Formic Acid → US9321721, Example 3

HRID 631774Notes

Reaction equation

HRID 631774 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14].I[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.C(NCC)C.C(O)=O>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19](/[C:22](/[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:23]\[C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14]

Participants

7

Reactant 4

HCID 284Formic AcidHCID 8021DiethylamineHCID 696764-IodoanisoleHCID 903870243-{4-[({[2-Fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide

Product 1

HCID 78209993US9321721, Example 3Yield 31.1%

Reagents, catalysts & solvents 2

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
75 °C

Procedure

A mixture of 3-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide (31.0 mg, 0.085 mmol), 4-iodoanisole (0.010 mL, 0.089 mmol), diethylamine (0.029 mL, 0.281 mmol), formic acid (0.0083 mL, 0.221 mmol), and bis(dibenzylideneacetone)palladium(0) (3.4 mg, 0.006 mmol) in 1.4 mL EtOAc (degassed) was heated at 75° C. for 20 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed with dilute aqueous HCl, then aqueous NaHCO3, brine, and dried with anhydrous Na2SO4 to give 20 mL of EtOAc solution of crude material. The EtOAc solution was filtered past a plug of silica gel eluting with EtOAc, evaporated, and the resulting solid chromatographed eluting with EtOAc/CHCl3 to give the title compound as a grey-purple solid (12.5 mg, 31%). 1H NMR (Acetone-d6) δ: 8.80 (d, J=7.6 Hz, 1H), 8.42 (s, 2H), 7.32-7.45 (m, 4H), 7.21-7.26 (m, 2H), 7.10-7.16 (m, 2H), 6.98 (br. s., 1H), 6.88-6.94 (m, 2H), 6.63 (br. s., 1H), 6.43 (s, 1H), 3.81 (s, 3H).

Workup

  1. customThe reaction was partitioned between EtOAc and H2O/brine mixture
  2. washThe EtOAc layer was washed with dilute aqueous HCl
  3. dry with materialaqueous NaHCO3, brine, and dried with anhydrous Na2SO4
  4. customto give 20 mL of EtOAc solution of crude material
  5. filtrationThe EtOAc solution was filtered past a plug of silica gel eluting with EtOAc
  6. customevaporated
  7. customthe resulting solid chromatographed
  8. washeluting with EtOAc/CHCl3

Sources & evidence

ORD record
ord-7b72a913e07840eb8dd175d517dfc01c
Source dataset
uspto-grants-2016_04
Patent number
US09321721B2

Reaction notes

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