Nitrogen → HCID 71503251, compound

Participants

Reaction Steps

300 mg erlotinib was dissolved in 200 mL CH2Cl2 at −78° C. cooled by dry-ice/acetone bath. A mixture of F2 and N2 gas containing 20% F2/80% N2 was passed through the reaction vessel continuously at a flow rate of 2 L/min. Reaction was stopped after 30 min and the solvent was removed under vacuum. Dried reaction products were dissolved in 3 mL acetonitrile and was separated on an Agilent Zorbax C8 250×4.6 mm column, gradient elution from 30% MeOH/70% 0.1% formic acid in dd-H2O to 90% MeOH/10% 0.1% formic acid in dd-H2O, 1 ml/min total flow rate. Each fraction was analyzed by mass spectrometry. Fractions containing reaction products without excess amount of the starting material erlotinib, were mixed to form the modified erlotinib mixture compound library for drug property screening to identify components with improved properties over erlotinib. A component with m/z value corresponding to mono-chlorinated erlotinib was isolated and purified by successive preparative HPLC separations. The purified compound was analyzed by LC-MS/MS and NMR to provide the structure of the title compound. The observed m/z value 428.1374 (Thermo Finnigan LTQ Orbitrap, positive ion mode), is consistent with calculated m/z of protonated mono-chlorinated erlotinib (m/z(calc)=428.1372), molecular formula: C22H23ClN3O4+. High resolution MSn (n=2-4) experiments on LTQ orbitrap indicate the fluorine substitution is on the 3-ethynylphenyl ring (or ethynyl group) of erlotinib (fragment at m/z 152.0259, calc: 152.0261 for C8H7ClN+). 1H-NMR spectra data indicate the chlorine substitution is at the 4-position of the 3-ethynylphenyl ring of erlotinib. 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.36 (s, 6H), 3.78 (m, 4H), 4.36 (m, 4H), 4.68 (s, 1H), 7.39 (s, 1H), 7.66 (d, J=8.8, 1H), 7.86 (dd, J=8.8, 2.4, 1H), 8.06 (d, J=2.4, 1H), 8.46, (s, 1H), 8.89 (s, 1H).

Provenance & Evidence