Diisopropylcarbodiimide → 4-(4-Iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide

HRID 2180194Notes

Reaction equation

HRID 2180194 reaction equation
N1C=CC=CC=1.[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH2:29].CC(C)N=C=NC(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH:29][C:21]([C:14]1([C:11]2[CH:10]=[CH:9][C:8]([I:7])=[CH:13][CH:12]=2)[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]1)=[O:23]

Participants

6

Reactant 3

HCID 12734DiisopropylcarbodiimideHCID 457602Benzenemethanamine, 3,5-dichloro-HCID 685340374-(4-Iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid pyridine salt

Product 1

HCID 685341524-(4-Iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamideYield 11.5%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

To a solution of 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid pyridine salt (0.44 g, 1.04 mmol, see Example 6) and 3,5-dichlorobenzylamine (0.22 g, 1.24 mmol, 1.2 eq) in anhydrous DMF (5 mL) was added DIC (0.326 mL, 2.08 mmol, 2 eq) followed by DMAP (0.006 g, 0.052 mmol, 5%). The mixture was stirred at room temperature for 16 h and then it was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was separated, washed with H2O (3×40 mL) and saturated brine (50 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude material was purified by silica gel chromatography by eluting with 10% MeOH/EtOAc to give 60 mg (11%) of 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide as a white solid. MS(ESI): 503.1/505.1. To a flask containing 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide (60 mg, 0.12 mmol) was added Pd(PPh3)4 (3.2 mg, 0.012 mmol, 10 mol %), 3-cyanophenylboronic acid (26.4 mg, 0.18 mmol, 1.5 eq.) and Na2CO3 (0.21 g, 2 mmol). The mixture was suspended in toluene (2 mL), EtOH (1 mL) and H2O (1 mL) and heated at 90° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (10 mL) and saturated Na2CO3 (5 mL). The organic layer was washed with saturated Na2CO3 (3×5 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by HPLC to give 4-(3′-cyano-biphenyl-4-yl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide as a white solid (0.05 g, 0.0105 mmol, 10%). 1H NMR (300 MHz, CDCl3): δ 7.88 (m, 2H), 7.71 (m, 3H), 7.52 (d, 2H), 7.31 (t, 1H), 7.00 (dd, 2H), 6.55 (t, 1H), 4.55 (br, 1H), 4.44 (d, 2H), 3.76 (m, 2H). 3.32 (m, 2H), 2.94 (s, 3H), 2.86 (m, 2H). 2.52 (t, 2H). MS (ESI): 478.1/480.1.

Workup

  1. customit was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL)
  2. customThe organic layer was separated
  3. washwashed with H2O (3×40 mL) and saturated brine (50 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated by rotary evaporation
  7. customThe crude material was purified by silica gel chromatography
  8. washby eluting with 10% MeOH/EtOAc

Sources & evidence

ORD record
ord-7890610a6d79440dbcf01d88a9ed3a51
Source dataset
uspto-grants-2005_05
Patent number
US06887889B2

Reaction notes

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