Author Topic: Enantiomerically pure d-methamphetamine
Rhodium
Administrator posted 11-23-98 09:01 AM
--------------------------------------------------------------------------------
What do you say? Benzene is acylated under Friedel-Crafts condition with chiral N-Acetyl-N-methyl-alanyl chloride to give N-acetyl-methcathinone, which protecting group is hydrolyzed and carbonyl moiety reduced in one pot to give enantiomerically pure d-methamphetamine. Probably high yields too.
KrZ
Member posted 11-23-98 10:19 AM
--------------------------------------------------------------------------------
Looks beautiful, we'll have to see how it comes out in testing....
drone 342
Member posted 11-23-98 03:57 PM
--------------------------------------------------------------------------------
Quite elegant, though I must admit I'm a little skeptical. N-Acetyl-N-methyl-alanyl chloride isn't available at Wall-Mart (yet), which I imagine will require several steps to produce (methylation of alanine, acetylation of N-methylalanine, reaction of M-methylalanine with thionyl clhoride, POCl3, or soemthing...) Aside from this, I like it a lot -- the utilization of the carbonyl to deactivate the benzene from subsequent substitution is quite nice. I know there's an obvious reason, but my brain isn't functioning -- why again do you acetylate the amine here?
Perhaps a simper version, using alanyl chloride to form cathinone would be worth looking into as well (I've tried cathinone in the form of khat, but wasn't impressed; however reduction to dextroamphetamine would thrill me.)
-drone #342
Rhodium
Administrator posted 11-23-98 07:39 PM
--------------------------------------------------------------------------------
I was afraid the amino acid chloride would polymerize if it wasn't protected. I just liked the looks of these two final steps, and by the way, no rare or expensive chemicals are used in the synthesis either.
drone 342
Member posted 11-23-98 08:27 PM
--------------------------------------------------------------------------------
...No rare or expensive chemicals...except chiral N-Acetyl-N-methyl-alanyl chloride. True, it can be made from less expensive chemicals, but look at the number of steps.
I see the polymerization thing, but I thought that perhaps the amine wouldn't be as attracted to a carbonyl chloride. Clearly, I was in fact smoking a fat bowl of crack at the time, since it would be even *more* interested in reacting than if it were a mere aliphatic amine.
-drone #342
beagle_boy
Member posted 11-23-98 08:51 PM
--------------------------------------------------------------------------------
I like it.I don't know about that last step happening in 1 pot tho. Will Zn/Hg cleave that N-Ac? And would d-alanine be the correct configuration for d-meth?
drone 342
Member posted 11-23-98 09:10 PM
--------------------------------------------------------------------------------
I believe the hydrolysis and reduction could be readily done in a one-pot-shot, but those prior 4 or 5 steps sure couldn't.
-drone #342
Rhodium
Administrator posted 11-23-98 10:17 PM
--------------------------------------------------------------------------------
Natural S-alanine is of the right configuration to yield d-meth. I got the idea from a paper that was already making chiral phenylalkylamines, although using trifluoroacetyl protected S-alanyl chloride.
beagle_boy
Member posted 11-24-98 09:14 AM
--------------------------------------------------------------------------------
I remain unconvinced that Zn/Hg will cleave the N-Ac, but I guess that it could still be done on one pot by hydrolyzing the N-Ac first w/ HCl and then adding the Zn/Hg to reduce the ketone.
Rho: In the ref that you took this from, were they making N-unsubstituted phenylalkylamines, or were they leaving the trifluoroacetyl on the final cpd? In other words, did they use this N-Me,N-Ac alanine or just the N-Ac alanine? Seems like the N-Me,N-Ac alanyl chloride will be alot of trouble to make, but just using the N-Ac alanyl chloride to get d-amphet. would be easier.
Rhodium
Administrator posted 11-24-98 10:15 AM
--------------------------------------------------------------------------------
BB: It isn't the Al/Hg that cleaves the amide, it's the concentrated HCl the reduction is carried out in that does.
In the original ref, they used plain N-trifluoroacetyl alanyl chloride. The reason the fluorinated protecting group was used was that they let the rest of the molecule undergo a pretty vigorous fluorination before they hydrolyzed the amide (with NaOH).
Wizard X
Moderator posted 11-24-98 08:51 PM
--------------------------------------------------------------------------------
Interesting , I had this very same dream approx 4 years ago. Went on to eliminate the acid chloride step and the Al/Hg reduction step. Some interesting reading , " Cyclidehydration of beta -Phenylethylamides " with POCl3 and
Friedel-Craft catalysts , JOC Vol 35 pg 825 (1970) .
drone 342
Member posted 11-24-98 09:22 PM
--------------------------------------------------------------------------------
Noting the huge numbers of trees destroyed by my own personal ref collecting, in conjugation with my laziness, I wanted to ask you what exactly you meant by eliminating the acid chloride and reduction step? How did you do this? You have my attention, Wizard X.
-drone #342
