Reaction Steps
A solution of Example 1 Part H, 1,1-dimethylethyl(4R,6S)-(E)-(6-{2-[4-(4-fluorophenyl)-2-isopropyl-8-methanesulfonyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl]ethenyl}-2,2-dimethyl-[1,3]dioxan-4-acetate (28.4 g, 0.047 mol) in THF/MeOH (5:2, 315 mL) was cooled to 15° C. An aqueous solution of HCl (6 N, 23.5 mL, 0.141 mol) was added over 15 min. The reaction mixture was stirred at 15° C. for 2.5 h. An aqueous solution of NaOH (2 N, 118 mL, 0.235 mol) was added over 15 min at 15° C. The mixture was stirred for an additional 1 h. Water (80 mL), heptane (80 mL), and MTBE (80 mL) were added, and the two phases were separated. The aqueous phase was acidified with aqueous HCl (3 N) to pH 2.7, then extracted with ethyl acetate (2 times, 160 mL and 80 mL, respectively). The organic phases were combined and Ca(OH)2 (1.82 g, 0.030 mol) was added. The mixture was stirred at room temperature for 16 h. The solvent was removed at 45° C. under reduced pressure until a total volume of 210 mL remained. The resultant solution was heated to 55° C. The solution was cooled to 0° C. over 90 min, while seed crystals of Example 24 compound (34 mg) were added at 10° C. The resulting slurry was stirred at 0° C. for an additional 30 min. Heptane (85 mL) was added over 30 min, and the slurry was stirred for 1 h at 0° C. The solids were collected by filtration. After drying at 70° C. under vacuum, (E)-(3R,5S)-7-[4-(4-fluorophenyl)-2-isopropyl-8-methanesulfonyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid, Ca salt was obtained as a white solid (23.0 g, 93% yield): mp 215-220° C.; 1H NMR (400 MHz, CDCl3) δ 0.98-1.04 (m, 1H), 1.20 (d, J=6.0 Hz, 6H), 1.30-1.37 (m, 1H), 1.76-1.82 (m, 2H), 1.91 (dd, J=8.9, 8.9 Hz, 1H), 2.04 (dd, J=3.6, 3.9 Hz, 1H), 2.29 (t, J=6.4 Hz, 2H), 2.50-2.51 (m, 2H), 3.31-3.38 (m, 1H), 3.58 (s, 3H), 3.60-3.62 (m, 1H), 3.76 (t, J=5.6 Hz, 2H), 4.00-4.04 (m, 1H), 5.27 (dd, J=5.2, 5.7 Hz, 1H), 6.13 (d, J=15.6 Hz, 1H), 7.11-7.17 (m, 2H), 7.20-7.26 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 178.4, 162.6, 160.2, 159.3, 148.7, 140.8, 134.5, 131.3, 131.2, 125.4, 123.0, 117.3, 115.7, 115.6, 69.5, 66.5, 45.6, 45.2, 44.8, 43.9, 32.2, 26.3, 23.6, 23.4.
