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

HRID 251144
Notes
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Reaction equation

HRID 251144 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=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([O-])(O)=O.[Na+]>C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:8]([N:33]1[CH2:34][CH2:35][CH:30]([N:29]([CH2:28][C:22]2[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][N:23]=2)[CH2:36][C:37]2[C:42]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:40]=[CH:39][N:38]=2)[CH2:31][CH2:32]1)=[O:9]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 104392-AminopyridineHCID 682631,1'-CarbonyldiimidazoleHCID 516892Sodium BicarbonateHCID 58997074(3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine

Product 1

HCID 589971674-[(3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid pyridin-2-ylamide
Yield 81%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 2-aminopyridine (69 mg, 0.73 mmol) in CH2Cl2 (5 mL) was added 1,1′-carbonyldiimidazole (122 mg, 0.75 mmol) and the reaction stirred at reflux for 2 h 15 min. after which a solution of (3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidine-4-yl-amine (87 mg, 0.247 mmol) in CH2Cl2 (3 mL) was added and the reaction stirred at reflux for 2.5 h. The solution was cooled, treated with saturated aqueous NaHCO3 (25 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:1:1 then 50:1:1) provided COMPOUND 284 (94 mg, 81%) as a colorless oil: 1H NMR (CDCl3) δ 0.92 (d, 6H, J=6.9 Hz), 1.62-1.75 (m, 2H), 1.92-1.98 (m, 3H), 2.16 (s, 3H), 2.28 (s, 3H), 2.72-2.85 (m, 4H), 3.77 (s, 2H), 3.83 (s, 2H), 4.17-4.21 (m, 2H), 6.92 (dd, 1H, J=6.6, 5.4 Hz), 7.14 (dd, 1H, J=7.8, 4.8 Hz), 7.24 (br s, 2H), 7.50 (dd, 1H, J=7.8, 1.2 Hz), 7.63 (dt, 1H, J=6.9, 1.8 Hz), 8.01 (d, 1H, J=8.4 Hz), 8.19 (s, 1H), 8.33 (dd, 1H, J=4.8, 1.5 Hz). 13C NMR (CDCl3) δ 18.29, 18.45, 23.60, 27.45, 44.80, 54.32, 57.34, 113.61, 118.62, 123.18, 132.28, 133.19, 133.86, 138.48, 139.06, 144.39, 146.08, 146.65, 147.81, 153.27, 154.03, 154.42, 156.23. ES-MS m/z 495 (M+Na). Anal. Calcd. for C28H36N6O.0.8CH2Cl2: C, 63.99; H, 7.01; N, 15.55. Found: C, 64.33; H, 7.28; N, 15.68.

Workup

  1. additionwas added
  2. stirringthe reaction stirred
  3. temperatureat reflux for 2.5 h
  4. temperatureThe solution was cooled
  5. extractionextracted with CH2Cl2 (3×20 mL)
  6. dry with materialThe combined organic extracts were dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification of the crude material by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:1:1

Sources & evidence

ORD record
ord-cc7e47d5cb614867b18ef9cb4575a714
Source dataset
uspto-grants-2011_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07863293B2

Reaction notes

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