I'm guilty of always asking people to provide a facile synthesis for the novel compounds sometimes posted. It's not to be contrary but because if you can't produce it, you cannot confirm activity and safety profiles. But at least as importantly, it's key to becoming a competent medicinal chemist. Yes, ultimately the head of a team may only provide in-silico models (or properly calculated Drieding models) BUT only after they have spent decades at the 'coalface' finding practical, scalable production methodologies.
The compound that has haunted me for the last ohhh, thirty years is the 'reversed ester' of nortilidine. I used inverted commas because in fact the cyclohexene ring of (nor)tilidine is substituted for a cyclopentane. Neat fact - the cyclohexane homologue if nortilidine is far, far less potent than the parent. I strongly suspect one key reason for the development of tilidine was it's simple synthesis. Yes, one of the precursors is very costly on the open market BUT I presume that the makers have telescoped the synthesis. Coupled to the fact that tilidine is a rare example of the trans-pair having advantages of the pure enantiomer, thus clawing back some of the costs. In addition, the unwanted cis-pair can be epimerized so nothing is wasted (yield goes up). Dextilidine (or rather it's metabolite - nortilidine) is an opiod and DRI while laevotilidine has NMDA activity.
US4291059A Cycloaliphatic compounds, analgesic compositions thereof and method of use thereof as analgesics
It's worth a quick look at the parent and metabolites of both.
As you can see, of the four possible enantiomers, it's the trans-pair that is used medically but as mentioned, the cis-pair can easily be isolated and racemized so it doesn't get wasted. Obviously the optimized route isn't in the public domain.
Forgive the cyclopentane rings not being quite to scale but the KEY elements are that the benzene ring perfectly overlays the A-ring of morphine, the ester function overlays the E (dihydrofuran) ring of morphine and the basic nitrogen or, more specifically, the N: lone-pair overlays that of morphine. The cyclohexene or cyclopentane rings do not appear to overlay any of the rings seen in morphine. No, it merely acts as a scaffold to place the three key moieties in the appropriate relative spatial positions.
So at first glance, the reversed-esters don't appear any more complex than tilidine itself. But like quite a few medicines, researchers homed in on a Diels-Alder reaction possibly because it's regarded as the 'Mona Lisa' of chemical reactions but more pragmatically, because it's such a powerful tool.
But as you see in the patent, that reversed ester is a pain. Yes, there are references to the selective O-acetylation of other compounds BUT in this case it's esterification of a tertiary hydroxyl, propionylation rather than acetylation is required and in such systems it appears that a large excess of the carboxylic acid derivative are required.
As I've previously mentioned, while acetic anhydride, ethane-1,1-diyl diacetate and propanoic anhydride are all controlled chemicals, the mixed anhydrides and mixed diyls are yet to be controlled. Still imperfect BUT feasible? Well, things only get worse from that shaky start. I figured that the patents choice of (cyclopent-1-en-1-yl)benzene is still likely the best option but it's a rare and costly beast. That's going to be 4 steps to the raecemic produce. About the only upside is that most routes will produce almost purely the trans isomers.
I've been down some frankly hideous pathways in my mind. One was the direct aminohydroxylation using N-(2,4-dinitrophenoxy)methanamine... but try finding THAT material.
It seems like every time I go down a new path, some obstacle gets in the way.
It's not as if isonortilidine is a particularly potent compound. It's my opinion that the researchers at Glaxo were hoping that like the phenylpiperidine class, reversing the ester function might increase activity in a similar manner. For a compound x10 M, it might have been a practical proposition but tests suggest that it's no more potent that the parent.
Now as far as I know, nobody has ever studied derivatives in which the cyclohexene or cyclopentane rings were further substituted. I suggest the reason for that is the sheer COST of doing so would make it impractical.
But every year or so I go back to the papers, try out some more ideas and give up again. It's by no means with the intent of producing the compound, it's merely to see if the application of more modern reactions make it a facile target.
BTW why not try overlaying isonortilidine with cypenamine.
The compound that has haunted me for the last ohhh, thirty years is the 'reversed ester' of nortilidine. I used inverted commas because in fact the cyclohexene ring of (nor)tilidine is substituted for a cyclopentane. Neat fact - the cyclohexane homologue if nortilidine is far, far less potent than the parent. I strongly suspect one key reason for the development of tilidine was it's simple synthesis. Yes, one of the precursors is very costly on the open market BUT I presume that the makers have telescoped the synthesis. Coupled to the fact that tilidine is a rare example of the trans-pair having advantages of the pure enantiomer, thus clawing back some of the costs. In addition, the unwanted cis-pair can be epimerized so nothing is wasted (yield goes up). Dextilidine (or rather it's metabolite - nortilidine) is an opiod and DRI while laevotilidine has NMDA activity.
US4291059A Cycloaliphatic compounds, analgesic compositions thereof and method of use thereof as analgesics
It's worth a quick look at the parent and metabolites of both.

As you can see, of the four possible enantiomers, it's the trans-pair that is used medically but as mentioned, the cis-pair can easily be isolated and racemized so it doesn't get wasted. Obviously the optimized route isn't in the public domain.

Forgive the cyclopentane rings not being quite to scale but the KEY elements are that the benzene ring perfectly overlays the A-ring of morphine, the ester function overlays the E (dihydrofuran) ring of morphine and the basic nitrogen or, more specifically, the N: lone-pair overlays that of morphine. The cyclohexene or cyclopentane rings do not appear to overlay any of the rings seen in morphine. No, it merely acts as a scaffold to place the three key moieties in the appropriate relative spatial positions.
So at first glance, the reversed-esters don't appear any more complex than tilidine itself. But like quite a few medicines, researchers homed in on a Diels-Alder reaction possibly because it's regarded as the 'Mona Lisa' of chemical reactions but more pragmatically, because it's such a powerful tool.
But as you see in the patent, that reversed ester is a pain. Yes, there are references to the selective O-acetylation of other compounds BUT in this case it's esterification of a tertiary hydroxyl, propionylation rather than acetylation is required and in such systems it appears that a large excess of the carboxylic acid derivative are required.
As I've previously mentioned, while acetic anhydride, ethane-1,1-diyl diacetate and propanoic anhydride are all controlled chemicals, the mixed anhydrides and mixed diyls are yet to be controlled. Still imperfect BUT feasible? Well, things only get worse from that shaky start. I figured that the patents choice of (cyclopent-1-en-1-yl)benzene is still likely the best option but it's a rare and costly beast. That's going to be 4 steps to the raecemic produce. About the only upside is that most routes will produce almost purely the trans isomers.
I've been down some frankly hideous pathways in my mind. One was the direct aminohydroxylation using N-(2,4-dinitrophenoxy)methanamine... but try finding THAT material.
It seems like every time I go down a new path, some obstacle gets in the way.
It's not as if isonortilidine is a particularly potent compound. It's my opinion that the researchers at Glaxo were hoping that like the phenylpiperidine class, reversing the ester function might increase activity in a similar manner. For a compound x10 M, it might have been a practical proposition but tests suggest that it's no more potent that the parent.
Now as far as I know, nobody has ever studied derivatives in which the cyclohexene or cyclopentane rings were further substituted. I suggest the reason for that is the sheer COST of doing so would make it impractical.
But every year or so I go back to the papers, try out some more ideas and give up again. It's by no means with the intent of producing the compound, it's merely to see if the application of more modern reactions make it a facile target.
BTW why not try overlaying isonortilidine with cypenamine.
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