Wednesday, July 2, 2014

Process Wednesday: This stinks! (until it doesn't)

A new Organic Process Research and Development paper by Reeves et al. [1] talks about a route to a sulfone... and then another route to the sulfone for a very interesting reason: 

While this route effectively provided initial quantities of 3, the use of NaSMe, even as the more convenient aqueous solution, was not desirable due to its potent stench, which proved difficult to eliminate even with the most rigorous containment procedures.  
A “stench-free” protocol was subsequently explored in which NaSMe was replaced with thiourea and iodomethane. Thus, heating chloride 6 with thiourea in EtOH at 65 °C resulted in an SNAr reaction to give the thiouronium salt 8 in 95% yield (Scheme 3). Conveniently, the thiouronium salt was isolated simply by direct filtration of the cooled reaction mixture. Treatment of a water solution of 8 with aqueous NaOH and MeI resulted in hydrolysis of the thiouronium salt to the 2-mercaptopyridine sodium salt and urea, with subsequent S-methylation to give the sulfide 7. Again, 7 was not isolated but was directly oxidized by AcOOH to give sulfone 3 in 70% yield after crystallization. This process avoided the stench associated with the NaSMe process, as thiourea and the thiouronium salt 8 were odorless solids.
It doesn't surprise me that they designed a route to avoid the use of NaSMe, but I am surprised to learn that they couldn't keep the smell contained, even with "the most rigorous containment procedures." Neat that they were able to use thiourea in its place, though. I'll bet the plant/kilo lab operators (and their friends and their families) were pleased with this new route.

1. Reeves, J.T.; Tan, Z.; Reeves, D.C.; Song, J.J.; Han, Z.S.; Xu, Y.; Tang, W.; Yang, B.-S.; Razavi, H.; Harcken, C.; Kuzmich, D.; Mahaney, P.E.; Lee, H.; Busacca, C.A.; Senanayake, C.H. "Development of an Enantioselective Hydrogenation Route to (S)‑1-(2-(Methylsulfonyl)pyridin-4-yl)propan-1-amine." Org. Process Res. Dev. ASAP DOI: dx.doi.org/10.1021/op5001513  

8 comments:

  1. "I'll bet the plant/kilo lab operators (and their friends and their families) were pleased with this new route"
    Yes probably they were... but if they knew something about MeI, maybe they shouldn't be as pleased ;)

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    1. You reminded me of this (http://www.bbc.co.uk/news/uk-wales-north-east-wales-25362121) from last year.

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    2. Agreed. I mean antioxidant (methane thiol, the source of stench) vs alkylating agent! Which is worse?

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  2. I believe they settled on methanesulfinic acid sodium salt to accomplish the SNAr in order to avoid oxidizing the sulfide up after installation.

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    1. Yep, you're right -- they wanted to avoid the safety issues with peracetic acid on scale.

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  3. the acceptability/unacceptability of a reagent, intermediate or a process depends on what is the management of the pilot plant comfortable with, and under how much time pressure they are. So the final choice may seem arbitrary if you don't know the circumstances and the people involved in making these decisions.

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  4. "they couldn't keep the smell contained". Nor could I the only time I worked with sodium methyl mercaptan. Just avoid it at all cost.

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  5. It's probable that N,N-dimethylthioformamide could be used instead of thiourea. Thioformamide is a liquid and the reaction could be run neat simplifying the process even more. All the thioformamide could be recovered by distillation and reused.

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