Methyl Acetate → (S)-3-(2-Chloro-3-fluorophenyl)-3-((R)-2-methylpropane-2-sulfinylamino)propionic acid methyl ester

HRID 339816Notes

Reaction equation

HRID 339816 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[Cl:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:26]=[N:27]/[S:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29].[Cl-].[NH4+]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3].C(OCC)(=O)C>[CH3:17][O:16][C:13](=[O:15])[CH2:14][C@@H:26]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[Cl:18])[NH:27][S@@:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29]

Participants

9

Reactant 5

HCID 6584Methyl AcetateHCID 7912DiisopropylamineHCID 25517Ammonium ChlorideHCID 88924234(NE)-N-[(2-chloro-3-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamideHCID 178418339Butyllithium

Product 1

HCID 68309451(S)-3-(2-Chloro-3-fluorophenyl)-3-((R)-2-methylpropane-2-sulfinylamino)propionic acid methyl ester

Reagents, catalysts & solvents 3

HCID 11673339ChlorotitaniumtriisopropoxideCatalystHCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-75 °C

Procedure

To diisopropylamine (4.13 ml), dissolved in THF (200 ml), was slowly added dropwise 1.6 N butyllithium (17.55 ml) at 0° C., and then the mixture was stirred for thirty minutes. Subsequently, the mixture was cooled to −75° C. and methyl acetate (2.13 ml) dissolved in THF (5 ml) was added, and the mixture was stirred for a further thirty minutes. Then chlorotitanium triisopropoxide (56.15 ml, 1 molar in hexane) was added dropwise at the same temperature and the mixture was stirred again for thirty minutes. N-[1-(2-Chloro-3-fluorophenyl)meth-(E)-ylidene]-2-methylpropane-2-sulfinamide was dissolved in THF (10 ml) and added dropwise at −75° C., and the mixture was stirred at the same temperature for three hours. The mixture was poured onto cold saturated ammonium chloride solution and admixed with ethyl acetate, and stirred for fifteen minutes. The phase mixture was then clarified using kieselguhr, the organic phase was removed and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (silica gel 40-63 μm, ethyl acetate). This gave the product (4.1 g) with a de of 72% by NMR.

Workup

  1. additionwas added
  2. stirringthe mixture was stirred for a further thirty minutes
  3. stirringthe mixture was stirred again for thirty minutes
  4. additionadded dropwise at −75° C.
  5. stirringthe mixture was stirred at the same temperature for three hours
  6. stirringstirred for fifteen minutes
  7. customthe organic phase was removed
  8. extractionthe aqueous phase was extracted with ethyl acetate (2×50 ml)
  9. dry with materialThe combined organic phases were dried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe residue was purified by chromatography (silica gel 40-63 μm, ethyl acetate)

Sources & evidence

ORD record
ord-30a95196d9d54c8c80d6583bfbcd07db
Source dataset
uspto-grants-2014_11
Patent number
US08895547B2

Reaction notes

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