Pyridine → HCID 59275730, compound

HRID 555113Notes

Reaction equation

[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32](=[NH:35])[NH:33][OH:34])[CH2:31][CH2:30]5)[CH:24]=[CH:23][C:22]=4[CH3:37])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.N1C=CC=[CH:40][CH:39]=1.C(Cl)(=O)C>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32]6[N:35]=[C:39]([CH3:40])[O:34][N:33]=6)[CH2:30][CH2:31]5)[CH:24]=[CH:23][C:22]=4[CH3:37])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1

Participants

Conditions

Temperature: 115 °C

Procedure

To a mixture of 2-(4-fluorophenyl)-5-(5-(1-(N-hydroxycarbamimidoyl)cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide (46.5 mg, 0.093 mmol, crude) in pyridine (0.5 mL, 6.18 mmol) at r.t. under N2 was added acetyl chloride (0.020 mL, 0.279 mmol). The mixture was stirred at 115° C. for 2 hours. The mixture was cooled to r.t., diluted with MeOH and purified by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 7.64-7.95 min. (UV detection at 220 nm). The residue obtained after evaporation of the combined fractions was further purified by preparative TLC, 10% MeOH/CH2Cl2, two 20 cm×20 cm×0.5 mm plates. Rf about 0.67 (10% MeOH/CH2Cl2). 1H NMR (500 MHz, CD3OD) δ 7.98 (m, J=9.00, 5.34, 2H), 7.81 (s, 1H), 7.80 ((m overlapped with s, J=2.14, 1H), 7.66 (d, J=8.55, 1H), 7.65 (d, J=1.22, 1H), 7.43 (d, J=8.55, 1H), 7.36 (dd, J=8.55, 1.83, 1H), 7.28 (m, J=8.70, 2H), 2.96 (s, 3H), 2.54 (s, 3H), 2.35 (s, 3H), 1.59 (m, 2H), 1.43 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: PHENOMENEX® Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=525.07, HPLC Rt=1.682 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=6.67 min; Column: XBridge phenyl 3.5 um, 4.6×150 mm, Rt=5.22 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: XBridge phenyl 3.5 um, 4.6×150 mm, Rt=12.36 min.

Workup

temperatureThe mixture was cooled to r.t.
custompurified by Shimadzu-VP preparative reverse phase HPLC
customthe separation method
customB=100, Gradient time=10 min
customtime=12 min, Flow Rate=25 mL/min, Column
customWaters-Sunfire 19×100 mm S5, Fraction Collection
custom7.64-7.95 min. (UV detection at 220 nm)
customThe residue obtained
customafter evaporation of the combined fractions
customwas further purified by preparative TLC, 10% MeOH/CH2Cl2, two 20 cm×20 cm×0.5 mm plates
customB=100, Gradient time=2 min
customtime=3 min, Flow Rate=5 ml/min, Column
customB=100, Gradient time=15 min
customtime=18 min, Flow Rate=1 ml/min, Column
customB=100, Gradient time=15 min
customtime=18 min, Flow Rate=1 ml/min, Column

Sources & evidence

ORD record: ord-0d36d28fd115490a87a16a5fca9c8f6e
Source dataset: uspto-grants-2011_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08048887B2

Reaction notes

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