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

Synthetic route optimization proposal of Gamendazole - Experimental male oral contraceptive


Original synthesis procedure and route
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


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.

Lastly, a “step 0” could be added by using the 4-bromo-2-fluoro-(trifluoromethyl)benzene (5.5 cheaper) to obtain the starting material by an acylation through an organocuprate (obtained by a organozinc). But since the acetophenone derivative is liquid, an oxime should be prepared (hoping it is solid) to isolate the compound, which also make simpler the step of cyclization, by avoiding the 3-amino by product.

Efficient Synthesis of FunctionalizedOrganozinc Compounds by the Direct Insertion of Zinc into Organic Iodides andBromides; A. Krasovski, V. Malakhov, A. Gavryushin, P.Knochel, Angew. Chem. Int. Ed., 2006, 45, 6040-6044. 

NewPractical Synthesis of Indazoles via Condensation of o-Fluorobenzaldehydes andTheir O-Methyloximes with Hydrazine. LUKIN*, K.; HSU, M. C.; FERNANDO, D.;LEANNA, M. R.; J. Org. Chem. 71 (2006) 21, 8166-8172).

I didn't add it in the synthesis, since the solvent must be anhydrous (add cost), and there is most probably time to spend to have a “plant ready” process. Also, i don't like to use metal coupling at plant scale due to a robustness consideration.

Synthetic route  


Step 1: 3-methyl indazole (11)

I think this step could be done in a mix water/DME in presence of a very weak base like sodium acetate to keep a pH near 5 and below to avoid a hydrazone or make an equilibrium displacement to the hydrolysis of the hydrazone if there is some in the mixture (see hydrolytic stability of hydrazones and oximes). A reaction temperature and kinetic study should be done to ensure an aromatic SN without a cyclization with the hydrazone.

Step 2: Alkylation (11) (one pot possible)
Naturally 1-N alkylation is the predominant isomer, but 2-N alkylation occurs at nearly 15 %. This step could probably be chained with the previous one, and a purification here or later, to eliminate the 2-N isomer.

Step 3: N-acylation (12)

To ensure a good deprotonation of the 3-methyl, 2-N must be acylated. The resulting salt is probably soluble in DME, depending the stability and behavior, use AcOCl or Ac2O. My preference would be Ac2O if sufficiently stable, because the counter ion AcO- could play the role of base. If the indazolium salt is not soluble, an appropriate solvent should be found to make it soluble, and this solvent should be also used for the step 4.

Step 4: Preparation of the imine (13) (optional if the tosylate way is used)

To activate the glyoxylate for the coupling, preparation of an imine with aniline in DME with azeotropic distillation to remove the water in presence of sodium acetate and a PTC like aliquat 336.

Inspired from personal experience.

Step 5: Coupling reaction (14) (with no isolated compounds from step 3 and 4 => sort of one-pot)

The imine is activated by addition of Ac2O onto the solution of step 4. Process the coupling by adding dropwise at a determined temperature the solution of step 3. The difficulty here is where will be the double bond: there is the presence of AcONa / AcOH in the mixture, formation of an uncharged molecule with no elimination of the anilide part or elimination of the anilide and the double bond in the good place. To displace the double bond if the anilide remains in place, the mixture could be acidified with AcOH and heated. Once the elimination occurred, make an aqueous basic treatment followed by an acidification to liberate the 2-N and the acid to obtain the targeted molecule.

Varia : If the methylene derivative is sufficiently nucleophile, the ethyl glyoxylate could be added directly with maybe LiCl, followed by an activation of the alpha hydroxy group by TsCl which could lead to an elimination via an alpha carbocation (see reference).

Varia 2: Use a Lewis acid to make the imine-ène coupling, but to afford the aniline elimination, make an acetylation.

Step 6: saponification and removal of the acyl part (9) (one pot possible)
The conditions should be mild.

The product must be of course recrystallized.

Costing (reaction considered as quantitative to facilitate the evaluation)

Original synthesis: 2404$/kg (998.47$/mol)

Optimized synthesis: 1745$/kg (719.37$/mol)

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.

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