反应详情

Under a nitrogen atmosphere, trimethylaluminum (2M in toluene, 1206 μl, 2.41 mmol) was slowly added (gas evolution) to an ice cooled solution of ethylamine (2M in THF) (1206 μl, 2.41 mmol) in 7 ml of toluene. The reaction was allowed to warm to room temperature and stirred for 2 hours. Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate, (Intermediate 204, 190 mg, 0.32 mmol) was added as a solution in toluene (3 ml). The reaction was stirred at 45° C. for 18 hours. The reaction was quenched drop wise (vigorous gas evolution) with 2 ml of 1N HCl. The crude reaction was filtered to remove solids, diluted with water and extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, dried over MgSO4 and concentrated to give an oil. The oil was purified by silica gel column chromatorgraphy using a gradient of hexanes to ethyl acetate. Fractions were combined and concentrated to give the title compound. (170 mg, 0.288 mmol, 90%).

1. stirringThe reaction was stirred at 45° C. for 18 hours
2. customThe reaction was quenched drop wise (vigorous gas evolution) with 2 ml of 1N HCl
3. customThe crude reaction
4. filtrationwas filtered
5. customto remove solids
6. additiondiluted with water
7. extractionextracted twice with ethyl acetate
8. washwashed twice with brine
9. dry with materialdried over MgSO4
10. concentrationconcentrated
11. customto give an oil
12. customThe oil was purified by silica gel column chromatorgraphy
13. concentrationconcentrated