Ammonia → 2-(3-(1-Oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol

3-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-fluorobenzaldehyde [Aromatic Intermediate 5] (5.0 g) was added to a solution of 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate [Example 9, step a] (9.3 g) and acetic acid (1.0 mL) in N-methyl-2-pyrrolidinone (50 mL). The resulting mixture was stirred for 15 min, then cooled in an ice bath. Sodium triacetoxyborohydride (5.64 g) was then added and the mixture was stirred overnight. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution:brine (1:5) and extracted four times with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to afford an oil. The oil was dissolved in THF (100 mL) and treated with TBAF (1M in THF, 18.0 mL). The resulting solution was stirred at room temperature for 50 minutes, then more TBAF (1M in THF, 18.0 mL) was added and the mixture was stirred for a further 100 minutes. The solution was then concentrated in vacuo to afford an oil. The oil was dissolved in methanol (100 mL), the solution was treated with ‘880’ aqueous ammonia (20 mL), stirred at room temperature for 50 minutes, then concentrated in vacuo to give an oil. The oil was dissolved in methanol and concentrated onto flash silica in vacuo. The resulting powder was purified by flash chromatography on silica eluted with ‘880’ aqueous ammonia:methanol:dichloromethane (1:10:89) to afford the subtitled compound as a yellow oil. Yield 5.8 g, 60% pure. Used crude.

1. temperaturecooled in an ice bath
2. stirringthe mixture was stirred overnight
3. customThe reaction mixture was quenched by the addition of saturated sodium bicarbonate solution
4. extractionbrine (1:5) and extracted four times with ethyl acetate
5. dry with materialThe combined organic phases were dried (MgSO4)
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customto afford an oil
9. stirringThe resulting solution was stirred at room temperature for 50 minutes
10. stirringthe mixture was stirred for a further 100 minutes
11. concentrationThe solution was then concentrated in vacuo
12. customto afford an oil
13. stirringstirred at room temperature for 50 minutes
14. concentrationconcentrated in vacuo
15. customto give an oil
16. concentrationconcentrated onto flash silica in vacuo
17. customThe resulting powder was purified by flash chromatography on silica
18. washeluted with ‘880’ aqueous ammonia:methanol:dichloromethane (1:10:89)

ORD record

ord-3f7d806f82f944a092ca84f85c69a20e

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08476265B2