2-Chloroethanol → HCID 118277055, compound

HRID 1053694Notes

Reaction equation

HRID 1053694 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([CH:8]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]=1.Cl[CH2:28][CH2:29][OH:30].Br[CH2:32][CH2:33][OH:34].C(=O)([O-])[O-].[Ca+2].[I-].[K+].[OH-].[Na+]>O>[OH:30][CH2:29][CH2:28][N:1]([CH2:32][CH2:33][OH:34])[C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([CH:8]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:7]=1

Participants

8

Reactant 6

HCID 342-ChloroethanolHCID 4875Potassium IodideHCID 10112Calcium Carbonate2×HCID 108982-BromoethanolHCID 14798Sodium HydroxideHCID 118276910HCID 118276910, compound

Product 1

HCID 118277055HCID 118277055, compound

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

Variant B: Adapting literature known protocols (Palmer, et al., J. Med. Chem. 1990, 33(1), 112-121; Coggiola, et al., Bioorg. Med. Chem. Lett., 2005, 15(15), 3551-3554; Verny et al., Cmpds Radiopharm., 1988, 25(9), 949-955; and Lin, Bioorg. Med. Chem. Lett., 2011, 21(3), 940-943), a reaction mixture of tert-butyl 3-(5-amino-2-methyl-phenyl)-4-(tert-butoxycarbonylamino)butanoate (9d) (3.65 g, 10.0 mmol) and commercial 2-chloroethanol (2.68 mL, 3.22 g, 40.0 mmol) or commercial 2-bromoethanol (2.84 mL, 5.0 g, 40.0 mmol), calcium carbonate (CaCO3) (2.0 g, 20.0 mmol, 2.0 equivalents) in water (about 35 mL), and a catalytic amount of potassium iodide (KI) (166 mg, 1.0 mmol, 10 mol-%) is heated at reflux for about 12-24 hours. The reaction is followed by TLC and/or LC/MS to completion. Additional amounts of 2-halogeno ethanol and CaCO3 may be added and the reaction times may be extended an additional 8-24 h for completion. The pH of the reaction mixture is adjusted to ˜7 with a 2.5 M (10 wt-%) aqueous solution of sodium hydroxide (NaOH). The aqueous phase is extracted with ethyl acetate (4×) and the combined organic extracts are washed with 1.0 M hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3), and brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents removed under reduced pressure using a rotary evaporator to yield the target compound tert-butyl 3-[5-(bis(2-hydroxyethyl)amino)-2-methyl-phenyl]-4-(tert-butoxycarbonylamino)butanoate (9e). The crude residue may be further purified by silica gel column chromatography using EtOAc, methanol (MeOH), dichloromethane (DCM), and hexanes, or mixtures of any of the foregoing to furnish the purified target compound.

Workup

  1. temperatureat reflux for about 12-24 hours
  2. customthe reaction times
  3. extractionThe aqueous phase is extracted with ethyl acetate (4×)
  4. washthe combined organic extracts are washed with 1.0 M hydrochloric acid
  5. dry with materiala saturated aqueous solution of sodium hydrogen carbonate (NaHCO3), and brine, dried over anhydrous magnesium sulfate (MgSO4)
  6. filtrationfiltered
  7. customthe solvents removed under reduced pressure
  8. customa rotary evaporator

Sources & evidence

ORD record
ord-3baa496d4bd343539bac206a16c6719f
Source dataset
uspto-grants-2016_07
Patent number
US09394236B2

Reaction notes

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