Sodium hydride → (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-({5-[5-(3,5-dimethyl-1-propyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl]-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one

HRID 531278Notes

Reaction equation

HRID 531278 reaction equation
[F:1][C:2]([F:48])([F:47])[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[C:27]([O:39][CH3:40])=[N:28][CH:29]=[C:30]([C:32]5[C:33]([CH3:38])=[N:34][NH:35][C:36]=5[CH3:37])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:41]4[CH2:44][CH:43]([F:45])[CH2:42]4)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].I[CH2:52][CH2:53][CH3:54]>C1COCC1>[F:48][C:2]([F:47])([F:1])[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[C:27]([O:39][CH3:40])=[N:28][CH:29]=[C:30]([C:32]5[C:33]([CH3:38])=[N:34][N:35]([CH2:52][CH2:53][CH3:54])[C:36]=5[CH3:37])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:41]4[CH2:44][CH:43]([F:45])[CH2:42]4)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 336431-IodopropaneHCID 72192733(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-({5-[5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl]-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one

Product 1

HCID 72192736(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-({5-[5-(3,5-dimethyl-1-propyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl]-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-({5-[5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl]-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 17, 0.020 g, 0.029 mmol) in THF (2 mL) was added sodium hydride (0.011 g, 0.29 mmol) at 0° C. The resulting mixture was stirred for 10 minutes at room temperature, after which iodopropane (0.075 g, 0.044 mmol) was added. The resulting mixture was stirred for 24 hours at room temperature until the starting material was consumed completely. Water (1 mL) was added to quench the reaction. The aqueous layer was extracted with Ethyl acetate (2×2 mL), the combined organic layer was concentrated in vacuum and the residue was dissolved in 1 mL of DMSO and filtered. This clear DMSO filtrate was purified by preparative HPLC (reverse phase, Waters SunFire Prep C18 OBD5 um 19×100 mm) eluting with acetonitrile/water+0.14% HCOOH (30% to 100% organic in 5 minutes, 25 mL/minutes). Related fractions were pooled and evaporated under reduced pressure to afford a fluffy white solid of 2.8 mg as the titled compound. LCMS (M+H)+: 722.4. 1H NMR (DMSO-d6, 500 MHz): δ 8.24 (s, 1H), 8.16-8.14 (d, J=8.5 Hz, 2H), 7.92 (s, 2H), 7.62 (s, 1H), 5.87 (d, J=8.5 Hz, 1H), 5.60 (s, 1H), 5.42 (s, 1H), 4.53-3.98 (br m, 4H), 3.84 (s, 3H), 2.52 (s, 3H), 2.10 (m, 3H), 2.04 (m, 2H), 1.68 (m, 1H), 1.60-1.44 (m, 2H), 0.83 (t, J=6.5 Hz, 3H), 0.54 (d, J=6.5 Hz, 3H). RTA IC50: 12 nM

Workup

  1. stirringThe resulting mixture was stirred for 24 hours at room temperature until the starting material
  2. customwas consumed completely
  3. additionWater (1 mL) was added
  4. customto quench
  5. customthe reaction
  6. extractionThe aqueous layer was extracted with Ethyl acetate (2×2 mL)
  7. concentrationthe combined organic layer was concentrated in vacuum
  8. dissolutionthe residue was dissolved in 1 mL of DMSO
  9. filtrationfiltered
  10. customThis clear DMSO filtrate was purified by preparative HPLC (reverse phase, Waters SunFire Prep C18 OBD5 um 19×100 mm)
  11. washeluting with acetonitrile/water+0.14% HCOOH (30% to 100% organic in 5 minutes, 25 mL/minutes)
  12. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-f15c02b055924d6ea9d391bdf7ac389f
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Reaction notes

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