Diisopropylethylamine → N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide

HRID 1972604Notes

Reaction equation

HRID 1972604 reaction equation
[N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH2:18][N:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:29]1[N:34]=[CH:33][C:32]([C:35]([OH:44])([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[CH:31][N:30]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:29]3[N:30]=[CH:31][C:32]([C:35]([OH:44])([C:36]([F:37])([F:38])[F:39])[C:40]([F:42])([F:43])[F:41])=[CH:33][N:34]=3)[C@@H:14]([CH2:18][N:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 66582584N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamideHCID 866703482-(2-Chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol2×

Product 1

HCID 86670402N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamideYield 17.2%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A 5-mL vial was charged with N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.170 g, 0.386 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.124 g, 0.442 mmol, Intermediate D), DIPEA (0.202 mL, 1.16 mmol), and 1,4-dioxane (2 mL). The vial was sealed and stirred at 100° C. for 21 h. The reaction mixture was allowed to cool to room temperature and partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (20 mL) and the combined organic extracts were washed with saturated aqueous NaCl (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica gel, 40 to 100% EtOAc in hexanes followed by 0-10% (2M NH3 in MeOH) in CH2Cl2) to afford N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.0454 g) as a brown solid.

Workup

  1. customThe vial was sealed
  2. temperatureto cool to room temperature
  3. custompartitioned between water (20 mL) and EtOAc (20 mL)
  4. extractionThe aqueous phase was extracted with EtOAc (20 mL)
  5. washthe combined organic extracts were washed with saturated aqueous NaCl (40 mL)
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by column chromatography (25 g of silica gel, 40 to 100% EtOAc in hexanes followed by 0-10% (2M NH3 in MeOH) in CH2Cl2)

Sources & evidence

ORD record
ord-24467f5ac35242d68a1a45bb188e4964
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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