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

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

実験手順: To (1S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.4 g, 6.8 mmol) in THF (35 mL) and H2O (35 mL) was added Na2CO3 (1.4 g. 13.6 mmol) and CbzCl (1.1 mL, 7.5 mmol). After 18 h, the reaction mix was diluted with H2O and extracted with CH2Cl2 (2×). The combined organics were dried (Na2SO4) to give 2.4 g of the title compound as a clear oil that was used without further purification. the reaction mix extracted with CH2Cl2 (2×) The combined organics were dried (Na2SO4)

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

実験手順: To 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (390 mg, 1.9 mmol) in CH2Cl2 (18 mL) at 0° C. was added DMF (15 μL, 0.2 mmol) and oxalyl chloride (190 μL, 2.3 mmol). After 20 min, the 0° C. ice bath was removed and the reaction allowed to warm to rt. After 30 min the mixture was concentrated, diluted with CH2Cl2 (9 mL) and added to (1S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (260 mg, 1.3 mmol) in CH2Cl2 (9 mL) and TEA (390 μL, 2.9 mmol). After judged complete by TLC and LC-MS, the reaction was diluted further with CH2Cl2 and washed with 1 N KHSO4. The aqueous layer was with CH2Cl2. The combined organics were dried (Na2SO4) to give a yellow foam. Purification via silica gel using 40-100% EtOAc in hexanes gave 656 mg (86%) of the title compound as a colorless oil. MS (ESI) mass calcd. C20H24FN5O3, 401.44; m/z found 346.0 [M−C(CH3)3]+. the 0° C. ice bath was removed After 30 min the mixture was concentrated diluted with CH2Cl2 (9 mL) washed with 1 N KHSO4 The combined organics were dried (Na2SO4) to give a yellow foam Purification via silica gel using 40-100% EtOAc in hexanes

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 28, substituting (1R,6S)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate for (1S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate. MS (ESI) mass calcd. C15H16FN5O, 301.32; m/z found 302.0 [M+H]+.

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

実験手順: To 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (406 mg, 1.5 mmol) in PhCH3 (5 mL) was added SOCl2 (117 μL, 1.6 mmol). The flask was heated with an oil bath to 50° C. for 1 h. To (1S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (260 mg, 1.3 mmol) and Na2CO3 (519 mg, 4.9 mmol) in PhCH3 (5 mL) and H2O (5 mL) at 0° C. was added the above solution dropwise. The reaction was allowed to warm slowly to rt and stir for 15 h and extracted with DCM (2×). The combined organics were dried (Na2SO4). Purification via silica gel chromatography (1-7% 2M NH3/MeOH in CH2Cl2) gave 335 mg (68%) of the title compound. MS (ESI) mass calcd. C20H24FN5O3, 401.44; m/z found 346.1 [M−C(CH3)3]+. to warm slowly to rt extracted with DCM (2×) The combined organics were dried (Na2SO4) Purification via silica gel chromatography (1-7% 2M NH3/MeOH in CH2Cl2)

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

実験手順: To a mixture of Intermediate 24 (570 mg, 2.69 mmol), 6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid (603 mg, 2.95 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1200 mg, 2.69 mmol) in DCM (15 mL) was added TEA (1.1 mL, 8.06 mmol). The resulting mixture was stirred for 5 h at ambient temperature at which time water (30 mL) was added. The aqueous layer was extracted with DCM (15 mL) three times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by FCC (SiO2, ethyl acetate/hexanes, 0-40%) to yield (1S,6R)-tert-butyl 8-(6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinoyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.05 g, 98%). MS (ESI) mass calcd. for C20H26N6O3, 398.2; m/z found, 399.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.48-8.38 (m, 1H), 7.82-7.79 (m, 1H), 7.77-7.64 (m, 1H), 7.33-7.23 (m, 1H), 4.53-4.27 (m, 2H), 4.06-3.89 (m, 1H), 3.80-3.36 (m, 4H), 3.01-2.90 (m, 1H), 2.62-2.58 (m, 3H), 2.03-1.76 (m, 2H), 1.53-1.42 (m, 9H). was added The aqueous layer was extracted with DCM (15 mL) three times dried over Na2SO4 filtered concentrated under reduced pressure The crude residue was purified 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 ThalesNano 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 ThalesNano 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): 4.18-4.00 (m, 1H), 3.85-3.57 (m, 3H), 3.44-3.34 (m, 1H), 3.28 (dt, J=13.1, 6.5 Hz, 1H), 3.24-3.13 (m, 1H), 2.82-2.72 (m, 1H), 1.93-1.83 (m, 1H), 1.82-1.70 (m, 1H), 1.48 (s, 9H). After 16 hours the resulting mixture was removed from the ThalesNano 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