Dichloromethane → 1-[2-(cyclopropyloxy)ethyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide dihydrochloride

HRID 2168999Notes

Reaction equation

HRID 2168999 reaction equation
C([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:16])=C.C([Zn]CC)C.CCC[CH2:51][CH2:52][CH3:53].ICI.[Cl:57]CCl>Cl>[ClH:57].[ClH:57].[CH:51]1([O:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[C:15]([N:17]([CH2:39][CH:40]([CH3:41])[CH3:42])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:25])[CH2:21][NH:20][CH2:19]2)=[O:16])[CH2:52][CH2:53]1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 6346DiiodomethaneHCID 58355228tert-butyl(3S,5R)-3-[({1-[2-(ethenyloxy)ethyl]-1H-benzimidazol-2-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylateHCID 178443585HCID 178443585, compound

Product 1

HCID 673202261-[2-(cyclopropyloxy)ethyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide dihydrochloride

Reagents, catalysts & solvents 1

HCID 313Hydrochloric AcidSolvent

Procedure

To a solution of tert-butyl (3S,5R)-3-[({1-[2-(ethenyloxy)ethyl]-1H-benzimidazol-2-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (323 mg) and 1M diethylzinc-hexane solution (2.5 ml) in dichloromethane (5 ml) was added dropwise diiodomethane (443 μl) at room temperature over 5 min, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (5 ml), 4M hydrogen chloride-ethyl acetate (5 ml) was added and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (35 mg).

Workup

  1. extractionthe mixture was extracted with ethyl acetate
  2. washThe extract was washed with saturated brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. customThe solvent was evaporated under reduced pressure
  5. dissolutionThe residue was dissolved in methanol (5 ml)
  6. addition4M hydrogen chloride-ethyl acetate (5 ml) was added
  7. stirringthe mixture was stirred at room temperature for 5 hr
  8. concentrationThe reaction mixture was concentrated
  9. concentrationthe eluted fraction was concentrated under reduced pressure
  10. additionThe residue was diluted with aqueous sodium bicarbonate
  11. extractionthe mixture was extracted with ethyl acetate
  12. washThe extract was washed with saturated brine
  13. dry with materialdried over anhydrous sodium sulfate
  14. addition4M Hydrogen chloride-ethyl acetate (1 ml) was added
  15. stirringthe mixture was stirred for 5 min
  16. customThe solvent was evaporated under reduced pressure

Sources & evidence

ORD record
ord-e44a7483ceb24f3d8ed6561c01990312
Source dataset
uspto-grants-2015_06
Patent number
US09045436B2

Reaction notes

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