Acetonitrile → 2-(N-(4-((4'-chloro-[1,1'-biphenyl]-4-carbonyl)oxy)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetic acid

HRID 923558Notes

Reaction equation

HRID 923558 reaction equation
Br[C:2]1[CH:50]=[CH:49][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[C:17](=[O:40])[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=4[C:35]([F:38])([F:37])[F:36])=[CH:20][CH:19]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:57][C:58]1[CH:63]=[CH:62][C:61](B(O)O)=[CH:60][CH:59]=1.C(#N)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:57][C:58]1[CH:63]=[CH:62][C:61]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:41][C:42]([OH:44])=[O:43])[C:17](=[O:40])[C:18]4[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:39])[CH2:26][C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=5[C:35]([F:37])([F:38])[F:36])=[CH:22][CH:23]=4)=[CH:13][CH:14]=3)=[O:7])=[CH:49][CH:50]=2)=[CH:60][CH:59]=1

Participants

7

Reactant 4

HCID 6342AcetonitrileHCID 10340Sodium CarbonateHCID 742994-Chlorophenylboronic acidHCID 892849964-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)phenyl 4-bromobenzoate

Product 1

HCID 892536122-(N-(4-((4'-chloro-[1,1'-biphenyl]-4-carbonyl)oxy)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetic acidYield 31%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

Prepared using General Procedures 16 then 8: To 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)phenyl 4-bromobenzoate INT-10 (50 mg, 0.07 mmol) in a microwave vessel were added Na2CO3 (15 mg, 0.15 mmol), 4-chlorobenzene boronic acid (17 mg, 0.07 mmol), acetonitrile (1 mL) and water (0.1 mL). The suspension was degassed with N2 then treated with PdCl2(dppf) (2.6 mg, 3.64 μmol) and degassed further. The reaction mixture was heated in the microwave at 100° C. for 30 min with stirring. The reaction mixture was diluted with DCM (10 mL) and passed through a phase separator cartridge. The organic layer was isolated and concentrated to 3 mL then TFA (2 mL) was added. After stirring for 2 h at room temperature, the solvent was concentrated and the product was purified by preparative HPLC to provide 17 mg (31%) of 2-(N-(4-((4′-chloro-[1,1′-biphenyl]-4-carbonyl)oxy)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetic acid 282. LCMS-ESI (m/z) calculated for C39H30ClF3N2O7: 731; found 732 [M+H]+, tR=8.89 min (Method 9).

Workup

  1. customPrepared
  2. customThe suspension was degassed with N2
  3. customdegassed further
  4. additionThe reaction mixture was diluted with DCM (10 mL)
  5. customThe organic layer was isolated
  6. concentrationconcentrated to 3 mL
  7. additionTFA (2 mL) was added
  8. stirringAfter stirring for 2 h at room temperature
  9. concentrationthe solvent was concentrated
  10. customthe product was purified by preparative HPLC

Sources & evidence

ORD record
ord-2a998c09127b42baa225f4a6b131d9b1
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

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