Sodium Bicarbonate → 4-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-(1-methylethyl)-2-piperazinone

HRID 1972564Notes

Reaction equation

HRID 1972564 reaction equation
[CH3:1][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][N:15]([S:17]([C:20]3[S:21][C:22]([N+:25]([O-])=O)=[CH:23][CH:24]=3)(=[O:19])=[O:18])[CH2:14][CH2:13][N:12]2[C:28]2[N:33]=[CH:32][C:31]([C:34]([OH:43])([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])=[CH:30][N:29]=2)[CH2:8][CH2:7][NH:6][C:5]1=[O:44])[CH3:3].C([O-])(O)=O.[Na+]>C(O)(=O)C.[Fe]>[NH2:25][C:22]1[S:21][C:20]([S:17]([N:15]2[CH2:14][CH2:13][N:12]([C:28]3[N:29]=[CH:30][C:31]([C:34]([OH:43])([C:35]([F:36])([F:38])[F:37])[C:39]([F:40])([F:41])[F:42])=[CH:32][N:33]=3)[C@@H:11]([CH2:10][N:9]3[CH2:8][CH2:7][NH:6][C:5](=[O:44])[CH:4]3[CH:2]([CH3:3])[CH3:1])[CH2:16]2)(=[O:18])=[O:19])=[CH:24][CH:23]=1

Participants

5

Reactant 2

HCID 516892Sodium BicarbonateHCID 866703983-(1-methylethyl)-4-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-2-piperazinone

Product 1

HCID 866703994-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-(1-methylethyl)-2-piperazinone

Reagents, catalysts & solvents 2

HCID 23925IronCatalystHCID 176Acetic AcidSolvent

Conditions

Temperature
50 °C

Procedure

3-(1-methylethyl)-4-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-2-piperazinone (228 mg, 0.337 mmol) and iron filings (94 mg, 1.69 mmol, Sigma-Aldrich, St. Louis, Mo.) were combined in acetic acid (7.18 mL). The reaction mixture was stirred at 50° C. for 1.5 h. The mixture was allowed to cool to room temperature and saturated aqueous NaHCO3 was slowly added. After partitioning with EtOAc, the aqueous phase was extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The crude product was purified by silica gel chromatography (25 to 75% EtOAc in hexanes gradient) to give a mixture of diastereomers which were separated via preparative SFC (Chrialpak® ASH (21×250 mm, 5 μm)), eluting with liquid CO2 in 30% methanol with 20 mM NH3, at a flow rate of 65 mL/min (40° C.), to give two products in >95% diastereomeric excess and >98% purity:

Workup

  1. temperatureto cool to room temperature
  2. customAfter partitioning with EtOAc
  3. extractionthe aqueous phase was extracted with EtOAc (×3)
  4. dry with materialThe combined organic extracts were dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto give a light brown oil
  8. customThe crude product was purified by silica gel chromatography (25 to 75% EtOAc in hexanes gradient)
  9. customto give
  10. additiona mixture of diastereomers which
  11. customwere separated via preparative SFC (Chrialpak® ASH (21×250 mm, 5 μm))
  12. washeluting with liquid CO2 in 30% methanol with 20 mM NH3, at a flow rate of 65 mL/min (40° C.)
  13. customto give two products in >95% diastereomeric excess and >98% purity

Sources & evidence

ORD record
ord-8efdb2735aa04876bdee98e8a05d94e1
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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