Oxalyl chloride → 6-Fluoro-4-methoxy-biphenyl-3-carboxylic acid 3-nitro-benzylamide

HRID 2229566Notes

Reaction equation

HRID 2229566 reaction equation
[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]([OH:16])=O)=[C:4]([O:17][CH3:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[N+:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33])([O-:28])=[O:27]>ClCCl.CN(C=O)C>[N+:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:14]([C:5]1[CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([F:1])=[CH:3][C:4]=1[O:17][CH3:18])=[O:16])([O-:28])=[O:27]

Participants

6

Reactant 3

HCID 65578Oxalyl chlorideHCID 2724030Benzenemethanamine, 3-nitro-, hydrochloride (1:1)HCID 184681996-Fluoro-4-methoxy-biphenyl-3-carboxylic acid

Product 1

HCID 220934696-Fluoro-4-methoxy-biphenyl-3-carboxylic acid 3-nitro-benzylamideYield 65%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
40 °C

Procedure

A stirring slurry of 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid (1.0 g, 4.06 mmol) in dichloromethane (8.2 mL, 0.5 M) was treated with oxalyl chloride (1.1 mL, 12.2 mmol) and DMF (1 drop). The mixture was heated to 40° C. until the solution was clear (1-2 h). Next, the mixture was allowed to cool to room temperature, concentrated under reduced pressure, and then diluted with dichloromethane (8.2 mL, 0.5 M). To the stirring mixture at 0° C. was added diisdpropylethyl amine (1.8 mL, 10.2 mmol) followed by 3-nitrobenzylamine hydrochloride salt (1.2 g, 6.1 mmol). Stirring under nitrogen, the solution was gradually warmed to room temperature and stirred overnight. The mixture was then diluted with dichloromethane and washed with 2N HCl (2×50 mL) and saturated aq NaCl (1×100 mL) The organic layer was dried over Na2SO4, filtered, and concentrated to afford a yellow oil. Purification by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid 3-nitro-benzylamide (1.0 g, 65%) as a yellow solid: Rf 0.33 (50% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 8.90 (bd t, J=6.2 Hz, 1H), 8.10 (dd, J1=7.2 Hz, J2=2.4 Hz, 1H), 7.84 (d, J=9.3 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.52-7.43 (m, 5H), 7.40-7.34 (m, 1H), 7.20 (d, J=12.9 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 3.96 (s, 3H).

Workup

  1. custom(1-2 h)
  2. temperatureto cool to room temperature
  3. concentrationconcentrated under reduced pressure
  4. additiondiluted with dichloromethane (8.2 mL, 0.5 M)
  5. temperaturethe solution was gradually warmed to room temperature
  6. stirringstirred overnight
  7. washwashed with 2N HCl (2×50 mL) and saturated aq NaCl (1×100 mL) The organic layer
  8. dry with materialwas dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto afford a yellow oil
  12. customPurification by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min)

Sources & evidence

ORD record
ord-fec3668cad5441eea14174f9e168cfa5
Source dataset
uspto-grants-2002_07
Patent number
US06420426B1

Reaction notes

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