反应详情

A solution of 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate [Example 9, step a] (4.5 g) in NMP (30 mL) was treated with acetic acid (0.6 mL), stirred for 5 minutes, and then added in one portion to tert-butyl 2-(N-cyclohexyl-3-(3-formylphenethoxy)propanamido)ethyl(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)carbamate [Examples 81-175, step f] (6.6 g), completing the transfer with more NMP (30 mL). The resulting solution was stirred at room temperature for 4 hours and then cooled in an ice-water bath and treated with sodium triacetoxyborohydride (3.3 g) in one portion. The resulting suspension was stirred at room temperature overnight, then more sodium borohydride (2.2 g) was added and the mixture was stirred for a further 5 hours. The mixture was cautiously poured into saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried (MgSO4), filtered and concentrated onto flash silica (100 mL) in-vacuo. The resulting powder was purified by flash chromatography on silica eluted with acetic acid:methanol:dichloromethane (1:5:94) to elute off the benzyl alcohol corresponding to reduced starting material, 100% dichloromethane to wash the column free from acetic acid, then triethylamine:methanol:dichloromethane (1:5:94) to elute off the product. Fractions containing the desired product were combined and concentrated in-vacuo to afford the subtitled compound as an off-white foam. Yield 4.6 g.

1. stirringThe resulting solution was stirred at room temperature for 4 hours
2. temperaturecooled in an ice-water bath
3. stirringThe resulting suspension was stirred at room temperature overnight
4. stirringthe mixture was stirred for a further 5 hours
5. extractionextracted twice with ethyl acetate
6. washThe combined organic phases were washed three times with water
7. dry with materialonce with brine, then dried (MgSO4)
8. filtrationfiltered
9. concentrationconcentrated onto flash silica (100 mL) in-vacuo
10. customThe resulting powder was purified by flash chromatography on silica
11. washeluted with acetic acid:methanol:dichloromethane (1:5:94)
12. washto elute off the benzyl alcohol corresponding
13. washto wash the column free from acetic acid
14. washtriethylamine:methanol:dichloromethane (1:5:94) to elute off the product
15. additionFractions containing the desired product
16. concentrationconcentrated in-vacuo