Phosgene → (1-benzylcyclobutyl)methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1r)-1-phenylethyl]amino}ethyl)pentylcarbamate

HRID 1180737Notes

Reaction equation

HRID 1180737 reaction equation
C([CH:3]([C:5]1([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6]1)[OH:4])C.[C:16](Cl)(Cl)=[O:17].[NH2:20][C@@H:21]([CH2:35][CH2:36][CH2:37][CH3:38])[CH:22]([OH:34])[C:23]([NH:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])=[O:24].C(N(CC)CC)C>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:34][CH:22]([C@@H:21]([NH:20][C:16](=[O:17])[O:4][CH2:3][C:5]1([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:7][CH2:8]1)[CH2:35][CH2:36][CH2:37][CH3:38])[C:23](=[O:24])[NH:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]

Participants

8

Reactant 4

HCID 6371PhosgeneHCID 8471TriethylamineHCID 11265560(3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamideHCID 69240190Ethyl(1-benzylcyclobutyl)methanol

Product 1

HCID 58979674(1-benzylcyclobutyl)methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1r)-1-phenylethyl]amino}ethyl)pentylcarbamateYield 99.7%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 100 mg (0.57 mmol) of ethyl (1-benzylcyclobutyl)methanol in 3 mL of tetrahydrofuran was added 0.68 mL (1.31 mmol) of 1.93 M phosgene in toluene in one portion. The reaction was stirred overnight at room temperature. The mixture was concentrated under vacuum. The remaining oil was dissolved in 1 mL tetrahydrofuran and added to a solution of 136 mg (0.516 mmol) of (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide and 0.079 mL (0.568 mmol) of triethylamine in 5 mL tetrahydrofuran. The reaction was stirred at room temperature for 3 h, diluted with ethyl acetate, and washed with 1M hydrochloric acid. The organic phase was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 240 mg (99%) of (1-benzylcyclobutyl)methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate. 1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J=9 Hz, 1H), 7.17-7.36 (m, 10H), 6.57 (d, J=9 Hz, 1H), 5.57 (d, J=6 Hz, 1H), 4.90-5.02 (m, 1H), 3.89-3.94 (m, 1H), 3.75-3.84 (m, 3H), 2.77 (s, 2H), 1.70-1.93 (m, 6H), 1.25-1.53 (m, 9H), 0.88 (t, J=7 Hz, 3H). ES-LCMS m/z 489 (M+Na).

Workup

  1. concentrationThe mixture was concentrated under vacuum
  2. dissolutionThe remaining oil was dissolved in 1 mL tetrahydrofuran
  3. stirringThe reaction was stirred at room temperature for 3 h
  4. washwashed with 1M hydrochloric acid
  5. washThe organic phase was washed with brine
  6. dry with materialdried over magnesium sulfate
  7. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-f45c69f0bab24612be8ada08b397c36a
Source dataset
uspto-grants-2007_10
Patent number
US07282512B2

Reaction notes

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