Isonicotinic Acid → {4-[Bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-pyridin-4-yl-methanone

HRID 1592548Notes

Reaction equation

HRID 1592548 reaction equation
[C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[C:18]([CH2:23][N:24]([CH2:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:19][CH:20]=[CH:21][CH:22]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.[OH-].[Na+].CCOC(C)=O.CN(C=O)C>[CH3:16][C:17]1[C:18]([CH2:23][N:24]([CH2:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:25]2[CH2:30][CH2:29][N:28]([C:1]([C:2]3[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=3)=[O:9])[CH2:27][CH2:26]2)=[N:19][CH:20]=[CH:21][CH:22]=1

Participants

10

Reactant 4

HCID 5922Isonicotinic AcidHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 58996965Bis-(3-methyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine

Product 1

HCID 58997194{4-[Bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-pyridin-4-yl-methanoneYield 42%

Reagents, catalysts & solvents 5

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 14798Sodium HydroxideSolvent

Conditions

Temperature
0 °C

Procedure

To a cold (0° C.), stirred, mixture of isonicotinic acid (130 mg, 1.05 mmol) in CH2Cl2 (10 mL) was added DMF (1 mL) followed by oxalyl chloride (0.46 mL, 5.27 mmol). The mixture was warmed to room temperature. After 15 minutes the mixture was concentrated under reduced pressure and provided a white solid. To a solution of COMPOUND 249 (60 mg, 0.19 mmol) in THF (7 mL) was added the white solid from above followed by DIPEA (1.20 mL, 6.88 mmol). The resultant mixture was stirred at room temperature for 2.5 hours then diluted with 1.0 N NaOH (10 mL) and EtOAc (50 mL). The phases were separated and the organic phase was washed with 1.0 N NaOH (3×10 mL) and brine (10 mL), dried (Na2SO4), and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) provided 33 mg (42%) of COMPOUND 266 as a white solid. 1H NMR (CDCl3) δ 1.50-1.76 (m, 2H), 1.80-2.04 (m, 2H), 2.09 (s, 6H), 2.57-3.02 (m, 3H), 3.65-3.91 (m, 5H), 4.76-4.84 (m, 1H), 7.09 (dd, 2H, J=7.5, 4.8 Hz), 7.27 (d, 2H, J=5.7 Hz), 7.38 (d, 2H, J=7.5 Hz), 8.35 (d, 2H, J=4.8 Hz), 8.69 (d, 2H, J=5.7 Hz); ES-MS m/z 416 (M+H).

Workup

  1. temperatureThe mixture was warmed to room temperature
  2. concentrationAfter 15 minutes the mixture was concentrated under reduced pressure
  3. customprovided a white solid
  4. customThe phases were separated
  5. washthe organic phase was washed with 1.0 N NaOH (3×10 mL) and brine (10 mL)
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated
  8. customPurification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH)

Sources & evidence

ORD record
ord-cf372766408d4035878dfc16fbab97c9
Source dataset
uspto-grants-2007_11
Patent number
US07291631B2

Reaction notes

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