Alternate route proposal Part IV for VX-970 an ATR inhibitor: Final stage

Alternate route part III pyrazine (23)

Alternate route proposal for VX-970 Part IV

VX-970 (28)

Route proposal to (28)

Method A

Method B

Final stage

Method A details

Ester cleavage / sulfide oxidation (24)

A patent was published by SmithKline Beecham for oxidation of sulfide to sulfone in buffered conditions. Since the patent is applicable to a specific molecule configuration, the procedure described therein can be used.

The procedure uses first an alkali solution, which in this case permit the saponification of the ester without altering the ketal. Secondly, the pH of the mixture is adjusted at 7 to 8.5 and a ketone is added as cosolvent and as source to prepare the dioxirane, followed by Oxone. The reaction mixture is stirred at room temperature (or between 10 and 50°C) to give the sulfone. The mixture is then acidified, which here is premature due to the decarboxylation and the ketal cleavage.

This procedure could be adapted by replacing the ketone by an alcohol to have a better solubility for the ester cleavage. Oxidation of sulfide to sulfone could be done in this type of binary system, but the oxidation of sulfide to obtain the sulfone versus the sulfoxide is dependent of the solvent type, so it should be studied (aqueous mixture gives preferably a sulfone, organic mixture gives preferably a sulfoxide).

The pyrazine core will be also oxidized (mono or di, i don’t know, only mono showed), which diminish the basicity/nucleophilicity of the amino group, and therefore limit/avoids an internal cyclization with the ketone (6 member ring).

Lastly, it is better to isolate the carboxylate instead of make the acidification here, due to the subsequent oxidative decarboxylation and the need of keeping the ketal in place during the reaction (alpha halogenation of ketone in alcoholic mixture). Also a distillation to remove the alcohol is risky, since the ketal could be removed at 80°C in water without an acid catalyst, or the distillation must be conducted at a reduced pressure.

References:

WO1994021603 A1

Catalyst-free approach for solvent-dependent selective oxidation of organic sulfides with oxone, Bing Yu, An-Hua Liu, Liang-Nian He, Bin Li, Zhen-Feng Diao and Yu-Nong Li, Green Chem., 2012,14, 957-962.

Chemoselective oxidation of sulfides to sulfones with potassium hydrogen persulfate, Barry M. Trost, Dennis P. Curran, Tetrahedron Letters Volume 22, Issue 14, 1981, Pages 1287-1290.

Oxidation methods for aromatic diazines: substituted pyrazine-N-oxides, pyrazine-N,N’-dioxides, and 2,2':6’,2"-terpyridine-l,l"-dioxide, Scott E. McKay, Joseph A. Sooter, Satish G. Bodige and Silas C. Blackstock, Ηeterocyclic Communication, Vol. 7, No 4, 2001.

Decarboxilative oxidation (25)

The preliminary decarboxylation could be done in acetonitrile and AcOH as proton source in non-aqueous conditions to avoid a ketal cleavage.

The challenge in this step is to make the decarboxylative oxidation without the ketal cleavage, since a ketal cleavage most probably opens the way to a α-keto bromination, essentially due to the diketone configuration, but i have only saw a α-keto bromination in an alcoholic media.

The first solution is to make the reaction in non-aqueous conditions. Unfortunately, the yield in 100% acetonitrile is poor (50%), most probably by a lack of Oxone® solubility in this system. Therefore, a PTC could be used to help (crown ether or ammonium salt), as the oxidation of alcohol in non aqueous media with TEMPO/Bu­₄NBr/Oxone.

The second solution is to have a cyclic ketal (azirine opening with ethylene glycol see part II compound (21)), which will be more resistant to aqueous conditions near pH=4 at room temp.

The residual Oxone® could be eliminated by sodium sulfite before isolation or chaining with oximation, if the mixture has a good behavior. If this step is chained with the oximation, the residual Oxone® must be quenched by sodium sulfite in a stoichiometric amount or slightly shorter than the stoichiometry to avoid decomposition of bisulfite into SO­₂ during the ketal cleavage. The other solution is to “degrade” the Oxone® at pH=9 (see technical data from Dupont here).

Thiosulfate cannot be used, since it could degrade the SST in acidic conditions (pitting corrosion).

References:

Novel Synthetic Methodologies for Bioactive Molecules, thesis, Kulbhushan A. Sasane, 06/2013, chapter 2b, “A simple protocol for oxidative decarboxylation using oxone and iodobenzene”.

Oxidative bromination of ketones using ammonium bromide and oxone®, Arun Kumar Macharla, Rohitha Chozhiyath Nappunni, Mahender Reddy Marri, Swamy Peraka, Narender Nama, Tetrahedron Letters Volume 53, Issue 2, 11 January 2012, Pages 191–195.

Catalytic Synthesis of Aldehydes and Ketones under Mild Conditions Using TEMPO/Oxone, C. Bolm, A. S. Magnus, J. P. Hildebrand, Org. Lett., 2000, 2, 1173-1175.

Method B details

The other way is to make the saponification, isolate the product, in a organic aprotic solvent, acidify with acetic acid to make the first decarboxylation, which is probably easy, make the successive oxidations.

Ester cleavage (27)

In this case, the salt must be isolated by methods which minimize the presence of water and avoids a drying. Also, i would not use Li+ as counter ion because of potential complexation between amine and ketal which weaken the ketal (6 member ring complex). Two references below could help to evaluate the water quantity in a minimal amount.

References:

Lithium hydroxide/aqueous methanol: mild reagent for the hydrolysis of bile acid methyl esters, B. Dayal, G. Salen, B. Toome, G.S. Tint, S. Shefer, J. Padia, Steroids, Volume 55, Issue 5, May 1990, Pages 233-237.

Solvent effects in the hydrolysis of diethyl malonate, P.S. Radhakrishnamurti, P.C. Patro, Tetrahedron, Volume 26, Issue 23, 1970, Pages 5503-5505.

The kinetics of the alkaline hydrolysis of diethyl malonate, diethyl succinate and diethyl sebacate in water-dioxane mixtures, W. J. Svirbely, August D. Kuchta, J. Phys. Chem., 1961, 65 (8), pp 1333–1337.

Another method involve a TMS-I in-situe generation, but it also remove the ketal. I give the references for information only.

References about TMS-I:

Chlorotrimethylsilane-Sodium Iodide, Journal of Synthetic Organic Chemistry, Japan, Vol. 39 (1981) No. 10 p973-977 (in Japanese).

Silane/iodine-based cleavage of esters and ethers under neutral conditions, Tse-Lok Ho and George A. Olah, Proc. Nati. Acad. Scd. USA Vol. 75, No. 1, pp. 4-6, January 1978.

Silicon Reagents for Organic Synthesis, William Weber, p30 and references therein:

Cleavage of Esters and Ethers with Iodotrimethylsilane, Ho, T.L., Olah, G.A., Agew. Chem. Int. Ed., 15, 774 (1976).

Synthetic Methods and Reactions; 321. Mild and Effective Cleavage of Esters and Ethers with Phenyltrimethylsilane/Iodine Reagent, Ho, T.L., Olah, G.A., Synthesis, 417 (1977).

Synthetic methods and reactions. 62. Transformations with chlorotrimethylsilane/sodium iodide, a convenient in situ iodotrimethylsilane reagent, Olah, G.A., Narang, S.C., Gupta, B.G.B., Malhotra, R., J. Org. Chem., 44, 1247 (1979).

A Convenient Synthesis of Iodotrimethylsilane and its Use in the Preparation of Silylketenes, Sakurai, H., Shirahata, A., Sasaki, K., Hosomi, A., Synthesis, 740 (1979).

Decarboxylation/Oxidation (sulfone and decarboxylative oxidation) (25)

Same remark as in method A about the first decarboxylation with AcOH in non-aqueous system to avoid the ketal removal.

Same remark as in method A, in non-aqueous system, the oxidation is less efficient, but a PTC could help. Also, in these conditions, the oxidation of sulfide most probably leads to the sulfoxide, except if the PTC has a positive effect.

Therefore, after completion of the decarboxylative oxidation, the pH must be adjusted to 7 by an aqueous solution of NaHCO₃ to pursue the oxidation to sulfone if the oxidation is stopped to the sulfoxide.

(25) could be isolated here, or chained with the oximation if the reaction mixture has a good behavior (there are only mineral compounds except impurities).

References:

See method A

Final stage details

Oximation/Ketal cleavage/isoxazole/N-oxide reduction (26)

If the reaction is chained with the previous step, a small amount of oxime could be cleaved by residual Oxone® which was not quenched or degraded.


Adding AcOH on the mixture and heating should cleave the ketal if this is an acyclic ketal, but it must be sure to not have no presence of sulfite which could produce SO2 in acidic conditions, or a scrubbing tower with NaOH solution must be present on the blowhole.

The cyclisation to obtain the isoxazole could be done by adding Na2CO3 which firstly neutralize the AcOH and secondly deprotonate the oxime.

Lastly, the N-oxide could be reduced by sodium dithionite, which give a less water soluble compound.

References:
Efficient and Regioselective One-Pot Synthesis of 3-Substituted and 3,5-Disubstituted Isoxazoles, S. Tang, J. He, Y. Sun, L. He, X. She, Org. Lett., 2009, 11, 3982-3985.

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.


Final deprotection (28)

Reference:
Method used by Vertex


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.