1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide

HRID 1093809Notes

Reaction equation

HRID 1093809 reaction equation
CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:58]=2[Cl:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[Cl:64][C:58]1[CH:59]=[CH:60][C:61]([F:63])=[CH:62][C:57]=1[O:56][CH:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:51][CH2:52]1

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 234450471-Phenyl-1H-imidazole-4-carboxylic acidHCID 665915752-Amino-1-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride

Product 1

HCID 578744441-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amideYield 55%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

DIPEA (186 mg, 1.44 mmol) was added to a stirred solution of 1-phenyl-1H-imidazole-4-carboxylic acid (60 mg, 0.32 mmol) in DMF (5 mL) followed by HOBt (47 mg, 0.35 mmol) and EDCI (153 mg, 0.8 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (119 mg, 0.37 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Cold water was added and the precipitate formed was collected to afford the residue. The residue was purified by preparative HPLC to afford 80 mg (55% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 457.14, 96.27%. 1H NMR (300 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.14 (s, 1H), 8.1 (t, 2H), 7.8 (d, 2H), 7.6-7.4 (m, 4H), 7.32 (d, 1H), 6.9 (t, 1H), 4.9 (bs, 1H), 4.2 (d, 2H), 3.8 (b, 2H), 3.55 (b, 2H), 2.1 (d, 2H), 1.8 (d, 2H).

Workup

  1. additionwas added
  2. stirringthe resulting mixture was stirred at ambient temperature overnight
  3. customthe precipitate formed
  4. customwas collected
  5. customto afford the residue
  6. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-aafa4c3ef0684951afd2680be807c65f
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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