Screw acetic anhydride

[resorcinol]

I saw a post in a thread recently about nicomorphine, the dinicotinate ester of morphine.

Somebody mentioned the fact that, well, literally tons of esters of morphine with relatively simple carboxylic acids could be made.

This is of course obvious, but we often overlook the most obvious things. Opiophiles have a certain fixation with heroin, there's no doubt about that. It delivers a rush right up there with hydromorphone when injected intravenously, but has some legs unlike hydromorphone. Oxymorphone has legs too, and some say a better rush than heroin or hydromorphone... but how many people can acquire oxymorphine in a form that can be prepped for IV use? Opana IR is pretty much it right now, and doctors are very hesitant to Rx opana IR because they know how high the abuse liability is. Opana ER is a cinch to get if you're a CP patient, since the TIMERx extended release mechanism is extremely difficult to defeat, and makes a gelly mess. Snorting is possible with opana ER and give better bio-avaliability than oral use, but it's still pretty low, and it doesn't give the famed oxymorphone rush when insuffulated. Oxymorphone orally has one of the worst bioavaliabilities of all opioids... an abysmal 10%. Insuffulated gets it up to around 30%, but that's still pretty awful. Oxymorphone is so potent though, that insuffulated use of it is still far more potent than oxycodone even with the still shitty bioavaliability.

So, in many ways, heroin is still the opiate of choice of opiophiles around the world.

Now, many opiophiles have desire to synthesize their own heroin -- possible sources of precursor morphine being Rx morphine pills like Kadian, Avinza, MSContin, MSIR, etc, OR good old papaver somniferum pods. The pill way requires you to deal with the antiabuse mechanisms that gel things up if you try to dissolve the morphine. With some creative solvent and acid/base extraction and solvent washes, morphine can be had in relatively pure form from morphine pills.

Codeine pills are easier to extract since there's less gacks in them, because, well, the pharm companies know nobody is gonna inject codeine. However, to get morphine this way you have to demethylate the codeine after you extract it. There are several ways to do this reaction out there, but it certainly adds a layer of annoyance to the procedure over getting morph out of morph pills. However, if one was to become proficient at demethylating codeine into morphine... getting good yields, one could get far more product this way than from morphine pills since codeine pills contain much larger dosages of codeine than morphine pills do of morphine, and codeine is ubiquitously avaliable. In most countries it's OTC, and in the US, although it's not OTC, docs are pretty loose about Rx for it compared to stronger opioids.

The third way, getting morph from papaver somniferum, I actually think might be the easiest, provided you have a pH meter. Poppy tea would be made first, of course. Morphine is soluble in water in both acidic and very basic solutions, since it's amphoteric. It does, however, prefer to act as a base. A very basic, like pH 11 or a little more, solution of PT would be treated with nonpolar solvent to get out some plant matter crap. Then, the pH would be brought down to acidic, say, pH 4, and once again, washed with a nonpolar solvent. Then the pH would be brought to 9.1 (use a pH meter) and freebase morphine will precipitate out of the solution. Upon filtering the stuff in the filter will be freebase morph.

Then after any of these ways of getting pure or at least pretty pure morphine, most would want to turn it into H. However, there's the problem of acquiring Acetic anhydride. Unless you snatch some from a lab at uni or something, buying AA will attract unwanted attention to you. Sure, you could just be happy with the morph, but there is another way...

You see, heroin, aka diacetylmorphine, isn't as unique as opiophiles make it out to me. The truth is, many, many 3,6-diesters of morphine are just as good as heroin, hell, some are probably better. In fact, any morphine diester with two relatively simple carboxylic acid groups... simple carboxylic acid groups that are very hydrophilic... would yield a very heroinlike opioid. There is NO shortage of carboxylic acids that result in VERY lipophilic esters, including esters with morphine.

A little birdie told me that a simple carboxylic acid with an aromatic phenyl group tends to be create lipophilic esters. Want an example of one such carboxylic acid?

benzoic acid
http://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/Benzoic_acid.svg/120px-Benzoic_acid.svg.png

Look at that.... simple, aromatic ring, no functional groups attached that would ruin the lipophilic nature of esters of this compound...

Guess what? Benzoic anhydride isn't a watched chemical. The DEA can't watch ever single carboxylic acid anhydride... like the poster in the other thread pointed out.

Heating your morphine you acquired in some way or another with benzoic anhydride is almost certian to esterify benzoyl groups onto those -OH groups at positions 3 and 6 on morphine.

You would almost certainly end up with dibenzoylmorphine. This compound, to my eyes, looks extremely lipophilic and very vulnerable to hydrolysis in the CNS... just like our good friend diacetylmorphine.

In fact, I'd betcha it'd be tough to tell between diacetylmorphine and dibenzoylmorphine if given an IV injection of both.

This is just the tip of the iceberg folks. Heroin ain't unique. This is just one example. I'd guess that any carboxylic acid anhydride that lacks functional groups that would decrease their lipophilicity would be great candidates. Aromatic rings, especially phenyl, are really, really good... very lipophilic.

None of these carboxylic acid anhydrides are watched. The DEA watches AA, but clearly, they miss the big picture... that AA only creates the most famous highly lipophilic morphine ester. There are many, many other options. The big, bad DEA can't ban people from buying every acid anhydride out there.

Just something for you guys to think about.


EDIT: the benzoic anhydride and morphine rxn would probably need to be carried out it completely dry toluene or any other nonpolar solvent, since i think benzoic anhydride may be a solid

[robojunkie]

Benzoic anhydride, mp around 40 C. Just add the morphine some benzoate salt and heat just like the regular reaction. BA is more electrophilic anyway so one would likely not even need to heat it as highly or for as long.

BTW I know BBr3 isn't on the average opiophiles shelf but the oldest methyl aryl ether demethylation reagent is just concentrated HBr. Easily made with any bromide salt and sulfuric acid with a gas vent into water (Ie, drop the sulfuric onto the bromide salt, HBr vapor goes into water, simple).

Also if one learns the equations to calculate buffer solutions (just need to understand pKa's and so forth, simple logarithms) one could do without pH paper/meters. As having all the acetate/meconate salts and ammonium chloride one already has a reasonable buffer with the hydroxide neutralized.

[dharma bum]

Yeah, I know what you mean. That's exactly what I was thinking.

[devilsdrug]

ok if its so f-in easy why isnt it done or is it whats the draw backs, u gave the positives whats the negs

[robojunkie]

I imagine cuz most of the people (ie chemists) who can easily get whatever anhydride/chloride can also get AA and why go with a stranger when you can make an old friend...

[Synack]

how about that, I've got opana IR.. and ER... fucking w00t.

Look up L-Selectride.. good shit ...

[resorcinol]

In fact, any morphine diester with two relatively simple carboxylic acid groups... simple carboxylic acid groups that are very hydrophilic...

Whoops!! I meant to say "two relatively simple carboxylic acid groups... simple carboxylic acid groups that are very hydroPHOBIC", not hydroPHILIC.

When ya type fast it's easy to make mistakes like that, I 'spose. What makes it even more likely in a situation like that is how there is repetitive jargon that means the same thing --

hydroPHOBIC = lipoPHILIC

and

hydroPHILIC = lipoPHOBIC

...in most cases.

If a mod wants to change that, feel free to do so, but it's no biggie if it stays. I just happened to catch it on a second read through.

You want a hydrophobic / lipophilic ester group on positions 3 and 6 on morphine to get a drug with an intense flash / rush when used intravenously.

Adding to this discussion... ethers of morphine at position 6 are probably pretty rockin drugs too... in stark contrast to ethers of morphine at position 3 (codeine is the methylether at position 3). Ethers at position 3 on morphine dramatically reduce the potency of the resulting drug, and the larger the ether group, generally, the weaker the drug becomes.

To get a drug of acceptable potency that has a methylether on position 3 in the realm of morphine-like opioids, the double bond at positions 7 to 8 must be saturated to a single bond and the hydroxide at position 6 must be replaced by the more oxidized carbonyl group -- hydrocodone and oxycodone are examples of this.

Ethers of morphine at position 6, however, are potent mu agonists. The methylether of morphine at position 6, heterocodeine, is 6x more potent than morphine. Since it's also more lipophilic than morphine is (covering an -OH group up almost always increases fat solubility), it would likely have quite a rush, too. I'm sure other morphine position 6 ethers are pretty good too (analogs of heterocodeine).

If you're not sure of the difference between an ether and an ester, read these:

Ethers at wikipedia (http://en.wikipedia.org/wiki/Ether)
Esters at wikipedia (http://en.wikipedia.org/wiki/Ester)

Yeah, I know, it's wikipedia, meh. Wikipedia has problems, but it's really a phenominal starting place for research... a place to help you find more scholarly information to jump into from the sources at the bottom of their pages. And even without that, the hardcore frequent editors of wikipedia take it seriously... they really do. Hence, wikipedia is usually pretty credible, especially for non-controversial topics. Wikipedia has problems, but not so much that it's fair to say that you should take EVERYTHING there with a grain of salt. it's better than a grain of salt, and frequently better than erowid for drug info (not bashing erowid, just sayin... erowid isn't updated frequently enough).

[chemchem]

Good thinking, its all about how fast in can cross over and bind to those receptors. It would be very interesting to try this out sometime.. I do have access to AA but I think I may need a different anhydride if I ever have a dream of fent synth.

Now, lets say one has oxymorphone/codone, does adding esters on the 14th position cause it to cross the BBB as fast? And are they as easily hydrolized? Because I know you can get very potent compounds with them but it seems that you would need to make an ether to prevent it from come off
great thinking by the way, i'll be keeping my eyes out for anhydrides, they're a little too scary for me to make at the moment.


Edit: Just so people know the numbering, I still dont have it memorized
http://i453.photobucket.com/albums/qq256/Uisgdlyast/200px-Morphinan.png

[alowishus]

http://forum.opiophile.org/attachment.php?attachmentid=654&d=1164143533


More H bake sales. :D

[Narkotikon]

Just answer me this: can I make nicomorphine out of a pack of smokes and some poppy seeds / pods? If so, I'm on board. :D

[poonwhalla]

Just answer me this: can I make nicomorphine out of a pack of smokes and some poppy seeds / pods? If so, I'm on board. :D

yeah as long as you have some duct tape, a george forman grill and bubble gum spit, to get it all to bind McGuiver

[Narkotikon]

yeah as long as you have some duct tape, a george forman grill and bubble gum spit, to get it all to bind McGuiver

That's funny. When I first told an ex-friend about pods, they called me the McGuiver of drugs, because they had never heard of such a thing before. Funny stuff.

[resorcinol]

Just answer me this: can I make nicomorphine out of a pack of smokes and some poppy seeds / pods? If so, I'm on board. :D

LMAO :D

Seriously though, no you can't, but you knew that :p

Nicotinic acid is related to nicotine though. Oxidizing nicotine (with pretty much any oxidizing agent -- an example would be potassium permanganate) yields nicotinic acid.

Removing water from nicotinic acid and creating that oxygen bridge yields nicotinic anhydride. It's almost ALWAYS easier to buy the anhydride though, instead of making it. Making anhydrides from their acid is especially difficult. The acid form is more energetically stable than the anhydride, so you're trying to push a car up a cliff.

Nicotinic anhydride isn't watched either afaik, so buying it would be the way to go. From there, what to do with NA and morphine is pretty straightforward.

Same goes for benzoic anhydride and morphine.

Chemchem: I think ester groups at pos 14 on morphinan opioids such as oxycodone are more stable than ester groups on pos 3 or 6. This is simply because that region is sterically hindered and thus harder to attack by hydrolysis. I'm not saying it doesn't happen, and in fact the hydrolysis products of these 14 ester opioids are likely active metabolites, but for sure the 14 esters would stick around (have a much longer half life) than the 3 or 6 esters, which is good, because that ester group at 14 increases potency majorly in many cases.

However, you're also correct in that an ether group would be preferable. Ether groups are much harder to metabolically attack and pos 14 substitutions increase potency, so we'd want a group there that resists metabolic attack, and ethers > esters. Of course both ethers AND esters are better substituants at pos 14 than a simple -OH, potency wise. And -OH is much better than leaving that position unsubstituted with just a plain hydrogen. Oxycodone is clearly more potent than hydrocodone.

Good job brainstorming, chemchem. The chemistry in this thread is pretty awesome :D

[resorcinol]

Salicylic anhydride is another pretty good option.

So benzoic anhydride, nicotinic anhydride, and salicylic anhydride would all be interesting acid anhydrides to try to react with morphine.

Disalicyloylmorphine (not sure of the spelling there) would probably be pretty decent, although that hydroxide group on the aromatic ring would possibly make it less desirable than dibenzoylmorphine.

Dinicotinylmorphine is already in medical use in some european countries under the chemical name nicomorphine (brand name Vilan). Nicomorphine is very similar chemically to dibenzoylmorphine -- one of the carbons in the aromatic ring is simply replaced with a nitrogen atom.

Out of these four drugs (diacetylmorphine [Heroin], nicomorphine [Vilan], dibenzoylmorphine, and disalicyloylmorphine) I'd say that they'd line up like this in order of best to lesser IV rush (although they'll all have a damn good IV rush):

dibenzoylmorphine > nicomorphine > diacetylmorphine (heroin) > disalicyloylmorphine

Nicomorphine and diacetylmorphine can both be had pharmaceutically in some countries. The others are speculative compounds, I doubt any human anywhere has tried them.

I betcha dibenzoylmorphine is better than heroin though. Those benzoic acid groups are very very lipophilic -- better than acetic acid groups in heroin. They're about equally as easily hydrolyzed in the brain as acetyl groups in heroin, so we can probably control for that feature.

Of course, all these drugs probably feel very similar and have a similar rush, we're talking small differences here. We're junkies, even a little better of a rush makes our mouths water. And man, does dibenzoylmorphine look TASTY.

[Indy]

just so you know, nicomorphine would have none of the effects of nicotine, since it's not related to nicotine at all. nicotinic acid is just called that because it used to be prepared using nicotine. thus the use of nicotinic acid is kind of obsolete: it's called niacin now aka vitamin b3

[resorcinol]

just so you know, nicomorphine would have none of the effects of nicotine, since it's not related to nicotine at all. nicotinic acid is just called that because it used to be prepared using nicotine. thus the use of nicotinic acid is kind of obsolete: it's called niacin now aka vitamin b3

I know that, Indy. I'm quite aware that it's just called nicotinic acid because it was originally prepared as the oxidation product of nicotine. The THP ring is totally opened, destroying affinity to nAchRs.

[Morfiend]

"In these circumstances there sprang up a very considerable manufacture of other esters of morphine, analogous in every way to heroin, and having no medical advantages whatsoever. The other esters were in fact simply manufactured to supply narcotics for addiction. The chief one was benzoylmorphine; another was [B]acetylpropionylmorphine.
At the time, international control over heroin was still very weak, but was being established in the European manufacturing countries; whereas control over the manufacture of the new morphine esters in those countries was completely non-existent, and the esters also, for a time, escaped control of the national laws in some other countries, where they were distributed into the illicit traffic, or finally consumed.
Of course, some attempt had been made in the Conventions to forestall such a transparent subterfuge on the part of drug traffickers. However the slowness of countries to react when the drug use was not within their own borders made the weak provisions of the Conventions almost completely ineffective for some time.
The 1912 Convention had made its control measures applicable "To all new derivatives of morphine, of cocaine, or of their respective salts, and to every other alkaloid of opium, which may be shown by scientific research, generally recognized, to be liable to similar abuse and productive of like ill-effects." The requirement that the scientific research be "generally recognized," without any machinery provided by which this could be done, almost cancelled the significance of this provision."


-UNODC* (http://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1953-01-01_2_page009.html#fr001)

[OverDriven]

This is a very interesting thread, but in the end it doesn't really make it any easier for someone to synth heroin-like chemicals. There are no carboxylic acid anhydrides that are easily available to individuals that I know of. They are not exactly OTC type chemicals, and most chemical supply companies will only supply these chemicals to companies. Also, even though they are not on some DEA list, an individual attempting to order these would undoubtedly raise some red flags. Chemical supply companies will report ANY suspicious activity even if they aren't required to. In the end, most of the required chemicals are only easily available to those in a lab environment, and really...what lab doesn't already have acetic anhydride?

[resorcinol]

Idk that buying ANY carboxylic acid anhydride would raise red flags. The have so many uses. It doesn't simply scream "OMG they're gonna use it to add ester groups to the alcohol groups on morphine OMFG!"

The hardest part would be getting suitable morphine precursor. Morphine PILLS are loaded with gacks to curtail IV use ... that's all the "gelling up" when they hit water ... and pods are loaded with organic plant goop and other alkaloids.

The actual rxn for diesterifying morphine once you've got morphine, the desired anhydride, and some basic lab equipment (that doesn't look suspicious; lots of people who don't use or sell drugs do home chemistry as a hobby that needs basic lab equipment), and of course basic common reagents. The rxn to substitute the groups from an anhydride onto morphine at 3 and 6 in place of the hydrogen (resulting in an ester of course) is not temperamental or difficult. Just ask peeps from NZ where they HAVE to synth their own "homebake" H because H doesn't come into the country (AA is thus sold readily on the black market to make up for the lack of prepared H).

My vote still goes to dibenzoylmorphine. Benzoic acid ester of morphine seems perfect to me for penetrating the BBB the quickest. 6-monobenzoylmorphine would be super-ideal and is likely very potent and euphoric (more than dibenzoylmorph b/c the diesters are inactive until at least the 3-ester is stripped which happens quickly in vivo by hydrolysis but removing that step and leaving a very lipophilic active mu agonist is even better).

[Pikasso35]

Just thought I'd bring this thread back to life:)

I did a lot research regarding morphine to (di)benzoylomorphine and found very little. One book from the late 19th century states:

"Dibenzoylmorphine, prepared by melting morphine and benzoic anhydride, forms a hydrochloride, C31H27NO5, HCl + H2O."This is weird as "C31H27NO5" is actually Fmoc-O-benzyl-L-tyrosine. It's just a derivative of Tyrosine with a benzoyl group attached to it. Somewhat puzzled as to why it would be formed..

Aside from that however, shouldn't refluxing morphine with benzoic anhydride alone work? After all, the BP of benzoic anhydride is only 40 degrees Celsius, so a NP solvent like toluene really isn't needed. I expect the rxn to take the usual amount of time it takes to form 3,6 esters. If morphine base is used at the start, wouldn't one be left with the "benzoate" salt at the end? I am unsure if you'd just be able to evaporate the remaining benzoic anhydride/acid in an analogous manner you would be an acetic anhydride reaction. Perhaps the next step would be to basify the salt, extract with a NP (ie ether), and then titrate/gas with hydrochloric acid to obtain the HCl salt.

And in regards to oxycodone/oxymorphone and position 14, wouldn't refluxing either in some Cinnamyl Chloride and an organic base as a catalyst (pyridine/triethylamine) work just fine? From what I've heard, doing this will increase the potency of the parent compound 114x!!

Resorcinol, what do you think?

[jacky]

reticuline and salutaridine are morphine precursor isoquinolines that are found in a variety of plant sources, including a few medicinal herbs that are avialable commercially...

feed reticuline to tobacco plants and the tobacco plant's biosynthesis pathways will uptake the reticuline and produce a morphine containing tobacco leaf.

sure, one would have to isolate the compounds of interest....but to my knowledge, they are not controlled substances.

perhaps the resulting synthesis requirements would be too technical for most people?

[Pikasso35]

Jacky, that is very interesting information, did not know that. Did some research and apparently reticuline is one of the constituents of opium, but can be found in the plant Lindera aggregata, better known as the "Japanese evergreen spicebush". As far as salutaridine, is is only found in the opium poppy, which defeats the purpose a little if one were to try to obtain morphine w/o growing poppies. On the other hand, for poppy growers, since both these compounds are in the latex, depending on the conversion ratio using a little biochemistry, morphine yields could be increased drastically!

But regarding my benzoic anhydride/morphine theory, does it sound plausible?

~P