1,1'-Carbonyldiimidazole → 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid pyridazin-3-ylamide

HRID 1592584Notes

Reaction equation

HRID 1592584 reaction equation
[NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8](N1C=CN=C1)(N1C=CN=C1)=[O:9].[CH3:20][C:21]1[C:22]([CH2:28][N:29]([CH2:36][C:37]2[C:42]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:8]([N:33]2[CH2:34][CH2:35][CH:30]([N:29]([CH2:28][C:22]3[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][N:23]=3)[CH2:36][C:37]3[C:42]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:40]=[CH:39][N:38]=3)[CH2:31][CH2:32]2)=[O:9])[N:3]=1

Participants

5

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 230373AminopyridazineHCID 58997074(3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine

Product 1

HCID 589970604-[(3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid pyridazin-3-ylamideYield 28.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 3-aminopyridazine (62 mg, 0.65 mmol) (Wermuth, C.-G. J. Het. Chem. 1998, 35, 1091-1100) in CH2Cl2 (5 mL) was added 1,1′carbonyldiimidazole (128 mg, 0.79 mmol). After stirring at room temperature for 1.5 h, the mixture was heated to 50° C. After 45 min, (3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidine-4-yl-amine (115 mg, 0.33 mmol) was added and stirring was continued for 50° C. After 2 h, the reaction mixture was cooled, diluted with CH2Cl2 (20 mL), and washed with saturated NaHCO3 (3×20 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a pale yellow oil. Purification by radial chromatography on silica gel (1 mm plate; using CH2Cl2-/MeOH/NH4OH; 50:1:1) afforded COMPOUND 315 as a pale yellow oil (44 mg, 28%). 1H NMR (CDCl3) δ 0.93 (d, 6H, J=6.0 Hz), 1.64-1.75 (m, 2H), 1.96-1.99 (m, 2H), 2.16 (s, 3H), 2.28 (s, 3H), 2.75-2.84 (m, 4H), 3.78 (s, 2H), 3.84 (s, 2H), 4.21 (s, 1H), 4.26 (s, 1H), 7.15-7.17 (m, 1H), 7.38-7.42 (m, 1H), 7.50 (dd, 1H, J=6.0, 3.0 Hz), 7.99 (s, 1H), 8.18 (s, 1H), 8.32 (d, 1H, J=3.0 Hz), 8.33 (d, 1H, J=3.0 Hz), 8.80 (s, 1H). 13C NMR δ 18.30, 18.46, 23.61, 27.46, 44.89, 53.83, 54.34, 57.27, 118.83, 123.22, 128.28, 132.33, 133.19, 133.88, 139.08, 144.40, 146.12, 146.70, 147.89, 153.74, 154.38, 156.21, 156.96. ES-MS m/z 496 [M+H]+. Anal. Calcd. for C27H35N7.1.4CH2Cl2.0.5H2O: C, 56.71; H, 6.50; N, 16.30. Found: C, 56.48; H, 6.32; N, 16.54.

Workup

  1. temperaturethe mixture was heated to 50° C
  2. waitAfter 45 min
  3. stirringstirring
  4. customwas continued for 50° C
  5. waitAfter 2 h
  6. temperaturethe reaction mixture was cooled
  7. washwashed with saturated NaHCO3 (3×20 mL)
  8. dry with materialThe organic layer was dried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto afford a pale yellow oil
  12. customPurification by radial chromatography on silica gel (1 mm plate; using CH2Cl2-/MeOH/NH4OH; 50:1:1)

Sources & evidence

ORD record
ord-5d8078cd4c5d45da8c1b92e68e3c41ab
Source dataset
uspto-grants-2007_11
Patent number
US07291631B2

Reaction notes

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