Hydrochloric Acid → HCID 11329989, compound

HRID 29092Notes

Reaction equation

[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[C:12]=3[N:11]=[C:10]([CH:22]([CH3:24])[CH3:23])[C:9]=2[CH:25]=[CH:26][CH:27]2[O:32]C(C)(C)[O:30][CH:29]([CH2:35][C:36]([O-:38])=[O:37])[CH2:28]2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+].O>C1COCC1.CO.CC(OC)(C)C.CCCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[C:12]=3[N:11]=[C:10]([CH:22]([CH3:23])[CH3:24])[C:9]=2/[CH:25]=[CH:26]/[C@@H:27]([OH:32])[CH2:28][C@@H:29]([OH:30])[CH2:35][C:36]([OH:38])=[O:37])=[CH:4][CH:3]=1

Participants

Conditions

Temperature: 15 °C

Procedure

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.

Workup

stirringThe mixture was stirred for an additional 1 h
customthe two phases were separated
extractionextracted with ethyl acetate (2 times, 160 mL and 80 mL
stirringThe mixture was stirred at room temperature for 16 h
customThe solvent was removed at 45° C. under reduced pressure until a total volume of 210 mL
temperatureThe resultant solution was heated to 55° C
temperatureThe solution was cooled to 0° C. over 90 min, while seed crystals of Example 24 compound (34 mg)
additionwere added at 10° C
stirringThe resulting slurry was stirred at 0° C. for an additional 30 min
additionHeptane (85 mL) was added over 30 min
stirringthe slurry was stirred for 1 h at 0° C
filtrationThe solids were collected by filtration
dry with materialAfter 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

Sources & evidence

ORD record: ord-58e84068e10b4cdb8734c3b87b901575
Source dataset: uspto-grants-2008_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07420059B2

Reaction notes

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