QDIS Blog

Most chemists know that a solvent change can have a dramatic effect the course of a reaction but what is not commonly appreciated is that a change of solvent can dramatically reduce impurities formed in a reaction and make the subsequent purification much easier or allow it to be eliminated entirely. I recently came across an example of this sort of can be seen in the following article:

The Synthesis of a Novel Inhibitor of B-Raf Kinase (Org. Process Res. Dev. 2006, 10, 70–77)

The reaction of 7-hydroxyisoquinoline with (CF3SO2)2O in EtOAc–pyridine gave the triflate in moderate yield (48%) after an aqueous work-up and a thin-film vacuum distillation. Quite a bit of material is lost in the course of the distillation due to the use of ethylene glycol which was used as a lubricant and to solubilize pyridinium salts.

Changing the reaction solvent from EtOAc to t-BuOMe led to more efficient removal of the salts during the aqueous work-up, the use of less ethylene glycol which gave a higher yield (75-85%) as well as allowing the distillation to proceed at a lower temperature. All this from a simple change from EtOAc to t-BuOMe.

I’ll be honest, this wasn’t the reason this article first caught my eye. I read it because I noticed they used a Negishi coupling in their synthesis. I received my PhD from Purdue University under the supervision of Dr. Negishi and spent quite a bit of time working on this sort of coupling back in the late 80’s. I’m always pleased to see the words “Negishi coupling” and “uneventful” in the same sentence. It was interesting, although disturbing, to see some of the same problems we experienced back 20 years ago. This includes control of temperature for the Li halogen exchange and that the Pd catalyst nature is vital. It would have been interesting to look at other ligands. My experience is that trifurylphosphine instead of triphenylphosphine sometimes gives much better results. It would also be interesting to investigate using the Pd catalyst for the amination as well (Buchwald coupling) instead of dealing with the hydrogen evolution resulting from deprotonation of the amine with NaH and then coupling with the aryl chloride.

Technorati Tags: process development, solvent change

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Back in mid-May, Neurocrine Bioscience received both good and bad news from the FDA regarding their insomnia medication Indiplon.

Neurocrine Receives Approvable Letter for indiplon Capsules and Non-Approvable for indiplon Tablets for the Treatment of Insomnia: Financial News - Yahoo!

The capsules were approved, but the tablets were not. The capsules were a lower dose (5 and 10 mg) whereas the tablets were 15 mg. It was also interesting that the FDA admitted to not having time to review all of the information submitted in the new drug application (NDA). Although not specified, I certainly hope that the reason for not approving the 15 mg tablets was simply because they hadn’t reviewed that data. If this is the case, it is good to see the FDA go ahead and send the approvable letter for the capsules and not hold those up.

Neurocrine has listed on their web page the webcast response to the FDA letter but it appears to no longer be available. It will be interesting to see how the insomnia market share will develop since their have been several recent entrants in this area such as Lunesta and the Ambien (which has been around for quite some time). I personally have used Ambien and it works well for me, especially for dealing with jet lag when traveling to Europe on business.

Technorati Tags: FDA, Indiplon, Neurocrine

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