Total Synthesis proposal (batch mode) of VX-661 a CFTR modulator against Cystic fibrosis disease, actually in Phase III

Target

Key words: oxidation, oxone, aromatic nucleophilic substitution, malonic synthesis, indolization, bromination, cross-coupling, lactonization,  decarboxylative cyclopropanation, decarboxylation, amidification, hydromethylation, fisher base, alkylation, Oppenauer, Vilsmeier, Haack, Wittig, Horner, Corey, Chaykovsky

Complete proposal here 

Route proposal

Introduction

 

Actually in Phase III, this molecule is planed to be manufactured commercially in a continuous flow chemistry type. More information here: Manufacturing Trends: In Continuous Mode

I didn’t find any publication about a synthetic route for this molecule, but i didn’t make a deep search. So i decided on paper to elaborate from scratch a total synthesis in a batch mode with the goal of industrial scale exploitation, with starting materials as cheap as possible, and the simpler chemistry as possible.

There is always numerous way which lead to the targeted molecule, this proposal is one among others.

I think the building block (5: indole) and (11: cyclopropyl phenyl carboxylic acid derivative) could be manufactured by a third party, and the convergence by flow chemistry with the constraint of absence of suspension (which is not the case in this proposal) to avoids a clogging of the installation.

Total steps: 15 with 10 isolations

Update (i have finally found a document describing the route)

I have finally found the patent (CA2796642A1), here the original route with 15 steps. I prefer my version about the indol part synthesis because it is not necessary to make a cross-coupling, or use a Grignard, perchlorate and dihydrogen. This is globally the same numbers of steps (7) and starting materials cost is similar.

About the cyclopropyl moiety, their starting materials for the two versions (only one showed) are expensive, it would be better to use the benzodioxole and make the bromination (2nd version not showed, 1 step shorter). My version is very explorative with the lactone opening, also the cross-coupling method must be tested (i have seen in a publication an analog of (8) without the Cl, cross-coupled by a Pd catalyst, so the cross-coupling is probably tolerated by (8)).

Update:
Added an optimized route for the alternate route access to the cyclopropyl moiety, shortening the synthesis by 2 steps.

Original route published by Vertex (15 steps)

Complete proposal 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. 

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.