Hydrochloric Acid → Ethyl 4-(6-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate

HRID 967366Notes

Reaction equation

HRID 967366 reaction equation
[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[N+:20]([O-])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.CCN(CC)CC.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>CCO.C(Cl)Cl.[OH-].[Na+].[Zn]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[NH:20][C:32]2=[O:34])[CH2:8][CH2:7]1)=[O:5])[CH3:2]

Participants

9

Reactant 4

HCID 313Hydrochloric Acid2×HCID 8471TriethylamineHCID 94429TriphosgeneHCID 137921661-Carbethoxy-4-(5-chloro-2-nitroanilino)-piperidine

Product 1

HCID 13792190Ethyl 4-(6-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate

Reagents, catalysts & solvents 4

HCID 23994ZincCatalyst2×HCID 702EthanolSolventHCID 6344DichloromethaneSolventHCID 14798Sodium HydroxideSolvent

Procedure

To a stirred solution of 0.50 g (1.52 mmol) of 4-(5-chloro-2-nitro-phenylamino)-piperidine-1-carboxylic acid ethyl ester in EtOH (15.0 mL) was added concentrated HCl (3.0 mL) followed by 0.99 g (15.2 mmol) of zinc powder. After 1 h, additional concentrated HCl (1.5 mL) followed by 0.99 g (15.2 mmol) of zinc powder was added and the reaction was stirred for 1.5 h. The mixture was filtered through a pad of celite and was washed with 5% MeOH/CH2Cl2. The mixture was diluted with saturated NaHCO3 and a precipitate formed. The layers were separated and the aqueous phase was extracted (3×5% MeOH/CH2Cl2). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure to afford a brown oil. The crude oil was diluted with CH2Cl2 (15.0 mL) and 0.64 mL (4.56 mmol) of Et3N was added followed by 0.45 g (1.52 mmol) of triphosgene. The reaction was allowed to stir overnight and was then diluted with 1 N NaOH (20 mL) and stirred for an additional 1 h. The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by flash chromatography (silica, 0-5% MeOH/CH2Cl2) afforded 0.33 g (67% over 2 steps) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.5. MS (electrospray): m/z calculated for C15H18ClN3O3 [M++Na] 346.10, observed 346.0. 1H NMR (400 MHz, CDCl3): 9.41 (s, 1H), 7.11 (d, J=2.0 Hz, 1H), 7.04 (d, J=1.8 Hz, 1H), 7.02 (s, 1H), 4.48-4.33 (m, 3H), 4.20 (q, J=7.1 Hz, 2H), 2.92 (t, J=12.5 Hz, 2H), 2.30 (dq, J=12.9, 4.6 Hz, 2H), 2.10 (d, J=12.6 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H).

Workup

  1. additionwas added
  2. filtrationThe mixture was filtered through a pad of celite
  3. washwas washed with 5% MeOH/CH2Cl2
  4. additionThe mixture was diluted with saturated NaHCO3
  5. customa precipitate formed
  6. customThe layers were separated
  7. extractionthe aqueous phase was extracted (3×5% MeOH/CH2Cl2)
  8. dry with materialThe combined organic layers were dried over Na2SO4
  9. customthe solvent was removed under reduced pressure
  10. customto afford a brown oil
  11. additionwas added
  12. stirringto stir overnight
  13. stirringstirred for an additional 1 h
  14. customThe layers were separated
  15. extractionthe aqueous phase was extracted with CH2Cl2 (3×20 mL)
  16. dry with materialThe combined organic extracts were dried over Na2SO4
  17. customthe solvent was removed under reduced pressure
  18. customPurification by flash chromatography (silica, 0-5% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-7ff307d1d6ad460b923cc5856f6b287d
Source dataset
uspto-grants-2005_10
Patent number
US06953793B2

Reaction notes

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