Batch‐ and Continuous‐Flow Aerobic Oxidation of 14‐Hydroxy Opioids to 1,3‐Oxazolidines—A Concise Synthesis of Noroxymorphone

Abstract

14-Hydroxymorphinone is converted to noroxymorphone, the immediate precursor of important opioid antagonists, such as naltrexone and naloxone, in a three-step reaction sequence. The initial oxidation of the N-methyl group in 14-hydroxymorphinone with in situ generated colloidal palladium(0) as the catalyst and molecular oxygen as the terminal oxidant constitutes the key transformation in this new route. This oxidation results in the formation of an unexpected oxazolidine ring structure. Subsequent hydrolysis of the oxazolidine under reduced pressure followed by hydrogenation in a packed-bed flow reactor using palladium(0) as the catalyst provides noroxymorphone in high purity and good overall yield. To overcome challenges associated with gas-liquid reactions with molecular oxygen, the key oxidation reaction was translated to a continuous-flow process.

The Use of Molecular Oxygen in Pharmaceutical Manufacturing: Is Flow the Way to Go?

“…Thelack of uniform mixing in flow can cause stoichiometry imbalance and poor controlo fr esidence in the channels, [41] resultingi nad rop in process performance. [45] This is done in the context of providing an efficient and "green" accesst oavariety of different opiate-derived APIs,w here the N-methyl group contained in the naturally occurring alkaloids (e.g.,i nm orphine, codeine,t hebaine,o ro ripavine) needs to be removedt oa fford access to potent N-alklyated opioid receptora ntagonists such as naloxone andn altrexone (Scheme 8). [5][6][7] The residence time is kept constant by using higher flow rates, which involves ap otential change in superficial velocity.…”

“…Scale-up through increasing the reactor volumei sa chieved by using al onger channel and/orl arger channel diameter. [45] Standard procedures for the removal of the N-methyl group in opiate alkaloids to obtain the so-called nor-compounds (i.e.,n oroxymorphone, 13)g enerallyi nvolve environmentally undesirable multistep protocols that employ highly toxic/corrosive reagents in stoichiometric amounts, thus generating stoichiometric amountso fw aste products. Consequently,s caleup can often result in ac hange in performance, owing to ac hange in the flow regime within the reactor.…”

“…[5][6][7] The residence time is kept constant by using higher flow rates, which involves ap otential change in superficial velocity. [45] Based on the pioneering work of Hudlicky, [46] the aforementioned consortium has developed environmentally friendly continuous-flow procedures for catalytic N-demethylation methods (11!12)t hat rely on the use of molecular oxygen ast erminal oxidant (Scheme 8). One approach to overcome this problem is to apply "smartd imensioning" by using the appropriate reactor modules at the right locations.…”

“…Consequently,s caleup can often result in ac hange in performance, owing to ac hange in the flow regime within the reactor. [45] In particular, the aerobic N-demethylation of 14-hydroxymorphinone 3,14-diacetate 11 was successfully carriedo ut on ao ne-kilogram scale by using pure O 2 in a1 00 mL stainless steel flow reactor (combination of Lonza FlowPlate A6 and coiled tube) (Scheme 8, Figure 2). [42] The flow behavior inside ar eactor module can be optimized by choosing the right structure geometry for the required gasliquid mixing function.…”

“…One approach to overcome this problem is to apply "smartd imensioning" by using the appropriate reactor modules at the right locations. [45] The scaled setup shows ac ombination of reactor modules where the plate module playedthe role of an excellent gas-liquid mixer and the coil reactor to provide the residence time required by the reaction. [43] Moreover this mixingb ehavior can be predicted and comparedt oaf low regime map leading to reactor module designsthat are scalable.…”