4-Methylmorpholine → 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzyl)benzamido) acetic acid

HRID 923593Notes

Reaction equation

HRID 923593 reaction equation
C([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:30])([F:29])[F:28])=[CH:12][CH:11]=1)(C)(C)C.CN1CCOCC1.ClC(OCC(C)C)=O.[OH:59][N:60]=[C:61]([NH2:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>O1CCOCC1.CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([N:8]([CH2:7][C:6]([OH:43])=[O:5])[CH2:33][C:34]3[CH:42]=[CH:41][C:37]([C:38]4[O:59][N:60]=[C:61]([C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=5)[N:68]=4)=[CH:36][CH:35]=3)=[O:32])=[CH:15][CH:14]=2)=[O:31])=[C:20]([C:27]([F:28])([F:30])[F:29])[CH:21]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 69186N'-HydroxybenzenecarboximidamideHCID 710768754-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid

Product 1

HCID 710767902-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzyl)benzamido) acetic acidYield 14%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (129 mg, 0.22 mmol) and 4-methylmorpholine (52.0 μL, 0.47 mmol) in dioxane (2 mL) was added isobutyl chloroformate (28.0 μL, 0.22 mmol). After 1 h, the reaction mixture was added to a stirring solution of N′-hydroxybenzimidamide (32.0 mg, 0.24 mmol) in DMF (2 mL). After a further 1 h, the reaction mixture was heated to 120° C. for 1 h. The reaction mixture was allowed to cool to room temperature then poured onto citric acid (50 mL, 0.1 M aqueous solution) and extracted with EA(2×20 mL). The combined organic extracts were washed with NaHCO3 (20 mL), dried over MgSO4 and the solvents evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was dissolved in DCM (2 mL) and treated with TFA (2 mL). After 2 h, the solvents were concentrated and the residue purified by preparative HPLC to afford 19 mg (14%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzyl)benzamido) acetic acid 368 as a white solid. LCMS-ESI (m/z) calculated for C34H27F3N4O6: 644; found 645 [M+H]+, tR=7.56 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 10.34 (s, 1H), 8.22-8.16 (m, 2H), 8.15-8.08 (m, 2H), 7.81-7.49 (m, 7H), 7.49-7.29 (m, 3H), 7.29-7.05 (m, 2H), 4.78 (s, 1H), 4.71 (s, 1H), 4.05 (s, 1H), 3.98 (s, 1H), 3.91-3.77 (s, 5H).

Workup

  1. waitAfter a further 1 h
  2. temperatureto cool to room temperature
  3. additionthen poured onto citric acid (50 mL, 0.1 M aqueous solution)
  4. extractionextracted with EA(2×20 mL)
  5. washThe combined organic extracts were washed with NaHCO3 (20 mL)
  6. dry with materialdried over MgSO4
  7. customthe solvents evaporated
  8. customThe crude material was purified by column chromatography (EA/isohexanes)
  9. dissolutionThe isolated material was dissolved in DCM (2 mL)
  10. additiontreated with TFA (2 mL)
  11. waitAfter 2 h
  12. concentrationthe solvents were concentrated
  13. customthe residue purified by preparative HPLC

Sources & evidence

ORD record
ord-b1e085cfb51941feba80d1859a22cc04
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

Loading…