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

HRID 923571Notes

Reaction equation

HRID 923571 reaction equation
[OH:1][NH:2][C:3]([C:5]1[CH:44]=[CH:43][C:8]([CH2:9][N:10]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[C:11](=[O:34])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[C:29]([F:32])([F:31])[F:30])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[CH3:54][C:55]1[CH:63]=[CH:62][C:58]([C:59](Cl)=O)=[CH:57][CH:56]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([N:10]([CH2:35][C:36]([OH:38])=[O:37])[CH2:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]4[N:4]=[C:54]([C:55]5[CH:63]=[CH:62][C:58]([CH3:59])=[CH:57][CH:56]=5)[O:1][N:2]=4)=[CH:44][CH:43]=3)=[O:34])=[CH:13][CH:14]=2)=[O:33])=[C:22]([C:29]([F:32])([F:30])[F:31])[CH:23]=1

Participants

7

Reactant 4

HCID 134054-Methylbenzoyl ChlorideHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 178490478HCID 178490478, compound

Product 1

HCID 711116232-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acidYield 56%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent2×

Procedure

Prepared using General Procedures 20 and 8: To a stirring solution of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-33 (128 mg, 0.21 mmol) and DIEA (0.058 mL, 0.31 mmol) in dioxane (4 mL) was added a solution of 4-methylbenzoyl chloride (0.028 mL, 0.21 mmol) in dioxane (1 mL). After stirring at room temperature for 1 h, the reaction mixture was heated to 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature, diluted with DCM (4 mL), shaken with NaHCO3 (10 mL), split through a hydrophobic frit and evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was dissolved in DCM (2 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h then evaporated and re-slurried from acetonitrile (6 mL) to afford 77 mg (56%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 355 as a white solid. LCMS-ESI (m/z) calculated for C35H29F3N4O6: 658; found 659 [M+H]+, tR=7.97 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.81 (s, 1H), 10.34 (s, 1H), 8.10 (d, J=6.1 Hz, 2H), 8.09-8.05 (m, 2H), 7.70-7.56 (m, 3H), 7.53-7.41 (m, 4H), 7.38 (d, J=8.0 Hz, 2H), 7.26-7.14 (m, 2H), 4.76 (s, 1H), 4.68 (s, 1H), 4.04 (s, 1H), 3.97 (s, 1H), 3.91-3.79 (m, 5H), 2.45 (s, 3H).

Workup

  1. customPrepared
  2. temperaturethe reaction mixture was heated to 120° C. for 2 h
  3. temperatureto cool to room temperature
  4. customsplit through a hydrophobic frit
  5. customevaporated
  6. customThe crude material was purified by column chromatography (EA/isohexanes)
  7. dissolutionThe isolated material was dissolved in DCM (2 mL)
  8. additionTFA (2 mL) was added
  9. stirringThe reaction mixture was stirred at room temperature for 2 h
  10. customthen evaporated

Sources & evidence

ORD record
ord-9c08df91a095432cbc2dc44459b10e0e
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

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