Alternate route proposal for VX-970 an ATR inhibitor (for fun only)

Target

Presentation

The original route published by Vertex begins with the already synthesised pyrazine core (9 to 12 steps depending if the boronic acid is bought or synthesised) with 2 metal catalyzed cross-coupling. This route is obviously the shorter access to the target, but suffers of two drawbacks which are inevitable:
- 2 Pd Cross-coupling which sometimes could be capricious under scale up
- Use of boronic derivative recognized now as mutagen.

Considering these facts, i have chosen to first optimize the original route (process only) except the 2 cross-coupling, and secondly to propose an alternate route which avoids cross-coupling reactions with the construction of the Pyrazine core, which is very prospective.

This is a good chemistry exercise only, since the stability of intermediates is unknown, especially at the end of the synthesis starting at part III, and there are a larger number of steps, but i have some fun chemically speaking, even if this route is less efficient.

Also, it could give some ideas, which is the second role of this blog, like:

• In-situe oxidation of KCN to N2 as post-reaction treatment (inspired from mining industry) – part II
• Azirine opening by α-amino nitrile to give amino-pyrazine (inspired from α-amino ester/azirine reaction and hydroxyiminoketones/aminoacetonitriles reaction) – part III
• Oxone® as friendly oxidizing reagent for various oxidations types – part IV
• Friedel & Craft on Zeolite (avoiding the use of AlCl3) – part I and II
• Possible replacement of “wet-alumina” which needs a preparation by pseudo-Boehmite – part II

About Zeolite, i think this is a catalyst of choice for the flow chemistry (zeolite cartridge).

This proposal is divided in four parts because this is a very long report with nearly 20-21 steps (there are more than 20 chemicals transformations, but by using minerals reagents in many cases, and expected 9 isolations), and multiple proposals for the first step of the sulfonyloxime (19) synthesis, considering starting material prices and chemistry:

• Alternate route part I sulfonyloxime (13),
• Alternate route part II sulfonyloxime (19),
• Alternate route part III convergence: Azirine preparation and Pyrazine synthesis (two Neber rearrangement and convergence using azirine opening)
• Alternate route part IV VX-970 (trickier due to ketal fragility during the cascading oxidation)

Key words: Friedel and Craft, Acylation, Zeolite, reduction, oximation, Neber Rearrangement, azirine, imidoyle chloride, Oxone, oxidation, cyanation, pseudo-Boehmite, alpha-amino nitrile, alpha-amino ketone, alpha-amino ketal, decarboxylation, oxidative decarboxylation, isoxazole, amino pyrazine, malonic.

Original route published by Vertex

Alternate route proposal Part I: Sulfonyloxime (13) preparation

Alternate route proposal Part II: Sulfonyloxime (19) preparation

Alternate route proposal Part III: Pyrazine (23) preparation

Alternate route proposal Part IV: VX-970 (28)
Method A

Method B

Final stage

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.