| 96% |
With hydrazine hydrate; In methanol; at 20 - 65℃; for 12.0h; |
diazabicyclo[3.2.1 loctan-6-yl hydrogen sulfate (Compound 725) Step 1: Synthesis of tert-butyl 3-(2-hydrazinyl-2-oxoethyl)azetidine-l -carboxylate: To a solution of teri-butyl 3-(2-methoxy-2-oxoethyl)azetidine-l-carboxylate (25.0 g, 109 mmol) in MeOH (150 mL) was added NuEta2NuEta220 (27.3 g, 546 mmol) at rt. The mixture was heated at 65 °C for 12 hrs and then concentrated. The residue was diluted with DCM (400 mL), washed with water (2x) and saturated sodium chloride (2x), dried over Na2S04, and concentrated to give ieri-butyl 3-(2-hydrazinyl-2-oxoethyl)azetidine-l-carboxylate (24.0 g, 96percent) as a yellow gum. ESI-MS (EI+, m/z): 252 [M+Na]+. Step 2: Synthesis of 'tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-l,6-diaza bicyclo[3.2. l]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)azetidine-l -carboxylate: HATU (19.6 g, 52.2 mmol) and DIPEA (16.6 g, 130.5 mmol) were added to a 0 °C solution of (25',5 ?)-6-(benzyloxy)-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (12.0 g, 43.5 mmol), ieri-butyl 3-(2-hydrazinyl-2-oxoethyl)azetidine-l-carboxylate(11.3 g, 49.8 mmol) in CH2C12 (360 mL). The mixture was allowed to warm to rt then the mixture was stirred at rt for 12 hrs. The mixture was then diluted with CH2C12 (300 mL), washed with water (2x)and saturated sodium chloride(2x), dried and concentrated. The residue was purified by silica gel column chromatography (0-20percent gradient elution EtOAc/petroleum ether) to afford ieri-butyl 3-(2-(2-((25',5)-6-(benzyloxy)-7-oxo-l,6-diaza bicyclo[3.2.1 ]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)azetidine- 1 -carboxylate ( 19.3 g, 93percent) as a white solid. ESI-MS (EI+, m/z): 488 [M+H]+. Step 3: Synthesis of tert-butyl 3 -((5-((2S, 5R)-6-(benzyloxy )-7-oxo-l, 6-diaza- bicyclo[3.2. l]octan-2-yl)-l, 3, 4-oxadiazol-2-yl)methyl)azetidine-l -carboxylate: To s solution of PPh3 (2.2 g, 8.2 mmol) in dry DCM (60 mL) was added I2 (2.1 g, 8.2 mmol). After I2 was dissolved completely, TEA (1.7 g, 16.4 mmol) was added quickly at rt. The mixture was stirred for 15 mins. 7ri-butyl 3-(2-(2-((25',5 ?)-6-(benzyloxy)-7-oxo-l ,6-diaza bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)azetidine-l-carboxylate (2.0 g, 4.1 mmol) was added. The mixture was stirred at rt for 1 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (gradient elution 0-40percent EtOAc/petroleum ether) to afford ieri-butyl 3-((5-((2S,5fl)-6-(benzyloxy)-7- oxo- l,6-diaza-bicyclo[3.2.1]octan-2-yl)-l ,3,4-oxadiazol-2-yl)methyl)azetidine-l-carboxylate (1.3 g, 66percent) as a white solid. ESI-MS (EI+, m/z): 470 [M+H]+. Step 4-6: Following Steps 3-5 in Example 4, replacing ieri-butyl (2-(5-((2S,5R)-6- (benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octan-2-yl)-l ,3,4-oxadiazol-2-yl)ethyl)carbamate in Step 3 with ieri-butyl 3-((5-((2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octan-2- yl)-l,3,4-oxadiazol-2-yl)methyl)azetidine-l -carboxylate, (2S,5R)-2-(5-(azetidin-3-ylmethyl)- l,3,4-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate was obtained as a white solid after prep-HPLC purification using ammonium formate buffer. ESI-MS (EI+, m/z): 360.2. 1H NMR (300 MHz, D20) 4.74 (d, / = 6.4 Hz, 1H), delta 4.23 - 4.15 (m, 3H), 3.95 (dd, / = 11.5, 7.5 Hz, 2H), 3.50 - 3.30 (m, 1H), 3.25 (d, / = 6.0 Hz, 2H), 3.17 - 3.14 (m, 1H), 2.88 (d, / = 12.0 Hz, 1H), 2.27 - 2.05 (m, 3H), 1.95-1.85 (m, 1H). |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
