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Oxalyl chloride → 2-methyl-N-{3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-yl}-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanamide

HRID 386918
Notes
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Reaction equation

HRID 386918 reaction equation
[CH3:1][C:2]([S:7][CH2:8][CH2:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1)([CH3:6])[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[CH3:30][C:31]([C:42]1[CH:46]=[C:45]([NH2:47])[O:44][N:43]=1)([C@@H:33]([O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)[CH3:34])[CH3:32]>C(Cl)Cl.CN(C=O)C>[CH3:6][C:2]([S:7][CH2:8][CH2:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1)([CH3:1])[C:3]([NH:47][C:45]1[O:44][N:43]=[C:42]([C:31]([CH3:30])([C@@H:33]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH3:34])[CH3:32])[CH:46]=1)=[O:5]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 592532413-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-amineHCID 592532422-methyl-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanoic acid

Product 1

HCID 592532302-methyl-N-{3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-yl}-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanamide
Yield 55%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
60 °C

Procedure

Activation of 0.35 g (1.61 mmol) of 2-methyl-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanoic acid as the corresponding acid chloride is achieved by treatment with oxalyl chloride (0.28 mL, 3.22 mmol) and DMF (cat., 0.01 mL) in DCM (15 mL) at room temperature for 3 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in THF (5 mL) and concentrated under reduced pressure. This process is repeated. Then the crude acid chloride is dissolved in anhydrous THF (10 mL) and 0.32 mL (1.81 mmol) of N,N-diisopropylethylamine are added followed by 0.17 g (0.66 mmol) of 3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-amine. After complete addition the reaction is heated to 60° C. for 17 h. The reaction is cooled to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate (20 mL) and washed with saturated aqueous NaHCO3 solution (2×5 mL) and 1M aqueous HCl solution (2×5 mL). The organic layer is dried (Na2SO4) and filtered. The filtrate is concentrated under reduced pressure and the residue purified by column chromatography (silica, eluent heptanes, 30% ethyl acetate) to yield 133 mg of 2-methyl-N-{3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-yl}-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanamide. Yield: 55%; ES-MS: m/z 453 [M−H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm approx 1:1 mixture of diastereoisomers: 1.00 (4H, d, J=6.24 Hz), 1.14-1.20 (4H, m), 1.22-1.39 (11H, m), 1.41-1.91 (27H, m), 1.94-2.13 (2H, m), 2.20-2.36 (2H, m), 2.48-2.67 (4H, m), 3.26-3.38 (2 H, m), 3.41-3.55 (2H, m), 3.63-3.98 (12H, m), 4.53-4.59 (1H, m), 4.74 (1H, t, J=3.12 Hz), 6.31 (1H, s), 6.35 (1H, s), 9.50 (2H, s)

Workup

  1. concentrationThe reaction mixture is concentrated under reduced pressure
  2. dissolutionThe residue is dissolved in THF (5 mL)
  3. concentrationconcentrated under reduced pressure
  4. dissolutionThen the crude acid chloride is dissolved in anhydrous THF (10 mL)
  5. additionAfter complete addition the reaction
  6. temperatureThe reaction is cooled to room temperature
  7. customthe solvent is removed under reduced pressure
  8. dissolutionThe residue is dissolved in ethyl acetate (20 mL)
  9. washwashed with saturated aqueous NaHCO3 solution (2×5 mL) and 1M aqueous HCl solution (2×5 mL)
  10. dry with materialThe organic layer is dried (Na2SO4)
  11. filtrationfiltered
  12. concentrationThe filtrate is concentrated under reduced pressure
  13. customthe residue purified by column chromatography (silica, eluent heptanes, 30% ethyl acetate)

Sources & evidence

ORD record
ord-ea51bef8b0954db98cf17a3414a1cff1
Source dataset
uspto-grants-2013_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08372874B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes