Alternate route proposal Part I for VX-970 an ATR inhibitor: sulfonyloxime (13)

Target

Alternate route proposal for VX-970 Part I

Introduction

The only way to avoids metal catalyzed cross-coupling is to construct the pyrazine core, which implies the synthesis of α-amino ketone or azirine for each blocks, and a selective addition-elimination to a avoids the bad regio-isomere. Also one of the methods to synthesize the isoxazole avoiding a metal catalyzed reaction is an 1,3-diketone, which must be present before the pyrazine formation. Lastly, to have the amino group on the pyrazine core, a nitrile group is necessary to form an “amidine section” on the core.

Consequently, with these constraints, each block which serves to the pyrazine construction will be an azirine, and for one of them, ethanolized to give an amino ketal. The difficult part in this route is for one block, the presence of multiple functional groups, and consequently an uncertainty about his stability.


Sulfonyl oxime (13) preparation

Route proposal to (13)

Acylation (10)

Instead of using the traditionnal AlCl₃ or FeCl₃, i have chosen a greener method with Zeolite. In the cited references, methoxy-naphtalene is used as bicyclic compound substrate, which is the most “similar” with the diphenyl bisulfide. Also, CH3CN is a possible solvent, but with a longer reaction time (Advances in Friedel-Crafts Acylation Reactions: Catalytic and Green Processes, p101-102), which is interesting for the next step involving CH₃CN/Water as solvent. The product has a good probability to be soluble in the solvent since the starting material is soluble in polar solvent like THF, a simple filtration to remove the catalyst permits to chaining with the next step.

References:
Acetylation of aromatics over acid zeolites: Seeking a viable alternative to Friedel–Craftscatalysts*, Matteo Guidotti1, Jean-Marie Coustard, Patrick Magnoux and Michel Guisnet, Pure Appl. Chem., Vol. 79, No. 11, pp. 1833–1838, 2007.

Acylation of 2-Methoxynaphthalene over Ion-Exchanged Beta Zeolite, İsmail Cem Kantarli, Dissertation Msc, 2002.

Catalytic activity of the beta zeolite with enhanced textural  properties in the Friedel-Crafts  acylation of aromatic compounds, R.A. García*, D.P. Serrano, G. Vicente, D. Otero and M. Linares, Studies in Surface Science and Catalysis Volume 174, Part 2, 2008, Pages 1091-1094.

Zeolite coated structures for the acylation of aromatics, A.E.W Beers, T.A. Nijhuis, F. Kapteijn, J.A. Moulijin, Microporous and Mesoporous Materials, 48, 2001, 279-284. 


 Disulfide bond reduction and S-alkylation (11) (one-pot possible)

If the reaction solvent of the previous step is CH­₃CN, after the filtration, AlCl₃, Zinc and water could be added, to afford the Zinc dithiolate. If a standard Friedel-Crafts is used, since Aluminium chloride is already present, there is only need to add Zinc and water, but in this case, the reaction mixture will be most probably biphasic, which could be a problem, and the solvent must be suitable versus Zinc metal (nitrobenzene forbidden).

The hydrolysis of AlCl₃ provides necessaries protons for the reduction. Instead of using this solid which is difficult to manipulate, i would use an alternate method by replacing anhydrous AlCl₃ and water with AcOH, and when the reduction is complete, neutralize with an aqueous solution of saturated NaHCO₃, or in a solid form added per portion through an airlock for introduction of solid to limit the water quantity. The targeted pH is between 6 and 8.6 (to avoid the precipitation of Zn(OH)₂ and make the deprotonation of thiophenol pKa = 6) which is easily reachable with NaHCO₃ without a pH control. The zinc thiolate is then formed, since Zn²⁺ has a great affinity with sulphur compounds. 2-Bromo-propane could be added after the neutralization to make the S-alkylation. Zn²⁺ should be in a solid form of ZnBr₂/Zn(OAc)₂, and the product probably liquid, which lead to a simple metal salt filtration at a low temperature after water removal (distillation or dessicant depending the quantity) if present, to prepare the next step.

References:
Formation of Zinc Thiolates by Reductive Cleavage of Disulfides with the Zn/AlCl3 System in Aqueous Media, and their Use for Michael Addition, Barahman Movassagh and Yousef Zakinezhad, Z. Naturforsch.61b, 47 - 49 (2006).

Synthesis of organic sulfides from disulfides using a Zn/AlCl3 system in aqueous media, Barahman Movassagh,* Moslem M. Lakouraj and Zahra Fadaei, J. Chem. Research (S),2000, 350–351.


Oximation - benzenesulfonylation (12) (13) (chained with previous step possible)

Hydroxylamine could react on a nitrile group to give an amidoxime, but the acetophenone derivative is surely more electrophilic. I would then not heat too high if needed to avoid the side reaction with the solvent. Also, if water is a problem, a distillation could be made to remove it from the mixture if in a high quantity (if not performed in the previous step), or use a dessicant agent like anhydrous Na₂SO₄.

The sulfonylation of the oxime could be made at 0°C with benzensulfonyl chloride with K₂CO₃ even if water is present. If these conditions are not sufficient for the sulfonylation, the product must be filtered / washed, re-engaged in another solvent (THF), Benzenesulfonyl replaced by p-toluenesulfonyl (cheaper), K₂CO₃, PTC and catalytic amount of DMAP or pyridine.

In all cases, the product must be not in presence of a protic solvent and protons at the end of this stage, which means isolation of (12) or (13). If (12) is isolated, (13) must be synthesized in the solvent which will be used for the azirine and pyrazine preparation. Also, the tosyloxime could be unstable and sometimes represent some health and safety issues if isolated. Then, it is probably better to chaining with the next step and isolate (12).

The Neber rearrangement in the next step to form the azirine could suffer of a side reaction, the Beckmann rearrangement, especially if there is a vinyl nitrene intermediate (see references) and the base is not strong enough (equilibrium by deprotonation/protonation of the carbanion after the tosylate has leaving, giving the Beckmann rearrangement intermediate forming a π-complex specific to oxime containing a phenyl), which leads to the amide. If this side reaction occurs significantly and cannot be avoided, to change the phenyl’s behavior, the thioalkyl oxidation by Oxone® could be made before the oximation.

Reference:
Synthetic applications of 2-aryl-4-piperidones. X Synthesis of 3-aminopiperidines, potential substance P antagonists, Anna Diez, Aline Voldoire, Isabel Lopez, and Mario Rubiralta, Victor Segarra, Luis Pages, and José M. Palacios, Tetrahedron 1995; 51(17):5143–5156.

Beckmann Rearrangement (π-complex from oxime of acetophenone): Is the Beckmann Rearrangement a Concerted or Stepwise Reaction? A Computational Study, Shinichi Yamabe, Noriko Tsuchida, and Shoko Yamazaki, J. Org. Chem. 2005, 70, 10638-10644.

Neber Rearrangement (mechanism, three pathways): Organic Reactions, Vol. 78, Chapter 2, pp. 321-410, The Neber Rearrangement, William Frost Berkowitz.


Alternate route part II sulfonyloxime (19)

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.