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

HRID 531282Notes

Reaction equation

HRID 531282 reaction equation
[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]=1

Participants

4

Reactant 2

HCID 3939Lithium HydroxideHCID 90009151HCID 90009151, compound

Product 1

HCID 721887714-{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

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

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

Workup

  1. customhydrolysis
  2. customThe reaction was quenched
  3. additionby adding 0.375 mL of 1N HCl
  4. extractionThe reaction was extracted with ethyl acetate
  5. dry with materialThe ethyl acetate layer was dried over sodium sulfate
  6. filtrationfiltered
  7. customevaporated
  8. customPurified on Biotage SNAP 13 g C18 column
  9. washeluting with 25-100% CH3CN/water (0.05% TFA)
  10. customrecovering
  11. custompurified fractions
  12. customby partitioning them between pH 7 phosphate buffer and ethyl acetate
  13. extractionExtracted the aqueous a second time with ethyl acetate
  14. washwashed the combined organics with pH 7.0 buffer
  15. dry with materialThe organic was dried over sodium sulfate
  16. filtrationfiltered
  17. customevaporated

Sources & evidence

ORD record
ord-2369a8971e2c44b4ad9cfa93486d4b29
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Reaction notes

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