Braenden, Eddy & Halbach (1955), summarizing the relationship between chemical structure and analgesic action, said "In morphine and its derivatives the methyl substituent on nitrogen seems essential because its substitution by other alkyl groups reduces or abolishes analgesic action." It is...
www.unodc.org
In the 1950s someone tried various different N-substitutions of levorphanol. Some a lot more potent than their parent. However, it's important to realize that they only used animal models and in related compounds we have seen modification of the N-substituent increase every metric available from Ki to EC50 to LogP and whatever else you can think of that would STRONGLY suggest that the modification would result in a much more potent compound... only to discover that in man, it was no more potent. I speak of oxymorphone and N-phenylethylnoroxymorphone in this case. So while uncertain, those digitized images in the link are sort of interesting.
But you still have to obtain your norlevorphanol from somewhere.
While people have certainly improved on the original Grewe et al. synthesis, I would suggest that the KEY improvement is that chiral catalyst I mentioned. If it's possible to produce enantiopure
dextromethorphan, it's equally possible to use a chiral catalyst to produce
levomethorphan.
As you can see from the above, the intermediate is resolved but I'm sure I've read earlier works that used small molecule chiral catalysts.
But even so, unless those potent derivatives I've linked to are as potent in man, it isn't a great target. I mean, you can quite legally obtain the immediate precursor to things more potent than
levorphanol. Then I guess you could also play with the N-substituants.
Hi 4DQSAR. Those are very interesting observations that you posted. It is something I need to reflect on. I will also read the papers you have linked as soon as I find the time (especially the one about the asymmetric synthesis). You seem to know a lot about chemistry. More than I do. I wish you were in Germany because I would love to work with people like you and cooperatively create something potentially great. It sucks to do these things alone and not get any live input from fellow chemists. Might I ask from which country you hail? Hmmm, lemme guess...you be an Aussie? Profile pic gives me an Aussie vibe somehow haha.
Anyway, went off on a little tangent there. Thanks again for the papers, your comment and have a nice day wherever you are.
Here the synthesis is here:
en.wikipedia.org
Hey Smyth2. I'm already aware of that synthesis but please pay attention to what the text says in the very first sentence:
"ONE of the syntheses [...]"
This does not mean that the synthesis as described in wiki is the route of choice. Aside from a dramatic inter-individual yield variance which impacts the cost efficiency from route to route (trust me when I tell you that this is by far the MOST important factor when it comes to a pharma company's decision on which route to synthesize the drug in question), the reagents themselves determine the route of choice by a secondary degree. Since I don't know the yield of the wiki synthesis I cannot say with any confidence whether that synthesis is a more sound choice for manufacture, but my past experience in the industry would give a negative to that (yes past, so maybe that changed in recent years? I'm open to being corrected on that one if someone has any information). I can tell you what I often like to do if yield is unknown to me. I try to make an educated guesstimate of the yields based on similar reactions I know of for all of the routes I want to compare, after which I then proceed to check the prices of the individual reagents used in those routes, add them all up, compare them with the total prices of those individual routes, extrapolate those figures to the assumed theoretical yield, make comparisons to the current market prices of the final products in question and then finally see where the profit margin is the greatest. So if we end up with three ratios, 0.3, 0.6 and 0.15, then the synthesis route that gives 60% profit margin is very likely gonna be the industry-standard route.
P.S.: this ofc totally ignores the type, quantity, solubility and toxicity of all the byproducts which are also a huge factor in the choice of synthesis. A good example is actually the Levorphanol patent I linked. The inventor Joseph P. Haar mentioned that his novel route solves the issue of the hitherto industry-standard route that produced byproducts that could partially not be removed from the final product, which, if you think about the implications of it, is actually a horrifying admission. If I haven't misunderstood what he said, then two pharmacomps might be selling you both the same preparation, but if they used different manufacturing methods for the production, one ending up with residual mercury sulphide (let's hypothetically assume elemental mercury had to be used for some reaction) which is notoriously insoluble in water and is acid and base resistant and therefore, once in the body, won't ever leave the system, then you as the consumer will take those toxins into your body, even though the package insert gives you the wrong impression that the preparation is, irrespective of manufacturer, a pure product. That depends very much on the synthesis used though. I assume this is possible due to some legal loophole?
So all in all the byproduct profile of the route and its cost efficiency are the main determinants which synthesis a manufacturer uses.
I know, which is why I already wrote twice in this thread that the whole "levorotatory" thing that I mindlessly dropped earlier in regards to DXM was based on a confusion (false association with a closely related compound).
opiophiliclab.blogspot.com
