tert-Butyl acetate → Delamanid

HRID 1909095Notes

Reaction equation

HRID 1909095 reaction equation
[O:1]1[CH2:29][C@:2]1([CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl[C:32]1[NH:33][CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[N:36]=1.C([O-])(=O)C.[Na+].C(OC(C)(C)C)(=O)C.[OH-].[Na+]>C(OCC)(=O)C.O.CO>[CH3:30][C@@:2]1([CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([N:11]3[CH2:16][CH2:15][CH:14]([O:17][C:18]4[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:28])[F:27])=[CH:22][CH:23]=4)[CH2:13][CH2:12]3)=[CH:9][CH:10]=2)[O:1][C:32]2=[N:36][C:35]([N+:37]([O-:39])=[O:38])=[CH:34][N:33]2[CH2:29]1

Participants

9

Reactant 5

HCID 10908tert-Butyl acetateHCID 14798Sodium HydroxideHCID 517045Sodium AcetateHCID 25121191(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-[4-(trifluoromethoxy)phenoxy]piperidineHCID 178526855HCID 178526855, compound

Product 1

HCID 6480466DelamanidYield 73.7%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-[4-(trifluoromethoxy)phenoxy]piperidine (10.0 g, 23.6 mmol, optical purity of 94.3% ee), 2-chloro-4-nitroimidazole (4.0 g, 27.2 mmol), sodium acetate (0.4 g, 4.9 mmol), and t-butyl acetate (10 ml) were mixed and stirred at 100° C. for 3.5 hours. Methanol (70 ml) was added to the reaction mixture, and then a 25% sodium hydroxide aqueous solution (6.3 g, 39.4 mmol) was added thereto dropwise while cooling with ice. The resulting mixture was stirred at 0° C. for 1.5 hours, and further stirred at approximately room temperature for 40 minutes. Water (15 ml) and ethyl acetate (5 ml) were added thereto, and the mixture was stirred at 45 to 55° C. for 1 hour. The mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The precipitated crystals were subsequently washed with methanol (30 ml) and water (40 ml). Methanol (100 ml) was added to the resulting crystals, followed by stirring under reflux for 30 minutes. The mixture was cooled to room temperature. The crystals were then collected by filtration and washed with methanol (30 ml). The resulting crystals were dried under reduced pressure, obtaining 9.3 g of the objective product (yield: 73%).

Workup

  1. temperaturedropwise while cooling with ice
  2. stirringThe resulting mixture was stirred at 0° C. for 1.5 hours
  3. stirringfurther stirred at approximately room temperature for 40 minutes
  4. stirringthe mixture was stirred at 45 to 55° C. for 1 hour
  5. temperatureThe mixture was cooled to room temperature
  6. filtrationthe precipitated crystals were collected by filtration
  7. washThe precipitated crystals were subsequently washed with methanol (30 ml) and water (40 ml)
  8. additionMethanol (100 ml) was added to the resulting crystals
  9. stirringby stirring
  10. temperatureunder reflux for 30 minutes
  11. temperatureThe mixture was cooled to room temperature
  12. filtrationThe crystals were then collected by filtration
  13. washwashed with methanol (30 ml)
  14. customThe resulting crystals were dried under reduced pressure

Sources & evidence

ORD record
ord-e922d4f9b0074e83bface9585c9b6862
Source dataset
uspto-grants-2013_12
Patent number
US08598358B2

Reaction notes

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