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

Monday, September 28, 2015

Synthetic route optimization proposal of Gamendazole - Experimental male oral contraceptive

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,
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

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.

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.