L-Valinol → (S)-2-(4-Fluorophenyl)-5-(3-(4-isopropyl-4,5-dihydrooxazol-2-yl)phenyl)-N-methylbenzofuran-3-carboxamide

HRID 555053Notes

Reaction equation

HRID 555053 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C@@H:30]([CH:33]([CH3:35])[CH3:34])[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]5[O:32][CH2:31][C@H:30]([CH:33]([CH3:35])[CH3:34])[N:2]=5)[CH:4]=4)=[CH:28][C:13]=3[C:14]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:19]=1

Participants

5

Reactant 2

HCID 640993L-ValinolHCID 592751625-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Product 1

HCID 59275465(S)-2-(4-Fluorophenyl)-5-(3-(4-isopropyl-4,5-dihydrooxazol-2-yl)phenyl)-N-methylbenzofuran-3-carboxamideYield 18.3%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 7964ChlorobenzeneSolvent

Procedure

Zinc chloride (8 mg, 0.054 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and (S)-2-amino-3-methylbutan-1-ol (111 mg, 1.080 mmol) in PhCl (3 mL) at rt. It was subjected for two 1 hr iterations to microwave irradiation at 200° C. The reaction was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (9 mg, 17%). 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (1H, s), 7.93-7.99 (2H, m), 7.89-7.93 (2H, m), 7.86 (1H, d, J=7.63 Hz), 7.63-7.69 (2H, m), 7.56 (1H, t, J=7.78 Hz), 7.26 (2H, t, J=8.70 Hz), 4.52 (1H, t, J=9.31 Hz), 4.30 (1H, t, J=8.09 Hz), 4.15-4.22 (1H, m), 2.98 (3H, s), 1.86-1.96 (1H, m), 1.04 (3H, d, J=6.71 Hz), 0.97 (3H, d, J=6.71 Hz). LC-MS retention time: 1.63 min; m/z (MH+): 457. 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=10.06 min, purity=95%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 μm, Rt=10.53 min, purity=95%.

Workup

  1. customwas subjected for two 1 hr iterations
  2. customirradiation at 200° C
  3. concentrationThe reaction was concentrated
  4. custompurified by preparative reverse phase HPLC on a C18 column
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-435c6fc8dc5c46d1ae59290babd2bf43
Source dataset
uspto-grants-2011_11
Patent number
US08048887B2

Reaction notes

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