Aniline → 5-cyano-N-(2-(4-methylpiperidin-1-yl)-4-morpholinophenyl)furan-2-carboxamide

HRID 646857Notes

Reaction equation

HRID 646857 reaction equation
[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:11]=[CH:12][C:13]=2[N+:14]([O-])=O)[CH2:4][CH2:3]1.NC1C=CC=CC=1.[C:30]([C:32]1[O:36][C:35]([C:37](O)=[O:38])=[CH:34][CH:33]=1)#[N:31].C(Cl)(=O)C(Cl)=O.ON1C(=O)CCC1=O.CCN(C(C)C)C(C)C>[Pd].C1COCC1.ClCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:11]=[CH:12][C:13]=2[NH:14][C:37]([C:35]2[O:36][C:32]([C:30]#[N:31])=[CH:33][CH:34]=2)=[O:38])[CH2:4][CH2:3]1

Participants

10

Reactant 6

HCID 6115Aniline3×HCID 65578Oxalyl chlorideHCID 80170N-HydroxysuccinimideHCID 81531DiisopropylethylamineHCID 108555165-cyanofuran-2-carboxylic AcidHCID 586385024-[3-(4-Methyl-piperidin-1-yl)-4-nitro-phenyl)-morpholine

Product 1

HCID 117109485-cyano-N-(2-(4-methylpiperidin-1-yl)-4-morpholinophenyl)furan-2-carboxamideYield 65%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

The procedure of Example 4, step (c) was followed using 101 mg (0.331 mmol) of 4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-morpholine (as prepared in the previous step) and 40 mg of 10% palladium on carbon (50% by weight water) in 5 mL THF to prepare the corresponding aniline. However, 5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester was used to acylate the aniline instead of 5-cyanofuran-2-carbonyl chloride. (5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester was previously prepared from 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), oxalyl chloride, N-hydroxysuccinimide and DIEA following the procedure of Example 4, step (c).) The aniline prepared above in 3.0 mL of anh dichloromethane was treated with 77.5 mg (0.331 mmol) of 5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester. After stirring for 1 h, an additional 77.5 mg (0.331 mmol) of 5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester was added. After 3 h, a final 77.5 mg (0.331 mmol) of 5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester was added and the mixture stirred 18 h. Concentration in vacuo and chromatography on a 10-g silica SPE column with 2-4% EtOAc-dichloromethane afforded 85.1 mg (65%) of the title compound as a light yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.60 (br s, 1H), 8.32 (d, 1H, J=8.9 Hz), 7.22, 7.26 (AB q, 2H, J=3.7 Hz), 6.78 (d, 1H, J=2.7 Hz), 6.71 (dd, 1H, J=8.9, 2.7 Hz), 3.86-3.88 (m, 4H), 3.13-3.15 (m, 4H), 2.98-3.01 (m, 2H), 2.70-2.15 (m, 2H), 1.83-1.86 (m, 2H), 1.5-1.7 (br m, 1H) and 1.43-1.53 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C22H26N4O3, 395.2 (M+H), found 395.2.

Workup

  1. waitAfter 3 h
  2. stirringthe mixture stirred 18 h
  3. concentrationConcentration in vacuo and chromatography on a 10-g silica SPE column with 2-4% EtOAc-dichloromethane

Sources & evidence

ORD record
ord-e365b5c6eb294d17a8049acdcb221a62
Source dataset
uspto-grants-2010_04
Patent number
US07705042B2

Reaction notes

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