Organic synthesis and methodology in your (free?) time
Sunday, November 8, 2009
Antipsychotic Asenapine
In August of this year, the drug asenapine (sold as Saphris by Shering-Plough) was approved by the FDA for treatment of schizophrenia and manic episodes of biopolar I disorder, according to a recent news article in Nature Reviews Drug Discovery (doi:10.1038/nrd3027). Asenapine is an atypical antispychotic. The tricyclic 6-7-6 ring structure is common to most of the the atypical antispychotics (including clozapine and olanzapine, but not risperidone). What makes them atypical is that they not only treat the "positive" symptoms of schizophrenia (hallucinations, delusions, mania) but the "negative" ones as well (depression, cognitive impairment).
A SciFinder search revealed 3 patents with published syntheses of the drug; surprisingly, no papers so far with SAR studies or anything of the sort, and just enough clinical trials to allow the drug to be marketed. The drug wasted no time getting to the market - at least, according to the literature I looked through - which for a mental disorder like schizophrenia for which there is no truly good treatment, only adequate treatment, is wonderful.
Two patents had two different approaches (and the others were either duplicates or elaborations), and the most recent was an elaboration on one of the others. The first, from 2006, sought to make the trans-pyrrolidine as efficiently as possible to improve upon the former synthesis. The synthesis on a whole, though, is extremely steppy. The second, in 2008 (Int. Pat. #: WO 2008/003460) instead chopped the molecule in two via a cyclization between a stilbene and an in-situ generated azomethine, followed by an Ullman condensation to connect the phenol with the other ring; use of the trans-stilbene naturally leads to the trans-ring juncture.
To make the stilbene, HWE:
You can obviously see where there's room for synthesizing analogues here by using a different benzyl bromide in the first step. The coupling partner used in the next step is activated in-situ by CsF or TFA. I think it looks like a handy synthesis.
I really liked your post. Hopefully you don't mind I'm using it as an example in my cheminfo retrieval class for the projects my students are required to do.
Thank you! Of course I don't mind. Let me know if there's anything I can to do help, or if you think similar types of posts would be helpful to your students in the future.
hi Crystallinity, its a good post, but i want to point out a detail: on the retrosynthetic scheme, the disconnection concerning the Ullmann reaction have to be drawn on the opposite aryl-oxygen bond.
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I really liked your post. Hopefully you don't mind I'm using it as an example in my cheminfo retrieval class for the projects my students are required to do.
ReplyDeleteThank you! Of course I don't mind. Let me know if there's anything I can to do help, or if you think similar types of posts would be helpful to your students in the future.
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Egon, of course not!! Thanks so much!
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ReplyDeletehi Crystallinity,
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This drug is very strong, o Knew a man who used to use that drug now he's died, that's the reason I feel so identify and interested reading this article.
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