Trifluoroacetic acid → 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide

HRID 1832251Notes

Reaction equation

HRID 1832251 reaction equation
[C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O.[OH-].[K+]>C(Cl)Cl>[CH3:3][CH:2]([CH3:4])[C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5]

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acid2×HCID 14797Potassium HydroxideHCID 22049110HCID 22049110, compound

Product 1

HCID 219572582-methyl-N-[4-(4-piperidinyl)phenyl]propanamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of tert-butyl 4-(4-aminophenyl)-1-piperidinecarboxylate (8.20 g, 29.7 mmol) and triethylamine (8.4 mL, 60 mmol) in dry THF (100 mL) at 0° C. was slowly added a solution of 2-methylpropanoyl chloride (3.84 g, 36.0 mmol) in THF (50 mL). The reaction mixture was then warmed up to room temperature and stirred for 2 h. After removing the solvent in vacuo, the crude product was purified by recrystallization (hexane/THF), affording the desired amide, tert-butyl 4-[4-(isobutyrylamino)phenyl]-1-piperidinecarboxylate, as a white solid (8.60 g, 84%). The tert-butyl 4-[4-(isobutyrylamino)phenyl]-1-piperidinecarboxylate was dissolved in CH2Cl2 (50 mL) at room temperature, TFA (13.68 g, 120 mmol, 5 equiv.) was added by syringe. The reaction mixture was stirred for 3 or 4 h and another 5 equivalents of TFA was added and the mixture was stirred for 2 or 3 more hours. The reaction solution was then basified to pH>14 by KOH (aq, 2 M). The solution was extracted with CH2Cl2 (8×200 mL). The combined organic layer was dried over K2CO3. Removal of solvent under reduced pressure gave the free amine, 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide, as a brownish solid (5.99 g, 98%). 1H NMR (400 MHz, CDCl3) δ 7.55–7.35 (m, 2H), 7.35–6.9 (m, 3H), 3.26–2.98 (m, 2H), 2.84–2.64 (m, 2H), 2.64–2.53 (m, 1H), 2.53–2.32 (m, 1H), 1.90–1.68 (m, 2H), 1.68–1.36 (m, 3H), 1.22 (d, 6H, J=6.0 Hz); ESMS m/e: 247.1 (M+H)+.

Workup

  1. stirringthe mixture was stirred for 2 or 3 more hours
  2. extractionThe solution was extracted with CH2Cl2 (8×200 mL)
  3. dry with materialThe combined organic layer was dried over K2CO3
  4. customRemoval of solvent under reduced pressure

Sources & evidence

ORD record
ord-d6d68f0ac7ab4f30a4f994664dea035a
Source dataset
uspto-grants-2006_06
Patent number
US07067534B1

Reaction notes

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