Sodium hydride → Delamanid

HRID 856383Notes

Reaction equation

HRID 856383 reaction equation
[F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[H-].[Na+].Br[C:29]1[N:30]([CH2:37][C@:38]2([CH3:41])[CH2:40][O:39]2)[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[N:33]=1>CN(C=O)C>[CH3:40][C@@:38]1([CH2:41][O:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:11][CH2:10][CH:9]([O:8][C:7]4[CH:22]=[CH:23][C:4]([O:3][C:2]([F:1])([F:24])[F:25])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[O:39][C:29]2=[N:33][C:32]([N+:34]([O-:36])=[O:35])=[CH:31][N:30]2[CH2:37]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 10467858(R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazoleHCID 11653258SS-3227

Product 1

HCID 6480466DelamanidYield 33%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
72.5 °C

Procedure

4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (693 mg, 1.96 mmol) was dissolved in N,N′-dimethylformamide (3 ml), and sodium hydride (86 mg, 2.16 mmol) was added while cooling on ice followed by stirring at 70-75° C. for 20 minutes. The mixture was cooled on ice. To the solution, a solution prepared by dissolving (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (720 mg, 2.75 mmol) in N,N′-dimethylformamide (3 ml) was added followed by stirring at 70-75° C. for 20 minutes. The reaction mixture was allowed to return to room temperature, ice water (25 ml) was added, and the resultant solution was extracted with methylene chloride (50 ml) three times. The organic phases were combined, washed with water 3 times, and dried over magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=3/1). Recrystallization from ethyl acetate/isopropyl ether gave (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (343 mg, 33%) as a light yellow powder.

Workup

  1. temperaturewhile cooling on ice
  2. temperatureThe mixture was cooled on ice
  3. customTo the solution, a solution prepared
  4. additionwas added
  5. stirringby stirring at 70-75° C. for 20 minutes
  6. customto return to room temperature
  7. extractionthe resultant solution was extracted with methylene chloride (50 ml) three times
  8. washwashed with water 3 times
  9. dry with materialdried over magnesium sulfate
  10. filtrationAfter filtration
  11. concentrationthe filtrate was concentrated
  12. customthe residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=3/1)
  13. customRecrystallization from ethyl acetate/isopropyl ether

Sources & evidence

ORD record
ord-abb21c737a234c84990d7f82dabc4b06
Source dataset
uspto-grants-2007_08
Patent number
US07262212B2

Reaction notes

Loading…