8-methyl-3,8-diazabicyclo[3.2.1]octane

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: A mixture of 8-methyl-3,8-diazabicyclo[3.2.1]octane (3.8 g, 30 mmol), 2-chloro-6-nitroquinoline (6.2 g, 30 mmol), diisopropylethylamine (10.5 ml, 60 mmol) and dioxane (100 ml) was stirred at reflux for 15 h. Aqueous ammonia (50 ml, 1 M) was added followed by extraction with dichloromethane (3×50 ml). Chromatography on silica gel with methanol:dichloromethane:aqueous ammonia (1:9:1%) as solvent gave the title compound as a solid. Yield 3.1 g (35%). Mp 152.1-154.5° C. at reflux for 15 h followed by extraction with dichloromethane (3×50 ml)

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

Procedure: A mixture of 8-methyl-3,8-diazabicyclo[3.2.1]octane (3.8 g, 30 mmol), 2-chloro-6-nitroquinoline (6.2 g, 30 mmol), diisopropylethylamine (10.5 ml, 60 mmol) and dioxane (100 ml) was stirred at reflux for 15 h. Aqueous ammonia (50 ml, 1 M) was added followed by extraction with dichloromethane (3×50 ml). Chromatography on silica gel with methanol:dichloromethane:aqueous ammonia (1:9:1%) as solvent gave the title compound as a solid. Yield 3.1 g (35%). Mp 152.1-154.5° C. at reflux for 15 h followed by extraction with dichloromethane (3×50 ml)

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

Procedure: Was prepared in the same manner as 8-methyl-3,8-diazabicyclo[3.2.1]octane, from benzylamine instead of methylamine.

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

Procedure: To a degassed by argon solution of 3-benzyl-8-methyl-3,8-diazabicyclo[3.2.1]octane (17.6 g, 0.08 mol) in methanol (50 ml), 10% Pd/C (1.0 g) was added and hydrogen passed into reaction mixture for 24 h. The catalyst was filtered off, the filtrate evaporated and the residue distilled on Büchi oven for distillation at 100° C. and 0.1 mbar. Yield 8.5 g (85%). was added The catalyst was filtered off the filtrate evaporated the residue distilled on Büchi oven for distillation at 100° C.

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

Procedure: Following general amide formation method 1, 6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (100 mg, 0.254 mmol, 1.0 eq) was combined with 8-Methyl-3,8-diaza-bicyclo[3.2.1]octane (55.5 mg, 0.279 mmol, 1.1 eq) which gave 7-cyclopentyl-2-[5-(8-methyl-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as solid (77 mg) in 60% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56-1.76 (m, 4H) 2.01 (br. s., 6H) 2.44 (br. s., 4H) 3.06 (br. s., 8H) 3.33 (br. s., 4H) 3.49 (br. s., 4H) 4.76 (quin, J=8.84 Hz, 1H) 6.66 (s, 1H) 7.82-7.88 (m, 1H) 8.33-8.41 (m, 2H) 8.85 (s, 1H) 10.05 (s, 1H)

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

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

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