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. 2013 Mar 20;54(12):1546-1549.
doi: 10.1016/j.tetlet.2013.01.024.

Efficient Synthesis of ESI-09, A Novel Non-cyclic Nucleotide EPAC Antagonist

Haijun Chen  1 , Chunyong Ding, Christopher Wild, Huiling Liu, Tianzhi Wang, Mark A White, Xiaodong Cheng, Jia Zhou
Affiliations

Efficient Synthesis of ESI-09, A Novel Non-cyclic Nucleotide EPAC Antagonist

Haijun Chen et al. Tetrahedron Lett. .

Abstract

A concise and efficient synthetic approach to producing a novel non-cyclic nucleotide EPAC antagonist ESI-09 and its new analogs is reported. Key features of the synthesis include a mild and reliable one-pot procedure for an isoxazole synthon, as well as a modified one-pot protocol for the cyanomethyl ketone key intermediate. The synthesis requires inexpensive starting materials and only three linear steps for the completion in a total yield of 53%.

Keywords: EPAC antagonist; ESI-09; cyanomethyl ketone; isoxazole; modified Kowalski's protocol.

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Figures

Figure 1
Figure 1
Structure of ESI-09 (1).
Scheme 1
Scheme 1
Retrosynthetic analysis of ESI-09 (1).
Scheme 2
Scheme 2
One-pot synthesis of 5-tert-butylisoxazole-3-carboxylic acid ethyl ester 6.
Scheme 3
Scheme 3
Synthesis of 2-bromo-1-(5-tert-butylisoxazol-3-yl)ethanone 7.
Scheme 4
Scheme 4
Synthesis of 3-(5-tert-butylisoxazol-3-yl)-3-oxo-propionitrile 8.
Scheme 5
Scheme 5
Synthesis of 3-(5-tert-butylisoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile 1.
Scheme 6
Scheme 6
Synthesis of 3-(5-tert-butylisoxazol-3-yl)-3-oxo-propionitrile 8 from 6.
Scheme 7
Scheme 7
Synthesis of ESI-09 analogs 12a-d.
See this image and copyright information in PMC

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