1,1'-Carbonyldiimidazole → HCID 57741526, compound

HRID 416014Notes

Reaction equation

HRID 416014 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O.C(OC([N:50]1[CH2:55][CH2:54][CH:53]([NH2:56])[CH2:52][CH2:51]1)=O)(C)(C)C>ClCCl>[NH:50]1[CH2:55][CH2:54][CH:53]([NH:56][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:4]3[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][CH:9]4[CH2:13][CH2:12][N:11]([CH:14]5[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]5)[C:10]4=[O:20])=[C:6]([Cl:21])[CH:5]=3)=[CH:27][CH:26]=2)=[O:29])[CH2:52][CH2:51]1

Participants

5

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 12682914-Amino-1-Boc-piperidineHCID 59299497HCID 59299497, compound

Product 1

HCID 57741526HCID 57741526, compoundYield 82.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Dissolve racemic 3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (0.200 g, 0.448 mmol) in dichloromethane (5 mL) and add 1,1′-carbonyl-diimidazole (0.125 g, 0.760 mmol). Stir under argon atmosphere at room temperature and check reaction progress via TLC. Add 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.180 g, 0.90 mmol) and continue to stir until the starting material has been fully consumed. Dilute the reaction with dichloromethane (50 mL) and wash with 1.0 N sodium hydroxide (30 mL) then brine (30 mL). Collect the organic phase, dry over anhydrous magnesium sulfate and concentrate under reduced pressure. Purify via flash chromatography by eluding with gradient (0-100%) dichloromethane to 15% ammonia methanol/85% dichloromethane. After concentrating, dissolve the 4-{[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester in dioxane (20 mL), add 4N hydrochloric acid -dioxane (10 mL) and stir ½ hour to obtain an oily residue in reaction vessel. Concentrate the mixture under vacuum then dilute in dichloromethane (100 mL). Quench with saturated aqueous sodium bicarbonate solution (50 mL), dry the organic phase over magnesium sulfate and concentrate to obtain 0.195 g (82%) of a yellow foam: MS (m/z): 530 (M+2).

Workup

  1. customreaction progress via TLC
  2. stirringto stir until the starting material
  3. customhas been fully consumed
  4. additionDilute
  5. customthe reaction with dichloromethane (50 mL)
  6. washwash with 1.0 N sodium hydroxide (30 mL)
  7. customCollect the organic phase
  8. dry with materialdry over anhydrous magnesium sulfate
  9. concentrationconcentrate under reduced pressure
  10. customPurify via flash chromatography
  11. concentrationAfter concentrating
  12. dissolutiondissolve the 4-{[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester in dioxane (20 mL)
  13. additionadd 4N hydrochloric acid -dioxane (10 mL)
  14. stirringstir ½ hour
  15. customto obtain an oily residue
  16. customin reaction vessel
  17. concentrationConcentrate the mixture under vacuum
  18. additionthen dilute in dichloromethane (100 mL)
  19. customQuench with saturated aqueous sodium bicarbonate solution (50 mL)
  20. dry with materialdry the organic phase over magnesium sulfate
  21. concentrationconcentrate

Sources & evidence

ORD record
ord-7a126f821061496396418168b39826bb
Source dataset
uspto-grants-2012_01
Patent number
US08088776B2

Reaction notes

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