HCID 86612965, compound → (R)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide

HRID 1993604Notes

Reaction equation

HRID 1993604 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)=[N:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[N:6][CH:7]=1.[CH2:27]([Mg])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(OC)(C)C.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:6][CH:7]=1

Participants

5

Reactant 2

HCID 86612965HCID 86612965, compoundHCID 178507043HCID 178507043, compound

Product 1

HCID 66814189(R)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamideYield 72%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 15413tert-Butyl methyl etherSolvent

Procedure

To a solution of (R)-N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-2-methylpropane-2-sulfinamide (1.09 g, 2.68 mmol) in anhydrous TBME (45 mL) at −78° C. under argon was added BF3Et2O (0.57 mL, 5.38 mmol). After 5 min, benzylmagnesium grignard (5.38 mL, 5.38 mmol, 1.0M in ether) was added dropwise with stirring. After 40 min, LCMS indicated that the reaction was complete and the cold solution was quenched with saturated NaCl (ca 20 mL), transferred to a separation funnel and the organic phase extracted with EtOAc (3×20 mL). The combined organic portions were dried, decanted, concentrated and purified by silica gel ISCO chromatography. 2×120 g cartridge columns were used 0-60% EtOAc/hexanes over 20 min. A trace amount of minor diastereomer eluted first followed by the major diastereomer (R)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (0.97 g, 72% yield). Rf 0.4 (Hexane:EtOAc 2:1) LCMS: 2.15 min [M+1] 499.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 4.15 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 99%; NMR: 400 MHz 1H (CDCl3) 8.65 ppm, d, 1H, J=2.6 Hz; 7.62 ppm, dd, 1H, J=2.6 and J=8.8 Hz; 7.36 ppm, 4H, m; 7.29 ppm, 1H, m; 7.24 ppm, 1H, m; 7.14 ppm, 2H, m; 6.99 ppm, 1H, d, J=10.1 Hz; 6.81 ppm, 1H, d, J=6.6 Hz; 4.09 ppm, 1H, d, J=13.2 Hz; 3.69 ppm, 1H, d, J=13.2 Hz; 1.18 ppm, 9H, s.

Workup

  1. additionwas added dropwise
  2. waitAfter 40 min
  3. customthe cold solution was quenched with saturated NaCl (ca 20 mL)
  4. customtransferred to a separation funnel
  5. extractionthe organic phase extracted with EtOAc (3×20 mL)
  6. customThe combined organic portions were dried
  7. customdecanted
  8. concentrationconcentrated
  9. custompurified by silica gel ISCO chromatography
  10. customover 20 min
  11. washA trace amount of minor diastereomer eluted first

Sources & evidence

ORD record
ord-c4294b4e30fc479191e05023fd768ac9
Source dataset
uspto-grants-2010_01
Patent number
US07652023B2

Reaction notes

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