2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl → 1,1,1-trifluoro-2-(4-((S)-2-(((S)-3-methylmorpholino)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol

HRID 1972408Notes

Reaction equation

HRID 1972408 reaction equation
[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])[CH2:12][CH2:11][NH:10]1.Br[C:24]1[CH:29]=[CH:28][C:27]([C@:30]([OH:36])([CH3:35])[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.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(O)C.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:10]2[CH2:11][CH2:12][N:13]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:17])[CH2:14][C@@H:9]2[CH2:8][N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[CH:29][CH:28]=1)([OH:36])[CH3:35]

Participants

10

Reactant 4

HCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 23676156Sodium t-butoxideHCID 25129233(R)-alpha-Methyl-alpha-(trifluoromethyl)-4-bromobenzenemethanolHCID 66582524(3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine

Product 1

HCID 665832941,1,1-trifluoro-2-(4-((S)-2-(((S)-3-methylmorpholino)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-olYield 50.2%

Reagents, catalysts & solvents 5

HCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylCatalystHCID 66572931HCID 66572931, compoundCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
60 °C

Procedure

A 1-L pressure vessel was charged with (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine (10.50 g, 30.4 mmol), 100 mL of toluene, (2R)-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (9.81 g, 36.5 mmol, Example 243, Step 1), and sodium tert-butoxide (7.30 g, 76 mmol). Nitrogen gas through the solution for 3 min then RuPhos Palladacycle (1.107 g, 1.520 mmol) and dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine, RuPhos (0.709 g, 1.520 mmol) were added. The vessel was sealed and heated at 60° C. for 12 h. The mixture diluted with water and extracted with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (0-70% EA/Hex) to give a tan foam. To this foam was added 200 mL of IPA and stirred at rt for 1 h. The white solid that had formed was collected by filtration, dissolved in MeOH, then dried under high vac at 70° C. for 1 h to give pure 1,1,1-trifluoro-2-(4-((S)-2-(((S)-3-methylmorpholino)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol (8.15 g). This material was identical to peak 2 in example 45.

Workup

  1. customThe vessel was sealed
  2. extractionextracted with EtOAc
  3. dry with materialThe combined organics were dried with MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified by column chromatography on silica gel (0-70% EA/Hex)
  7. customto give a tan foam
  8. customThe white solid that had formed
  9. filtrationwas collected by filtration
  10. dissolutiondissolved in MeOH
  11. customdried under high vac at 70° C. for 1 h

Sources & evidence

ORD record
ord-bc687b3e17f641bb970a56d7d9a2c1a3
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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