Toluene → 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c] pyridine

HRID 895556Notes

Reaction equation

HRID 895556 reaction equation
Cl.[CH2:2]([NH:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[CH:7][C:6]=1[NH2:14])[CH3:3].C[Al](C)C.C1(C)C=CC=CC=1.CO[C:28](=O)[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]1[S:36][CH:37]=[CH:38][N:39]=1>C(Cl)Cl>[CH2:2]([N:4]1[C:5]2[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[CH:7][C:6]=2[N:14]=[C:28]1[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)[CH3:3]

Participants

6

Reactant 4

HCID 1140TolueneHCID 16682925TrimethylaluminumHCID 68495873(2-Thiazol-2-yl-imidazol-1-yl)-acetic acid methyl esterHCID 86587612N4-ethyl-6-isopropyl-pyridine-3,4-diamine hydrochloride

Product 1

HCID 223800441-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c] pyridine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a suspension of N4-ethyl-6-isopropyl-pyridine-3,4-diamine hydrochloride (126 mg, 0.582 mmol) in CH2Cl2 (5 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (0.35 mL, 0.728 mmol). The dark solution is then stirred at room temperature for 45 min. Next, a solution of (2-Thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester (65 mg, 0.291 mmol) in CH2Cl2 (2 mL) is added via cannula followed by a 1 mL rinse. The reaction mixture is stirred at reflux overnight. After cooling, it is treated with MeOH (˜0.5 mL) and then diluted with 0.5 N NaOH and additional CH2Cl2. The mixture is stirred vigorously for 15 min and then extracted thrice with CH2Cl2 containing some (˜5%) MeOH. The combined extracts are dried over K2CO3 and concentrated to 156 mg of a crude mixture of the desired 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine and N-(4-amino-6-isopropyl-pyridin-3-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide. This material is then dissolved in AcOH (6 mL), and the resulting solution is stirred at reflux for 5 h. After cooling, the reaction mixture is concentrated in vacuo. The residue is dissolved in CH2Cl2 and washed with 0.5 N NaOH. The aqueous layer is reextracted twice with CH2Cl2, and the combined extracts are dried over K2CO3 and concentrated. The crude material is purified by preparative TLC. Developing with 15:1 CHCl3 yields 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 400 MHz) δ 9.01 (s, 1H), 7.83 (d, J=3.2 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.15 (s, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 6.32 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 3.17 (sept, J=6.8 Hz, 1H), 1.34 (d, J=6.8 Hz, 6H), 1.10 (t, J=7.2 Hz, 3H) ppm.

Workup

  1. washrinse
  2. stirringThe reaction mixture is stirred
  3. temperatureat reflux overnight
  4. temperatureAfter cooling
  5. additionit is treated with MeOH (˜0.5 mL)
  6. additiondiluted with 0.5 N NaOH and additional CH2Cl2
  7. stirringThe mixture is stirred vigorously for 15 min
  8. extractionextracted thrice with CH2Cl2 containing some (˜5%) MeOH
  9. dry with materialThe combined extracts are dried over K2CO3
  10. concentrationconcentrated to 156 mg of a crude mixture of the desired 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine and N-(4-amino-6-isopropyl-pyridin-3-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide
  11. dissolutionThis material is then dissolved in AcOH (6 mL)
  12. stirringthe resulting solution is stirred
  13. temperatureat reflux for 5 h
  14. temperatureAfter cooling
  15. concentrationthe reaction mixture is concentrated in vacuo
  16. dissolutionThe residue is dissolved in CH2Cl2
  17. washwashed with 0.5 N NaOH
  18. dry with materialthe combined extracts are dried over K2CO3
  19. concentrationconcentrated
  20. customThe crude material is purified by preparative TLC

Sources & evidence

ORD record
ord-cae5df45c878463a94871d390200a263
Source dataset
uspto-grants-2005_07
Patent number
US06916819B2

Reaction notes

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