4-Methylmorpholine → tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(4'-methyl-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate

HRID 923579Notes

Reaction equation

HRID 923579 reaction equation
[C:1]([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=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)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.O[N:60]=[C:61]([C:63]1[CH:68]=[CH:67][C:66]([C:69]2[CH:74]=[CH:73][C:72]([CH3:75])=[CH:71][CH:70]=2)=[CH:65][CH:64]=1)[NH2:62].C([O-])(O)=O.[Na+]>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:14]=[CH:15][C:10]([C:9]([N:8]([CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:43])[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([C:38]4[O:40][N:62]=[C:61]([C:63]5[CH:64]=[CH:65][C:66]([C:69]6[CH:74]=[CH:73][C:72]([CH3:75])=[CH:71][CH:70]=6)=[CH:67][CH:68]=5)[N:60]=4)=[CH:41][CH:42]=3)=[O:32])=[CH:11][CH:12]=2)=[O:31])=[C:20]([C:27]([F:29])([F:30])[F:28])[CH:21]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 516892Sodium BicarbonateHCID 6860451N'-hydroxy-4-(p-tolyl)benzamidineHCID 710768754-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid

Product 1

HCID 71111624tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(4'-methyl-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetateYield 35%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent2×

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 (150 mg, 0.25 mmol) in dioxane (4 mL) were added N-methylmorpholine (60.0 μl, 0.55 mmol) and isobutyl chloroformate (34.0 μl, 0.26 mmol). After stirring at room temperature for 1 h, the reaction mixture was added drop wise to a stirring solution of N′-hydroxy-4′-methyl-[1,1′-biphenyl]-4-carboximidamide INT-40 (62.0 mg, 0.275 mmol) in dioxane (2 mL) and DMF (2 mL). The reaction mixture was allowed to stir at room temperature for 1 h, then heated to 90° C. for 2 h, and then heated to 120° C. for 16 h. The reaction mixture was allowed to cool to room temperature then poured into NaHCO3 (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (EA/isohexanes) to yield 77 mg (35%) of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-41. LCMS-ESI (m/z) calculated for C45H41F3N4O6: 791; no m/z observed, tR=3.26 min (Method 10). 1H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.35-8.04 (m, 4H), 8.04-7.80 (m, 2H), 7.80-7.28 (m, 11H), 7.28-7.08 (m, 2H), 4.80 (s, 1H), 4.70 (s, 1H), 4.00 (s, 2H), 3.92-3.79 (m, 5H), 2.40 (s, 3H), 1.47 (s, 4.5H), 1.33 (s, 4.5H).

Workup

  1. stirringto stir at room temperature for 1 h
  2. temperatureheated to 90° C. for 2 h
  3. temperatureheated to 120° C. for 16 h
  4. temperatureto cool to room temperature
  5. extractionextracted with DCM (3×20 mL)
  6. dry with materialThe combined organic extracts were dried over MgSO4
  7. concentrationconcentrated
  8. customThe crude product was purified by column chromatography (EA/isohexanes)

Sources & evidence

ORD record
ord-dc7372d6e79d42718cb7401ffb928fa6
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

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