Trifluoroacetic acid → 2-Isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)aniline

HRID 536344Notes

Reaction equation

HRID 536344 reaction equation
[I-].[CH:2]([O:5][C:6]1[C:7]([N+:20]([O-])=O)=[CH:8][C:9]([CH3:19])=[C:10]([C:12]2[CH:17]=[CH:16][N+:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)([CH3:4])[CH3:3].[BH4-].[Na+].C(O)(C(F)(F)F)=O>CO.O=[Pt]=O>[CH:2]([O:5][C:6]1[CH:11]=[C:10]([CH:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[C:9]([CH3:19])=[CH:8][C:7]=1[NH2:20])([CH3:4])[CH3:3]

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 4311764Sodium borohydrideHCID 670711704-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-1-methyl-pyridinium iodide

Product 1

HCID 597643702-Isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)aniline

Reagents, catalysts & solvents 2

HCID 345198Adams' catalystCatalystHCID 887MethanolSolvent

Conditions

Temperature
0 °C

Procedure

4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-1-methyl-pyridinium iodide (Step 4, 0.697 mmol) was dissolved in CH3OH (20 mL) and cooled to 0° C. NaBH4 (264 mg, 6.97 mmol, 10 equiv.) was slowly added. After this addition was complete, the cooling bath was removed and the reaction was stirred at room temperature for 1 h. The reaction was quenched by the slow addition of 1N aqueous HCl (14 mL). The CH3OH was partially removed by vacuum. The resulting residue was partitioned between EtOAc and 1 N aqueous NaOH. Additional 50% aqueous NaOH was added until the aqueous layer had a pH>12. The EtOAc layer was washed with 1 N aqueous NaOH (2×), the organic layer was then dried over sodium sulfate, filtered, and concentrated under vacuum. After concentration, the crude product (175 mg) was dissolved in acetic acid (10 mL). TFA (0.15 mL, 3 equiv.) and PtO2 (53 mg, 30% w/w) were added and the reaction was placed under 50 psi H2 gas in a Parr Shaker for 14 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The resulting residue was partitioned between EtOAc and 1 N aqueous NaOH. Additional 50% aqueous NaOH was added until the aqueous layer has a pH>12. The EtOAc layer was washed with 1 N aqueous NaOH (2×), the organic layer was then dried over sodium sulfate, filtered, and concentrated under vacuum to give 2-isopropoxy-5-methyl-4-(1-methyl-piperidin-4-yl)-phenylamine, which was used in subsequent steps without further purification: ESMS m/z 263.2 (M+H+).

Workup

  1. additionAfter this addition
  2. customthe cooling bath was removed
  3. customThe reaction was quenched by the slow addition of 1N aqueous HCl (14 mL)
  4. customThe CH3OH was partially removed by vacuum
  5. customThe resulting residue was partitioned between EtOAc and 1 N aqueous NaOH
  6. additionAdditional 50% aqueous NaOH was added until the aqueous layer
  7. washThe EtOAc layer was washed with 1 N aqueous NaOH (2×)
  8. dry with materialthe organic layer was then dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under vacuum
  11. concentrationAfter concentration
  12. dissolutionthe crude product (175 mg) was dissolved in acetic acid (10 mL)
  13. waitthe reaction was placed under 50 psi H2 gas in a Parr Shaker for 14 h
  14. filtrationThe reaction mixture was filtered
  15. concentrationthe filtrate was concentrated under vacuum
  16. customThe resulting residue was partitioned between EtOAc and 1 N aqueous NaOH
  17. additionAdditional 50% aqueous NaOH was added until the aqueous layer
  18. washThe EtOAc layer was washed with 1 N aqueous NaOH (2×)
  19. dry with materialthe organic layer was then dried over sodium sulfate
  20. filtrationfiltered
  21. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-42988434a97448dc87b559b517a7920d
Source dataset
uspto-grants-2014_10
Patent number
US08859574B2

Reaction notes

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