Author Topic: Route to Unsymmetrically Substituted Piperazines  (Read 830 times)

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Route to Unsymmetrically Substituted Piperazines
« on: September 02, 2003, 12:03:00 PM »
Route to Unsymmetrically Substituted Piperazines      

When I am researching a synth, I like to find ways to do it that are non-smelly, don't use very toxic (or suspicious) chemicals, quick, easy, simple, cheap, and don't result in toxic waste products or contaminants.
 Thus, I was pleased to find the following:

Patent US2362276

"Beneficiation of Acidic Minerals

...Higher monoacyl derivatives of piperazine

A mixture of 21 grams of piperazine hexahydrate and 28 grams of oleic acid was heated in an open beaker with agitation to 200 degrees C, then cooled to room temperature. The product was a brown paste readily and completely soluble in dilute acetic acid to give a clear solution..."

I chose stearic acid instead, as it is easily available, being used by hobbyists in the manufacture of craft candles, and, cheap. The chief contaminant in stearic acid of commerce is palmitic acid, which is similar enough that it wouldn't/doesn't/didn't make any difference.
I mixed equimolar amounts of piperazine hexahydrate and stearic acid in a suspended open beaker and heated the bottom with a 1500 watt heat gun, moving the gun around the bottom surface. There was some boiling at first, accompanied by a mildly strongish ammonia smell (H2O boiling off, taking a bit of the piper with it). I used a candy thermometer to discern the neccesary 200 degrees C.
 Afetr a few minutes everything became liquid, and the boiling stopped. I stopped heating it. Within five minutes after that, the compound had solidified on the bottom, and was devoid of odor.
 Dissolved the compound, N-stearoyl piperazine, in warm dry isopropanol, which produced a champagne-colored solution. The compound seemed to detract from the odor of isopropanol.
Upon cooling, a large amount of very white crystals precipitated out, looking neither like piperazine nor stearic acid. The isopropanol odor returned.
 Test of the soln with universal test paper produced a green color (PH 7). Test of an isopropanol soln of stearic acid produced a light red color.
 My idea is to react this in some alcohol or another with an arylalkyl halide, then remove the stearoyl group before adding an alkyl group to the 2nd nitrogen. A Russian piperazine chemist suggested I could remove the stearoyl group with concentrated or gaseous HCL and heat, it would probably precipitate out.
 Then, I will add the de-stearoylated compound to methanol
(without isolating it first), add enough KCO3 to neutralize the HCL, and add the 2nd alkyl halide with more KCO3.
 I wanted to see if the  stearoyl compound is soluble in naptha (petroleum benzin, "Ronsonol" lighter fluid) as it is nonpolar, low boiling, cheap and easily available. (Piperazine can be trouble as it is so soluble in polar solvents, perhaps N-stearoyl will not be, haven't tested that yet, other than a pinch, which did not dissolve)
 Thus when the first alkyl halide is added, the HX formed will bond to the compound and precipitate it out, hopefully. Doing the reaction in nonpolar solvents will hopefully get the yields up above 75%, quanitative even, I pray.
 But, if it works in alcohol, that's fine too.
There's more to the piperazine molecule than most suspect. I saw a patent recently that indicated the analogue of mescaline in which the amine group is replaced by piperazine is a sedative/hypnotic (didn't save or print, the number escapes me). I wouldn't be surprised if there is a way to incorporate piperazine into every class of drug, with novel results, and without any troublesome, suspicious and dangerous reductions.
 I have a theory that the activities of the piperazine moiety are somehow related to it's similarity to 2,5-diketo piperazine, also known as glycine anhydride. Glycine certainly is important in neurochemistry, and the anhydride may exist as a discrete intermediate in the body, in several neurochemical processes.
 I have found much of use, when looking through patents, by clicking on the patents cited as references. Also, whereas the US Patent Office only allows term searches back to 1976, Espacenet, the european patent office, I have found US patents going all the way back into the one millions using search terms.