tert-Butyl methyl ether → 2-(4-((2R)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

HRID 1972336Notes

Reaction equation

HRID 1972336 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:15]([O:22][CH2:23][C@@H:24]1[NH:29][CH2:28][CH2:27][N:26]([S:30]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)(=[O:32])=[O:31])[CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].COC(C)(C)C>O.C1(C)C=CC=CC=1>[CH2:15]([O:22][CH2:23][C@H:24]1[CH2:25][N:26]([S:30]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:32])[CH2:27][CH2:28][N:29]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1

Participants

7

Reactant 4

HCID 15413tert-Butyl methyl etherHCID 23676156Sodium t-butoxideHCID 583472902-(4-Bromophenyl)-1,1,1-trifluoropropan-2-olHCID 70655680(3R)-3-((benzyloxy)methyl)-1-(2-thiophenylsulfonyl)piperazine

Product 1

HCID 665825382-(4-((2R)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanolYield 74%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
65 °C

Procedure

A 1-L pressure vessel was charged with 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (43.8 g, 163 mmol, Example 27, Step 1), (3R)-3-((benzyloxy)methyl)-1-(2-thiophenylsulfonyl)piperazine (47.8 g, 136 mmol), 200 mL of toluene, and sodium tert-butoxide (32.6 g, 339 mmol). After bubbling nitrogen gas through the solution for 5 min, chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (RuPhos Palladacycle) (0.99 g, 1.36 mmol, Strem Chemicals, Newburyport, Mass.) and 2-dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.63 g, 1.36 mmol, Strem Chemicals, Newburyport, Mass.) were added. The vessel was sealed and heated at 65° C. for 12 h. After that time, the mixture was diluted with water and extracted with EtOAc, dried (MgSO4), filtered, and concentrated. Purification by column chromatography on silica gel (0 to 60% EtOAc in hexanes) gave 2-(4-((2R)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (54.4 g) as a yellow foam.

Workup

  1. customAfter bubbling nitrogen gas through the solution for 5 min
  2. customThe vessel was sealed
  3. extractionextracted with EtOAc
  4. dry with materialdried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by column chromatography on silica gel (0 to 60% EtOAc in hexanes)

Sources & evidence

ORD record
ord-13e60965966c4ce98fb5c469f11a5224
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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