1,4-Cyclohexadiene → HCID 53372380, compound

HRID 340803Notes

Reaction equation

HRID 340803 reaction equation
C1(C2C=CC=CC=2)C=CC(C[N:8]2[C:12]3[CH:13]=[C:14]([F:39])[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([N:32]6[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]6)=[O:31])=[CH:26][CH:25]=5)=[CH:20][CH:19]=4)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:40][CH:41]2[CH2:46][CH2:45][CH:44]([C:47]([O:49]CC)=[O:48])[CH2:43][CH2:42]2)=CC=1.C1CC=CCC=1.O([Si](C)(C)C)[K]>CCOC(C)=O.CCO.C1COCC1.[OH-].[OH-].[Pd+2]>[F:17][C:16]1[C:11]2[N:10]=[C:9]([O:40][CH:41]3[CH2:46][CH2:45][CH:44]([C:47]([OH:49])=[O:48])[CH2:43][CH2:42]3)[NH:8][C:12]=2[CH:13]=[C:14]([F:39])[C:15]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)=[O:31])=[CH:26][CH:25]=2)=[CH:22][CH:23]=1

Participants

8

Reactant 3

HCID 123431,4-CyclohexadieneHCID 67408859HCID 67408859, compoundHCID 178504318HCID 178504318, compound

Product 1

HCID 53372380HCID 53372380, compound

Reagents, catalysts & solvents 4

HCID 9942167Palladium hydroxideCatalystHCID 702EthanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of ethyl 4-{[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-{4′-[(4-hydroxypiperidin-1-yl)carbonyl]biphenyl-4-yl}-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (isomer B, 0.057 g, 0.074 mmol) and Pd(OH)2 (0.014 g, 0.019 mmol) in 0.8 mL of EtOAc and 0.4 mL of EtOH was added 1,4-cyclohexadiene (0.180 mL, 1.91 mmol). The resulting black suspension was microwaved at 130° C. for 2 h, then filtered through a Celite™ pad, and washed with EtOAc. The resulting filtrate was concentrated in vacuo to give a crude residue. The crude residue was dissolved in 2 mL of THF and treated with KOTMS (0.028 g, 0.222 mmol). The reaction mixture was stirred for 18 h at ambient temperature, and then concentrated. The resulting crude residue was purified by reverse phase Gilson™ HPLC (35-100% MeCN/H2O) to provide the title compound as a white solid. LCMS: calculated for C32H31F2N3O5 575.60, observed m/e 576.1 (M+H)+ (Rt 1.99/4 min). 1H NMR (500 MHz, CD3OD): 7.80 (d, 2H), 7.76 (d, 2H), 7.55 (d, 2H), 7.52 (d, 2H), 7.05 (d, 1H), 4.98-4.90 (m, 1H), 4.27-4.16 (m, 1H), 3.95-3.86 (m, 1H), 3.79-3.67 (m, 1H), 3.42-3.33 (m, 1H), 2.43-2.34 (m, 1H), 2.34-2.26 (m, 2H), 2.16-2.06 (m, 2H), 2.03-1.90 (m, 2H), 1.90-1.78 (m, 2H), 1.75-1.42 (m, 5H).

Workup

  1. customThe resulting black suspension was microwaved at 130° C. for 2 h
  2. filtrationfiltered through a Celite™ pad
  3. washwashed with EtOAc
  4. concentrationThe resulting filtrate was concentrated in vacuo
  5. customto give a crude residue
  6. concentrationconcentrated
  7. customThe resulting crude residue was purified by reverse phase Gilson™ HPLC (35-100% MeCN/H2O)

Sources & evidence

ORD record
ord-a16b387c28a34a5c98d2e6b4de5fc259
Source dataset
uspto-grants-2014_11
Patent number
US08895596B2

Reaction notes

Loading…