反应详情

To a vial was added 5-fluoro-2-oxo-3-((7-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (19-5) (41 mg, 0.086 mmol), then DMF (0.6 mL) followed by 3,3-DIFLUOROAZETIDINE HYDROCHLORIDE (38 mg, 0.293 mmol), then DIPEA (100 μL, 0.573 mmol). The reaction mixture was then permitted to stir at room temperature for 20 minutes, then added ACETIC ACID (150 μL, 2.62 mmol). The reaction mixture was then permitted to stir at room temperature for 2 hrs (capped, but not under N2). Followed by LC/MS. After 2 hours at room temperature added SODIUM CYANOBOROHYDRIDE (33 mg, 0.525 mmol) in one portion to the reaction mixture at room temperature. After another hour at room temperature; the reaction mixture was diluted with MeOH/DMSO/drops TFA/drops H2O, stirred for ˜10 minutes, then filtered (syringe filter), then purified (without workup) by reverse phase chromatography (5-65% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions concentrated (GENEVAC), then dissolved in MeOH/DCM & added a saturated solution of HCl in EtOAc (˜4N) & concentrated to yield 3-((7-(3,3-difluoroazetidin-1-yl)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride (19-6). HRMS [M+H] calculated; 552.0982, observed; 552.0982. 1H NMR (400 MHz, CD3 OD): δ 8.21 (s, 1H); 7.79 (d, J=5.5 Hz, 1H); 7.24-7.18 (m, 3H); 7.01 (d, J=9.3 Hz, 1H); 5.18-5.01 (m, 2H); 4.99-4.88 (m, 4H); 3.83-3.74 (m, 1H); 3.44-3.40 (m, 1H); 3.03-2.94 (m, 2H); 2.69-2.59 (m, 1H); 2.29-2.22 (m, 1H); 1.79-1.67 (m, 1H).

1. stirringto stir at room temperature for 2 hrs (
2. customcapped
3. waitAfter another hour at room temperature
4. stirringstirred for ˜10 minutes
5. filtrationfiltered
6. filtration(syringe filter)
7. custompurified (without workup) by reverse phase chromatography (5-65% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column)
8. concentrationdesired fractions concentrated (GENEVAC)
9. dissolutiondissolved in MeOH/DCM
10. additionadded a saturated solution of HCl in EtOAc (˜4N)
11. concentrationconcentrated