Vertex Pharmaceuticals, Inc.

Stefania Leonardi

Andrea L C Robidoux

Petra Dieterich

Jeffrey Douglas Wilson

Neil Storer

Siro Serafini

John Stibbard

Petra Dietrich

The invention relates to a process for synthesizing piperazic acid and similar, ring-containing acids. The invention also relates to a process for simultaneously N(2)-acylating piperazic acid or an ester thereof and forming a bicyclic ring structure. The invention also relates to the use of either or both processes in a method of synthesizing a bicyclic compound useful as an intermediate for the production of an inhibitor of a caspase, particularly an inhibitor of interleukin-1&bgr; converting enzyme (&ldquo;ICE&rdquo;).

Method of preparing bicyclic intermediates from piperazic acid or an ester thereof useful in the manufacture of caspase inhibitors

This invention provides a concise, asymmetric synthesis of piperazic acid and derivatives thereof, whereby either the (3S)- or (3R)-enantiomeric form may be obtained with high optical purity. (3S)-piperazic acid is derived from D-glutamic acid through an (R)-2,5-dihydroxyvalerate ester intermediate. After the hydroxy groups are converted to suitable leaving groups, such as mesylates, the ester is treated with a bis-protected hydrazine to provide the desired (3S)-piperazic acid derivative. The (3R) enantiomer of piperazic acid may be similarly obtained starting with L-glutamic acid. The method may also be used to obtain piperazic acid derivatives that have moderate optical purity or are racemic. By this method, piperazic acid derivatives may be obtained that are useful as intermediates for pharmacologically active compounds. For example, certain intermediates of this invention are useful for preparing caspase inhibitors, particularly inhibitors of ICE, through additional steps known in the art.

Asymmetric synthesis of piperazic acid and derivatives thereof

The invention relates to a process for simultaneously N(2)-acylating piperazic acid or an ester thereof and forming a bicyclic ring structure. The invention also relates to the use of that process step in a method of synthesizing a bicyclic compound useful as an intermediate for the production of an inhibitor of a caspase, particularly an inhibitor of interleukin-1&bgr; converting enzyme (&ldquo;ICE&rdquo;).

Method for synthesizing caspase inhibitors

Process for forming an N-acylated, N,N-containing bicyclic ring from piperazic acid or an ester thereof especially useful as an intermediate in the manufacture of a caspase inhibitor

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Wallingford, United Kingdom

Stefania Leonardi