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Synfacts 2011(10): 1041-1041  
DOI: 10.1055/s-0030-1261043
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of a 5HT7/5HT2 Dual Antagonist

Contributor(s):Philip Kocienski
J. T. Liang*, X. Deng, N. S. Mani
Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, USA
Convergent Synthesis of a 5HT7/5HT2 Dual Antagonist
Org. Process Res. Dev.  2011,  15:  876-882  
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Publication History

Publication Date:
20 September 2011 (online)

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Key words

5HT7/5HT2 dual antagonist - nitroaldol reaction - pyrazole ring formation

Significance

The target pyrazolo[3,4-d]azepane is a 5HT7/5HT2 dual antagonist that was of interest for the treatment of depression, psychosis, anxiety and sleep disorders. This notably short synthesis features (1) the regioselective construction of pyrazole E by reaction of hydrazone D with nitroalkene C and (2) the four-step, one-pot reductive annulation sequence converting E into the target azepane.

Comment

Hydrazone D was prepared in 98% yield (crude) by the reaction of benzyl-N-(3-oxopropyl)carbamate with isopropylhydrazine in the presence of Et3N (1.2 equiv) in refluxing i-PrOH. The reaction of C and D was conducted in Et3N as solvent in order to efficiently capture the HNO2 eliminated during the pyrazole annulation.

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