Route to parafluoro-4-methylaminorex

[Bandil]

Hi!

Swim is going to play around with some parafluoro-4-methylaminorex in the near future, to see what kind of potency and subjective effects this compound has. The starting material will be pure 4-fluorobenzaldehyde. As this is a little more expensive than plain benzaldehyde, swim would like some general suggestions on the route, so that the risk of failure is minimized.

4-fluorobenzaldehyde -> para-fluoro(phenylnitropropanol) via Henry rxn:
Swim was thinking of following

this

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/phenyl-2-nitropropanol.html) route to the compound. The heavily substituted 2,4,5-benzaldehyde turned out to be very insoluble in methanol, and thus required higher temperatures. The Merck index, states that 4-fluorobenzaldehyde is soluble in the lighter alcohols and ethers. Thus a candidate for this route, could be a reaction run in cold methanol. Does this sound reasonable?

para-fluoro(phenylnitropropanol) -> para-fluoro(phenylaminoalcohol)
This seems easy enough. Just a standard Zn/formic acid reductions. Any reason why this shouldn't be a breeze?

Formation of the oxazoline ring
Standard cyanate route i suppose...

And finally dose
There has been some discussions in past post's about the supposed potency of this critter. Someone suggested on the basis of some animal studies that it could be ultra potent, and some disagreed. Can any of you remember if they ever concluded anything. What kind of dose should be expected, and what would be a descent dose to test first? I don't suppose it dust-mask-all-the-time potent?

Thank you for you feedback!

Regards
Bandil

[Megatherium]

Aminorex has an ED₅₀ of 5.8 mg/kg in rats, p-fluror-aminorex has one of 1.2 mg/kg (oral administration).  Therefore, I suggest you use a dose that is 5 times lower than your normal 4-MAR dose.

By the way, I think your proposed synthesis will work   .

The Merck index, states that 4-fluorobenzaldehyde is soluble in the lighter alcohols and ethers. Thus a candidate for this route, could be a reaction run in cold methanol. Does this sound reasonable?

Yes, it does   .

This seems easy enough. Just a standard Zn/formic acid reductions. Any reason why this shouldn't be a breeze?
Good idea.  Or mabey a Pd/C - KOOCH CTH à la Barium for higher yields.

Standard cyanate route i suppose...

  - this was a rethorical question, wasn't it   ?


One final remark, I guess the p-fluorophenyl-2-nitropropan-1-ol will dehydrate more easily to the 2-nitropropene than the non-substituted compound.

Keep us informed about this nice project.

[Vitus_Verdegast]

You say p-fluoro-aminorex has an ED(rat) of 1.2 mg/kg , but Bandil wants to synthesize p-fluoro-4-methylaminorex.
Is it reasonable to assume it will be even more potent?

Maybe it is best to start with 1/10th of a usual 4-MAR dose, and carefully increasing the dose?

[Bandil]

One final remark, I guess the p-fluorophenyl-2-nitropropan-1-ol will dehydrate more easily to the 2-nitropropene than the non-substituted compound.

Why do you think that it will do that more readily? Flourine is very electronegative and will thus withdraw the electrons from the aromatic system inductively. The dehydration works AFAIK by creating an intermediate carbocation at the 1-ol oxygen, and later at the corresponding carbon atom. This would be destabilized from the eletronegative group, would it not? Thus dehydration should occur at a lower frequency? Maybe im missing something, i don't know

Regards
Bandil

[Vitus_Verdegast]

R-CH(OH)SO₂ONa + NaCHCH₃NO₂ -> R-CH(OH)CHCH₃-NO₂ + Na₂SO₃

I can't see where, if using the bisulfite adduct, the slight basic conditions could dehydrate the nitroalkanol.

It should precipitate without acidifying, n'est-ce pas?

Also, I can't see dehydration happening when triethylamine is used.

BTW: A fluoro group on the ring is weakly deactivating, a bit more than the unsubstituted benzene ring.

[Rhodium]

Bandil: I agree with you on the dehydration issue. 4-Methoxy-phenyl-2-nitroalkan-1-ols dehydrate more readily than unsubstituted phenyl-2-nitroalkan-1-ols, which in turn dehydrate more readily than 4-fluoro-phenyl-2-nitroalkan-1-ols - This due to the reasons you mention.

[Megatherium]

You say p-fluoro-aminorex has an ED(rat) of 1.2 mg/kg , but Bandil wants to synthesize p-fluoro-4-methylaminorex.
Is it reasonable to assume it will be even more potent?

Of course it will be more potent than the usual trans-4-methylaminorex.  Since the fluoro has a potency enhancing effect of 5 in aminorex, I suspect it will do too in trans-4-methylaminorex.  Hence, I said to cut the trans-4-methylaminorex dose by 5.

R-CH(OH)SO2ONa + NaCHCH3NO2 -> R-CH(OH)CHCH3-NO2 + Na2SO3

I can't see where, if using the bisulfite adduct, the slight basic conditions could dehydrate the nitroalkanol.

It should precipitate without acidifying, n'est-ce pas?

Also, I can't see dehydration happening when triethylamine is used.

I was not worrying about dehydration during the Henry reaction, but about dehydration in acidic conditions like in a Zn / acetic (or formic) acid reduction of the nitroalcohol.  But indeed, there is no reason to worry about it: the benzylic cation isn't likely to be formed because of the electronegative fluoro atom (the resonance structures of the aryl seem indeed a bit unfavourable   ).

Sorry for the mistake Bandil, I wasn't thinking straight due to some chemical substance .

This project has most definately a GO!

[Antoncho]

There's a formula for neurochemical extrapolation from animals to human beings:

Dose_human = Dose_animal*(Weight_human/Weight_animal)^0,7


...according to which, dosage of 4-F-aminorex would bee ~14mg per a 70kg human.

Also, a single dose of straight aminorex, according to this formula is ~68mg - which is a damn good match, i say, to the actual EC50 - given that, as an anorectic, it is prescribed in 37-75mg dosages (according to Rh's).

Of course, we don't know the ED50 of fluoro-4-MAR, so we can only extrapolate it to those 3.5-4.7mgs...

OTOH - with pharmacology, you never know...




Antoncho

P.S. The above beautiful formula was aqcuired from the article on "MDMA pharmacology and clinical pharmacology" submitted by Methyl_Ethyl (

Post 459064 (missing)

(methyl_ethyl: "The Pharmacology and Clinical Pharmacology of MDMA", General Discourse))


P.P.S. GO BANDIL !!!