2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl → 1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol

HRID 1972479Notes

Reaction equation

HRID 1972479 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][N: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>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:10]2[CH2:11][CH2:12][N:13]([S:15]([C:18]3[S:19][CH:20]=[CH:21][N:22]=3)(=[O:17])=[O:16])[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

7

Reactant 4

HCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 23676156Sodium t-butoxideHCID 583472902-(4-Bromophenyl)-1,1,1-trifluoropropan-2-olHCID 66582844(3S)-3-methyl-4-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-2-piperazinyl)methyl)morpholine

Product 1

HCID 569324701,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanolYield 6.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A 20-mL vial was charged with (3S)-3-methyl-4-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-2-piperazinyl)methyl)morpholine (210 mg, 0.61 mmol), 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (326 mg, 1.21 mmol, Example 27, Step 1), sodium tert-butoxide (175 mg, 1.82 mmol), Pd2(dba)3 (55.5 mg, 0.061 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (42.4 mg, 0.091 mmol, Strem Chemicals, Newburyport, Mass.) and toluene (5 mL). the vial was sealed and heated to 100° C. for 3 h. The reaction was filtered, concentrated and purified via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min) to give 1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (20 mg) that was a mixture of two isomers.

Workup

  1. customthe vial was sealed
  2. filtrationThe reaction was filtered
  3. concentrationconcentrated
  4. custompurified via reverse-phase preparative HPLC
  5. washeluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min)

Sources & evidence

ORD record
ord-16653f8c09b14cf3a3c4b89967315281
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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