Analogue bees, attention: 3,4-dimethyl-amphetamine

[Rhodium]

4-methyl-benzaldehyde -> 3-bromo-4-methyl-benzaldehyde

Org Prep Proced Int 6, 251 (1974)

3-bromo-4-methyl-benzaldehyde -> 3-bromo-4-methyl-benzaldehyde ethylene acetal (I can post this if there is any interest)

J Med Chem 33(3), 976 (1990)

[toad]

hi bees,

found an interesting tid bit in sasha's book regarding
the 4-methyl and 3,4-dimethyl-amphetamine.

from pihkal #54:
"The 3,4-isomer, 3,4-dimethylamphetamine or xylopropamine, is an adrenergic agent and it has been found to be an analgesic in man at as little as 10 milligrams. This was assayed, rather remarkably, by attaching electrodes to the tooth fillings of the experimental subjects. But with this base, cardiovascular effects were not observed until doses of about 100 milligrams were administered, and toxic effects (nausea and vomiting) were reported at 150 milligrams. There was no suggestion of anything psychedelic.
All three isomers of monomethylamphetamine have also been looked at in man. The ortho- and meta-isomers, 2-methyl- (and 3-methyl- ) amphetamine are weak anorexics. At doses of up to 150 milligrams orally, there were signs of stimulation noted--talkativeness and loss of appetite. The para-isomer, 4-methyl-amphetamine or Aptrol, is more potent. At 75 milligrams (orally, in man) there is clear adrenergic stimulation, and at twice this dosage there are signs of mild toxicity such as salivation, coughing and vomiting."

I believe the ref sasha is referring to is:

Harris, S. C. and Worly, R. C. (1957). Analgesic
properties of  xylopropamine, Proc. Soc. Exp.
Biol. Med. 95:212-215.

Some further info from Glennon on the subject:

Higgs RA, Glennon RA.
Pharmacol Biochem Behav 1990 Dec;37(4):835-7
Stimulus properties of ring-methyl amphetamine analogs.

"There are three possible ring-substituted methyl amphetamines (or tolylaminopropanes; TAPs): oTAP, mTAP and pTAP. These agents are positional isomers of methamphetamine. Although all three isomers have been previously reported to possess amphetamine-like character, few studies have examined all three agents in comparison with (+)amphetamine. Using rats trained to discriminate 1 mg/kg of (+)amphetamine from saline under a variable-interval 15-sec schedule of reinforcement, tests of stimulus generalization were conducted with the three positional isomers. Only oTAP (ED50 dose = 4.1 mg/kg) completely substituted for (+)amphetamine. mTAP and pTAP resulted only in partial (ca. 50% amphetamine-appropriate responding) generalization. It is concluded that oTAP is capable of producing amphetamine-like stimulus effects and that it is approximately one-tenth as potent as (+)amphetamine; however, because the partial generalization produced by mTAP and pTAP was followed by disruption of behavior at slightly higher doses, it cannot be reliably stated that these latter two isomers lack amphetamine-like character."

It could be guestimated that perhaps the p and m position
methyl's may be effecting serotonin in similar fashion as other p sub amphetamines. specially considering the recent
report of 4-methyl-methcat having a rush akin to honey.
seems like some toxicity testing would be prudent measure
before engaging in extensive trials, especially considering p-halogen, p-methoxy, and p-methylthio toxicity.  
 
happy hunting!

toadie

[Lilienthal]

This is the Glennon article: DOI:

10.1016/0091-3057(90)90571-X

(using the new [doi] markup tag - see the link page and the FAQ).

[Kinetic]

It could be guestimated that perhaps the p and m position
methyl's may be effecting serotonin in similar fashion as other p sub amphetamines. specially considering the recent
report of 4-methyl-methcat having a rush akin to honey.

Well I certainly agree there . The high is rather short lasting, only about 45 minutes if snorted. Maybe this could be extended to a few hours if it was eaten. The rush of 4-methyl methcat seems to be more than just plain stimulant, so maybe there is something in the serotonin-related 4-position theory here too.

Note also that this bee's toxicity tests took him to 600mg intransally over a period of about 6 hours, with no noticeable side effects, except for the obvious lack of appetite and difficulty concentrating. A lower dosage would have been more sensible, but at least we now know that 4-methylmethcathinone is 'safe' at 600mg whereas 150mg 4-methylamphetamine produces mild toxic symptoms. It would probably be wise to proceed with care on any trial of 3,4-dimethylamphetamine; it's structural similarity to indanylamphetamine which Rhodium says to proceed with caution on in

https://www.thevespiary.org/rhodium/Rhodium/chemistry/iap.html

also suggests this, although it would be nice for any bee who actually knows something about pharmacology to give a more knowledgeable reply.

[foxy2]

although it would be nice for any bee who actually knows something about pharmacology to give a more knowledgeable reply.

If only brains were that simple.  We wouldn't even need to do research.  There is no way to look at a molecule and say how it will act.  Sure you can make an educated guess, but how many people here look at and think of these things in 3D which is reality.  Thats the first little step towards an educated guess on activity, then there are probly 5 other important factors to add in.


We don't have anyone here who knows anything about pharmacology do we?  

[cattleprodder]

[moo]

You are throwing wild guesses of the actions of compounds yet unexplored in the air... just like a user called Redmonn_16 did a few months ago. It is interesting to see you quote the Wu Tang Clan too, just like he did in a PM. The sketchy outlines of synthetical routes also sound quite familiar not to mention the attitude. I wonder, would he had needed to register a new account?  

Would you like someone to test these compounds for you, sir?
"Don't talk the talk if you can't walk the walk" --the Wu Tang Clan

[Antoncho]

moo:      

[catastrophe]

Okay, firstly way to go moo!! Yeah!

Secondly, about possible syntheses 4-methyl compounds, could something like this work for say DOM?...

2,5-Dimethoxybenzaldehyde ---> Clemmensen ---> 2,5-Dimethoxytoluene?

SWIM has a reference where they do the exact same reduction on vanillin to obtain 1-methyl-3-methoxy-4-hydroxybenzene in 60-65% yield. Is this reduction of aldehydes applicable to other structures?

Thirdly, about making the -propyl compounds. Would a Clemmensen reduce an allyl group??? Could one go like this for 2C-P?...

2,5-Dimethoxyallylbenzene ---> Clemmensen ---> 2,5-Dimethoxypropylbenzene??

2,5-Dimethoxyallylbenzene is outlined on Rhodium's, seems facile. That would be GREAT!!

Finally, SWIM still can't figure out a way to make the 4-ethyl compounds. 2C-E looks like such an amazing compound, contrary to what yellium noted. It seems one has to make the acetophenone with non-OTC chems. Then reduce with Clemmensen, then formylate with most possibly a chloromethylation.

[Masquerade]

2,5-Dimethoxybenzaldehyde will most definetly reduced by  clemmensen to the toluen. It seems like waste of benzaldehyde! About a allyl group being reduced, it might work to make the propyl. It seems like a good way to make 4-propyl compounds, good idea! Of course stronger reducing agents will work, but clemmensen? not sure. The moderator Rhodium know best here.

For your trouble in 2C-E, how about this idea. You can make acetic anhydride OTC, so reflux with 1,4-dimethoxybenzene to obtain the acetate (don't have patent# with now, but they say any CH3COA work. Email, you remember the address right?). React acetate with 1.2 mol equiv. AlCl3 (not so OTC, but a chemist named mountain_girl mentions making AlBr3 easy). This gives the acetophenone. No acetyl chloride.
Also, GB patent #633,724 shows use of P2O5(again not OTC) and acetic acid to make acetophenone.

[Lilienthal]

I just found this patent as an old printout between my documents:

Patent GB1036290

. It contains a procedure to 3,4-methyl-amphetamine (Xylopropamine) from 1-amino-3,4-dimethyl-benzene.

[Aurelius]

GB Patent 1036290

A Process for the Manfacture of Phenyl-Amino-Propane Derivatives

Abstract:

The process provided by the present invention, which is a technically simple process and enables the xylopropamine to be obtained in a pure form (that is to say, free from undesired isomers), comprises diazotizing 1-amino-3,4-dimethylbenzene, reacting the diazonium product with formaldoxime, hydrolyzing the resulting 3,4-dimethylbenzaldoxime, condensing the 3,4-dimethylbenzaldehyde  obtained with nitroethane, reducing the resulting 3,4-beta-trimethyl-beta-nitrostyrene and, if desired, converting the resulting 1-(3,4-dimethylphenyl)-2-aminopropane into an acid addition salt.

Example 1:

A mixture of 46g of paraformaldehyde, 105g of hydroxylamine hydrochloride and 680ml of water heated on the steam-bath in a 2L RB flask until complete solution had occurred.  204g of sodium acetate were then added and the solution obtained was boiled under reflux on an oil-bath for 15-20minutes.  The solution was then cooled to 10*C and decanted into a 6L flask which was fitted with a stirring device, a reflux condensor, a thermometer and a dropping funnel.  4g of sodium sulfate, 25g of copper sulfate and a solution of  660g of sodium acetate in 720ml of water were then added to the solution. 

121g of 1-amino-3,4-dimethyl-benzene in powder form were introduced into a mixture of 228ml of concentrated hydrochloric acid, 200ml of water and 400g of ice; 1-amino-3,4-dimethylbenzene hydrochloride crystallized out.  A solution of 70g of sodium nitrite in 100ml of water was added dropwise with stirring and ice-cooling in such manner that the temperature did not rise  above 5*C.  A solution of 130g of sodium acetate in 200ml of water was then added and the ice-cooled diazonium solution thus obtained was added dropwise over 30 minutes to the solution of formaldoxime obtained according to the data in the first paragraph of this Example; during the addition, the temperature was held at 10-15*C.  A black tar-like precitate formed.  The mixture was stirred for ca 1 hour and then acidified with 200-300 ml of concentrated hydrochloric acid.  A furthur 920ml of  concentrated hydrochloric acid were added and the mixture was heated at reflux for 2 hours and then distilled with steam.  The distillate (ca 5L) was neutralized with 350g of sodium bicarbonate and extracted with 1L of ether.  The yellow oily residue obtained after concentration of the ether extract was heated at ca 60*C with stirring for 2 hours with 360ml of a 40% solution of sodium sulfite.  About 1300ml of water and 500ml of ether were added to the cooled mixture and the ethereal phase was separated.  The aqueous solution was heated at reflux for 30 minutes with 180ml of conc. sulfuric acid and 180 ml of water.  The mixture was then extracted with about 1000ml of ether and the extract was dried over sodium sulfate and evaporated to dryness.  The yellowish residue was distilled at 97-99*C/10mmHg to yield 59g of pure 3,4-dimethylbenzaldehyde as a colorless liquid that had; n_D ²³ = 1.5490 

A mixture of 100g of 3,4-dimethylbenzaldehyde, 100ml of toluene, 180g of nitroethane, 5 ml of butyl amine, 5ml of glacial acetic acid and 0.35g of paratoluenesulfonic acid was heated at reflux in a 500ml rb flask fitted with a reflux condensor and a water separator.  The resulting solution was concentrated under reduced pressure and the oily residue taken up in 100ml of absolute ethanol. Upon cooling to –10*C, yellow crystals were filtered off and washed with ice-cold ethanol and air-dried.  118g of material were obtained.

The alcoholic mother liquor was evaporated to dryness and the residue was taken up in ether.  The resulting solution was washed with aqueous sodium carbonate, water, 3N HCl and once again with water and dried over sodium sulfate.  The solvent was evaporated and the residue  (ca 20g) was distilled under reduced pressure.  The fraction boiling at 155-160*C/9mmHg was collected, dissolved in 12ml of absolute ethanol and crystallized at –10*C to yield ca 9g of material.  Two crops of material were combined to give 127g of yellow crystals that had; MP: 36-37*C  Which after recrystallization from 130ml of methanol gave 121g of pure 3,4-beta-trimethyl-beta-nitrostyrene in the form of light yellow crystals that had; MP: 37-38*C

19.1g of the product above in a mix of 200ml of methanol and 2ml of 48% HBr were hydrogenated at RT in a 500ml hydrogenation flask in the presence of 5g of 5% Pd/C.  0.2mol of H₂ was taken up  within ca 8 hours, after which time the catalyst was filtered and 5ml of 20% methanolic solution of ammonia were added to the solution.  The solution was evaporated to dryness and the residue was taken up in 200ml of ether.  Undissolved ammonium hydrobromide was filtered and the rest was hydrogenated in the presence of 15g of raney nickel which had previously been washed with methanol.  About 0.2 mol of H₂ was taken up in 8 hours.  The catalyst was then filtered and the solution was concentrated.  The residue was distilled under reduced pressure, the fraction which went over at 110-112*C/10mmHg being separated.  14g of pure 1-(3,4-dimethylphenyl)-2-amino-propane were obtained in the form of a clear liquid that had; n_D ²³ = 1.5178

The reduction can also be done using LiAlH₄

1-(3,4-dimethylphenyl)-2-aminopropane can also be obtained from the nitrostyrene in the following manner:

13.4g LiAlH₄ and 360ml of absolute ether were filled into a 1.5L, three-necked flask fitted with a reflux condensor and dropping funnel.  A solution of 19.1g of 3,4-beta-trimethyl-beta-nitrostyrene in 240ml of absolute ether was added dropwise with stirring within 2 hours and the mix obtained was boiled under reflux for 2 hours.  The mix was then cooled by means of an ice-bath and 90 ml of ice-cooled water were slowly added dropwise.  A white granular precipitate formed and was filtered off by suction and thoroughly  washed with ether.  The ethereal solution obtained was dried over sodium sulfate and concentrated.  The residue was distilled at 110-112*C/10mmHg to give 12.2g of pure 1-(3,4-dimethylphenyl)-2-aminopropane.

Also:

The fumarate salt was colorless crystals that had; MP: 187-188*C

The hydrochloride was colorless crystals that had; MP: 169-170*C