3-(p-Tolyl)acrylic acid → 5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one 4-methyl-cinnamate

Participants

Reaction Steps

5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (17.77 g) was dissolved in a mixture of tetrahydrofuran (89 mL) and water (89 mL). 4-methyl-cinnamic acid (6.02 g, predominantly trans) was weighed out and about one-quarter was added to the free base solution followed by seed crystals, obtained by the procedure of part e. The mixture was stirred and the remaining acid was added in portions over the following 1.5 h. The slurry was stirred for a further 4 h and then the slurry was filtered. The cake was washed with aqueous tetrahydrofuran (1:1 THF:water, 36 mL) and then with tetrahydrofuran (2×18 mL) to afford the title compound which was dried overnight under vacuum at 40-50° C. (yield: 16.916 g). 1H NMR (400 MHz, CD3OD; TMS as reference at δ(ppm) 0) δ(ppm): 1.39 (6H) s; 2.32 (3H) s; 2.79 (2H) t J=7.2 Hz; 2.92-3.03 (4H) m; 3.87 (2H) s; 5.25 (1H) d of d J=3.9 and 8.8 Hz; 6.44 (1H) d J=15.9 Hz; 6.63 (1H) d J=9.8 Hz; 6.86-6.93 (4H) m; 6.96 (1H) d J=8.3 Hz; 6.99-7.05 (4H) m; 7.15 (2H) d J=7.8 Hz; 7.19 (1H) d J=8.3 Hz; 7.36 (1H) d J=15.9 Hz; 7.38 (2H) d J=7.6 Hz; 8.34 (1H) d J=9.8 Hz. The crystalline product was characterized by XRPD and DSC.

Provenance & Evidence