Dichloromethane → 4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid (1H-benzoimidazol-2-yl)-amide

HRID 251193Notes

Reaction equation

HRID 251193 reaction equation
[C:1](N1C=CN=C1)([N:3]1C=CN=C1)=[O:2].[NH2:13][C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.CCN(C(C)C)C(C)C.[CH3:32][C:33]1[C:34]([CH2:39][N:40]([CH2:47][C:48]2[C:53]([CH3:54])=[CH:52][CH:51]=[CH:50][N:49]=2)[CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[N:35][CH:36]=[CH:37][CH:38]=1.[CH2:55]([Cl:57])[Cl:56]>>[CH2:55]([Cl:57])[Cl:56].[CH3:1][OH:2].[NH4+:3].[OH-:2].[NH:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[NH:13][C:1]([N:44]1[CH2:45][CH2:46][CH:41]([N:40]([CH2:47][C:48]2[C:53]([CH3:54])=[CH:52][CH:51]=[CH:50][N:49]=2)[CH2:39][C:34]2[C:33]([CH3:32])=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:42][CH2:43]1)=[O:2]

Participants

7

Reactant 5

HCID 6344DichloromethaneHCID 136242-AminobenzimidazoleHCID 682631,1'-CarbonyldiimidazoleHCID 81531Diisopropylethylamine2×HCID 58996965Bis-(3-methyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine

Product 2

HCID 21896990Dichloromethane methanol ammonium hydroxideHCID 589969434-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid (1H-benzoimidazol-2-yl)-amideYield 43%

Conditions

Temperature
60 °C

Procedure

A solution of 1,1′-carbonyldiimidazole (0.0713 g, 0.44 mmol), 2-aminobenzimidazole (0.0533 g, 0.40 mmol), and DIPEA (0.14 mL, 0.80 mmol) in CH2Cl2 (4 mL) was stirred at room temperature for 2.5 hours. The mixture was concentrated, then dissolved in DMF (4 mL), and DIPEA (0.14 mL, 0.80 mmol) and COMPOUND 249 (0.1242 g, 0.40 mmol) were added. The mixture stirred at 60° C. for 20 hours, then concentrated. Saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (3×40 mL). The combined organic extracts were washed with brine (2×30 mL), dried (Na2SO4), filtered and concentrated. Purification of the crude material by column chromatography on silica gel (75:1:1 then 50:1:1 CH2Cl2-MeOH—NH4OH) provided 0.0919 g (43%) of COMPOUND 347 as a white solid. 1H NMR (CDCl3) δ 1.66-1.70 (m, 4H), 1.94 (d, 2H, J=12.6 Hz), 2.07 (s, 6H), 2.69-2.77 (m, 3H), 3.81 (s, 4H), 4.41 (d, 2H, J=13.5 Hz), 7.06-7.15 (m, 4H), 7.29-7.31 (m, 2H), 7.36 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=3.0 Hz). 13C NMR (CDCl3) 18.36, 27.60, 44.78, 54.93, 57.89, 112.76, 122.11, 122.77, 133.77, 138.41, 146.22, 152.31, 157.51, 158.32. ES-MS m/z 470.3 (M+H). Anal. Calcd. for C27H31N7O.0.7CH2Cl2.0.1CH4O: C, 62.74; H, 6.21; N, 18.42. Found: C, 63.02; H, 6.24; N, 18.22.

Workup

  1. concentrationThe mixture was concentrated
  2. dissolutiondissolved in DMF (4 mL)
  3. concentrationconcentrated
  4. additionSaturated NaHCO3 (15 mL) was added
  5. extractionextracted with CH2Cl2 (3×40 mL)
  6. washThe combined organic extracts were washed with brine (2×30 mL)
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customPurification of the crude material by column chromatography on silica gel (75:1:1

Sources & evidence

ORD record
ord-77a8cf533a1e46658ea49d0be78e5392
Source dataset
uspto-grants-2011_01
Patent number
US07863293B2

Reaction notes

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