Phosgene → (3S,4S)-4-ethyl-4-methyl-2-oxotetrahydro-3-furanyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

HRID 750386

Reaction equation

HRID 750386 reaction equation
[CH2:1]([C@@:3]1([CH3:10])[CH2:7][O:6][C:5](=[O:8])[C@H:4]1[OH:9])[CH3:2].N1C(C)=CC=CC=1C.[C:19](Cl)(Cl)=[O:20].[NH2:23][C@@H:24]([CH2:38][CH2:39][CH2:40][CH3:41])[CH:25]([OH:37])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27].C(N(CC)CC)C>CCOCC.O1CCCC1.C(OCC)(=O)C>[OH:37][CH:25]([C@@H:24]([NH:23][C:19](=[O:20])[O:9][C@H:4]1[C@:3]([CH2:1][CH3:2])([CH3:10])[CH2:7][O:6][C:5]1=[O:8])[CH2:38][CH2:39][CH2:40][CH3:41])[C:26](=[O:27])[NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]

Participants

9

Reactant 5

HCID 6371PhosgeneHCID 79372,6-LutidineHCID 8471TriethylamineHCID 10986357(3S,4S)-4-ethyl-3-hydroxy-4-methyldihydro-2(3H)-furanoneHCID 11265560(3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide

Product 1

HCID 59752189(3S,4S)-4-ethyl-4-methyl-2-oxotetrahydro-3-furanyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateYield 47.1%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolvent2×HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 120 mg (0.83 mmol) of (3S,4S)-4-ethyl-3-hydroxy-4-methyldihydro-2(3H)-furanone and 0.11 mL (0.92 mmol) of 2,6-lutidine in 3 mL of ether was added 180 mg of 4 Å molecular sieves. The mixture was stirred for 45 min and let settle for 30 min. The supernatant was transferred via cannula to a solution of phosgene (2.6 mL, 1.93 M in toluene, 5.0 mmol) in 10 mL of ether at 0° C. After 30 min, the reaction mixture was allowed to warm to room temperature. It was stirred for 2 h, and then filtered through a celite plug with ether. The filtrate was concentrated to 1 mL, and added to a solution of 220 mg (0.83 mmol) of (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide and 0.13 mL (0.91 mmol) of triethylamine in 2 mL of tetrahydrofuran. The reaction mixture was stirred for 18 h at room temperature. It was then diluted with ethyl acetate, washed with 1N HCl, and dried over magnesium sulfate before being concentrated. The residue was purified by silica gel chromatography, eluting with 1:1 ethyl acetate:hexanes to afford 170 mg (47%) of (3S,4S)-4-ethyl-4-methyl-2-oxotetrahydro-3-furanyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate. 1H NMR (300 MHz, DMSO-d6) δ 7.99 (d, J=8 Hz, 1H), 7.23-7.29 (m, 5H), 7.16 (m, 1H), 6.85 (d, J=9 Hz, 1H), 5.53 (s, 1H), 4.87 (m, 1H), 4.10 (d, J=9 Hz, 1H), 3.98 (d, J=9 Hz, 1H), 3.83 (s, 1H), 3.73 (m, 1H), 1.15-1.55 (m, 11H), 0.97 (s, 3H), 0.76-0.81 (m, 6H). ES-LCMS m/z 435 (M+H).

Workup

  1. waitlet settle for 30 min
  2. waitAfter 30 min
  3. stirringIt was stirred for 2 h
  4. filtrationfiltered through a celite plug with ether
  5. concentrationThe filtrate was concentrated to 1 mL
  6. stirringThe reaction mixture was stirred for 18 h at room temperature
  7. washwashed with 1N HCl
  8. dry with materialdried over magnesium sulfate
  9. concentrationbefore being concentrated
  10. customThe residue was purified by silica gel chromatography
  11. washeluting with 1:1 ethyl acetate

Sources & evidence

ORD record
ord-83204517ab67405e9706df279156d90f
Source dataset
uspto-grants-2008_07
Patent number
US07402606B2

Linked notes

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