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

Target

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

http://pubs.acs.org/doi/abs/10.1021%2Fop200238p

Details of the publication is here: http://newdrugapprovals.org/2015/06/09/ag-014699-rucaparib/

Optimized route and process (starting material cheaper, 9 steps instead of 12, 5 isolations)

Optimization

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

Disclaimer:
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.

Synthetic route optimization proposal of Gamendazole - Experimental male oral contraceptive

Target

Key words: Fisher indolization, alkylation, imine, Fisher base, acylation, saponification

Complete report here

Original synthesis procedure and route

 

Total Syntheses of AF-2785 and Gamendazole—Experimental Male Oral Contraceptives,

Arava Veerareddy, Gogireddy Surendrareddy & P. K. Dubey,

Synthetic Communications

http://www.tandfonline.com/doi/full/10.1080/00397911.2012.696306

Volume 43, Issue 16, August 2013, pages 2236-2241

Details of the publication is here: http://newdrugapprovals.org/2015/08/19/gamendazole-a-novel-drug-candidate-for-male-contraception/

The synthesis presents few drawbacks:

• Solvent diversity
• Use of dihydrogen implying a specific reactor
• Manganese oxide and Wittig reagent which complicate the isolation
• Use of an hydride

Optimized route

Optimization

700$/kg cheaper based on kilogram scale (reaction assumed quantitative to facilitate the comparison – see costing) with a shorter route from 9 to 6 steps, reducing the reagent diversity (and probably solvent), avoiding the use of H2, DIBAL-H, MnO2 and Wittig reagent, adopt the Fisher base strategy with 3-methyl Indazole.

But instead of have the precursor of the 3-methyl which involve some reduction / oxidation steps, i have chosen to have it directly with the starting material. It is more expensive, but by reducing the total synthesis from 9 to 6 steps and 3 one pot 2in1, the starting material cost difference should be absorbed. By this way, i can use the “fisher base like behavior” to add the side chain by adding an acetyl on the 2-N. I don’t know the solubility in DME, the solvent process must be modified if it is inadequate. I have take it as reference, since it is used in the first step in the literature, is polar and miscible with water.

The part where i am a little dubitative is the 5th step with the elimination of the acetanilide. A varia could be the use of the ethyl glyoxylate directly without a pre-activation by an imine if the methylene derivative is sufficiently nucleophile, and activate the alpha hydroxy by a tosylation to afford an E1 type elimination, or make the coupling (imine-ene reaction) with a Lewis acid.

Complete report here

Disclaimer:
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 fails, chemistry is always an experimental science. This will make me pleased, thank you.

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