Triethylamine → tert-Butyl 2-(1-benzylpiperidin-4-ylcarbamoyl)-6-fluorophenylcarbamate

HRID 2355962Notes

Reaction equation

HRID 2355962 reaction equation
[C:1]([O:5][C:6]([NH:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:13])[CH2:21][CH2:22]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 4158521-Benzyl-4-piperidylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 112882942-(tert-Butoxycarbonylamino)-3-fluoro-benzoic acid

Product 1

HCID 59639684tert-Butyl 2-(1-benzylpiperidin-4-ylcarbamoyl)-6-fluorophenylcarbamate

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Procedure

To a solution of 2-(tert-butoxycarbonylamino)-3-fluoro-benzoic acid (37.1 g, 145 mmol), 4-amino-1-benzylpiperidine (35.6 mL, 1.20 equiv.), 1-hydroxybenzotriazole (21.6 g, 1.1 equiv.), and triethylamine (44.1 g, 3.0 equiv.) in ethyl acetate (450 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.7 g, 1.1 equiv.) in one portion. Initially, everything went into solution, but a precipitate formed very rapidly. The reaction was fitted with a reflux condenser and heated at reflux for 5 h. The reaction was diluted with ethyl acetate, washed with water (2×), then 1N sodium hydroxide (2×), then brine, dried over magnesium sulfate, and concentrated to give 67.0 g (quant.) as a white solid which was used without purification. 1H-NMR (CDCl3, 500 MHz) δ 1.48 (s, 9H), 1.55 (m, 2H), 1.99 (bd, J=11.0, 2H), 2.17 (dd, J=11.0, 11.0, 2H), 2.84 (bd, J=11.3, 2H), 3.51 (s, 2H), 3.94 (m, 1H), 6.13 (bd, J=7.6, 1H), 7.10-7.28 (m, 4H), 7.31 (m, 4H), 7.59 (s, 1H). Mass spec.: 428.41 (MH)+.

Workup

  1. customa precipitate formed very rapidly
  2. customThe reaction was fitted with a reflux condenser
  3. temperatureheated
  4. temperatureat reflux for 5 h
  5. washwashed with water (2×)
  6. dry with material1N sodium hydroxide (2×), then brine, dried over magnesium sulfate
  7. concentrationconcentrated
  8. customto give 67.0 g (quant.) as a white solid which
  9. customwas used without purification

Sources & evidence

ORD record
ord-340fc38c4b2c4b12a1446d75511babb3
Source dataset
uspto-grants-2010_07
Patent number
US07754732B2

Reaction notes

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