1,2-Dichloroethane → Di-tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-2-oxoazepan-3-yl]imidodicarbonate

HRID 881687Notes

Reaction equation

HRID 881687 reaction equation
[C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:9]([C:23]([OH:25])=O)[CH2:10][CH2:11][C@@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[F:22])[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:34][C:35]([CH3:38])([OH:37])[CH3:36].C(N(CC)C(C)C)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CCO>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:12]1[CH2:13][N:14]([CH2:34][C:35]([OH:37])([CH3:38])[CH3:36])[C:23](=[O:25])[C@H:9]([N:8]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]1

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 684091-Chloro-2-methylpropan-2-olHCID 81531Diisopropylethylamine2×HCID 181649HOAtHCID 516892Sodium BicarbonateHCID 67526479(5S)-N2,N2-Bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine2×

Product 1

HCID 21114341Di-tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-2-oxoazepan-3-yl]imidodicarbonate

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
75 °C

Procedure

A mixture of (5S) —N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (0.569 g, 1.24 mmol, described in Intermediate 4), 1-chloro-2-methyl-2-propanol (0.202 g, 1.86 mmol) and N,N-diisopropylethylamine (0.713 mL, 4.10 mmol) in EtOH (5 mL) was heated at 75° C. for 18 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in CH2Cl2 (20 mL), then EDC (0.358 g, 1.87 mmol), HOAT (0.252 g, 1.87 mmol) and N,N-diisopropylethylamine (0.650 mL, 3.73 mmol) were added. The resulting mixture was stirred at ambient temperature for 18 h, then aqueous NaHCO3 was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 65:35, to give the title compound. MS: m/z=513 (M+1).

Workup

  1. concentrationThe reaction mixture was concentrated to dryness under reduced pressure
  2. dissolutionthe residue was dissolved in CH2Cl2 (20 mL)
  3. customThe layers were separated
  4. extractionthe aqueous phase was extracted with CH2Cl2
  5. dry with materialThe combined organic extracts were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by silica gel chromatography
  9. washeluting with a gradient of hexane

Sources & evidence

ORD record
ord-4d10426047ea4e24a631703e310f80c5
Source dataset
uspto-grants-2015_03
Patent number
US08993588B2

Reaction notes

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