2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl → HCID 56932571, compound

HRID 1972496Notes

Reaction equation

HRID 1972496 reaction equation
Cl.Cl.[CH3:3][C@H:4]1[CH2:9][O:8][CH2:7][CH2:6][N:5]1[CH2:10][C@H:11]1[CH2:16][N:15]([S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:19])=[O:18])[CH2:14][CH2:13][NH:12]1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.CCOC(C)=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]>[F:34][C:33]([F:35])([F:36])[C:32]([C:29]1[CH:28]=[CH:27][C:26]([N:12]2[CH2:13][CH2:14][N:15]([S:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:19])[CH2:16][C@@H:11]2[CH2:10][N:5]2[CH2:6][CH2:7][O:8][CH2:9][C@@H:4]2[CH3:3])=[CH:31][CH:30]=1)([OH:41])[C:37]([F:38])([F:40])[F:39]

Participants

9

Reactant 4

HCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 232335702-(4-Bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-olHCID 23676156Sodium t-butoxideHCID 66584053HCID 66584053, compound

Product 1

HCID 56932571HCID 56932571, compoundYield 12.3%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

In a pressure tube (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine dihydrochloride (133 mg, 0.318 mmol, Example 82, Step 2), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (123 mg, 0.381 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), Pd2(dba)3 (18.28 mg, 0.032 mmol, Strem Chemicals, Newburyport, Mass.), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (14.83 mg, 0.032 mmol, Strem Chemicals, Newburyport, Mass.), and sodium tert-butoxide (122 mg, 1.272 mmol) were combined and suspended in toluene (5 mL). Nitrogen gas was bubbled through the solution for 5 min. The reaction vial was sealed and heated to 100° C. for 15 h. The reaction mixture was then diluted with water and EtOAc. The aqueous mixture was extracted with EtOAc (2×20 mL). The organic extracts were combined and dried over MgSO4, filtered, and concentrated. The crude material was purified by purified via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in MeCN/H2O (10% to 100% over 15 min) to afford 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (23 mg).

Workup

  1. customNitrogen gas was bubbled through the solution for 5 min
  2. customThe reaction
  3. customvial was sealed
  4. extractionThe aqueous mixture was extracted with EtOAc (2×20 mL)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude material was purified
  9. customby purified via reverse-phase preparative HPLC
  10. washeluting with 0.1% TFA in MeCN/H2O (10% to 100% over 15 min)

Sources & evidence

ORD record
ord-f303d5a2db8447789fe8ada98bd6bc37
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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