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

HRID 501147Notes

Reaction equation

HRID 501147 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](O)=[O:24])[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(C(C)C)CC)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CCO.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C@@H:9]1[CH2:10][CH2:11][C@@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:13][N:14]([CH2:34][C:35]([OH:37])([CH3:38])[CH3:36])[C:23]1=[O:24])[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

9

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-lysine

Product 1

HCID 21114341Di-tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-2-oxoazepan-3-yl]imidodicarbonateYield 33%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of (5S)-N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (0.569 g, 1.24 mmol), 1-chloro-2-methyl-2-propanol (0.202 g, 1.86 mmol) and diisopropylethylamine (0.529 g, 4.10 mmol) in EtOH (5 mL) was heated at 75° C. overnight. The reaction was concentrated to dryness, diluted with DCM (20 mL) and EDC (0.358 g, 1.87 mmol), HOAT (0.252 g, 1.87 mmol) were added followed by diisopropylethylamine (0.650 mL, 3.73 mmol). After stirring overnight, NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered, concentrated and the residue purified by silica gel chromatography (10%→35% EtOAc/hexanes) to give the title compound (0.21 g). MS 513.1 (M+1). 1H NMR (500 MHz, CD3OD) δ 7.1 (m, 3H), 5.24 (d, J=10.7 Hz, 1H), 4.02 (m, 1H), 3.69 (d, J=13.9 Hz, 1H), 3.60 (d, J=15.1 Hz, 1H), 3.39 (m, 1H), 3.24 (d, J=14.2 Hz, 1H), 2.4 (m, 1H), 2.1 (m, 3H), 1.5 (s, 18H), 1.20 (s, 3H), 1.16 (s, 3H).

Workup

  1. concentrationThe reaction was concentrated to dryness
  2. additionwere added
  3. customthe layers separated
  4. dry with materialThe combined organics were dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customthe residue purified by silica gel chromatography (10%→35% EtOAc/hexanes)

Sources & evidence

ORD record
ord-50c2195eb18a4f4198d00aafc3371fec
Source dataset
uspto-grants-2010_08
Patent number
US07772224B2

Reaction notes

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