Oxalyl chloride → 5-cyano-4-fluoro-2-methoxy-N-(3-nitro-benzyl)-benzamide

HRID 457983Notes

Reaction equation

HRID 457983 reaction equation
[C:1]([C:3]1[C:4]([F:14])=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.Cl.[N+:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38])([O-:33])=[O:32]>ClCCl.CN(C=O)C>[C:1]([C:3]1[C:4]([F:14])=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([NH:38][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1)=[O:10])#[N:2]

Participants

7

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 2724030Benzenemethanamine, 3-nitro-, hydrochloride (1:1)HCID 184682175-Cyano-4-fluoro-2-methoxy-benzoic acid

Product 1

HCID 184681795-cyano-4-fluoro-2-methoxy-N-(3-nitro-benzyl)-benzamideYield 63%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
40 °C

Procedure

To a stirring slurry of 5-cyano-4-fluoro-2-methoxy-benzoic acid (1.92 g, 9.8 mmol) in dichloromethane (20 mL, 0.5 M) was added oxalyl chloride (2.57 mL, 29.5 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 (20 mL, 0.5 M). To the stirring mixture at 0° C. was added diisopropylethyl amine (4.3 mL, 24.6 mmol) followed by 3-nitrobenzylamine hydrochloride salt (2.78 g, 14.8 mmol). The 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 (3×25 mL) and saturated aq NaCl (2×25 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 [5-cyano-4-fluoro-2-methoxy-N-(3-nitro-benzyl)-benzamide (2.0 g, 63%) as a yellow solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.55 (d, J=7.5 Hz, 1 H), 8.19 (9, 1 H), 8.15 (d, J=8.4 Hz, 1 H), 7.96 (bd s, 1 H), 7.70 (d, J=6.3 Hz, 1H), 7.54 (t, J=8.0 Hz, 5 H), 6.86 (d, J=10.5 Hz, 1 H), 4.76 (d, J=5.4 Hz, 1H), 4.07 (d, J=1.2 Hz, 3 H).

Workup

  1. custom(1–2 h)
  2. temperatureto cool to room temperature
  3. concentrationconcentrated under reduced pressure
  4. additiondiluted with dichloromethane (20 mL, 0.5 M)
  5. temperatureThe stirring under nitrogen, the solution was gradually warmed to room temperature
  6. washwashed with 2N HCl (3×25 mL) and saturated aq NaCl (2×25 mL)
  7. dry with materialThe organic layer was dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto afford a yellow oil
  11. customPurification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min)

Sources & evidence

ORD record
ord-ac8d3575f97b4a8188d98dc2da407ecb
Source dataset
uspto-grants-2007_03
Patent number
US07189749B2

Reaction notes

Loading…