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Dialkyl sulfoxide synthesis

The lab recently required some small (5-10g) samples of some simple dialkyl sulfoxides. This led us to investigate dialkylsulfide oxidation procedures capable of  producing these compounds selectively, with minimal overoxidation to sulfone byproducts.

There are, of course, many ways to go about this reaction. Hydrogen peroxide in the presence of a Lewis acid (1), Caro’s acid (2), and NaIO4 (3) are a few examples. At industrial scale DMSO is manufactured using a catalytic NO2 / O2 system, but this is difficult to manage in the lab. Although many of these reaction conditions are high- yielding and selective, most published procedures have drawbacks. These may include:

  •  long reaction times (NaIO4)
  • cost (Magnesium Monoperoxyphthalate)
  •  and safety (Potassium Peroxymonosulfate, sodium percarbonate, vanadium (V) oxide)  (4,5).

The selective oxidation of sulfides to sulfoxides is commercially relevant in the case of

lansoprazole1

Large scale sulfide oxidation: Prevacid ® (Lansoprazole)

Takeda’s proton pump inhibitor Prevacid® (Lansoprazole). The final step requires the oxidation of Lansoprazole sulfide, and a thoughtful analysis of oxidants appropriate for use on a manufacturing scale was recently published (5).

In our case, we decided to evaluate three options, all of which used a form of ‘activated’ hydrogen peroxide. The reagents were prepared to test:

  •  a variation of the Payne reaction (acetonitrile / H2O2)  (4)
  • A TMSCl-promoted oxidation (6)
  • an interesting PVP-supported hydroperoxide oxidation reagent (7)

 

 

Artie McKim.

(1) Watanabe, Y.; Numata, T.; Oae, S. Synthesis (1981) 204

(2) Lakouraj, M.M.; Movassagh, B.; Ghodrati, K. Synth. Commun. 32, (2002) 847 (3)

(3) Leonard, N.J.; Johnson, C.R. J. Org. Chem. 27 (1962), 282

(4) Page, P.C.B.; Graham, A.E.; Bethell, D.; Park, B.K. Synthetic Communications 23, 11  (1993) 1507-1514. The authors make the interesting comment that MCPBA ‘will soon be withdrawn from sale’. This paper was somewhat dated by the time I came across it, but has MCPBA supply been constrained?

(5)  Harrington, P. J. Pharmaceutical Process Chemistry for Synthesis: Rethinking the Routes to Scale-Up  John Wiley and Sons, Pubs. Hoboken, NJ (2011) p. 228-237

(6) Bahrami, K.; Khodaei, M.M.; Yousefi, B.; Arabi, M.S. Tetrahedron Letters 51 (2010) 6939-6941

(7) Lakouraj, M.M.; Aghajani, B.; Mokhtary, M. Phosphorus, Sulfur, and Silicon 185 (2010) 2393-2401

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