Tropafexor

[Smyth2]

This is a theoretical idea that occurred to me a few years ago but I have been very quiet on it.

It has never been made before and was only a theoretical "guess" on my part.
Instead of sextone you use 3-tropinone and arrive at the final product.
At this stage it is only a guess of mine since it has never been made before.

 

[specialrelativity]

?

 

[4DQSAR]

The chemistry surrounding building tropene systems is awful and endo-exo isomerism may result in that hydroxyl being jumbled making a total of four enantiomers.

 

[Smyth2]

Sorry I forgot to mention that it is an analog of venlafaxine or Wy-45,881 (wikipedia article anyone?) aimed at producing SNDRI type of activity.

If you see the middle synthesis, I think that a simple Grignard reaction should give predominantly the desired exo isomer.
But this is totally a guess at this point that Tropafexor would be a good drug. It has never been made before.

Studies on Synthesis of Antidepressant Venlafaxine[J]. Journal of China Pharmaceutical University, 1999, (4): 9-10.

 

[4DQSAR]

Because ir would be xtremely costly?

I count 8 steps and obviously that doesn't show the workups.

Whenever people suggest such things, I point to 2-CT-13 (I think that's the one). About 1Kg of precursor for under a gram of product. Now consider the solvents and then the glasswaree.

I've mentioned this before but reallly you want 3 or fewer steps, 4 if it's something potent. Beyond that the cost becomes INSANE.

Venlafaxine costs $134/Kg so unless you can demonstate utility for something I guesstimate to cost twenty times as much, I don't see it.

Tropinone IS commercially available but look at the price (or synthesis if you must go the hard way).

 

[Smyth2]

Maybe the synthesis is too complicated for now. In the abstract to the article I included it said it said it's 11% overall with 5 steps.

But these are inexpensive steps to make, assuming one wants the 3',4'-dichloro compound since this is the more potent.

That's assuming the original synthesis doesn't work out as expected.

I'm more concerned at this point if pharmacology would work out just purely of a "guess" about a change in molecular structure.

If you want to see an insanely complicated structure to synthesize then compare for Tropifexor (not to confuse with Tropafexor).

 

[4DQSAR]

Well yeah, but check the precusor prices for any telescoped synthesis.

If you are making something for research then cost isn't a big issue and yield only needs to be 'enough'.

But in the real world those costs ARE important.

Take a look at sertraline. It's been around for 30+ years and there are HUNDREDS of patents devoted to improving the synthesis. Because their is a niche for researchers whose job it is to find a cheaper way. That's many billions spent in the persuit of savings - so it only works at huge scales. But the price HAS dropped by an order of magnitude due ti that inbestment,

If I had to guess it would be that someone took venlafaxine and decided to see if a rigid analogue was worth the effort... and it wasn't.

With all these things, don't get tied up with that which appears to be the absolute apogee of development of a scaffold. None of us know why the stuff isn't a medicine... but it isn't.

 

[Rectify]

I Love To See Progress Like This! But, Remember, If You Make The Drug TOO Good, They Won't Approve It.