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

HRID 1832250Notes

Reaction equation

HRID 1832250 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][CH:29]([CH3:33])[C:30](Cl)=[O:31]>C1COCC1>[CH3:28][CH:29]([CH3:33])[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1)=[O:31].[C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)(=[O:31])[CH:29]([CH3:33])[CH3:28]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 62325Isobutyryl chlorideHCID 21940085tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylate

Product 2

HCID 219572582-methyl-N-[4-(4-piperidinyl)phenyl]propanamideHCID 22049110HCID 22049110, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

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. customAfter removing the solvent in vacuo
  2. customthe crude product was purified by recrystallization (hexane/THF)

Sources & evidence

ORD record
ord-aa862ddab10647c287c157e6e3262c54
Source dataset
uspto-grants-2006_06
Patent number
US07067534B1

Reaction notes

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