Cesium carbonate → (R)-2-(4-(morpholine-4-carbonyl)phenylamino)-6-(3-(2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinamide

HRID 2044063Notes

Reaction equation

HRID 2044063 reaction equation
[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.Br[CH2:33][CH2:34][CH2:35][C:36](OCC)=[O:37].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[N:26]1([C:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:10]3[N:9]=[C:8]([N:4]4[CH2:5][CH2:6][CH2:7][C@@H:2]([N:1]5[CH2:33][CH2:34][CH2:35][C:36]5=[O:37])[CH2:3]4)[CH:16]=[CH:15][C:11]=3[C:12]([NH2:14])=[O:13])=[CH:23][CH:22]=2)=[O:25])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 76300Ethyl 4-bromobutyrateHCID 49846316(R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide

Product 1

HCID 66832952(R)-2-(4-(morpholine-4-carbonyl)phenylamino)-6-(3-(2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinamideYield 28%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A solution of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (80 mg) and ethyl 4-bromobutanoate (37 mg, 1 eq.) in DMF (1 mL) was treated with Cs2CO3 (184 mg, 3 eq) and heated at 100° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with water, 10% LiCl, and concentrated. The residue was purified by MPLC chromatography (ISCO, 7% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 26 mg of (R)-2-(4-(morpholine-4-carbonyl)phenylamino)-6-(3-(2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinamide as a light yellow solid. LCMS: (M+H)+=493.27. 1H NMR (500 MHz, CDCl3) δ ppm 11.18 (1H, s), 7.67 (2H, d, J=8.80 Hz), 7.53 (1H, d, J=8.80 Hz), 7.36 (2H, d, J=8.80 Hz), 6.06 (1H, d, J=8.80 Hz), 5.68 (2H, br. s.), 4.20-4.45 (2H, m), 3.98-4.19 (1H, m), 3.71 (8H, br. s.), 3.42-3.49 (1H, m), 3.33-3.41 (1H, m), 2.92-3.00 (1H, m), 2.83-2.91 (1H, m), 2.44 (2H, t, J=8.25 Hz), 2.05 (2H, qd, J=7.61, 7.42 Hz), 1.94 (1H, dd, J=11.82, 3.57 Hz), 1.81-1.89 (1H, m), 1.59-1.80 (2H, m).

Workup

  1. washwashed with water, 10% LiCl
  2. concentrationconcentrated
  3. customThe residue was purified by MPLC chromatography (ISCO, 7% NH4OH/MeOH/CH2Cl2, 40 g silica gel column)

Sources & evidence

ORD record
ord-2e71628a6d4c45868e0105a5575dfea1
Source dataset
uspto-grants-2013_11
Patent number
US08586751B2

Reaction notes

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