Morpholine PCP-derivate

[Xicori]

High bees!

swim has no chance to get his hands on piperidine and pyrrolidine... and the reduction of pyridine is a bit tricky...

so he wants to try the morpholine analoge of PCP - as far is i know its 1/10 the potency of PCP....still potent enough

swim wants to try the route via bisulfite addukt of the cyclohexanone to form the carbonitrile, followed by grignard reaction with phenyl magnesium bromide...

https://www.thevespiary.org/rhodium/Rhodium/chemistry/pcp/cn_synth.html#pcc2

now some questions:

1.) can the piperidine  easily be substituted with morpholine in this reaction without change of the molar ratios? 

2.) anybody know: does the carbonitrile crystallise out of solution, or is a extraction with Et2O needed?

3.) Is there any danger of HCN-evolution when quenching the Grignard reaction mixture with aqueous HBr, and does the PCPm-HBr crystallise out of solution?

4.) anybee know if the morpholine-carbonitrile is soluble in ether, or must a ether/hexane mixture be used?

thanks much!
chilito

[Bwiti]

Yes, just use an equimolar amount of morpholine in place of the piperidine.. I was hoping someone would answer your questions, nobody has, so I'll take this time to give you info that you never asked for.. After 9/11, I'm afraid to buy any cyanide compounds. If you're worried about that also, then why not make a schiff base from your morpholine/cyclohexanone, then react it with an equimolar amount of anhydrous p-toluenesulfonic acid. - then you can still use phenyl-magnesium-bromide. Peace!
Love my country, fear my government.

[Xicori]

thanks for the answer, bwiti...

i have some NaCN lying around, but no p-tosic acid... so swib wants to go the cyanide-route...

peace!
chilito

[Ritter]

2.) anybody know: does the carbonitrile crystallise out of solution, or is a extraction with Et2O needed?


The carbonitrile will sometimes form crystals immediately, other times it will "oil out" leaving a blob of light yellow oil at the bottom of the flask.  If this occurs, simply chilling the flask with a crushed ice bath will convert the oil to beautiful crystals.  No extraction is necessary, simply filter the crystals out.

[Nemo_Tenetur]

There are some other interesting PCP analogs, namely:
N-propyl
N-methoxyethyl
N-methoxypropyl
All syntheses are easy, you don't require any cyanide nor forming of the irritating nitrile intermediate. All three analogs are schedule I drugs in Germany since a few years. They're pretty strong (dosage abt. 10-15 mg) and long-lasting (up to 10-12 hours). The only disadvantage is the use of an excess phenyllithium, which is expensive and for some bees hard to get. The required amines (propylamine, methoxyethylamine and methoxypropylamine) are probably not watched.

[Bwiti]

Listen to Nemo, he knows what he's talking about.
Love my country, fear my government.

[Xicori]

High bees!

swim performed the first step via the bisulfite method.... it was a real pain in the ass

When swim opened carefully the bottle containing KCN (all windows open, gloves, etc) very little HCN smell was noticed    - but without any health effects... maybe i´m very sensible to te smell of HCN, i dont know....

Now the mixture stirred overnight and is now sitting on the ice bath, waiting to crystallize...

The reaction is a 2-phase mixture - the upper phase is a little yellow, and the other (down) phase is nearly colourless....

Are there any dangers when vakuum filtering the solution? - may there be some unreacted KCN - i´m really scared of this stuff

Here are the ratios that were used:

NaHSO3 - 0,06 mol
Water - 21,5ml
Cyclohexanone - 5,3g (0,054 mol)
KCN - 0,06 mol
Morpholine - 0,062mol

so long....

xicori

[Xicori]

...it´s now on the ice bath for nearly 2 hours... and nothing crystallized out

how long does it take normally to cristallize out?

thank you!

[Xicori]

after 5 hours the toop layer was still a oily liquid....

the mixture was transferred into a sep funnel, and ~20ml toluene were added - the top layer was soluble in the touluene - the funnel was shaken several times, and the aquaeus (bottom) layer was seperated off - the organic layer was washed with water to remove residual KCN ....now swim will drie the organic layer with Na2SO4, and use this soln direct in the grignard reaction...

lg
xicori

[YourMomma7111]

What happens if you use methylenedioxyphenyl magnesium bromide, para-methoxyphenyl magnesium bromide, ortho-methoxyphenyl magnesium bromide, 3,4-dimethoxyphenyl magnesium bromide, 3,4,5-trimethoxyphenyl magnesium bromide, or 5-methoxy-3,4-methylenedioxyphenyl magnesium bromide instead of phenyl magnesium bromide in your (designer) PCP reactions?

Has anyone tried this?  Just Curious.

[Xicori]

i don´t think that anyone has tried to synth. this derivates... there are a lot of possible pcp-derivates which can´t be found in the literature....

i nearly found nothing about the Morpholine-Derivate - the only info i have is, that it is ~1/10 the potency of PCP...

________________________

the dried toluene solution with the carbonitrile in it sits now in an flask, waiting to meet phenylmagnesiumbromide tomorrow    - the solution is slight yellow....

i hope that everything went ok so far... would be very helpful if some pcp-synthesis-experienced people would give a comment on that....

thanks,
xicori

[moo]

Post 212050

(hms_beagle: "4-methoxy PCP", Novel Discourse) for example.

[Aurelius]

Hey Ritter, aurelius is sure you know this, but thought aurelius would mention it.  When using the methods you describe concerning "oiling out" and then cooling for crystallization, one needs to be aware that the oil crystallizing quickly like that will trap a lot of impurities.  a recrystallization would be in order unless you know that the possible impurities won't effect further reactions negatively and will be washed out before final product use/distribution.

[Aurelius]

you can use the following for tosic acid:

Post 288713

(Chromic: "Getting higher yields with p-tosic acid", Methods Discourse)

Post 261000

(Chromic: "p-toluenesulfonic acid", Chemistry Discourse)

[Xicori]

high there again...

everything seems to work good so far ... when adding the carbonitrile/ether/toluene-solution to the grignard reagent (in Et2O) white salts appeared (magnesium salts, i think), and a green precipitate also appeared - the solution was refluxed on the waterbath for 3 hours and then poured onto ice/NH4Cl/NH4OH - the pH of the aqueous layer is about 10 . between the two layers are sitting the Mg-Salts, what makes seperation not really easy(the green stuff dissolved!)... how can i get them into solution?

mfg
xicori

[chemotype]

People seldom remember my bredren, 'The Alchemist' from back in the day.  I wonder where he's @ right now but blessed be that he is safe.

Checkout [url = 

Post 101681 (missing)

(The Alchemist: "Dust for the masses...", Chemistry Discourse) The Alchemist: Post # 101681 'Dust for the masses' [/url]

There is a simple procedure for the pyrrolidine analogue of PCP, hence: PCPy.  Procedure is very much like the morpholine procedure.  Just remember that acid/base extraction.  With a compound 1/0th as potent as PCP, I would definitely make an HCl salt of the final, isolated base.  Not only does that remove most of the PCC contaminant, but it would allow for intranasal or IM administration of the drug (since mg per mg it is similar in potency to ketamine). 

Just remember, there is no need for toluene or or ether.  All syntheses were carried out in THF.  No I2 needed to initiate gringard either.  Very simple synth.  Just take the extra time to purify final product.  PCC contaminant is no good, nor are the Olney's lesions caused by such dissociatives.

Bee careful but please post your experience reports!!!

respect

[Xicori]

High!

just a report what happened so far:

the grignard reaction went fine - when adding the morpholin-1-cyclohexyl-carbonitrile in ether/toluene a white and a green solid formed. the mixture was refluxed for 4 hours.

then it was hydrolysed with a mixture of ~10g NH4Cl/10ml NH4OH w=25% on 200ccm of ice. (pH of solution was alkali!)

When the ice had melted the phases where seperated, and the aqueous phase was extracted 2 more times with Et2O - the organic phases were combined and washed with water.

Now the Et2O-Solution was extracted 2 times with 10% HCl, the acidic layers were combined, basified and extracted 2 times with ether.

- Now the solution was extracted again 2 times with diluted HCl, and the HCl-acidic solution was poured into a dish to evaporate. (i know, thats not a nice way of crytallisation, but i had no gassing setup on hand)

The ether phases and also the final acidic solution had a flowery smell (is that the smell of pcpm-base, or may there be some unreacted carbonitrile responsible for this very intense smell?)

After 1/2 of the solution evaporated away some crytalls were visible in the solution.... after everything evaporyted away i found 3,5g of slightly orange colored crystals - they were not really crystalline (hard to describe with my poor english) - more amorph, and sticked together like chewing gum. on the outer sectors of the dish (here were the xtals that formed at first) there were also some nice, white crytalls...

So i decided to recristallize the whole thing - the HCl salt (and all the impurities) were dissolved in hot methanol, and to the hot solution were added ~5ml of acetone to decrease solubility in the alcohol...

now the whole thing cools down, and i hope that nice xtals will appear soon

any suggestions?

LG
xicori

[chemotype]

Your ether washes might smell pungent but your final product should have a not-so-pungent smell.  This is for the pyrrolidine analogue of course. 

Just recrystallize the whole thing from isopropanol.  That's at least what the Merck says for phencyclidine HCl.  If that doesn't work, dissolve your compound in warm MeOH, add hexanes until slightly cloudy, add a few drops of MeOH (just enough to make the cloudiness go away with swirling) and let the whole thing cool down.

[Xicori]

High there again!

swib dissolved his "product" in boiling MeOH, and let it cool down - only very few crystals appeared - so swim decided to add some Et2O to decrease solubility of the HCl-Salt in the mixture - after one night in the freezer swim filtered the whole thing and got ~1g of product (awful yield!!) - FTIR-analysis will be done soon, to see if any nitrile compund is left... i´ll keep you up to date

Now swim wants to give the PCP-M a second chance - he´d like to use a route without any cyanide dangers (i don´t wanna work with KCN again, without an VERY effective fume hood!! - please, dont do it the way i did! )

- so there is one method available that looks very nice:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/pcp/bzp_synth.html

I think this method could also be applied to N-Benzoylmorpholine...

1. Let Morpholine and Benzoylchloride react under basic conditions, extract with toluene and distill under aspirator vacuum to yield N-Benzoylmorpholine (the procedure can be found @ www.orgsyn org - search fpr "benzoylpiperidine")

2. React the Benzoylmorpholine with 1,5-Dibromopentane as Mg-Grignard to yield PCPm - (

https://www.thevespiary.org/rhodium/Rhodium/chemistry/pcp/bzp_synth.html

)

Now some specific questions concerning step 2:

1. In the article is described to distill off the Et2O until the reaction mixture reaches 83°C. - the mixture is then hold at this temperature for 16 hours.
  - why distill off the solvent?
to increase reactivity? would it also work without distilling off the ether and keeping the mixture @ reflux for about 30 hours?

- may there be some danger of peroxide explosion (ether is from unopened bottle, about 6 months old) when distilling ooff the Et2O? - i think tehre shouldnt be to much danger, because there should be some liquid residue in the flask....

- is there any chance to find the boiling point of N-Benzoylmorpholine and the PCPm-freebase - please help here when possible?

-anyone tried this synthesis?

Many thanks!! I´ll make some photos on the synthesis and write an exclusive report

many thanks bees,
xicori

[Xicori]

i know that there is not a high interest in dissiociatives nowadays, but it would help me alot if any well-experienced be would help me with that questions....

thx!
xicori

[Aurelius]

your best bet would be asking Bwiti or Nemo_Tenetur

[hypo]

hi, xicori. i have no experience at all with cyclidines, but i am
very interested to hear about PCP analogs. i can only give very
general answers.

> why distill off the solvent?
> to increase reactivity? would it also work without distilling
> off the ether and keeping the mixture @ reflux for about 30 hours?

if the text says that 83° is needed for 16h, then it propably is so.
chances are big that the reaction will take an eternety and a half
at 40°.

> - may there be some danger of peroxide explosion (ether is from
> unopened bottle, about 6 months old) when distilling ooff the Et2O?

utfse on ether peroxides. there's everything you need: detection, destruction
and stabilisation.

> - is there any chance to find the boiling point of N-Benzoylmorpholine
> and the PCPm-freebase - please help here when possible?

beilstein crossfire. maybe someone is so kind?

other remarks:

why not use the tosic acid method? tosic acid is very easy to make.
check fallen_angels method:

Post 389646

(Antoncho: "Toluenesulfonic acid - tips and tricks.", Methods Discourse).
what worked very well for me was cooking until everything was dissolved,
adding a (calculated) minute amount of H2O (turning the whole mass into a
solid), recrystallising twice from conc HCl and drying over NaOH.

i think PCPm is a misnomer. it should be called PCM or PCMo.
(there's no more piperidine in it!)

have you thought about extracting piperidine from pepper?
that should be easy with an improvised soxhlet (or
even without) and i think many bees would profit from a
working pepper --> piperidine procedure.

[Xicori]

high hypo!!

thx for the response...

i´ll hope bwiti and others will find their way into this thread

I´ve chosen the Benzoylamine-Method because it can be carried out with nearly every amine, there are no highly toxic chemicals, benzoylchloride is pretty cheap, and the yields are high, etc... i´ll also want to try it because i found no experience-reports on this synthesis in the web...

>if the text says that 83° is needed for 16h, then it >propably is so.
>chances are big that the reaction will take an eternety >and a half at 40°.

i think you´re right Distilling of the ether shouldnt be that a problem, because the residue in the flask shouldnt be completely solid - so the mixture can´t come to complete dryness, making the peroxides detonate... - the ether is also in the original closed bottle, never exposed to air befor, so it shouldn´t be rich of peroxides.... i´ll see

...in our organix chemistry lab @ university ether (from opened bottle) is often evaporated to dryness on the rotovap...with no peroxide explosion yet - so i think the danger of peroxide-explosions isnt that high at all, but shouldn´t be underestimated....

you´re right, PCM is the name to give this compound

Piperidine from pepper isnt that a useful method i think.... the yield is just to low! - better methods would be reducing pyridine elektrochemically - would be great to get some literature concerning that...

>beilstein crossfire. maybe someone is so kind?

indeed if anyone could help out with that! - ive searched @ google, merck chemdat, acros.be, and in the catalogues of many other chem supplliers - without any results...

many thanks,
xicori

[Bwiti]

Exactly how is benzoylpiperidine made? Is benzoyl chloride the same as benzyl chloride?

[hypo]

is the acid chloride of benzoic acid.

[Xicori]

________________________
8.   If piperidine is available, benzoyl piperidine for use in the preparation of pentamethylene bromide (p. 428) may be prepared by direct benzoylation. A mixture of 105 g. of sodium hydroxide (2.6 moles), 170 g. of piperidine (2.0 moles) (b.p. 104–109°), and 800 cc. of water is treated with 280 g. (2 moles) of benzoyl chloride using the apparatus and procedure described above; the temperature is kept at 35–40°. The oily product is separated after dilution with 250 cc. of benzene if necessary (Note 5), dried with a small quantity of potassium carbonate and distilled. The portion boiling at 172–174° /12 mm. weighs 330–345 g. (87–91 per cent of the theoretical amount). The first few cubic centimeters of the distillate may be colored by a reddish impurity, in which case a forerun is collected separately.
________________________

Cahours, Ann. chim. phys. (3) 38, 87 (1853); Schotten, Ber. 17, 2545 (1884); 21, 2238 (1888).

i think tehre shouldnt be any problems applieing this syntheses to other amines!

Post 391039

(Xicori: "New route to PCP´s?", Novel Discourse) - if this would work, it would be another high yielding, universal synthesis for PCP-Like compounds...

[Bwiti]

"i think tehre shouldnt be any problems applieing this syntheses to other amines!"

  Yes! Thanks for sharing that ref.! I wouldn't use piperidine, but some other heavy primary amine should work fine. What about secondary amines?

  Btw, in my dreams, a bear made a schiff base from cyclohexanone/diethylamine, and reacted it with anhydrous p-tosic acid. This was added to a bromobenzene Grignard, reacted for a few hours without applied heat, water/ammonium chloride was added, extracted with non-polar solvent, blah, blah.. But the product was inactive. The bear has also done the same with benzylamine, and this was inactive also.. The bear could have sworn that everything was anhydrous both times, and is very pissed that he wasted his money..

[Osmium]

> ...in our organix chemistry lab @ university ether (from
> opened bottle) is often evaporated to dryness on the
> rotovap...with no peroxide explosion yet - so i think the
> danger of peroxide-explosions isnt that high at all, but
> shouldn´t be underestimated....

It only becomes a problem if the ether is really old, or even standing around in the open for longer times. Since diethylether has such a low boiling point I wouldn't worry too much since it will usually be evaporated before lots of peroxides can form.

THF is a whole other story though! Especially when the THF was used to clean glassware and stored in opened containers. This shit is evil, there have been many accidents. It can kill you, e.g. when rotovapping several liters to be reused for cleaning purposes, and the peroxides collect in the evaporation flask.

[Xicori]

High Bees!

Swim did a FTIR on his samples today... there were two samples:

1.) fine white xtals that seperated out very quickly after cooling from recrystallisation

2.) xtals that crystallized out after a lot of solvent was removed....

The spectra can be seen under

http://members.fortunecity.com/xicori/

Please look at the spectra... what could substance 1 bee??

Substance 2 is definitevly identified   

...there are no peaks for -CN compounds, so swim thinks there shouldnt be any carbonitrile left

the substance will be bioassayed today evening  

Conclusion:
The synthesis works without doubts, but the yield was very low (bad crystallisation method, a lot was lost during recrystallisation)

best wishes
xicori

[Xicori]

Bioassay of PCM (Morpholine PCP derivate):
ingesting form: nasal, PCM.HCl

The substance was snorted in ~25mg dosages every 15 minutes to find the best dosage...

First weak effects were felt with a total of 75mg - it reminded me of Ketamine, but the effects werent as strong as with 75mg of ketamine...

Even at a dosage of ~150mg there was only a slight dissiociative effect, but it wasnt worth the pain when snorting the hydrochloride...

conclusion:
The compound is definetively psychoactive, but the effects werent as strong as ketamine (i had no chance to try PCP yet). - It would be much wiser to use the chemicals to synthesise stronger PCP-like compunds....

best wishes
xicori