Stereoselective Synthesis of (Z)-1-Benzhydryl-4-cinnamylpiperazines via the Wittig Reaction

Abstract

A synthetic method of producing (E)- and (Z)-isomers of 1-benzhydryl-4-cinnamylpiperazines in a specific ratio from corresponding benzhydrylpiperazine is described. Of the three compounds synthesized (5a–c), the ratio of E/Z-isomers remained around 15:85. The key intermediates, 1-benzhydryl-4-(2,2-dimethoxyethyl)piperazine derivatives (3a–c), were prepared by nucleophilic substitution reaction of benzhydrylpiperazines (2a–c) with chloroacetaldehyde dimethylacetal in good yield (up to 88%). Hydrolysis of 3a–c gave the corresponding aldehydes 4a–c, which when subjected to the Wittig reaction followed by column purification to afford 1a–c (E-isomers) and 6a–c (Z-isomers) in pure form. The isolated compounds were characterized by NMR and mass spectral analysis.

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GRAPHICAL ABSTRACT

Keywords:

• Benzhydrylpiperazines
• cinnarizine
• clocinizine
• flunarizine
• Wittig reaction

ACKNOWLEDGMENTS

The authors thank Anil Kush, CEO of Vittal Mallya Scientific Research Foundation, Bangalore, for his kind support and encouragement, and A. C. Karunakara and Aparna Bhat for analytical help.

Notes

^a No baseline separation in HPLC and hence the discrepancy.