Hydrochloric Acid → 2-methyl-N-(thietan-3-yl)-4-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide

HRID 1770643Notes

Reaction equation

HRID 1770643 reaction equation
[CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C@:14]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[OH-].[Na+].C(N(CC)CC)C.[S:50]1[CH2:53][CH:52]([NH2:54])[CH2:51]1>ClCCl>[CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C@:14]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:18])([F:19])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:54][CH:52]1[CH2:53][S:50][CH2:51]1)=[O:6]

Participants

9

Reactant 7

HCID 313Hydrochloric AcidHCID 6228DimethylformamideHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 65578Oxalyl chlorideHCID 14594132Thietan-3-amineHCID 867270182-methyl-4-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzoic acid

Product 1

HCID 867270192-methyl-N-(thietan-3-yl)-4-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
30 °C

Procedure

To a solution of 2-methyl-4-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzoic acid (28.72 mmol, 13 g) in dichloromethane (100 mL) and N,N-dimethylformamide (0.2867 mmol, 0.0210 g) was added oxalyl chloride (4.836 g) dropwise at room temperature and under argon (the liberated hydrochloric acid gas was scrubbed with a sodium hydroxide 0.5N solution). The mixture was stirred at room temperature for 1 h and at 30° C. for 20 min until the gas evolution ceased. The reaction mixture was concentrated to dryness and redissolved in dichloromethane (100 mL), triethylamine (71.81 mmol, 7.340 g) was added at 0-5° C. under argon followed by dropwise addition of thietan-3-amine (28.72 mmol, 2.561 g). The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was extracted with aqueous hydrochloric acid (0.5N), water, brine, dried over MgSO4, filtered and evaporated affording the crude product. Purification over silica gel (eluent: CH2Cl2/EtOAc) yielded the title compound. LCMS (Method GR) RT 1.25 min, [M+H]+ 523/525; 1H-NMR (CDCl3, 400 MHz): 2.45 (s, 3H), 3.35 (m, 2H), 3.50 (m, 2H), 3.60 (d, 1H), 74.10 (d, 1H), 5.40 (q, 1H), 6.20 (d, NH), 7.40 (s, 1H), 7.51 (d, 1H), 7.40 (s, 1H), 7.50 (s, 2H), 7.65 (s, 2H). 19F-NMR (CDCl3, 376 MHz): −79.43.

Workup

  1. concentrationThe reaction mixture was concentrated to dryness
  2. dissolutionredissolved in dichloromethane (100 mL)
  3. temperatureto warm to room temperature
  4. stirringstirred for 16 h
  5. extractionThe mixture was extracted with aqueous hydrochloric acid (0.5N), water, brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. customaffording the crude product
  10. customPurification over silica gel (eluent: CH2Cl2/EtOAc)

Sources & evidence

ORD record
ord-b937993aad594f32a756884483cb982a
Source dataset
uspto-grants-2016_02
Patent number
US09247740B2

Reaction notes

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