Oxalyl chloride → 2-{[(2R)-1,4-dioxan-2-ylmethyl]sulfanyl}-2-methyl-N-{3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-yl}propanamide

HRID 386917Notes

Reaction equation

HRID 386917 reaction equation
[O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][S:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[CH3:21][C:22]([C:33]1[CH:37]=[C:36]([NH2:38])[O:35][N:34]=1)([C@@H:24]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH3:25])[CH3:23].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl.C1COCC1>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][S:8][C:9]([CH3:14])([CH3:13])[C:10]([NH:38][C:36]1[O:35][N:34]=[C:33]([C:22]([CH3:21])([C@@H:24]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH3:25])[CH3:23])[CH:37]=1)=[O:12]

Participants

8

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 592532413-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-amineHCID 592532592-{[(2R)-1,4-dioxan-2-ylmethyl]sulfanyl}-2-methylpropanoic acid

Product 1

HCID 592531802-{[(2R)-1,4-dioxan-2-ylmethyl]sulfanyl}-2-methyl-N-{3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-yl}propanamideYield 85.3%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

Activation of 145 mg (0.58 mmol) of 2-{[(2R)-1,4-dioxan-2-ylmethyl]sulfanyl}-2-methylpropanoic acid as its acid chloride is achieved by treatment with oxalyl chloride (0.1 mL, 1.16 mmol) and DMF (1 drop) in DCM (15 mL) at room temperature for 16 h. The solvent is removed under reduced pressure and the crude acid chloride is dissolved in anhydrous THF (5 mL) and added to a solution of 147 mg (0.58 mmol) of 3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-amine and N,N-diisopropylethylamine (0.30 mL, 1.73 mmol) in THF (10 mL). The reaction is heated to 60° C. for 18 h. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure. The residue is diluted with DCM (20 mL) and washed with saturated aqueous NaHCO3 solution (10 mL). The organic layer is dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (silica, eluent: heptanes, 0-30% ethyl acetate) to afford 226 mg of 2-{[(2R)-1,4-dioxan-2-ylmethyl]sulfanyl}-2-methyl-N-{3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-yl}propanamide of 63% purity. This intermediate is taken on in the next step without further purification. Yield: 54%, ES-MS: m/z 479 [M+Na]

Workup

  1. customThe solvent is removed under reduced pressure
  2. dissolutionthe crude acid chloride is dissolved in anhydrous THF (5 mL)
  3. temperatureAfter cooling to room temperature
  4. concentrationthe reaction mixture is concentrated under reduced pressure
  5. additionThe residue is diluted with DCM (20 mL)
  6. washwashed with saturated aqueous NaHCO3 solution (10 mL)
  7. dry with materialThe organic layer is dried (MgSO4)
  8. filtrationfiltered
  9. concentrationthe filtrate is concentrated under reduced pressure
  10. customThe residue is purified by column chromatography (silica, eluent: heptanes, 0-30% ethyl acetate)

Sources & evidence

ORD record
ord-bf46f7c04d624facb0529c771669e615
Source dataset
uspto-grants-2013_02
Patent number
US08372874B2

Reaction notes

Loading…