1,1'-Carbonyldiimidazole → HCID 66621611, compound

HRID 416009Notes

Reaction equation

HRID 416009 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[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(=O)[NH:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH:52]([NH2:56])[CH2:51]1)(C)(C)C.C(OC(=O)NC1CCCN(C(C2C=CC(C3C=C(Cl)C(CC4CCN(C5CCCCC5)C4=O)=C(Cl)C=3)=CC=2)=O)C1)(C)(C)C.Cl.O1CCOCC1>ClCCl.O1CCOCC1>[NH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH:52]([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:30])[CH2:51]1

Participants

8

Reactant 5

HCID 682631,1'-CarbonyldiimidazoleHCID 204431481,4-Dioxane hydrochlorideHCID 21979749tert-Butyl (3-aminocyclohexyl)carbamateHCID 59299497HCID 59299497, compoundHCID 66622263HCID 66622263, compound

Product 1

HCID 66621611HCID 66621611, compound

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

Dissolve racemic 3′, 5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (1.00 eq.) in dichloromethane (5-10 mL) and add 1,1′-carbonyl-diimidazole (1.50 eq.). Stir under argon atmosphere at room temperature and check reaction progress via TLC. Add (3-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.05-2.0 eq.) and continue to stir, checking progress via LC/MS. Once starting material has been fully consumed, dilute reaction with dichloromethane (50 mL) and wash with 1.0 N sodium hydroxide (30 mL) and 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 of 100% dichloromethane to 10% ammonia methanol/90% dichloromethane to recover {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester. Dissolve the {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester (0.40, 0.65 mmol) in dioxane (20 mL), add 4N hydrochloric acid -dioxane (10 mL) and stir 30 min. Concentrate under vacuum, dilute in dichloromethane (100 mL) and add saturated aqueous sodium bicarbonate (50 mL). Dry the organic phase with magnesium sulfate and concentrate to a foam: MS (m/z): 528 (M+).

Workup

  1. customreaction progress via TLC
  2. stirringto stir
  3. customOnce starting material has been fully consumed
  4. additiondilute
  5. customreaction with dichloromethane (50 mL)
  6. washwash with 1.0 N sodium hydroxide (30 mL) and brine (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. customto recover {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester
  12. stirringstir 30 min
  13. concentrationConcentrate under vacuum
  14. additiondilute in dichloromethane (100 mL)
  15. additionadd saturated aqueous sodium bicarbonate (50 mL)
  16. dry with materialDry the organic phase with magnesium sulfate
  17. concentrationconcentrate to a foam

Sources & evidence

ORD record
ord-7dc273d0d3d745a9b704b6a704465f8e
Source dataset
uspto-grants-2012_01
Patent number
US08088776B2

Reaction notes

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