Abstract
An efficient synthesis of esomeprazole via catalytic asymmetric oxidation of 1H-benzimidazolyl pyridinylmethyl sulfide by a titanium complex with a hexa-aza-triphenolic macrocycle ligand is described. Esomeprazole was prepared with 99.6% ee, which meets the high requirement of the European Pharmacopeia on enantiomeric purity.
GRAPHICAL ABSTRACT
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Notes
a Reaction conditions: 1 (165 mg, 0.5 mmol), H2O/L1 = 2/1 (mol/mol), NEt(Pr-i)2/L1 = 2/1 (mol/mol), CHP (80%, 110.5 mg, 0.65 mmol, 1.3 eq.), toluene (20 mL), rt.
b Measured by HPLC on Diamosil C18 column, acetonitrile/buffer solution (pH 7.5) = 27/73, 1.0 mL/min, 280 nm.
c Measured by HPLC on CHIRAL-AGP column, acetonitrile/buffer solution (pH 6.0) = 64/36, 0.6 mL/min, 302 nm.
a Reaction conditions: 1 (165 mg, 0.5 mmol), Ti(OPr-i)4 (66.7 mg, 0.235 mmol), L1 (67.1 mg, 0.065 mmol, 13 mol%), NEt(Pr-i)2 (16.8 mg, 0.13 mol), CHP (80%, 110.5 mg, 0.65 mmol, 1.3 eq.), toluene (20 mL), rt.
b Measured by HPLC on Diamosil C18 column, acetonitrile/buffer solution (pH 7.5) = 27/73, 1.0 mL/min, 280 nm.
c Measured by HPLC on CHIRAL-AGP column, acetonitrile/buffer solution (pH 6.0) = 64/36, 0.6 mL/min, 302 nm.
d No additional water was added.
a Reaction conditions: 1 (165 mg, 0.5 mmol), Ti(OPr-i)4 (66.7 mg, 0.235 mmol), L1 (67.1 mg, 0.065 mmol, 13 mol%), H2O/L1 = 2/1 (mol/mol), CHP (80%, 110.5 mg, 0.65 mmol, 1.3 eq.), toluene (20 mL), rt.
b Measured by HPLC on Diamosil C18 column, acetonitrile/buffer solution (pH 7.5) = 27/73, 1.0 mL/min, 280 nm.
c Measured by HPLC on CHIRAL-AGP column, acetonitrile/buffer solution (pH 6.0) = 64/36, 0.6 mL/min, 302 nm.
a Reaction conditions: 1 (165 mg, 0.5 mmol), Ti(OPr-i)4 (66.7 mg, 0.235 mmol), L1 (67.1 mg, 0.065 mmol, 13 mol%), H2O/L1 = 2/1 (mol/mol), NEt(Pr-i)2 (16.8 mg, 0.13 mol), solvent (20 mL), rt.
b Measured by HPLC on Diamosil C18 column, acetonitrile/buffer solution (pH 7.5) = 27/73, 1.0 mL/min, 280 nm.
c Measured by HPLC on CHIRAL-AGP column, acetonitrile/buffer solution (pH 6.0) = 64/36, 0.6 mL/min, 302 nm.