Catalytic Asymmetric Synthesis of Esomeprazole by a Titanium Complex with a Hexa-aza-triphenolic Macrocycle Ligand

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

Keywords:

• Asymmetric catalysis
• chiral macrocycles
• enantioselective sulfoxidation
• esomeprazole

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.