Methanol → Methyl (δS)-δ-[[(S)-(1,1-dimethylethyl)sulfinyl]amino]-3,5-difluoro-α,α-dimethylbenzenepentanoate

HRID 1866606Notes

Reaction equation

HRID 1866606 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:20][C:21]([S@@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].[BH4-].[Na+].CO>C1COCC1.[Cl-].[Na+].O.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[C:21]([S@@:24]([NH:26][C@H:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH2:10][CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[O:25])([CH3:23])([CH3:22])[CH3:20]

Participants

8

Reactant 4

HCID 887MethanolHCID 4311764Sodium borohydrideHCID 11355477tert-Butylsulfinamide, (S)-(-)-HCID 57974028Methyl 3,5-difluoro-α,α-dimethyl-δ-oxobenzenepentanoate

Product 1

HCID 66864959Methyl (δS)-δ-[[(S)-(1,1-dimethylethyl)sulfinyl]amino]-3,5-difluoro-α,α-dimethylbenzenepentanoate

Reagents, catalysts & solvents 3

HCID 76524Titanium tetraethoxideCatalystHCID 8028TetrahydrofuranSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

To a solution of methyl 5-(3,5-difluorophenyl)-2,2-dimethyl-5-oxopentanoate from Step D (500. mg, 1.85 mmol) and (S)-2-methylpropane-2-sulfinamide (336 mg, 2.78 mmol) in THF (6.5 mL), was added titanium tetraethoxide (616 mg, 2.52 mmol). The reaction vessel was quickly sealed and placed into a 60° C. bath for 3 hours. After cooling to ambient temperature a septum and nitrogen inlet were attached prior to cooling to 0° C. Sodium borohydride (191 mg, 5.05 mmol) was then added, and a complete reaction was observed after 15 minutes. Methyl alcohol was then slowly added until gas evolution had stopped. The reaction mixture was then diluted with saturated brine (6.5 mL) while experiencing rapid stirring. The resultant slurry was filtered through celite, washing with EtOAc as needed. The combined organics were then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of EtOAc:Hexanes—10:90 to 70:30, to give the title compound containing about 12% of the corresponding ethyl ester. MS: m/z=376 (M+1).

Workup

  1. customThe reaction vessel was quickly sealed
  2. customplaced into a 60° C.
  3. customfor 3 hours
  4. temperatureto cooling to 0° C
  5. customa complete reaction
  6. filtrationThe resultant slurry was filtered through celite
  7. washwashing with EtOAc
  8. washThe combined organics were then washed with brine
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customto give an oil
  13. customThis oil was purified by silica gel chromatography
  14. washeluting with a gradient of EtOAc

Sources & evidence

ORD record
ord-2106c71903be4392b41a455dc309e6a9
Source dataset
uspto-grants-2009_12
Patent number
US07629338B2

Reaction notes

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