3-(Trifluoromethyl)aniline → 1-(3-Trifluoromethyl-anilino)-4-[(6-chloro-pyridin-3-yl)-methyl]-3-methylisoquinoline

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Reaction Steps

Analogously to example 36, 0.70 g (2.3 mmol) of 1-chloro-4-[(6-methoxy-pyridin-3-yl)-methyl]-3-methylisoquinoline (contains traces of 1-chloro-4-[(6-chloro-pyridin-3-yl)-methyl]-3-methylisoquinoline as an impurity) in 15 ml of methanol are mixed with 741 mg (4.6 mmol) of 3-trifluoromethyl-aniline and 0.58 ml of 4 N HCl/dioxane and reacted for 18 h at 70° C. Extraction and column chromatography (SiO2, methylene chloride/diethylether 50:1→EtOAc→EtOAc/EtOH 10:1) yield 1-(3-trifluoromethyl-anilino)-4-[(6-chloro-pyridin-3-yl)-methyl]-3-methylisoquinoline 45a (m.p. 137° C.; FAB-MS: (M+H)+=428), followed by 1-(3-trifluoromethyl-anilino)-4-[(6-methoxy-pyridin-3-yl)-methyl]-3-methylisoquinoline 45b (m.p. 136-137° C.; FAB-MS: (M+H)+=424), and finally 1-(3-trifluororethyl-anilino)-4-[(6-hydroxy-pyridin-3-yl)-methyl]-3-methylisoquinoline 45c (m.p. 250-252° C.; FAB-MS: (M+H)+=410). The latter can also be obtained by demethylation (1. Me3Sil/CHCl3, 2. hydrolysis) from the 6-methoxy-pyridine derivative.

Provenance & Evidence