phenylpropanolamine from benzaldehyde

jackoozzi · specialist

I cut this out of a post at wd and was wondering if anyone has done this or has any more information

Uncle Fester says somewhere in SOMM that PPA can be made from benzaldehyde and alanine simply by heating the two together until CO2 evolution ceases. Hmmm. Cinnamon oil -> benzaldehyde, benzaldehyde -> PPA, PPA -> 4-MAR. OTC, and so simple that even pill-cooks might be able to do it. Is this the Next Big Drug Problem just waiting to happen?

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Astrum
New Dreamer

Posted - Mar 21 2005 : 3:27:22 PM
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Alright, I did a little digging on making phenylpropanolamine from benzaldehyde and alanine. It's known as the Akabori-Momotani reaction. It's the aldol condensation of amino acids with aromatic aldehydes to give amino alcohols.

So the reaction we're looking at is:
C3H7NO2 + C7H6O -> CO2 + C9H13NO

jackoozzi · specialist

And just witch isomer of alanine would you need there seems to be a few including

d alanine
l alanine
dl alanine
b alanine

Astrum · Tue Mar 22, 2005 8:07 am

Here's the diagram:

CherrieBaby · chouchou

The references (from the 13th Merck) are:
E. Takagi et al., J. Pharm. Soc. Japan 71, 648 (1951); 72, 812 (1952);
A. Lawson, H. V. Morley, J. Chem. Soc. 1955, 1695;
A. Lawson, ibid. 1956, 307;
K. Dose, Ber. 90, 1251 (1957);
H. V. Belikov et al., Izv. Akad. Nauk SSSR, Ser. Khim. 1969, 2336.

jackoozzi · specialist

Here is a pic prom the merck references

Guest · Wed Mar 23, 2005 1:12 pm

I cautiously assume this is why L- alanine can be used, since it becomes racemic(dl-alanine) in situ,

This is good reading, the akabori, has quite a destiny,

Abstract of JP11322684
PROBLEM TO BE SOLVED: To improve the isomerization process, in other words, racemization and epimerization for optically active amino acids, typically alanine, &alpha - aminobutanoic acid, valine, leucine, isoleucine, phenylalanine, tryptophane and methionine, in the presence of a lower fatty acid and an aldehyde and provide an high-efficiency isomerization process for amino acids with lowered energy consumption and easy recycle of the lower fatty acid and aldehyde as the isomerization catalyst. SOLUTION: An optically active amino acid is dispersed in an inert solvent that substantially does not dissolve amino acids, preferably an aromatic hydrocarbon such as benzene, toluene, xylene or halogenated benzene. A lower fatty acid, preferably a 1-5C saturated fatty acid as acetic acid, propionic acid or butanoic acid and an aliphatic aldehyde or an aromatic aldehyde, preferably an aromatic aldehyde such as benzaldehyde or salicylaldehyde are allowed to act on the dispersion to effect the isomerization. The mixture of the optical isomers of the crystallized amino acid separating from the solvent are collected by the solid-liquid phase separation.

Abstract of JP57123150
PURPOSE:The racemization of an optically active aminoacid is effected in the presence of a lower fatty acid and an aromatic aldehyde to give the racemi aminoacid in high yield through one step and this process is applicable to a variety of aminoacids and the racemization rate is high. CONSTITUTION:An optically active aminoacid such as alanine, arginine, asparaginic acid or proline is racemized in the presence of a saturated fatty acid of 1-3 carbon atoms and an aromatic aldehyde such as benzaldehyde which may be a substituent such as hydroxyl, nitro, amino, methoxy or the like wherein the amount of the aldehyde is about 0.001-0.3mol and the lower fatty acid is more than 10 (V/V)% based on the optically active aminoacid.

Very interesting reading,

syn

IndoleAmine · Dreamreader Deluxe

Since

a) 1-phenylpropan-1-ol-2-amine (PPA) used in nasal decongestants (and cold medications) is the racemic d,l-ppa.hcl (no brand names; but there are MANY! Wink

)

b) this racemic PPA.HCl can be used to produce 4-MAR, like described in https://synthetikal.com/synthforum/viewtopic.php?t=127 ,

..I would assume that the racemic d,l-alanine OR the optically pure d-alanine are the correct ones to use in the akabori-momotani rxn - no?

But since alanine is isomerized/racemized easily by refluxing with GAA/BzCHO in toluene according to the above japanese patent (good find!), this is just of theoretical interest I think.

i_a

IndoleAmine · Dreamreader Deluxe

Lets see, hope I got this right:

(edit: I just noticed that the second rxn depicted above is in fact an esterification - the whole thing is acid-catalysed, and two hydrogens and one oxgen have to leave the carbamoyl molecule before it can close this oxazole-type ring - and after this dehydration has occured, we have a C-O-C structure, which all together represents the classical definition of an esterification, if I'm not completely debile...(

) -

- Now the next question: what type is the rxn I didn't include, the one between PPA/"norephedrine" and KOCN? I didn't include it because I don't understand it, maybe someone can help?)

i_a

Astrum · Thu Mar 24, 2005 9:16 am

IndoleAmine · Dreamreader Deluxe

No, the d,l-cis-isomer of 4-MAR is the controlled CNS stimulant (according to merck) - but I am tempted to say that it doesn't matter as long as you use either d-, l- or racemic alanine; since PPA occurs just in one configuration, so you will end up with PPA no matter which isomer of alanine you use (at least ChemDraw 8.0 was not able to resolve the above "PPA" structure into optical isomers, so I would like to say there are no isomers in this case... then again I know nothing about stereochemistry and optical rotation.....)

(BTW in fact according to IUPAC "phenylpropanolamine" is a different compound and a secondary amine and the correct name is "1-phenylpropan-1-ol-2-amine"; but you all know what is meant with "PPA", right? Very Happy

)

And I'm dead sure that with d,l-alanine, you will get at least 50% of the given possible yield for the Akabori Laughing

(and you can racemize all stereoisomers of ala very easily, see above).....

(very tired too, see y'all tomorrow...)

i_a

Guest · Fri Mar 25, 2005 7:04 am

I believe both isomers of 4-mar are active,
As the L-alanine would be racemerized to DL-alanine in situ,

Wouldn't this them mean you would have then dl-PPA,

But then what happens to L-PPA in the KOCN,

What happens when L-alanine insitu becomes DL-alanine,
does the dl-alanie, keep getting processed until it all D-alanine, or D-PPA?

IS there only one optical molecular configuration for PPA?

SO accoring to the patents,
If you wanted all d-alanine, you would have to separate out D-isomer, and reprocess, a few times the remaing L-alanine?

What process to we have for separation of stereo isomers?

Tartaric acid?

I don't think it's of too much concern,
As long as you are happy with a racemic mix,
Which Is probably a good mix

syn

64bandil · Busy Bee

The cyanate route with norephedrine gives the trans isomer, whereas norephedrine with cyanogenbromide yields cis. norpseudoephedrine with CNBr gives trans and norpseudoephedrine with cyanogen bromide yields a crappy amide, thats completely inactive... phew! [edit: whops, i meant to say "norpseudoephedrine with cyanate yields a crappy amide, thats completely inactive

One of the trans isomers is actually the most potent one. But the less postent trans isomer, is the least potent of all the possible isomers... The potency list goes something like this:

trans-4-mar (isomer 1)
cis-4-mar(isomer 1)
cis-4-mar(isomer 2)
trans-4-mar(isomer 2)

So all in all they are pretty equipotent with respect to amount. 40 mg´s of either cis og trans will get me flying pretty high... Dont think I could tell them appart...

Regards
Bandil

IndoleAmine · Dreamreader Deluxe

Nice. So stereochemistry is not much of a concern in the PPA->4MAR step, I would say - right? Cool

And my understanding is that the akabori-momotani gives only 1-phenylpropan-1-ol-2-amine (PPA), regardless which d, l or racemic stereomer of alanine you use, although it is possible that only one optical isomer will give 100% conversion - but since alanine is dirt cheap, it really shoudln't matter, since there is no "wrong" compound produced that could present a waste of aldehyde...

I think I will just try, visit my local pharmacy right after easter and tell'em I need a LOT of alanine, all isomers they have in stock (maybe I will have a serious nutrition disequilibrium, have a little sister with apoor ill rabbit, or wanna become a 200pound muscle monster by ingesting amino acids or something like that, what do you think?), and try and decarboxylate them with some BzCHO - maybe one ala isomer will give nearly double yields compared to the others, or maybe even 2x as much as the racemic and one wont work at all - we'll see....

(any stereochemistry expert wanna comment?)

i_a

Guest · Sat Mar 26, 2005 7:31 am

It would be nice to see a bit of real world experimentation on this alanine species,

L-alanine comes in the HCL salt, i believe?
As i have sometimes noticed on the packaging,

syn

Astrum · Sat Mar 26, 2005 4:27 pm