Triethylamine → 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4'-methyl-[1,1'-biphenyl]-4-yl)-1,3,4-oxadiazol-2-yl)benzyl)benzamido)acetic acid

HRID 923592Notes

Reaction equation

HRID 923592 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:55]=[CH:54][C:16]([C:17]([N:19]([CH2:46][C:47]([O:49]C(C)(C)C)=[O:48])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][NH:30][C:31]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)=[CH:35][CH:34]=4)=[O:32])=O)=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:56]([F:59])([F:58])[F:57])[CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:19]([CH2:46][C:47]([OH:49])=[O:48])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[O:32][C:31]([C:33]5[CH:38]=[CH:37][C:36]([C:39]6[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=6)=[CH:35][CH:34]=5)=[N:30][N:29]=4)=[CH:25][CH:26]=3)=[O:18])=[CH:54][CH:55]=2)=[O:11])=[C:5]([C:56]([F:58])([F:57])[F:59])[CH:4]=1

Participants

5

Reactant 3

HCID 8471Triethylamine2×HCID 109867151H-Imidazolium, 2-chloro-4,5-dihydro-1,3-dimethyl-, chlorideHCID 71111628tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(2-(4'-methyl-[1,1'-biphenyl]-4-carbonyl)hydrazine carbonyl)benzyl)benzamido)acetate

Product 1

HCID 711121372-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4'-methyl-[1,1'-biphenyl]-4-yl)-1,3,4-oxadiazol-2-yl)benzyl)benzamido)acetic acidYield 8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirring solution of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(2-(4′-methyl-[1,1′-biphenyl]-4-carbonyl)hydrazine carbonyl)benzyl)benzamido)acetate INT-51 (138 mg, 0.17 mmol) and triethylamine (37 μL, 0.26 mmol) in DCM (4 mL) was added 2-chloro-1,3-dimethylimidazolinium chloride (32.0 mg, 0.19 mmol). After stirring at room temperature for 16 h, the reaction mixture was warmed to 40° C. After 1 h, additional triethylamine (37.0 μL, 0.26 mmol) was added. After a further 2 h, the reaction mixture was allowed to cool to room temperature then washed 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 diluted with DCM (2 mL), treated with TFA (2 mL) and allowed to stir for 1 h at room temperature. The solvents were concentrated and the residue purified by preparative HPLC to afford 10 mg (8%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,3,4-oxadiazol-2-yl)benzyl)benzamido)acetic acid 367 as a white solid. LCMS-ESI (m/z) calculated for C41H33F3N4O6: 734; found 735 [M+H]+, tR=8.40 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 10.36 (s, 1H), 8.26-8.09 (m, 4H), 7.99-7.87 (m, 2H), 7.77-7.50 (m, 6H), 7.47-7.31 (m, 5H), 7.26-7.14 (m, 2H), 4.76 (s, 1H), 4.69 (s, 1H), 4.04 (s, 1H), 3.96 (m, 1H), 3.88-3.77 (m, 5H), 2.38 (s, 3H).

Workup

  1. temperaturethe reaction mixture was warmed to 40° C
  2. waitAfter 1 h
  3. waitAfter a further 2 h
  4. temperatureto cool to room temperature
  5. washthen washed with NaHCO3 (10 mL)
  6. customsplit through a hydrophobic frit
  7. customevaporated
  8. customThe crude material was purified by column chromatography (EA/isohexanes)
  9. additionThe isolated material was diluted with DCM (2 mL)
  10. additiontreated with TFA (2 mL)
  11. stirringto stir for 1 h at room temperature
  12. concentrationThe solvents were concentrated
  13. customthe residue purified by preparative HPLC

Sources & evidence

ORD record
ord-b054a27fd218438499898da3c8dbe688
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

Loading…