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DOI: 10.1055/s-2007-1000883
A Practical Synthesis of a Key Chiral Drug Intermediate via Asymmetric Organocatalysis
Publikationsverlauf
Received
4 September 2007
Publikationsdatum:
21. Dezember 2007 (online)
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