Pyridine → N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-cyanophenyl)-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide

HRID 1908226Notes

Reaction equation

HRID 1908226 reaction equation
[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[C:5]([C:12]([OH:14])=O)=[CH:6][NH:7]2.[NH2:16][C:17]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]3[CH2:30][CH2:31][CH:26]2[CH2:27][CH2:28]3)=[CH:21][C:18]=1[C:19]#[N:20].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1>CC1CCCO1.C(OCC)(=O)C>[CH:29]12[N:25]([C:22]3[CH:23]=[CH:24][C:17]([NH:16][C:12]([C:5]4[C:4](=[O:15])[C:3]5[C:8](=[CH:9][CH:10]=[CH:11][C:2]=5[CH3:1])[NH:7][CH:6]=4)=[O:14])=[C:18]([C:19]#[N:20])[CH:21]=3)[CH:26]([CH2:31][CH2:30]1)[CH2:27][CH2:28]2

Participants

7

Reactant 4

HCID 1049PyridineHCID 111923Propylphosphonic anhydrideHCID 156185565-Methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acidHCID 575168442-Amino-5-(7-azabicyclo[2.2.1]heptan-7-yl)benzonitrile

Product 1

HCID 46194420N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-cyanophenyl)-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamideYield 49.3%

Reagents, catalysts & solvents 2

HCID 73012-MethyltetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 35 (162 mg, 0.80 mmol) and 2-amino-5-(7-azabicyclo[2.2.1]heptan-7-yl)benzonitrile 23 (170 mg, 0.80 mmol) in 2-methyltetrahydrofuran (1.5 mL) was added propyl phosphonic acid cyclic anhydride (50% solution in ethyl acetate, 949.5 μL, 1.605 mmol) and pyridine (126 mg, 129 μL, 1.60 mmol). The reaction was capped and heated at 100° C. for 65 min with microwave irradiation. The reaction was cooled to room temperature, diluted with ethyl acetate (10 mL), and quenched with saturated Na2CO3 solution (6 mL). The organic layer was dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-35% ethyl acetate in dichloromethane) provided N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-cyanophenyl)-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (157 mg, 49% yield). LC/MS m/z 399.3 [M+H]+, retention time 1.47 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min). 1H NMR (400.0 MHz, DMSO-d6) δ 12.77 (s, 1H), 12.75 (s, 1H), 8.77 (s, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.64-7.60 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.27 (dd, J=2.8, 9.1 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 4.32 (s, 2H), 2.91 (s, 3H), 1.65 (d, J=7.2 Hz, 4H), 1.42 (d, J=6.8 Hz, 4H).

Workup

  1. customThe reaction was capped
  2. temperatureThe reaction was cooled to room temperature
  3. customquenched with saturated Na2CO3 solution (6 mL)
  4. dry with materialThe organic layer was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by silica gel chromatography (0-35% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-2cb2af87a8e14e03a305e9c02398c1ca
Source dataset
uspto-grants-2013_12
Patent number
US08598205B2

Reaction notes

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