Isobutyryl chloride → 2-(4-Fluorophenyl)-5-(3-(5-isopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N-methylbenzofuran-3-carboxamide

HRID 555049Notes

Reaction equation

HRID 555049 reaction equation
[C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH:7]1[C:11]([C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)=[C:23]([C:33]([NH:35][CH3:36])=[O:34])[C:22]=4[CH:37]=3)[CH:15]=[CH:16][CH:17]=2)=NN=[N:8]1>N1C=CC=CC=1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[O:25][C:21]3[CH:20]=[CH:19][C:18]([C:14]4[CH:15]=[CH:16][CH:17]=[C:12]([C:11]5[O:5][C:1]([CH:2]([CH3:4])[CH3:3])=[N:8][N:7]=5)[CH:13]=4)=[CH:37][C:22]=3[C:23]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:31][CH:30]=1

Participants

4

Reactant 2

HCID 62325Isobutyryl chlorideHCID 178485244HCID 178485244, compound

Product 1

HCID 592751432-(4-Fluorophenyl)-5-(3-(5-isopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N-methylbenzofuran-3-carboxamideYield 20.7%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

Isobutyryl chloride (90 mg, 0.847 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (50 mg, 0.085 mmol) in pyridine (1 mL) at 100° C. It was allowed to stir overnight. The reaction was concentrated and diluted with EtOH (3 mL) and treated with excess 1N NaOH (500 μL) and stirred at 60° C. for 2 hours to hydrolyze the acylated amide. The mixture was filtered and the filtrate was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified on silica gel (BIOTAGE®, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (8 mg, 20%). 1H NMR (500 MHz, CD3OD) δ ppm 8.31-8.35 (1H, m), 8.03 (1H, d, J=7.94 Hz), 7.95-8.00 (3H, m), 7.93 (1H, d, J=7.93 Hz), 7.67-7.74 (3H, m), 7.25-7.30 (2H, m), 3.37-3.40 (1H, m), 2.99 (3H, s), 1.49 (6H, d, J=7.02 Hz). LC-MS retention time: 2.28 min; m/z (MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=14.30 min, purity=94%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 μm, Rt=12.50 min, purity=93%.

Workup

  1. concentrationThe reaction was concentrated
  2. additiondiluted with EtOH (3 mL)
  3. additiontreated with excess 1N NaOH (500 μL)
  4. stirringstirred at 60° C. for 2 hours
  5. filtrationThe mixture was filtered
  6. additionthe filtrate was diluted with EtOAc
  7. washwashed
  8. dry with materialThe organic phase was dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. custompurified on silica gel (BIOTAGE®, EtOAc/hexanes gradient, fraction collection at λ=254 nm)

Sources & evidence

ORD record
ord-071abdd3f51f49f589428e61ffcc21de
Source dataset
uspto-grants-2011_11
Patent number
US08048887B2

Reaction notes

Loading…