Cyclopropanecarboxaldehyde → 8-(2-Cyclopropyl-2-hydroxy-ethanesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one

HRID 2194186Notes

Reaction equation

HRID 2194186 reaction equation
[CH3:1][S:2]([N:5]1[CH2:26][CH2:25][C:8]2([C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li]CCCC.[CH:32]1([CH:35]=[O:36])[CH2:34][CH2:33]1>C1COCC1>[CH:32]1([CH:35]([OH:36])[CH2:1][S:2]([N:5]2[CH2:6][CH2:7][C:8]3([C:12](=[O:13])[N:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=4)[CH2:10][CH2:9]3)[CH2:25][CH2:26]2)(=[O:4])=[O:3])[CH2:34][CH2:33]1

Participants

5

Reactant 3

HCID 123114CyclopropanecarboxaldehydeHCID 595779498-Methanesulfonyl-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-oneHCID 178418339Butyllithium

Product 1

HCID 595778968-(2-Cyclopropyl-2-hydroxy-ethanesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-oneYield 47.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 8-methanesulfonyl-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (76 mg, 0.19 mmol) in THF at −78° C. was added n-BuLi (1.6M, 145 uL, 0.23 mmol) dropwise. The reaction mixture was stirred for 5 min followed by the addition of a solution of cyclopropanecarbaldehyde (54 mg, 0.78 mmol) in THF (500 uL) at −78° C. The dry ice bath was removed and the reaction mixture was warmed to 0° C. and stirring was continued for a further 30 min. The reaction mixture was quenched with AcOH (20 uL) and was then concentrated to dryness under reduced pressure. The crude residue was partitioned between ethyl acetate and water and the organic layer was then washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography to afford 8-(2-cyclopropyl-2-hydroxy-ethanesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (42 mg, 47%) as a white solid. MS (ESI): 463.2 (MH+)

Workup

  1. customThe dry ice bath was removed
  2. stirringstirring
  3. waitwas continued for a further 30 min
  4. customThe reaction mixture was quenched with AcOH (20 uL)
  5. concentrationwas then concentrated to dryness under reduced pressure
  6. customThe crude residue was partitioned between ethyl acetate and water
  7. washthe organic layer was then washed with brine
  8. dry with materialdried with Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customto give a crude residue which
  12. customwas purified by flash column chromatography

Sources & evidence

ORD record
ord-25cce12b00b7474d9674c344d9d49b2f
Source dataset
uspto-grants-2012_12
Patent number
US08329904B2

Reaction notes

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