Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → tert-butyl 2-(4-(2-(2,5-dimethoxyphenyl)acetamido)-N-(4-(3-(4'-methyl-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate

HRID 923609Notes

Reaction equation

HRID 923609 reaction equation
[NH2:1][C:2]1[CH:43]=[CH:42][C:5]([C:6]([N:8]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][CH:22]=4)[N:17]=3)=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.CO[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[C:47]=1[CH2:54][C:55]([OH:57])=O.CN([C:61]([O:65]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C.CC(=O)OCC>[CH3:53][O:52][C:48]1[CH:49]=[CH:50][C:51]([O:65][CH3:61])=[CH:46][C:47]=1[CH2:54][C:55]([NH:1][C:2]1[CH:43]=[CH:42][C:5]([C:6]([N:8]([CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][CH:22]=4)[N:17]=3)=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1)=[O:57]

Participants

7

Reactant 3

HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)3×HCID 189315722-(2,6-Dimethoxyphenyl)acetic acid2×HCID 89284665tert-butyl 2-(4-amino-N-(4-(3-(4'-methyl-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate

Product 1

HCID 71111955tert-butyl 2-(4-(2-(2,5-dimethoxyphenyl)acetamido)-N-(4-(3-(4'-methyl-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetateYield 40%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

Prepared using General Procedure 6. To a suspension of tert-butyl 2-(4-amino-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-64 (90 mg, 0.157 mmol) and 2-(2,6-dimethoxyphenyl)acetic acid (30.7 mg, 0.157 mmol) stirring in DMF (2 mL) were added HATU (65.5 mg, 0.172 mmol), DMAP (15 mg, 0.123 mmol) and TEA (54.6 μL, 0.392 mmol). After stirring at room temperature for 18 h 2-(2,6-dimethoxyphenyl)acetic acid (30.7 mg, 0.157 mmol), HATU (65.5 mg, 0.172 mmol) and TEA (21.83 μl, 0.157 mmol) were added. The reaction mixture was stirred at room temperature for 72 h then at 50° C. for 2 h and 60° C. for 2 h. The reaction mixture was cooled to room temperature and more HATU (65.5 mg, 0.172 mmol) was added. After 18 h the reaction mixture was diluted with EA (25 mL) and washed with NaHCO3 (2×25 mL), 1 M HCl (2×25 mL) and brine (25 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (EA/hexanes) to afford 47 mg (40%) of tert-butyl 2-(4-(2-(2,5-dimethoxyphenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-66. LCMS-ESI (m/z) calculated for C45H44N4O7: 752; found 753 [M+H]+, tR=2.79 min (Method 10).

Workup

  1. customPrepared
  2. additionwere added
  3. waitat 50° C. for 2 h
  4. wait60° C. for 2 h
  5. temperatureThe reaction mixture was cooled to room temperature
  6. washwashed with NaHCO3 (2×25 mL), 1 M HCl (2×25 mL) and brine (25 mL)
  7. dry with materialThe combined organics were dried over MgSO4
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by chromatography (EA/hexanes)

Sources & evidence

ORD record
ord-3517a46bff9a41788825ff7c3b0aba9c
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

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