HCID 59799756, compound → HCID 178466238, compound

HRID 2074465Notes

Reaction equation

HRID 2074465 reaction equation
[CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:12]3[CH:21]=[CH:22][C:23]([N+:25]([O-])=O)=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].I.CS[C:33]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)=[NH:34]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:12]3[CH:21]=[CH:22][C:23]([NH:25][C:33]([C:35]4[S:36][CH:37]=[CH:38][CH:39]=4)=[NH:34])=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2]

Participants

5

Reactant 2

HCID 59799756HCID 59799756, compoundHCID 66704664Methyl thiophene-2-carbimidothioate hydroiodide

Product 1

HCID 178466238HCID 178466238, compoundYield 55.6%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 702EthanolSolvent

Procedure

2-(4-Ethoxy-benzyl)-1-(1-methyl-piperidin-4-yl)-5-nitro-1H-benzimidazole 54 (120 mg, 0.304 mmol) was dissolved in anhydrous ethanol (10 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (32.4 mg, 0.0304 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 22 hours, thin layer chromatography in a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) shows complete conversion to 55, 2-(4-Ethoxy-benzyl)-1-(1-methyl-piperidin-4-yl)-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 10 mL) and the ethanolic solution of the amine 55 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide 9a (173.4 mg, 0.608 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 30 hours. The solvent was removed and the residue partitioned between H2O and ethyl acetate and 1M 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 product was purified using silica gel dry column chromatography eluting with a solvent system of 5% 2M NH3 in methanol/95% dichloromethane to afford a pale yellow-colorless residue 56 N-[2-(4-Ethoxy-benzyl)-1-(1-methyl-piperidin-4-yl)-1H-benzoimidazol-5-yl]-thiophene-2-carboxamidine Yield: 80 mg (55.5%). 1H NMR (DMSO) δ: 1.28 (t, 3H, J=6.9), 1.31-1.42 (m, 2H), 1.91 (br t, 2H, J=11.0), 2.19 (s, 3H), 2.19-2.35 (m, 2H), 2.81 (m, 2H), 3.96 (q, 2H, J=7.0), 4.16-4.32 (s, 2H, m, 1H), 6.36 (br s, 2H), 6.69 (dd, 1H, J=8.7, 1.6), 6.85 (d, 2H, J=8.7), 7.00 (d, 1H, J=1.5), 7.08-7.11 (m, 1H), 7.17 (d, 2H, J=8.5), 7.46 (d, 1H, J=8.5), 7.59 (d, 1H, J=5.3), 7.73-7.75 (m, 1H); MS (ESI): 474 (MH+, 80%), 377 (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 10 mL) and the ethanolic solution of the amine 55
  6. additionis charged to a small, argon purged flask
  7. customfitted with a magnetic stirbar
  8. stirringthe reaction was stirred under Ar at ambient temperature for 30 hours
  9. customThe solvent was removed
  10. customthe residue partitioned between H2O and ethyl acetate and 1M 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 product was purified
  21. customdry column chromatography
  22. washeluting with a solvent system of 5% 2M NH3 in methanol/95% dichloromethane

Sources & evidence

ORD record
ord-39e88e466b0a47179637da9d5ef1ddda
Source dataset
uspto-grants-2011_04
Patent number
US07919510B2

Reaction notes

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