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Topic: Trying to find route to 4-Phenylpiperidine from Piperidine.  (Read 717 times)

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Offline ShaneS

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Trying to find route to 4-Phenylpiperidine from Piperidine.
« on: December 25, 2021, 10:28:01 AM »
Hi Guys, after a lot of experimentation obviously I am doing something wrong. Time to ask for help lol. 4-Phenylpiperidine is a precursor that I need and I have an existing(and green) pathway to piperidine but from there I am stumped. All literature I can find seems to start from different reagents(but lists piperidine as a precursor "type of" relationship) Looking at the structure it basically adds a benzene ring to a piperidine ring but I am lost as to how to actually make this happen with available reagents. As I said I'm tied to having the piperidine as a starting point. Any help would be appreciated, even if it's to tell me an alternative and that it cant be done my way :)

Offline rolnor

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Re: Trying to find route to 4-Phenylpiperidine from Piperidine.
« Reply #1 on: December 25, 2021, 01:33:10 PM »
Its very difficult(impossible?) to put a phenyl group on to plain piperidine. One way is to add phenylmagnesium bromide to piperidin-4-one and reduce the tertiary alcohol. I think you can buy piperidine-4-one as hydrochloride so you need to use 2 equi. of the Grignard reagent or first make the free base of the piperidine-4-one. I think you can use catalytic hydrogenation under acidic conditions to reduce the alcohol.  I am a bit concerned, is this some drug synthesis?

You need to make the free base in its dry form:
https://www.sigmaaldrich.com/SE/en/product/aldrich/151769

Offline ShaneS

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Re: Trying to find route to 4-Phenylpiperidine from Piperidine.
« Reply #2 on: December 25, 2021, 04:48:05 PM »
Not a complete one no. But I am working on a synthesis from pepper to piperine to piperidine to 4-Phenylpiperidine. From there everything from insect repellent to SSRIs. https://en.wikipedia.org/wiki/Piperidine for a complete listing.
And yes I'm sure you're aware of certain analogs. I assure you if I wanted the end result of the synthesis taken in an opioid direction I would just order it and not try to find the "greenest" route to get there. The fact is that the pain management industry(as well as antidepressants) is massive and if I'm honest it's more that industry that I would approach with a workable synthesis than for example an insect repellent. To set your mind at ease, I'll tell you another synthesis in this industry that I am working on a green solution. The demethylation of codeine and tramadol analogs with iron powder, steel after oxidation with peroxide. Again working to lessen harsh reagents in already occurring processes. The kind of pathways I am following. Thanks for your input I will look into it.

Offline billnotgatez

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Re: Trying to find route to 4-Phenylpiperidine from Piperidine.
« Reply #3 on: December 25, 2021, 05:07:42 PM »
@ShaneS

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Offline ShaneS

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Re: Trying to find route to 4-Phenylpiperidine from Piperidine.
« Reply #4 on: December 25, 2021, 05:50:16 PM »
keep in mind as I said that even potassium hydroxide. Benzene etc. Are now controlled substances. If we're to avoid any chemistry that may impinge on these lists then I assure you your board is doomed. The substances I mentioned are not direct precursors. They are at best precursors of precursors. As you said commercially available. Security through obscurity doesn't work etc etc.

Offline rolnor

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Re: Trying to find route to 4-Phenylpiperidine from Piperidine.
« Reply #5 on: December 26, 2021, 02:09:58 AM »
Demethylation of codeine does sound no good, why would you want to do that except for drug synthesis?

Offline Borek

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Re: Trying to find route to 4-Phenylpiperidine from Piperidine.
« Reply #6 on: December 26, 2021, 04:14:07 AM »
Demethylation of codeine does sound no good, why would you want to do that except for drug synthesis?

OP specifically said that it IS about drug synthesis.

Still, I see nothing wrong in discussion about possible routes and general ideas, it is exact recipes that are off limits.
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Offline ShaneS

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Re: Trying to find route to 4-Phenylpiperidine from Piperidine.
« Reply #7 on: December 26, 2021, 12:53:36 PM »
Thanks for your responce.
Just thought I would clarify my position even more.
I said it's a precursor to many things. Insect repellent. SSRI's. Blood Pressure Meds. And opiates. I said that if I was pushing a new synthesis for that precursor, I'd probably choose the drug industry because of financial reasons. It's a "bugaboo" for me I must admit(a point of personal contention with the way things are legislated and why). When I was a kid(9 years old) I was already ordering reagents from chemical supply houses and doing extractions of amines(for soaps and perfumes) and making various pyrotechnical stuff.
Anyway, I simply couldn't do that today as the chemicals are on various watch lists. Things like Petroleum Ether, Nitric Acid, etc. I find it sad because someone trying to do chemistry is hindered by these laws whereas you can buy heroin on every street corner for less than the price of a Coke(I live in South Africa)
I believe the same situation exists more or less in cities worldwide. So here's a breakdown of my stance, if anyone cares lol.
I believe a) that these lists create more harm than good. Criminals are gonna do what they do anyway. I'd rather they be able to order Petroleum Ether than use petrol which they cant fully evaporate. leaving impurities that result in drugs like Krocodyl so named because they cause flesh to fall off the user's body. I guess that's a different conversation but  basically, I believe:
a) that the evil "normal" chemist gone bad and trying to order watched chemicals for drug synthesis is largely a myth.
b) The real cartels etc have access to all the chemicals and professional chemists they could ever want.
c) The experimenter that tries to create this stuff in their basement is not on any scale that is or ever has been a concern. This is why anything even approximating that happening IRL has become a series(breaking bad). That's how unusual it would be, and you can see why -> they would be breaking into a cartel-controlled scene and probably have a very short career.
d) I believe that obscuring knowledge is not the answer. More knowledge is the answer. For example research on K opioid receptors (and drugs affecting them), that can relieve pain without classic morphine symptoms.
e) New generations should have the freedom to follow along with science channel experiments without being put on a watch list for ordering some benign chemical that happens to be a reagent used IN MANY DIFFERENT syntheses. Which is obviously absurdly common in organic chemistry. Lewis Bases/Acids, Propionyl Chloride, Aniline etc. In many districts, these UBIQUITOUS chemicals would get you unwanted attention.
I feel like we need to absolutely not help(as you pointed out) in stuff that would make one morally and ethically culpable. But also let's have these conversations and not exclude(by proxy and legislatively) large swaths of the population(let's face it mostly non-whites and young people are affected as they are most likely to be stopped and listed when buying glassware for example) Which often are people we would like to see having the resources to get into chemistry, which is hands-on. One needs to actually experiment and do things to learn. We should make sure this is still possible instead of being led to ban and legislate everything due to(fearmongering and) a tiny minority who, I assure you, would be doing crime anyway. That's what criminals do.

Offline rolnor

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Re: Trying to find route to 4-Phenylpiperidine from Piperidine.
« Reply #8 on: December 26, 2021, 03:33:44 PM »
And to me it all ends up with that we should help you design synthetic routes to drugs to circumvent the laws that are there to make drug synthesis more difficult, it still sounds no good. As far as I understand that is exactly what we shall not do att this forum.

Offline wildfyr

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Re: Trying to find route to 4-Phenylpiperidine from Piperidine.
« Reply #9 on: December 27, 2021, 11:12:22 AM »
Until I saw the 10,000 word explanation, I was willing to give the benefit of the doubt and just focus on an interesting synthesis question. Now I am less inclined...

Offline Borek

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Re: Trying to find route to 4-Phenylpiperidine from Piperidine.
« Reply #10 on: December 27, 2021, 03:00:11 PM »
Until I saw the 10,000 word explanation, I was willing to give the benefit of the doubt and just focus on an interesting synthesis question. Now I am less inclined...

You are not alone. Even if I do agree laws governing the chemicals and glass are in many cases idiotic, rant on them doesn't compose well with green chemistry card played at the very beginning.

I am locking the topic.
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