Type a reaction class (ex: alkylation) or name (ex: Lossen rearrangement)

Tuesday, October 6, 2015

Synthetic route and process optimization proposal of Rucaparib a PARP inhibitor (PF-01367338 or AG-014699)


Key words: zeolite, acetalization, cross-coupling, acylation, nucleophilic aromatic substitution, indolization, hydrolysis, alkylation, reductive amination. leuckart

Complete report here

Original synthesis procedure and route

Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor
Chemical Research and Development, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom,
Organic Process Research and Development 2012, Vol 16, 1897−1904
Optimized route and process (starting material cheaper, 9 steps instead of 12, 5 isolations)

The publication indicate a poor global yield (2.9%) even if the process is optimized, also the chosen indolization method seems to be difficult, metal catalyzed reaction employing boronic acids which are now recognized as mutagenic, reduction with cyanoborohydride and numerous steps.

The “ideal” route i have chosen involves a Fisher indolization. Few steps are tricky due to some functional group fragility, but by designing the process correctly, some side reactions could be avoided. Even if undesirable reaction occurs significantly, i have indicated some alternatives which, unfortunately, involve a cost.

The key point of this route is the indolization, i have evaluated the feasibility by some lectures and by using the software Hulis (Huckel theory), to roughly make a comparison between the hydrazone intermediate and intermediates seen in the literature, especially the trifluoroacetyl one. Starting at 4, it is really more an exploration, that’s why i have indicated some alternatives.

Complete report here

This is some personal works on paper only, i have no responsibility in any way if somebody would try this route and has all sort of troubles, including but not limited to: injuries and money loss. This is for experienced chemists only, and tests must be conducted in a suitable lab only.

But if my work is used to synthesize the targeted molecule described here, please, send a word, even if it fail, chemistry is always an experimental science. This will make me pleased, thank you.

© David Le Borgne, 2015, specialist in chemical process development and optimization.