Formic Acid → US9321721, Example 2

HRID 631773Notes

Reaction equation

HRID 631773 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:29]=[C:30]([O:34][CH3:35])[CH:31]=[CH:32][CH:33]=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][CH:31]=[C:30]([O:34][CH3:35])[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 69839Benzene, 1-iodo-3-methoxy-HCID 903870243-{4-[({[2-Fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide

Product 1

HCID 78427115US9321721, Example 2Yield 30%

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), 3-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 17 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 CHCl3/MeOH to give the title compound as a light tan solid (12.0 mg, 30%). 1H NMR (Acetone-d6) δ: 8.80 (d, J=5.9 Hz, 1H), 8.46 (s, 1H), 8.42 (d, J=2.6 Hz, 1H), 7.33-7.47 (m, 4H), 7.23-7.29 (m, 1H), 7.15 (d, J=8.5 Hz, 2H), 6.91-7.00 (m, 2H), 6.82-6.87 (m, 2H), 6.65 (br. s., 1H), 6.47 (s, 1H), 3.77 (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 CHCl3/MeOH

Sources & evidence

ORD record
ord-cbd6507b896e4ea195d921b89f63ccc2
Source dataset
uspto-grants-2016_04
Patent number
US09321721B2

Reaction notes

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