Alternate route proposal Part III for VX-970 an ATR inhibitor: Pyrazine (23)

Alternate route part II sulfonyloxime (19)

Alternate route proposal for VX-970 Part III

Pyrazine (23)

Route proposal to (23)
Stability of every compound is unknown, especially starting at (20)

α-Amino ketal preparation through azirine (21)

To follow the previous optimisation proposal for this sequence, K₂CO₃ as base and crown ether to exalt the basicity of the carbonate ion. If this procedure doesn’t work, use the standard method KOEt/EtOH if an acyclic ketal is chosen (see below) or tBuOK (in THF) if a cyclic ketal would be attempted.

Due to the subsequent steps after the convergence involving multiple oxidations in one-pot conditions (decarboxylative oxidation, ketal removal, sulfone), the ketal must be “resistant” at room temp and at pH nearly 2 (issued from Oxone®) in presence of water, if the latter cannot be avoided. “Resistant” means slow kinetic of removal at room temp. This will be a pure process design with a tight latitude to hit the target (like in Star Wars Episode IV for purist ;o)... )

The ring opening should be tried first with EtOH and heating, if the ring opening doesn’t occur or if there are sides reactions instead, use an acid like TsOH, but there is a risk about the nitrile group in presence of an acid and alcohol to make a Pinner alcoholysis, conditions must be mild to avoid this reaction; this side reaction should be not a problem with ethylene glycol, it could be also sequenced with addition of TsOH after the first addition on the azirine is complete. Unfortunately, i didn’t saw any literature about azirine opening to give α-amino ketal with ethylene glycol, but i think it is feasible.

The Neber rearrangement is not clean generally, so an isolation should probably be done here.

By the way, most probably the more stable conformer is the trans-oxime by H-bonding interaction between oxime and ester, and oxygen doublet interaction from the oxime and the C of the carbonyl from ester. With this configuration, it could be the path A or C for the reaction mechanism, which seems to grab few yield points (see Organic Reaction reference page 324). Consequently, for (18, see here), thermodynamic control must be privileged, which mean not “kicking in the heap” with the reaction conditions.

References:
Organic Reactions, Vol. 78, Chapter 2, pp. 321-410, The Neber Rearrangement, William Frost Berkowitz.

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.


Azirine preparation (22)

As mentioned earlier in part I (here), to avoid a Beckmann rearrangement, the base must be strong enough to avoid an equilibrium once the tosylate has left, but for convenience, i would try first K₂CO₃ with crown ether 18,6 to exalt the basicity of the carbonate ion. If these conditions doesn’t works or produce side products significantly, there is the possibility to oxidize the thiol to sulfone to limit the electron-donating character of the phenyl; else a strong hindered base like tBuOK (in THF solution) should be used.

I would not isolate this product, even if a Neber Rearrangement is not clean usually, because 22 is most probably liquid, keep it in solution is then my first choice.

References:
Organic Reactions, Vol. 78, Chapter 2, pp. 321-410, The Neber Rearrangement, William Frost Berkowitz.

α-Amino Acetals: 2,2-diethoxy-2-(4-pyridyl)-ethylamine, Organic Syntheses, Coll. Vol. 7, p.149 (1990); Vol. 64, p.19 (1986).


Convergence

Pyrazine core synthesis (23)

After some readings, i think it is possible to make the pyrazine ring directly from α-amino nitrile and azirine following this mechanism:

Similar reactions are made with a α-amino ester (see reference1 p155 scheme 18 and reference2). Also, similar reactions are made with α-amino nitrile and α-amino ketone with or without a Lewis acid catalyst (FeCl₃ or TiCl₄) (see reference3, 4 and 5) to give pyrazine N-oxide. Lastly, it is known that Li⁺ can make complexes with nitrile groups and could assist the addition (reference5).

About the reference2, i think the mechanism is not detailed enough. As demonstrated by the yields, there is a +I effect due to the methyl groups in 1a versus 1c in the publication, which enhance the nucleophilicity of the aziridine. Then, i think there is first an addition of the electron doublet from the N of aziridine (“a” in the schema) to give a short life intermediate aziridine-amidine, before the ring opening (“b” in the schema). Consequently, the electrophile must be activated (which initiate the sequence) to increase the yield, since there is only H as substituent, and a carbonate ion to “help” the proton displacement. As showed in reference3, an activation of nitrile group increases the yield if a Lewis acid (in a stoichiometric amount unfortunately) is added. Lastly, i think the solvent (acetonitrile) is not a solvent of choice due to potential reactions with it.

Then, for this reaction, probably THF as solvent and lithium carbonate as base and electrophilic assistance could work. A PTC could be use too to accelerate the reaction. If the complexation constant of crown ether 12,6 with lithium ion is lower than with nitrile group, it could be use to exalt the basicity of the carbonate ion; otherwise aliqua 336 as PTC, which is my favourite, to help the solubilization and the kinetic.

If the electrophilicity of the azirine (22) is not enough due to the alkyl sulfide group, the sulfone will increase it.

As mentioned at the beginning of this part, this is in part IIIb where things begin to be really difficult (for french speakers: “comme dirait Napoléon, c’est là que les choses se corsent).

References:
Reference1: Heterocyclic Targets in Advanced Organic Synthesis, 2011, 7. 2H-Azirines as electrophiles p145, Maria José Alves and Flora Teixeira e Costa.

Reference2: Addition d’amino-esters ou d’α-hydroxy-esters sur des azirines, G. Alvernhe, A. Laurent et A. Masroua, Tetrahedron  Letters, Vol.24, No.ll, pp  1153-1156, 1983.

Reference3: Synthesis of 2-Amino-3-benzyl-5-(p-hydroxyphenyl)pyrazine, Hisae Kakoi, Chem. Pharm. Bull. 50(2), p301-302 (2002).

Reference4: Efficient Synthesis of substitued 2-aminopyrazines: FeCl3-promoted condensation of hydroxyiminoketones with aminoacetonitriles, Takahiro Itoh, Kenji Maeda, Toshihiro Wada, Koji Tomimoto, Toshiaki Mase, Tetrahedron Letters, Volume 43, Issue 51, 16 December 2002, Pages 9287–9290.

Reference5: 209. Pyrazine derivatives. Part XIII. Synthesis of 2-aminopyrazine 1-oxides by the condensation of α-amino-nitriles with oximinomethyl ketones, William Sharp and F. S. Spring, J. Chem. Soc., 1951, 932-934.

Reference6: Reactions of α-Dimethylaminophenylacetonitrile and Its Ethylation Product with Basic or Nucleophilic Reagents, Gene F. Morris, Charles R. Hauser, J. Org. Chem., 1962, 27 (2), pp 465–471.

Alternate route part IV VX-970 (28)

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.