tert-butyl (1R,6S)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the minor isomer product of Example 3E (2.4 g, 7.5 mmol) in 30 mL CH3OH was added 0.58 g of 20% Pd(OH)2/C (wet). This mixture was shaken under 60 psi of H2 for 16.5 h at 50° C. The mixture was filtered, concentrated to proved the title compound, suitable for use without further purification. MS (DCl/NH3) m/z 213 (M+H)+. The mixture was filtered concentrated suitable for use without further purification

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the minor isomer product of Example 3E (2.4 g, 7.5 mmol) in 30 mL CH3OH was added 0.58 g of 20% Pd(OH)2/C (wet). This mixture was shaken under 60 psi of H2 for 16.5 h at 50° C. The mixture was filtered, concentrated to proved the title compound, suitable for use without further purification. MS (DCl/NH3) m/z 213 (M+H)+. The mixture was filtered concentrated suitable for use without further purification

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the minor isomer product of Example 3E (2.4 g, 7.5 mmol) in 30 mL CH3OH was added 0.58 g of 20% Pd(OH)2/C (wet). This mixture was shaken under 60 psi of H2 for 16.5 h at 50° C. The mixture was filtered, concentrated to proved the title compound, suitable for use without further purification. MS (DCl/NH3) m/z 213 (M+H)+. The mixture was filtered concentrated suitable for use without further purification

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared in a manner analogous to Intermediate 12, Step B substituting Intermediate 34 for (1R,6S) 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester and Intermediate 16 for 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calculated for C22H23FN6O2, 422.19; m/z found, 423.2.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (1R,6S)-8-(4,5,6-Trimethylpyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane was prepared in a manner analogous to Intermediate 40, using Intermediate 66 and Intermediate 39 as starting materials. MS (ESI) mass calcd. for C13H20N4, 232.17; m/z found, 233.1 [M+H]+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a microwave safe vial was added Intermediate 39 (375 mg, 1.77 mmol), 2-chloro-6-methylpyridine (0.39 mL, 3.53 mmol), CH3CN (10 mL) and DIPEA (0.61 mL, 3.53 mmol). The resulting mixture was heated to 180 C in a microwave reactor. After 3 h the crude mixture was concentrated and purified directly by FCC (SiO2, ethyl acetate/hexanes, 0-40%) to yield (1R,6S)-tert-butyl 8-(6-methylpyridin-2-yl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (80 mg, 15%). MS (ESI) mass calcd. for C17H25N3O2, 303.2; m/z found, 304.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.31 (t, J=7.7 Hz, 1H), 6.50-6.40 (m, 1H), 6.09 (dd, J=45.4, 8.1 Hz, 1H), 4.44-4.27 (m, Hz, 2H), 4.04-3.89 (m, 1H), 3.84-3.66 (m, 2H), 3.60-3.22 (m, 2H), 2.86-2.72 (m, 1H), 2.37 (s, 3H), 2.07-1.96 (m, 1H), 1.92-1.80 (m, 1H), 1.44-1.28 (m, 9H). The resulting mixture was heated to 180 C in a microwave reactor After 3 h the crude mixture was concentrated purified directly by FCC (SiO2, ethyl acetate/hexanes, 0-40%)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (1R,6S)-tert-butyl 8-((S)-1-phenylethyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.5 g, 75%) in EtOH (50 mL) was added AcOH (1.5 mL). The resulting mixture was cycled through an H-Cube containing a 20% Pd(OH)2/C catalyst cartridge at 50° C. and 100 bar of hydrogen pressure. After 16 hours the resulting mixture was removed from the H-Cube and poured over a saturated sodium carbonate solution (100 mL). The aqueous layer was extracted with DCM (50 mL) four times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (755 mg, 75%) which was used in the next step without purification. MS (ESI) mass calcd. for C11H20N2O2, 212.2; m/z found, 213.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 4.21-4.02 (m, 1H), 3.84-3.59 (m, 3H), 3.47-3.36 (m, 1H), 3.33 (dd, J=8.3, 4.4 Hz, 1H), 3.28-3.20 (m, 1H), 2.91-2.71 (m, 2H), 1.94-1.81 (m, 1H), 1.81-1.68 (m, 1H), 1.46 (s, 9H). After 16 hours the resulting mixture was removed from the H-Cube poured over a saturated sodium carbonate solution (100 mL) The aqueous layer was extracted with DCM (50 mL) four times dried over Na2SO4 filtered concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To (1R,6S)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (166 mg, 0.8 mmol) and DIPEA (404 μL, 2.3 mmol) in ACN (3.4 mL) was added 2-chloro-4-(trifluoromethyl)pyrimidine (110 μL, 0.9 mmol). The reaction mixture was heated at reflux for 2 h, cooled to rt, diluted with water and extracted with CH2Cl2 (2×). The combined organics were dried (Na2SO4) and concentrated to give 185 mg (66%) of the title compound as a clear oil which was used without further purification. MS (ESI) mass calcd. For C16H21F3N4O2, 358.40; m/z found 359.1 [M+H]+ The reaction mixture was heated at reflux for 2 h extracted with CH2Cl2 (2×) The combined organics were dried (Na2SO4) concentrated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the minor isomer product of Example 3E (2.4 g, 7.5 mmol) in 30 mL CH3OH was added 0.58 g of 20% Pd(OH)2/C (wet). This mixture was shaken under 60 psi of H2 for 16.5 h at 50° C. The mixture was filtered, concentrated to proved the title compound, suitable for use without further purification. MS (DCl/NH3) m/z 213 (M+H)+. The mixture was filtered concentrated suitable for use without further purification