in ace bath and quenched by consecutive addition of water (0.5 ml), 15% NaOH (1.5 ml) and water (0.5 ml) and then stirred for 30 min. Precipitated sodium aluminate was filtered off and the filtrate was dried over MgSO4, filtered and evaporated to dryness to afford 9-methyl-3,9-diazabicyclo[4.2.1]nonane as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.08-1.67 (m, 4H) 1.74-1.92 (m, 1H) 2.01-2.31 (m, 2H) 2.41-2.46 (m, 3H) 2.66 (dd, J=13.09, 2.01 Hz, 1H) 2.77-3.00 (m,2H) 3.07-3.36 (m, 2H) 3.50-4.06 (m, 1H). the mixture was heated at reflux under nitrogen for 3-4 h Reaction mixture was cooled in ace bath quenched by consecutive addition of water (0.5 ml), 15% NaOH (1.5 ml) and water (0.5 ml) Precipitated sodium aluminate was filtered off the filtrate was dried over MgSO4 filtered evaporated to dryness

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9-Methyl-3,9-diazabicyclo[4.2.1]nonane (J. Org. Chem., 1960, 637 ). Conc. H2SO4 (6.25 ml, 0.117 mol) was added dropwise to a stirred cold (−5° C.) solution of 8-methyl-8-azabicyclo[3.2.1]octan-3-one (2.78 g, 0.02 mol) in CHCl3(25 ml) while keeping the temperature below 15° C. After cooling to 0-5° C., neat sodium azide (2.60 g, 0.040 mol) was added in small portions while maintaining pot temperature below 35° C. The mixture stirred at rt for 2 h and then heated at 50° C. for 2 h. Rxn mixture was poured into ice and neutralized with Na2CO3 and then basify with 50% NaOH. Organic layer separated and the aq. layer re-extracted with CHCl3 (2×25 ml). Combined organic layers were washed with water (10 ml), brine and dried (MgSO4). Evaporation of CHCl3 gave 9-methyl-3,9-diazabicyclo[4.2.1]nonan-4-one as a off-white solid (1.15 g, 37%). 1H NMR (400 MHz, CHLOROFORM-D) ppm 1.67-1.75 (m, 1H) 1.77-1.85 (m, 1H) 2.05-2.16 (m, 2H) 2.42 (s, 3H) 2.46 (ddd, J=16.05, 6.23, 2.14 Hz, 1H) 2.80-2.90 (m, 2H) 3.17 (t, J=6.42 Hz, 1H) 3.24 (t, J=6.30 Hz, 1H) 3.60 d), J=14.60 Hz, 1H) 5.90 (s, 1H). the temperature below 15° C while maintaining pot temperature below 35° C heated at 50° C. for 2 h Organic layer separated the aq. layer re-extracted with CHCl3 (2×25 ml) Combined organic layers were washed with water (10 ml), brine dried (MgSO4) Evaporation of CHCl3

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

Procedure: To a solution of 9-methyl-3,9-diazabicyclo[4.2.1]nonane (0.56 g) in 1,4-dioxane (10 ml) was added sulfamide (0.37 g) and the reaction mixture was then heated at reflux in 1,4-dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with 7N NH3/MeOH (200 ml). The eluent was then reduced in vacuo to yield 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g) as a yellow solid. A mixture of 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.31 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 5 step i), 0.25 g) in 1,4-dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield 0.35 g the reaction mixture was then heated The reaction mixture was purified eluting with 7N NH3/MeOH (200 ml)