1-Bromo-4-fluorobenzene → 8-[2-(4-Fluoro-phenyl)-2-hydroxy-cyclohexyl]-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one

HRID 347312Notes

Reaction equation

HRID 347312 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[N:21]1[CH2:37][CH2:36][C:24]2([C:28](=[O:29])[NH:27][CH2:26][CH:25]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:23][CH2:22]1.[Cl-].[NH4+]>C1COCC1>[CH3:15][OH:14].[NH4+:21].[OH-:14].[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[N:21]2[CH2:37][CH2:36][C:24]3([C:28](=[O:29])[NH:27][CH2:26][CH:25]3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:23][CH2:22]2)=[CH:3][CH:4]=1

Participants

7

Reactant 4

HCID 99931-Bromo-4-fluorobenzeneHCID 25517Ammonium ChlorideHCID 210825658-(2-Oxo-cyclohexyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-oneHCID 178418339Butyllithium

Product 2

HCID 112123738-[2-(4-Fluoro-phenyl)-2-hydroxy-cyclohexyl]-4-phenyl-2,8-diaza-spiro[4.5]decan-1-oneYield 134.9%HCID 21894508Ammonium hydroxide methanolYield 0.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 1-bromo-4-fluorobenzene (1.4 g, 8 mmol) in dry THF (5 mL) under argon at −78° C. was added BuLi (1.6 M in hexanes, 5 mL, 8 mmol) and the mixture maintained at this temperature for 1 h. To this solution was added a solution of 8-(2-oxo-cyclohexyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one (687 mg, 2 mmol) in dry THF (15 mL) and the reaction mixture allowed to warm up to −20° C. after 2 h before ammonium chloride (saturated, 20 mL) was added. The resulting mixture was then evaporated and water (20 mL) added. The product was extracted with ethyl acetate (3×15 mL) and the combined organic extracts washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated to leave a light brown solid. Purification by chromatography on silica gel eluting with DCM:MeOH—NH4OH (0.5%) (95:5 to 4:1) afforded the title compound (380 mg, 45%) which was obtained as a white solid. MS: m/e=423.5 (M+H).

Workup

  1. temperaturethe mixture maintained at this temperature for 1 h
  2. additionwas added
  3. customThe resulting mixture was then evaporated
  4. additionwater (20 mL) added
  5. extractionThe product was extracted with ethyl acetate (3×15 mL)
  6. washthe combined organic extracts washed with brine (10 mL)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. customevaporated
  10. customto leave a light brown solid
  11. customPurification by chromatography on silica gel eluting with DCM

Sources & evidence

ORD record
ord-5a4f405ebd334702a10ae2e920e68254
Source dataset
uspto-grants-2007_02
Patent number
US07173133B2

Reaction notes

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