Trifluoroacetic acid → 2-(4-(2-(2,6-difluoro-3-methoxyphenyl)acetamido)-N-(4-(5-(4'-methyl-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid

HRID 923601Notes

Reaction equation

HRID 923601 reaction equation
[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:63]=[CH:62][C:25]([C:26]([N:28]([CH2:54][C:55]([O:57]C(C)(C)C)=[O:56])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:40]=[C:39]([C:41]4[CH:46]=[CH:45][C:44]([C:47]5[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=5)=[CH:43][CH:42]=4)[O:38][N:37]=3)=[CH:32][CH:31]=2)=[O:27])=[CH:24][CH:23]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([NH:21][C:22]1[CH:63]=[CH:62][C:25]([C:26]([N:28]([CH2:54][C:55]([OH:57])=[O:56])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:40]=[C:39]([C:41]4[CH:46]=[CH:45][C:44]([C:47]5[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=5)=[CH:43][CH:42]=4)[O:38][N:37]=3)=[CH:32][CH:31]=2)=[O:27])=[CH:24][CH:23]=1)=[O:14]

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 65578Oxalyl chlorideHCID 38160422,6-Difluoro-3-methoxyphenylacetic acidHCID 89284998tert-butyl 2-(4-amino-N-(4-(5-(4'-methyl-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate

Product 1

HCID 711116712-(4-(2-(2,6-difluoro-3-methoxyphenyl)acetamido)-N-(4-(5-(4'-methyl-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acidYield 57%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

Prepared using General Procedures 7 and 8: To a stirred suspension of 2-(2,6-difluoro-3-methoxyphenyl)acetic acid in DCM (1.5 mL) and DMF (10 μL) was added oxalyl chloride (9.71 μL, 0.111 mmol). After 1 h a solution of tert-butyl 2-(4-amino-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-59 (50 mg, 0.074 mmol) and TEA (25.8 μL, 0.185 mmol) in DCM (1 mL) was added. After 18 h TFA (1 mL) was added and reaction stirred for 2 h. The solvent was removed from the reaction mixture and the residue purified by preparative HPLC to afford 30 mg (57%) of 2-(4-(2-(2,6-difluoro-3-methoxyphenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 441. LCMS-ESI (m/z) calculated for C46H32F2N4O6: 702; found 703 [M+H]+, tR=8.75 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 10.26 (s, 1H), 8.31-8.22 (m, 2H), 8.12-8.06 (m, 2H), 8.02-7.92 (m, 2H), 7.74-7.69 (m, 2H), 7.69-7.56 (m, 2H), 7.54-7.45 (m, 1H), 7.42-7.29 (m, 4H), 7.23-7.09 (m, 2H), 6.80-6.66 (m, 1H), 4.76 (s, 1H), 4.67 (s, 1H), 4.04 (s, 1H), 3.97 (s, 1H), 2.92-2.81 (m, 5H), 2.38(s, 3H).

Workup

  1. customPrepared
  2. customreaction
  3. customThe solvent was removed from the reaction mixture
  4. customthe residue purified by preparative HPLC

Sources & evidence

ORD record
ord-d713d1f833ae417d95f198640cfd8c74
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

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