Oxalyl chloride → 2-(2-fluoro-4-methanesulfonyl-phenylsulfanyl)-N-[3-(2-methoxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-propionamide

HRID 1809433Notes

Reaction equation

HRID 1809433 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O.C(Cl)(=O)C(Cl)=O.[CH3:25][O:26][CH2:27][C:28]([C:31]1[CH:35]=[C:34]([NH2:36])[O:33][N:32]=1)([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[S:12][C:13]([CH3:18])([CH3:17])[C:14]([NH:36][C:34]1[O:33][N:32]=[C:31]([C:28]([CH3:30])([CH3:29])[CH2:27][O:26][CH3:25])[CH:35]=1)=[O:16]

Participants

9

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 534418093-(1-Methoxy-2-methylpropan-2-YL)isoxazol-5-amineHCID 592679272-(2-Fluoro-4-methanesulfonyl-phenylsulfanyl)-2-methyl-propionic acid

Product 1

HCID 592678902-(2-fluoro-4-methanesulfonyl-phenylsulfanyl)-N-[3-(2-methoxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-propionamideYield 43%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 1140TolueneSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

Activation of 336 mg (1.15 mmol) of 2-(2-fluoro-4-methanesulfonyl-phenylsulfanyl)-2-methyl-propionic acid as its acid chloride is achieved by treatment with oxalyl chloride (0.3 mL, 3.45 mmol) and DMF (1 drop) in DCM (15 mL) at room temperature for 3 h. The solvent is removed under reduced pressure and the crude acid chloride is dissolved in toluene (5 mL) and added to a solution of 196 mg (1.15 mmol) of 3-(2-methoxy-1,1-dimethyl-ethyl)-isoxazol-5-ylamine and N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) in toluene. The reaction is heated to 50° C. for 18 h. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate (20 mL) and washed with 1M aqueous HCl solution (2×10 mL), water (2×10 mL), saturated aqueous NaHCO3 solution (2×10 mL), brine (10 mL). The organic layer is dried (Na2SO4), filtered and the filtrate is concentrated under reduced pressure. The residue is purified twice by column chromatography (silica, eluent: heptanes, 20-50% ethyl acetate, followed by heptanes, 10% ethyl acetate) to afford 220 mg of 2-(2-fluoro-4-methanesulfonyl-phenylsulfanyl)-N-[3-(2-methoxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-propionamide. Yield: 43%, ES-MS: m/z 445 [M+H]

Workup

  1. customThe solvent is removed under reduced pressure
  2. dissolutionthe crude acid chloride is dissolved in toluene (5 mL)
  3. temperatureAfter cooling to room temperature
  4. washwashed with 1M aqueous HCl solution (2×10 mL), water (2×10 mL), saturated aqueous NaHCO3 solution (2×10 mL), brine (10 mL)
  5. dry with materialThe organic layer is dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationthe filtrate is concentrated under reduced pressure
  8. customThe residue is purified twice by column chromatography (silica, eluent: heptanes, 20-50% ethyl acetate, followed by heptanes, 10% ethyl acetate)

Sources & evidence

ORD record
ord-bcd28b4d932745488c1b3865e4f07b56
Source dataset
uspto-grants-2013_01
Patent number
US08362039B2

Reaction notes

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