2-Amino-2-methyl-1-propanol → 5-(3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

HRID 1671885Notes

Reaction equation

HRID 1671885 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:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:33][C:30]1([CH3:34])[CH2:31][O:32][C:1]([C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[CH:11][C:12]4[O:16][C:15]([C:17]5[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=5)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=4[CH:28]=3)[CH:6]=[CH:7][CH:8]=2)=[N:2]1

Participants

5

Reactant 2

HCID 118072-Amino-2-methyl-1-propanol2×HCID 592751625-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Product 1

HCID 592752675-(3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideYield 14.6%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 7964ChlorobenzeneSolvent

Conditions

Temperature
200 °C

Procedure

Zinc chloride (1 mg) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and 2-amino-2-methylpropan-1-ol (10 mg, 0.108 mmol) in PhCl (3 mL) at 130° C. It was allowed to stir for 7 days. ˜20% conversion was observed. Additional amounts of ZnCl (8 mg) and 2-amino-2-methylpropan-1-ol (50 mg) were added and the reaction was heated in the microwave for 1 hr at 200° C. The reaction had progressed ˜50%. The mixture was concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, Rf˜0.2 in 50% EtOAc/hexanes; fraction collection at λ=254 nm) followed by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (7 mg, 14%). 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (1H, s), 7.97 (2H, dd, J=8.09, 5.65 Hz), 7.93 (1H, s), 7.88 (2H, dd, J=11.44, 8.39 Hz), 7.68 (2H, s), 7.57 (1H, t, J=7.78 Hz), 7.27 (2H, t, J=8.55 Hz), 4.25 (2H, s), 2.99 (3H, s), 1.42 (6H, s). LC-MS retention time 1.60 min; m/z (MH+): 443. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 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 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. 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=12.24 min, purity=95%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=10.02 min, purity=95%.

Workup

  1. concentrationThe mixture was concentrated
  2. custompurified on silica gel (Biotage, EtOAc/hexanes gradient, Rf˜0.2 in 50% EtOAc/hexanes; fraction collection at λ=254 nm)
  3. concentrationconcentrated

Sources & evidence

ORD record
ord-acaf33a46e3c452db3b4cde41a1e52a4
Source dataset
uspto-grants-2011_08
Patent number
US07994171B2

Reaction notes

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