Bromide ion → HCID 24905913, compound

HRID 1768472Notes

Reaction equation

HRID 1768472 reaction equation
[Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.Br[CH2:40][CH2:41][F:42].[H-].[Na+].[Br-].FC(F)(F)C(O)=O>CN(C=O)C>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:25]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:40][CH2:41][F:42])[CH2:30][CH2:31]2)[CH3:32])=[O:24])[C@:10]([CH2:9][OH:8])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=1

Participants

7

Reactant 5

HCID 259Bromide ionHCID 6422Trifluoroacetic acidHCID 129822-Fluoroethyl bromideHCID 24758Sodium hydride2×HCID 10098834HCID 10098834, compound

Product 1

HCID 24905913HCID 24905913, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To 60 mg (0.11 mmol) of amine 7-2 in DMF at 0° C. was added 13 μL (0.17 mmol) of 1-bromo-2-fluoroethane and 8 mg (0.17 mmol) of NaH (60% dispersion in oil). After warming to room temperature, another portion of NaH and the bromide were added, and the reaction was allowed to stir overnight. LC-MS indicated still 25% unreacted 7-2, so the mixture was heated to 60° C. for several hours. After cooling to room temperature, ˜500 μL of trifluoroacetic acid was added and the mixture was stirred for 1 h. The reaction was partitioned between EtOAc and 15% aqueous Na2CO3, the layers were separated, the organic phase was washed with saturated NaHCO3, water, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 12-1 as a white solid. Data for 12-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.4 (m, 1H), 4.8 (m, 1H), 4.6-4.4 (m, 4H), 4.0 (m, 1H), 3.75 (m, 1H), 3.1 (m, 2H), 2.9 (s, 3H), 2.75-2.65 (m, 2H), 2.2 (m, 2H), 1.9 (m, 3H), 1.7 (m, 1H) ppm. HRMS (ES) calc'd M+H for C26H30F3N3O2: 474.2363. Found: 474.2355. Resolution of the enantiomers was carried out chromatographically using a Chiralpak AD© 10×50 cm column with 30% isopropanol in hexanes (with 0.1% diethylamine) at 150 ml/min. Analytical HPLC analysis of the eluent on a 4×250 mm Chiralpak AD® column with 30% isopropanol in hexanes (with 0.1% diethylamine) at 1 ml/min indicated that inactive enantiomer has Rt=6.3 min and the active enantiomer has Rt=7.5 min.

Workup

  1. temperatureso the mixture was heated to 60° C. for several hours
  2. temperatureAfter cooling to room temperature
  3. stirringthe mixture was stirred for 1 h
  4. customThe reaction was partitioned between EtOAc and 15% aqueous Na2CO3
  5. customthe layers were separated
  6. washthe organic phase was washed with saturated NaHCO3, water, brine
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated by rotary evaporation
  9. customThe residue was purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc

Sources & evidence

ORD record
ord-3d8d08dde3ea4992add2809ab7cbcc1a
Source dataset
uspto-grants-2007_06
Patent number
US07235580B2

Reaction notes

Loading…