2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl → 1,1,1,3,3,3-hexafluoro-2-(4-(2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

HRID 1972393Notes

Reaction equation

HRID 1972393 reaction equation
Cl.[O:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]2[NH:14][CH2:13][CH2:12][N:11]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[CH2:10]2)[CH2:4][CH2:3]1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O.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].C1(C)C=CC=CC=1>[F:32][C:31]([F:33])([F:34])[C:30]([C:27]1[CH:26]=[CH:25][C:24]([N:14]2[CH2:13][CH2:12][N:11]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:17])[CH2:10][CH:9]2[CH2:8][CH:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)=[CH:29][CH:28]=1)([OH:39])[C:35]([F:36])([F:38])[F:37]

Participants

8

Reactant 4

HCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 232335702-(4-Bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-olHCID 23676156Sodium t-butoxideHCID 706554303-(tetrahydro-2H-pyran-4-ylmethyl)-1-(2-thiophenylsulfonyl)piperazine hydrochloride

Product 1

HCID 866703141,1,1,3,3,3-hexafluoro-2-(4-(2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanolYield 2.1%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A 100 ml, round-bottomed flask was charged with 3-(tetrahydro-2H-pyran-4-ylmethyl)-1-(2-thiophenylsulfonyl)piperazine hydrochloride (0.250 g, 0.681 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.330 g, 1.02 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), sodium tert-butoxide (0.196 g, 2.04 mmol) and 10 mL of toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.032 g, 0.068 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.031 g, 0.034 mmol, Strem Chemical Inc, Newburyport, Mass.). The mixture was heated at 100° C. for 12 h and then diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (MgSO4), concentrated, and purified by reverse-phase preparative HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), eluting with a 0.1% TFA in CH3CN/H2O (10% to 90% over 25 min)) to afford 1,1,1,3,3,3-hexafluoro-2-(4-(2-(tetrahydro-2H-pyran-4-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.008 g) as a mixture of two enantiomers.

Workup

  1. extractionextracted with EtOAc (2×20 mL)
  2. dry with materialThe combined organic extracts were dried (MgSO4)
  3. concentrationconcentrated
  4. custompurified by reverse-phase preparative HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm)
  5. washeluting with a 0.1% TFA in CH3CN/H2O (10% to 90% over 25 min))

Sources & evidence

ORD record
ord-76b5753702094ed88cfd5d5fa75ffdd6
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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