Reaction #160215

Reaction equation

Iodoethane

ammonium formate

[8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone hydrochloride salt

sodium hydride

→

[10-(ethoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

Yield 74.0%

Solvents

EtOAc

methanol

DMF

Conditions

Workup

1. 1
   workup.STIRRINGthe reaction mixture was stirred for 3 hours
2. 2
   Filtrationfiltered
3. 3
   Concentrationconcentrated in vacuo
4. 4
   OtherThe residue was purified by silica gel column chromatography
5. 5
   Otherto give the ether intermediate as pale yellow oil
6. 6
   FiltrationThe reaction mixture was filtered
7. 7
   Concentrationconcentrated in vacuo
8. 8
   workup.ADDITIONdiluted with ethyl acetate
9. 9
   Washwashed with 1:1 3M NaOH/
10. 10
    Dryingaq. NaHCO3, dried over MgSO4
11. 11
    Filtrationfiltered
12. 12
    Concentrationconcentrated in vacuo

Procedure

To [8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone hydrochloride salt (43 mg, 0.09 mmol) in DMF (0.5 mL) was added sodium hydride (11 mg, 0.30 mmol) and the reaction mixture was stirred for 20 minutes. Iodoethane (30 μL, 0.38 mmol) was added and the reaction mixture was stirred for 3 hours, then diluted with EtOAc, filtered, concentrated in vacuo. The residue was purified by silica gel column chromatography using 10-100 EtOAc/hexanes eluent to give the ether intermediate as pale yellow oil. The oil was dissolved in methanol (0.6 mL), and Pd (5 mg, 0.004 mmol) and ammonium formate (27 mg, 0.44 mmol) were added and the reaction mixture was heated at 75° C. for 40 minutes. The reaction mixture was filtered, concentrated in vacuo, diluted with ethyl acetate, washed with 1:1 3M NaOH/sat. aq. NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to give [10-(ethoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (25 mg, 74%) as a pale yellow oil. ESI-MS m/z calc. 390.5. Found 391.3 (M+1)+; Retention time: 1.17 minutes (3 min run).

Source