反应详情

温度

95 °C

2-Fluorobenzoic acid (22 mg, 0.15 mmol) and N4-(4-chlorophenyl)-6-pyrrolidin-1-yl-pyrimidine-4,5-diamine I-(17A-1)a (30 mg, 0.10 mmol) were dissolved in dioxane (0.7 ml) and 50% propanephosphoric acid cyclic anhydride in ethyl acetate (0.3 ml). The resulting mixture was shaken at 95° C. for 48 h. The reaction was cooled and diluted up to a volume of 1.8 ml with water for purification. The purification of the crude mixture was accomplished by reverse phase preparative Gilson 215 HPLC with the Hewlett Packard Series 1100MSD, and G1315A DAD using a Luna 5 micron C8(2) 250*21.2 mm Phenomenex column. The gradient eluant used was 0.1% formic acid in water (A) and acetonitrile (B) with trifluoroacetic acid as a buffer: 0.04 min.—80% A, 20% B; 20 min.—20% A, 80% B; 25 min.—100% B. The fractions with the desired compound were combined and evaporated to dryness to give title compound 18A-1. The residue was dissolved in methanol (1.5 ml) and treated with 4M HCl/dioxane (0.2 ml). The resulting mixture was shaken at 40° C. for 1 h then dried in a flow of nitrogen at 30° C. over 18 hours to obtain the hydrochloride salt of compound as a solid 18A-1 (4.2 mg, 10%): +ESI MS (M+1) 394.3; 1H NMR (500 MHz, CD3OD) δ 8.36 (s, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.59 (m, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.40–7.33 (m, 3H), 7.14 (t, J=9.3 Hz, 1H), 4.49 (br s, 2H), 3.84 (br s, 2H), 2.24 (br s, 4H).

1. temperatureThe reaction was cooled
2. customThe purification of the crude mixture
3. customevaporated to dryness