Trifluoroacetic acid → 2-(6-pyrrolidin-2-ylpyridin-3-yl)-1H-benzimidazole-4-carboxamide

HRID 564233Notes

Reaction equation

HRID 564233 reaction equation
C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=O)=[CH:15][N:14]=1)=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:36][C:37]1[C:45]([NH2:46])=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([NH2:41])=[O:40].FC(F)(F)C(O)=O>N1C=CC=CC=1.CN(C)C=O.ClCCl>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]=[CH:15][C:16]([C:17]2[NH:46][C:45]3[CH:44]=[CH:43][CH:42]=[C:38]([C:39]([NH2:41])=[O:40])[C:37]=3[N:36]=2)=[CH:20][CH:21]=1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 682631,1'-CarbonyldiimidazoleHCID 534228072,3-Diaminobenzamide dihydrochlorideHCID 667607276-(1-(Tert-butoxycarbonyl)pyrrolidin-2-yl)nicotinic acid

Product 1

HCID 667597102-(6-pyrrolidin-2-ylpyridin-3-yl)-1H-benzimidazole-4-carboxamide

Reagents, catalysts & solvents 3

HCID 1049PyridineSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
40 °C

Procedure

To a mixture of 6-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)nicotinic acid (3 g, 10.6 mmol) in pyridine (10 mL) and N,N-dimethylformamide (50 mL) at ambient temperature was added 1,1′-carbonyldiimidazole (2.2 g, 16 mmol). The mixture was heated at 40° C. for 1 hour, treated with 2,3-diaminobenzamide dihydrochloride (2.4 g, 10.6 mmol), stirred at ambient temperature, for 16 hours and concentrated. The residue was heated in acetic acid (100 mL) at 110° C. for 2 hours, cooled and concentrated. The residue was purified by flash chromatography on silica gel using ethyl acetate to provide the acyclic intermediate. This intermediate was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) and the mixture was stirred at room temperature for 16 hours and was concentrated. The residue was purified by HPLC (Zorbax C-8, 0.1% trifluoroacetic acid/acetonitrile/water) to provide the title compound. 1H NMR (methanol-d4) δ 2.04-2.36 (m, 3H), 2.49-2.74 (m, 1H), 3.39-3.72 (m, 2H), 4.98 (t, J=7.63 Hz, 1H), 7.17-7.49 (m, 1H), 7.69 (d, J=8.14 Hz, 1H), 7.81 (d, J=8.14 Hz, 1H), 7.99 (d, J=7.46 Hz, 1H), 8.64 (dd, J=8.31, 2.20 Hz, 1H), 9.42 (s, 1H).

Workup

  1. concentrationconcentrated
  2. temperatureThe residue was heated in acetic acid (100 mL) at 110° C. for 2 hours
  3. temperaturecooled
  4. concentrationconcentrated
  5. customThe residue was purified by flash chromatography on silica gel
  6. customto provide the acyclic intermediate
  7. concentrationwas concentrated
  8. customThe residue was purified by HPLC (Zorbax C-8, 0.1% trifluoroacetic acid/acetonitrile/water)

Sources & evidence

ORD record
ord-bc23ca5d15db4ac59f413856420061ab
Source dataset
uspto-grants-2011_11
Patent number
US08067613B2

Reaction notes

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