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| Credit: Cann et al. ORPD |
A final issue was the decomposition of 11 during drying. The penultimate 11 degraded by urea bond cleavage to form 2−3% of amino acid 14 and piperidinyl quinolinone 4 during drying at 50 °C. Laboratory experimentation revealed that any potential residual levels of HCl, LiOH, dimethylamine or LiCl were not the root cause of this degradation. This led us to speculate that the degradation may be facilitated by the carboxylic acid moiety of 11. This possibility is supported by 1H NMR studies, which showed that the indazole N−H resonance at 13.04 ppm in 11 was a rather broad peak of two protons between 12.4 and 13.4 ppm. This implies the potential existence of 11 as a zwitterion (Scheme 16), and the carboxylate anion may serve as the nucleophile to attack the urea carbonyl group to break the urea bond.
Decreasing the oven temperature to 40 °C limited decomposition to less than 0.1% over 63 h of drying while Dynochem modeling revealed that the rate of drying was controlled by moisture transport from inside the wet cake. To minimize drying time we utilized an agitated filter-dryer in a two stage protocol. The wet cake was first deliquored for at least 12 h at ambient temperature with minimum agitation, thus avoiding the formation of gummy balls. This was followed by warming to 40 °C with intermittent agitation. The telescoped process was then utilized to produce 1.7 kg of penultimate 11 in 80% yield and a purity of 95.6% and 99.3% ee.From the supporting information, it appears that the cake washes were water, then MTBE, and then they put it in an agitation dryer (I wonder what one of those babies cost?) and vacuum dried at 20°C without agitation for 16 hours. Only after then, did they turn up the heat to just 35°C.
As someone who occasionally sets dryer specs (and gets into arguments about them), it's interesting to see (and perhaps unsurprising) that increasing the drying temperature by 10°C would raise the level of an impurity by 2%. Something else to worry about!
1. Cann, R.O.*; Chen, H.C.; Gao, Q.; Hanson, R.L.; Hsieh, D.; Li, J.; Lin, D.; Parsons, R.L.; Pendri, Y.; Nielsen, R.B.; Nugent, W.A.; Parker, W.L.; Quinlan, S.; Reising, N.P.; Remy, B.; Sausker, J.; Wang, X.; "Selection of an Enantioselective Process for the Preparation of a CGRP Receptor Inhibitor." Org. Process Res. Dev., Article ASAP DOI: 10.1021/op3003097
Pop quiz: Notice anything fishy about the zwitterion structure?
ReplyDeleteWrong nitrogen protonated?
ReplyDeleteI just learned new English word: to deliquore. It describes action or process opposite to liquoring up/
ReplyDeletePJ: Right-o. The structure shown has lost aromaticity in the pyrazole ring, whereas protonating the other nitrogen of the pyrazole would be fine and still explain the NMR data.
ReplyDeleteA little more on this: The pKa of protonated pyrazole itself (at N2, not N1) is 2.5, whereas the pKa of N1-protonated pyrazole is expected to be much lower than N-protonated pyrrole, which has a pKa of -4. Hence, protonation at the position shown in the zwitterion above would lead to a massively strong acid.
It's still in ASAP! Time to write an e-mail!
DeleteLove the gummy balls... Drop in a quarter and turn the handle :)
ReplyDeleteA couple of years ago I was quoted about $100k for a used 0.25 m^2 Rosenmund agitated filter dryer (C-276 construction).
A long time ago, some chemists were working on a coating line trying to dry a coating in an oven. Since the oven wasn't doing the job, they turned up the heat. That solved the problem of dryness, but at the expense of degrading the coating. My proposal: increase the air flow rate. That not only solved the problem, but they could lower the oven temperature below what their lab experiments showed.
ReplyDeleteThis is one of my pet peeve areas where the value of a chemical engineering degree clearly trumps that of a chemistry degree. ChemE's get a whole course in heat transfer and learn about conduction, convection and radiation as modes of heat transfer. Heat transfer, not temperature. There is a very large difference.