Ethyl Acetate → 1,1-dimethylethyl (2S)-2-methyl-4-{[2-methyl-4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate

HRID 43380Notes

Reaction equation

HRID 43380 reaction equation
Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:17]([CH3:28])[CH2:16]1)(=[O:14])=[O:13].[C:29](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C@H:17]1[CH2:16][N:15]([S:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[CH3:29])(=[O:14])=[O:13])[CH2:20][CH2:19][N:18]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 574072TrimethylboroxineHCID 591520681,1-dimethylethyl (2S)-4-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-2-methyl-1-piperazinecarboxylate

Product 1

HCID 666493621,1-dimethylethyl (2S)-2-methyl-4-{[2-methyl-4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylateYield 90.6%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 1,1-dimethylethyl (2S)-4-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-2-methyl-1-piperazinecarboxylate (may be prepared as described in Description 23) (1.00 g, 2.05 mmol), potassium carbonate (0.737 g, 5.34 mmol) in 1,4-dioxane (43 ml) were stirred for 5 min then trimethylboroxin (0.743 ml, 5.34 mmol) and Pd(Ph3P)4 (0.403 g, 0.349 mmol) were added and the reaction mixture heated at 100° C. overnight. EtOAc (100 ml) was added, then the mixture was washed with aqueous sodium bicarbonate (100 ml), water (100 ml) and concentrated under vacuum. Flash chromatography (silica; linear gradient (0-20%) EtOAc in isohexane) gave 1,1-dimethylethyl (2S)-2-methyl-4-{[2-methyl-4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (0.785 g). This material was re-dissolved in DCM (10 ml) and 1,4-dioxane (3 ml), then HCl in dioxane (5 eq) was added and the mixture stirred at room temperature for 4 h. Aqueous sodium bicarbonate (20 ml) and EtOAc (20 ml) were added and the organic phase washed with aqueous sodium bicarbonate (2×10 ml), brine (10 ml) and dried using a hydrophobic frit. The solvent was removed under vacuum. The residue was re-dissolved in DCM (10 ml) and 1,4-dioxane (3 ml), then 4M HCl in 1,4-dioxane (6.97 mL, 27.9 mmol) added. The mixture was stirred at room temperature for 4 h. The solvent was evaporated under vacuum to give the title compound (0.615 g) as the hydrochloride salt.

Workup

  1. washthe mixture was washed with aqueous sodium bicarbonate (100 ml), water (100 ml)
  2. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-e798b76964c84564b6372d392669fbd2
Source dataset
uspto-grants-2013_09
Patent number
US08536183B2

Reaction notes

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