Lithium Hydroxide → 4-{5-[4-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoic acid
반응식
[F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:43]([CH3:44])=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][C:35]=5[CH3:45])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:46]4[CH2:49][CH:48]([F:50])[CH2:47]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Li+]>O1CCOCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:43]([CH3:44])=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=5[CH3:45])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:46]4[CH2:49][CH:48]([F:50])[CH2:47]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:4]=[C:3]([C:2]([F:53])([F:52])[F:1])[CH:8]=1참가 물질
4
실험 절차
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (Step A, 55.6 mg, 0.074 mmol) was dissolved in 1,4-dioxane (1500 μl). Added 0.5N lithium hydroxide (750 μl, 0.375 mmol) and stirred at room temperature for 3 hours at which time LCMS shows complete hydrolysis. The reaction was quenched by adding 0.375 mL of 1N HCl, followed by water. The reaction was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered and evaporated. Purified on Biotage SNAP 13 g C18 column, eluting with 25-100% CH3CN/water (0.05% TFA) and recovering purified fractions by partitioning them between pH 7 phosphate buffer and ethyl acetate. Extracted the aqueous a second time with ethyl acetate, then washed the combined organics with pH 7.0 buffer and brine. The organic was dried over sodium sulfate, filtered and evaporated to give the titled compound. LCMS (M+H)+: 734.5. 1H NMR (CDCl3, 500 MHz): δ8.17 (s, 1H), 8.04 (d, 1H), 7.89 (s, 1H), 7.86 (d, 2H), 7.75 (s, 2H), 7.30 (d, 1H), 5.71 (d, 1H), 5.51 (m, 0.5H), 5.40 (m, 0.5H), 4.71 (d, 1H), 4.45 (m, 3H), 4.30 (m, 2H), 4.00 (d, s, 4H), 2.16 (d, 6H), 0.75 (d, 3H). RTA IC50: 7 nM