To a solution of N-methoxy-N-methyl-2-(3,4,5-trimethoxyphenylamino)-pyrimidine-4-carboxamide (0.82 g, 2.30 mmol) in THF (40 ml) cooled to -78° under a nitrogen atmosphere was added phenylmagnesium bromide [Aldrich 1M/THF] (6.90 ml, 6.90 mmol) dropwise. On completion of addition the reaction was left to warm to room temperature over 3 h and aqueous NH4Cl solution (10 ml) was then added and the mixture concentrated under reduced pressure. The residue was partitioned between water (20 ml) and ethyl acetate (40 ml), the organic layer dried (MgSO4) and evaporated. The residue was subjected to column chromatography [silica 50% hexane-ethyl acetate] and after recrystallisation from ethyl acetate-hexane the title compound (123 mg) was obtained as a yellow solid m.p 135°. δH (CDCl3) 8.65 (1H, d, J 4.8 Hz), 8.05 (2H, dd, J 5.1, 2.0 Hz), 7.61 (1H, dd, J 5.3, 2.0 Hz), 7.46 (2H, m), 7.24 (1H, d, J 4.8 Hz), 3.79 (3H, m) and 3.63 (6H, m). MS m/z 366 (M+H)+. The pyrimidine-4-carboxamide used as starting material was prepared by treating a solution of 4-carboxy-N-(3,4,5-trimethoxyphenyl)-2-pyrimidineamine hydrochloride (2.0 g, 5.86 mmol) and triethylamine (2.0 ml, 14.0 mmol) in CH2Cl2 (40 ml), cooled to -20° under a nitrogen atmosphere, with isobutylchloroformate (1.1 ml, 7.0 mmol). The resulting mixture was stirred for 20 min. before N,O-dimethylhydroxylamine hydrochloride (683 mg, 7.0 mmol) and triethylamine (1.0 ml, 7.0 mmol) were added and the reaction allowed to warm to room temperature over 3 h. After washing with 2M hydrochloric acid (1×50 ml) and 2M NaOH solution (1×5 ml), the reaction was dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to column chromatography [silica ethyl acetate] to give the desired product (1.02 g), as a yellow oil. δH (CDCl3) 8.51 (1H, d, J 4.9 Hz), 7.21 (1H, br s), 6.92 (3H, br s), 3.86 (6H, s), 3.82 (3H, s), 3.69 (3H, br s) and 3.36 (3H, s). MS m/z 349 (M+H)+. The 4-carboxy-N-(3,4,5-trimethoxyphenyl)-2-pyrimidineamine hydrochloride was prepared by heating a solution of 4-cyano-N-(3,4,5-trimethoxyphenyl)-N-pyrimidineamine (2.88 g, 10.49 mmol) in aqueous 2N NaOH (60 ml) and ethanol (10 ml) at reflux for 3 h. On cooling the reaction mixtrure was adjusted to pH 3 with 2M hydrochloric acid, and the resulting precipitate collected and dried to give the desired product (2.7 g) as an orange solid m.p. 241°. MS m/z 306 (M+H)+. The 4-cyano-N-(3,4,5-trimethoxyphenyl)-2-pyrimidineamine was prepared by heating a solution of 2-chloro-4-cyanopyrimidine [G. Davies et al. J. Het. Chem. 1, 130-133, (1963)] (11.0 g, 78.8 mmol), 3,4,5-trimethoxy aniline (14.4 g, 79.4 mmol) and triethylamine (12.0 ml) in ethanol at reflux for 4 h. On cooling the resulting precipitate was collected and dried to give the desired product (13.70 g) as a yellow solid m.p. 165°. MS m/z 287 (M+H)+.
