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.