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

HRID 1946884Notes

Reaction equation

HRID 1946884 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 from the previous step (0.697 mmol) is dissolved in CH3OH (20 mL) and cooled to 0° C. NaBH4 (264 mg, 6.97 mmol, 10 equiv.) is slowly added. After this addition is complete, the cooling bath is removed and the reaction is stirred at room temperature for 1 h. The reaction is quenched by the slow addition of 1N aqueous HCl (14 mL). The CH3OH is partially removed by vacuum. The resulting residue is partitioned between EtOAc and 1 N aqueous NaOH. Additional 50% aqueous NaOH is added until the aqueous layer pH>12. The EtOAc layer is washed with 1 N aqueous NaOH (2×), the organic layer is then dried over Na2SO4, filtered, and concentrated under vacuum. After concentration, the crude product (175 mg) is dissolved in acetic acid (10 mL). TFA (0.15 mL, 3 equiv.) and PtO2 (53 mg, 30% w/w) are added and the reaction is placed under 50 psi H2 gas in a Parr Shaker for 14 h. The reaction mixture is filtered and the filtrate is concentrated under vacuum. The resulting residue is partitioned between EtOAc and 1 N aqueous NaOH. Additional 50% aqueous NaOH is added until the aqueous layer pH>12. The EtOAc layer is washed with 1 N aqueous NaOH (2×), the organic layer is then dried over Na2SO4, filtered, and concentrated under vacuum to give 2-Isopropoxy-5-methyl-4-(1-methyl-piperidin-4-yl)-phenylamine which is used in Step 4 without further purification: ESMS m/z 263.2 (M+H+).

Workup

  1. additionAfter this addition
  2. customthe cooling bath is removed
  3. customThe reaction is quenched by the slow addition of 1N aqueous HCl (14 mL)
  4. customThe CH3OH is partially removed by vacuum
  5. customThe resulting residue is partitioned between EtOAc and 1 N aqueous NaOH
  6. additionAdditional 50% aqueous NaOH is added until the aqueous layer pH>12
  7. washThe EtOAc layer is washed with 1 N aqueous NaOH (2×)
  8. dry with materialthe organic layer is then dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under vacuum
  11. concentrationAfter concentration
  12. dissolutionthe crude product (175 mg) is dissolved in acetic acid (10 mL)
  13. waitthe reaction is placed under 50 psi H2 gas in a Parr Shaker for 14 h
  14. filtrationThe reaction mixture is filtered
  15. concentrationthe filtrate is concentrated under vacuum
  16. customThe resulting residue is partitioned between EtOAc and 1 N aqueous NaOH
  17. additionAdditional 50% aqueous NaOH is added until the aqueous layer pH>12
  18. washThe EtOAc layer is washed with 1 N aqueous NaOH (2×)
  19. dry with materialthe organic layer is then dried over Na2SO4
  20. filtrationfiltered
  21. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-be291412ab5a45ffa1165c539cef378d
Source dataset
uspto-grants-2013_03
Patent number
US08399450B2

Reaction notes

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