2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl → HCID 86670308, compound

HRID 1972351Notes

Reaction equation

HRID 1972351 reaction equation
CC(C)([O-])C.[Na+].[CH:7]1([C@@H:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH2:9][CH2:8]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.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>[CH:7]1([C@H:10]2[NH:11][CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:29])([F:31])[F:30])[C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH2:15]2)[CH2:9][CH2:8]1

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 51634949HCID 51634949, compound

Product 1

HCID 86670308HCID 86670308, compound

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

A 20 mL vial was charged with toluene (1.2 mL), sodium tert-butoxide (69.2 mg, 720 μmol) were added to (R)-2-cyclopropyl-piperazine (59.7 mg, 300 μmol, Anichem, North Brunswick, N.J.), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (97 mg, 300 μmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos), (21.0 mg, 45.0 μmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (13.7 mg, 15.00 μmol, Strem Chemical Inc, Newburyport, Mass.). The reaction was heated to 90° C. for 40 h, then cooled to 23° C., and diluted with water (15 mL) and extracted with CH2Cl2 (15 mL). The organic layer was loaded onto an AccuBOND II SCX cartridge (Krackeler Scientific, Inc., Albany, N.Y.) (6 g), washed with MeOH (5 mL) and eluted with 2N NH3 in MeOH (10 mL) to give (R)-2-(4-(3-cyclopropylpiperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol. To this was added a solution of 2-thiophenesulfonyl chloride (54.8 mg, 300 μmol, Sigma-Aldrich, St. Louis, Mo.) and Hünig's base (57.5 μL, 330 μmol) in CH2Cl2 (0.6 mL). The reaction was stirred at 23° C. for 18 h and then concentrated to dryness. The crude material was purified by reverse-phase preparative HPLC using a Gemini C18 100 A column (150×30 mm), eluting with 0.1% TFA in CH3CN/H2O (10% to 90% over 12 min) to give 2-(4-((3R)-3-cyclopropyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.93 (dd, J=5.3 1.3 Hz, 1H), 7.71 (dd, J=3.7, 1.1 Hz, 1H), 7.46 (d, J=9.2 Hz, 2H), 7.18 (dd, J=4.8, 4.0 Hz, 1H), 6.95 (d, J=9.7 Hz, 2H), 2.67 (dd, J=12.5, 3.7 Hz, 1H), 2.52-2.60 (m, 4H), 1.30-1.42 (m, 1H), 0.35-0.56 (m, 6H). m/z (ESI, +ve ion) 515.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=5.0 μM.

Workup

  1. temperaturecooled to 23° C.
  2. extractionextracted with CH2Cl2 (15 mL)
  3. washwashed with MeOH (5 mL)
  4. washeluted with 2N NH3 in MeOH (10 mL)

Sources & evidence

ORD record
ord-5dff47952b6b421e95122c0dc732d64d
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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