2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → tert-Butyl 5-(benzyloxy)-2-{(1-[4'-({[tert-butyl(dimethyl)silyl]oxy}methyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine-4-carboxylate

HRID 1626780Notes

Reaction equation

HRID 1626780 reaction equation
Cl.[CH2:2]([O:9][C:10]1[C:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:12][C:13]([CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:14][C:15]=1[CH3:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:2]([O:9][C:10]1[C:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:12][C:13]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:32]3[CH:33]=[CH:34][C:35]([C:38]4[CH:43]=[CH:42][C:41]([CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])=[CH:40][CH:39]=4)=[CH:36][CH:37]=3)[CH2:20][CH2:19]2)=[N:14][C:15]=1[CH3:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 67156013tert-Butyl 5-(benzyloxy)-6-methyl-2-(piperidin-4-ylmethyl)pyrimidine-4-carboxylate hydrochlorideHCID 68193270[(4'-Bromobiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane

Product 1

HCID 68193315tert-Butyl 5-(benzyloxy)-2-{(1-[4'-({[tert-butyl(dimethyl)silyl]oxy}methyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine-4-carboxylateYield 61%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

tert-Butyl 5-(benzyloxy)-6-methyl-2-(piperidin-4-ylmethyl)pyrimidine-4-carboxylate hydrochloride (1.0 g, 2.3 mmol), [(4′-bromobiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane (0.92 g, 2.4 mmol), sodium tert-butoxide (0.67 g, 7.0 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-PHOS) (0.11 g, 0.23 mmol) and tris(dibenzylideneacetone)dipalladium (0.11 g, 0.12 mmol) were suspended in toluene (50 mL), followed by heating to reflux for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and filtered with celite, and subsequently the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.50 (hexane/ethyl acetate=2/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.98 g, 1.4 mmol) as a yellow oil (yield 61%).

Workup

  1. temperatureby heating
  2. temperatureto reflux for 3 hours under a nitrogen atmosphere
  3. filtrationfiltered with celite
  4. concentrationsubsequently the filtrate was concentrated under reduced pressure
  5. customThe resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate)
  6. concentrationa fraction corresponding to the Rf value=0.50 (hexane/ethyl acetate=2/1) by thin layer chromatography was concentrated under reduced pressure

Sources & evidence

ORD record
ord-103fd202fdfb4d42ace795086a7ea547
Source dataset
uspto-grants-2014_07
Patent number
US08785462B2

Reaction notes

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