A Practical Synthesis of a Key Chiral Drug Intermediate via Asymmetric Organocatalysis

Abstract

The versatility of asymmetric organocatalysis is demonstrated by the practical synthesis of methyl (2R,3S)-3-(4-methoxy­phenyl)glycidate, a key intermediate in the synthesis of diltiazem. Methyl (E)-4-methoxycinnamate underwent asymmetric epoxidation using a chiral dioxirane, generated in situ from Yang’s catalyst, to provide the product in both high chemical and optical yields. The crude reaction mixture was purified utilizing a novel and simple apparatus performing lipase-catalyzed transesterification, followed by continuous dissolution and crystallization to give the desired optically pure product and catalyst in excellent yields (74% and 91%, respectively). This protocol has addressed previous scale-up issues and has achieved validity as a process to secure the product and the recovered catalyst in high optical purity. In addition, the best possible syntheses of Yang’s catalyst and methyl (E)-4-methoxycinnamate, both critical for the entire process, were also optimized.

1 Introduction

2 A Key Intermediate for Diltiazem

3 Strategy

4 Synthesis of Yang’s Catalyst

4.1 Through an Intramolecular Ullmann Reaction

4.2 Through Catalytic Cyclization of a Monoglycidyl Ester

4.3 Through Improvement of the Original Method

4.3.1 Salt Resolution of 1,1′-Binaphthalene-3,3′-dicarboxylic Acid

4.3.2 Racemization of the Unwanted Enantiomer and Recycling

4.3.3 Formation of the 11-Membered Ring

5 Synthesis of Methyl (E)-4-Methoxycinnamate

6 Asymmetric Epoxidation of Methyl (E)-4-Methoxycinnamate

7 Separation and Purification of the Product and Yang’s Catalyst

8 Conclusion

Key words

drugs - asymmetric catalysis - epoxidations - biaryls - chiral resolution

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