HCID 59799749, compound → HCID 178466239, compound

HRID 2074456Notes

Reaction equation

HRID 2074456 reaction equation
[CH2:1]([O:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH3:21])[C:12]3[CH:22]=[CH:23][C:24]([N+:26]([O-])=O)=[CH:25][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].I.CS[C:34]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)=[NH:35]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH3:21])[C:12]3[CH:22]=[CH:23][C:24]([NH:26][C:34]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)=[NH:35])=[CH:25][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2]

Participants

5

Reactant 2

HCID 59799749HCID 59799749, compoundHCID 66704664Methyl thiophene-2-carbimidothioate hydroiodide

Product 1

HCID 178466239HCID 178466239, compound

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 702EthanolSolvent

Procedure

2-(4-Ethoxy-benzyl)-1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-5-nitro-1H-benzimidazole 34 (45 mg, 0.110 mmol) was dissolved in anhydrous ethanol (5 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (15 mg, 0.014 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 20 hours, thin layer chromatography in a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) shows complete conversion to 35 2-(4-Ethoxy-benzyl)-1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-benzoimidazol-5-ylamine, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (5 mL) and the ethanolic solution of the amine 35 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide 9a (110.6 mg, 0.388 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 67 hours. The solvent was removed and the residue partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude product. The reaction was repeated on a 67 mg scale and the combined crudes purified using silica gel dry column chromatography with a solvent system of (2.5% 2M NH3 in methanol/97.5% dichloromethane to 10% 2M NH3 in methanol/90% dichloromethane) then a second silica gel dry column with a solvent system of (10% methanol/90% dichloromethane to 100% methanol) to afford a beige solid 36 N-{2-(4-Ethoxy-benzyl)-1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-benzoimidazol-5-yl}-thiophene-2-carboxamidine. Yield: 48 mg (35.9%). 1H NMR (DMSO) δ: 1.29 (t, 3H, J=6.9), 1.35-1.49 (m, 2H), 1.54-1.69 (m, 3H), 1.77-1.90 (m, 1H), 1.95-2.05 (m, 2H), 2.08 (s, 3H), 2.84-2.95 (m, 1H), 3.98 (q, 2H, J=6.9), 4.06 (t, 2H, J=7.7), 4.20 (s, 2H), 6.33 (br s, 2H), 6.73 (dd, 1H, J=8.7, 1.6), 6.87 (d, 2H, J=8.8), 7.00 (d, 1H, J=1.6), 7.09 (dd, 1H, J=5.2, 3.8), 7.19 (d, 2H, J=8.6), 7.33 (d, 1H, J=8.4), 7.59 (d, 1H, J=5.4), 7.73-7.74 (m, 1H); MS (ESI): 488 (MH+, 60%), 244 (100%).

Workup

  1. customthe atmosphere from the flask evacuated by vacuum pump
  2. customThe atmosphere is evacuated from the flask
  3. filtrationThe mixture is filtered through a pad of celite
  4. customto remove insolubles
  5. washthe pad washed with anhydrous ethanol (5 mL)
  6. additionthe ethanolic solution of the amine 35 is charged to a small, argon purged flask
  7. customfitted with a magnetic stirbar
  8. stirringthe reaction was stirred under Ar at ambient temperature for 67 hours
  9. customThe solvent was removed
  10. customthe residue partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution
  11. additionadded
  12. customThe mixture was transferred to a separatory funnel
  13. customthe organic layer collected
  14. extractionThe aqueous layer was further extracted with ethyl acetate
  15. washthe combined organic layers were washed with brine (twice),
  16. dry with materialdried over magnesium sulphate
  17. filtrationfiltered
  18. concentrationconcentrated
  19. customto afford crude product
  20. customthe combined crudes purified
  21. dry with materialdry column chromatography with a solvent system of (2.5% 2M NH3 in methanol/97.5% dichloromethane to 10% 2M NH3 in methanol/90% dichloromethane)
  22. dry with materiala second silica gel dry column with a solvent system of (10% methanol/90% dichloromethane to 100% methanol)

Sources & evidence

ORD record
ord-a562bb6930f341aca43edc56864b7a87
Source dataset
uspto-grants-2011_04
Patent number
US07919510B2

Reaction notes

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