# Levorphanol (l-Dromoran) and Racemorphan Synthesis

## by DopaMan

I give most of the credit for this synthesis to a certain Lamont character, who posted a version of this synthesis at an alternate location, back in May of 1994, and a book that contained a version of it. It was apparently taken from a Loompanics book called "Recreational Drugs", which I would love to be able to find, and read, but which I have yet to come across. It sounds like an excellent resource. I already reccomend it to anyone who can find it. Buy it! Buy two! Buy a round for the whole family! I have re-written and re-compiled this synthesis as much as humanly possible, so as not to upset any copyright laws, and to keep my conscience clear ("yeah, right," you say?). Just so you know, I've added loads of extra information [some of it redundant, yes, yes] ), a lot of which I think, and hope, might help you in your endeavors both personal and chemical. All of the writing in this file, and my personal "steric" molecular graphic, is mine in origin, with the exception, depending on your choice of semantics, of the synthesis process itself, which I still reworded to quite an extent. The excess of information was all furnished by none other than yours anonymously, DopaMan. So, now it's mine, baby! I found it, revived it, nursed it back to health, and gave it a kick in the ass! Without me it never would have seen the light of day! So, ha-HA! My Quick-FAQ: (Who asked the questions, you may ask? It was Sir Not-Appearing-in-this-Film. Remember him?) What are racemorphan and levorphanol? These are both highly potent opioid (narcotic-)analgesics, chemically related to morphine, but produced synthetically. They are part of a small group of opioids in the morphine series known as morphinans, and are lacking certain chemical groupings of the original opium alkaloid, though still containing the fundamental, biologically active, portion of the molecule, known as N-methyl-morphinan, which is related to the narcotic opium alkaloids in a way analogous to that in which tropane is related to cocaine and the atropa belladonna alkaloids, such as atropine. Morphinan analgesic agonists are typically analgesically superior to morphine. Racemorphan is a racemate of levorphanol and dextrorphan. That is, it is an equal mixture of two optical isomers, one of which is the highly potent opioid levorphanol, and the other the compound dextrorphan, which is dissociative in higher doses, and resembles ketamine in it's actions. Dextrorphan is just like dextromethorphan, the over-the-counter cough suppressant, used also as a dissociative, but without a methyl (ether) group at the phenolic hydroxyl. In other words, dextromethorphan is dextrorphan methyl ether, and dextrorphan is the non-opioid optical isomer of levorphanol. Levomethorphan, or levorphanol methyl ether, by the way, is a powerful opioid analgesic, which I would place (making an educated "guesstimate"), on the opioid scale, at approximately the some potency level as hydrocodone (Vicodin), or one half as potent as morphine. How potent are racemorphan and levorphanol, and what is the average dose taken? Racemorphan is much more potent than even the aforementioned levomethorphan (but only half as potent as levorphanol), because of the free phenolic hydroxyl. It is about three to four times as powerful as morphine, somewhat more powerful than even heroin (diacetylmorphine), and much longer acting than either. The average fully-narcotizing dose of racemorphan is 6 milligrams orally, or 3 mg taken by IM or IV injection, or nasal insufflation (snorting), equivalent to 10-15 mg of parenteral morphine sulfate (morphine is very orally ineffective; it would take 60-70 milligrams of morphine sulfate, taken by mouth, to equal the racemorphan dose). The racemorphan dose may be raised to 7 mg orally, or 3.5 mg by injection or insufflation, when tolerance is gained to the product, or by one's own titration, if the original dose is deemed ineffective, but this is usually unnecessary within one or two weeks, and may not (and probably will not be) ever necessary, if using on occasion (chipping, that is). Levorphanol, or the pure opioid, and levorotatory component of racemorphan, is six to eight times as potent as morphine; almost three times as potent as heroin; and is twice as powerful as racemorphan. A highly potent analgesic, it also lasts (like racemorphan) more than twice as long as morphine: from eight to fourteen hours is normal; sometimes it is less long-acting, but never has a shorter duration than six hours, normally. The average fully-narcotizing dose of levorphanol is 3 milligrams orally, or 1.5 milligrams taken by injection or insufflation. (These dosages are equivalent to 10-15 mg of IM or IV morphine sulfate, or 60-70 milli-grams of morphine sulfate by mouth). The levorphanol dose may be titrated to 4 milligrams orally, or 2 by one of the other routes, if you find that it looses its effectiveness, though unlikely within a week. Remember that this and racemorphan are addictive drugs, quite similar to morphine in their dependence liability. What is the chemical structure of racemorphan, or levorphanol? This is the chemical structure of levorphanol. Racemorphan is shown as having the same chemical structure, if you can find it in books, though half of the molecules are essentially mirror images of the others. Obviously, it has the same molecular weight, and also has the same chemical designation, other than the fact that the d,l-(dextro-,levo-) prefix is used instead of the l-(levo-) prefix. The formula 17-methyl-morphinan-3-ol is the USP nomenclature specifically designated for levorphanol, describing the levorotatory isomer only - not the racemate. Not that this part really matters. Anyway, here it is! Levorphanol levo-3-Hydroxy-N-methylmorphinan (or) 17-Methylmorphinan-3-ol. May also be considered to be: levo-(4,5a),6-desepoxydesoxy-(4,5a),7,8-tetrahydromorphine(or) l-Desepoxydesomorphine (l-desepoxydihydrodesoxymorphine-D) (or) l-Desepoxy-6-desoxy-7,8-dihydromorphine (all with my nomenclature). ### Racemorphan/Levorphanol Synthesis, by DopaMan: Important Disclaimer: I, DopaMan, do not take responsibility for the results or effects of this synthesis on those who would dare to attempt it! I found much of this elsewhere on the internet, and it seemed to closely conform to what I already knew about the commercial synthesis of pharmaceutical levorphanol, and my extensive knowledge of opioid chemistry (aw, ...shucks). I request that the reader take into consideration the fact that these are addictive, federally controlled, and *highy* potent narcotic-analgesics. If you still decide to go about making these chemicals, it's out of my hands, and your personal ability to choose at work. I hereby renounce any and all responsibility for any biological health or legal trouble any person out there gets him(her)self into as a result of their own actions upon reading this. I provide this article for informational purposes only, and not to get people to make these substances. However, if you, the reader, are still planning on making them, you must know that they are extremely potent narcotics, and that taking more than just 3 to 4 milligrams of Levorphanol by mouth (or 1.5-2 mg by any other route); or 6 to 8 milligrams of Racemorphan by mouth (or 3 to 4 milligrams by any other route) without being very tolerant to opioids may be hazardous to your health, as overdose may occur. It might actually end your experimenting life. I don't think you would like that, but even if you would, it's not my problem any more. Thank you for taking the time to read this. Be safe and smart! Sincerely, the high-binding-affinity superhero you know as... DopaMan : )! What is needed or crucial for this synthesis: Equipment: CRUCIAL(!): A scale or system capable of measuring accurately down to 1 to 2 milligrams (mg). These are highly potent narcotic (opioid)-analgesics! Levorphanol is as potent as Dilaudid (hydromorphone), and much longer acting! Racemorphan is half as potent as levorphanol, but still more potent than heroin (diacetylmorphine)! Better measure carefully, when dosing yourself, or you are going to end up with permanent X's over your eyes, like in the comic strips, but not as funny. I actually have confidence in you guys, you know, but I feel it's my moral (as the selfless community and public servant that I am, being DopaMan) responsibility to say this stuff. NECESSARY -- A refluxing device: You should know how to acquire or make one! NECESSARY -- A device for evaporation in vacuo: Same here. A source or way of producing hydrogen (is needed): Look in Rhodium's archive for some of the great instructions offered there. A device for filtration, and filter paper (are needed): these are easy things to come by as you should so very well know. Chromatography column, alumina-filled: check around. Additionally: Also Necessary(!): Equipment for heating, crystallizing, etc.: pH paper (or a red cabbage indicator; one of these is necessary). There are other things required, as well. Check the synthesis directions, and decide in your mind what else you need to get. Probably plenty of other things. I'm just too lazy to do any more work for ya (as far as anything other than chemical information goes). Chemicals: 2-(1,4-Cyclohexadienyl)ethylamine: 6.2 grams. p-Methoxyphenylacetyl chloride: 9.4 grams. Phosphoryl chloride: 3 grams. Hydrobromic acid (judge the amount for yourself, damnit! For general info, there's lots of it at Rhodium's site). Check around (these things aren't watched, to my knowledge, but I would certainly have a ready explanation for what I wanted to use the one for that you're checking on, if calling a supply house. Look online, maybe. I might, later, do just that, and then ask Rhodium if he'll post it in this synth file (but it may be awhile, so don't hold your breath). Chemicals also needed: Hydrochloric acid (dilute solution): you can make this by mixing the moderately strong acid solutions (simple muriatic acid type HCl) with purified water. No matter what the strength, HCl is dangerous! Just be smart! (You can find muriatic acid [hydrochloric acid for swimming pools, also used by some for cleaning grease off bike chains and certain metals] at almost any hardware store, dirt cheap! It's like $3.00 for a shit-load of the stuff!) Caustic soda (strong). Be careful! You know why? It'll bite your head off, man! Seriously! Mucho caustico! IF DESIRED--l(levo)-Tartaric acid (if making levorphanol): if desired. For optical resolution--production of the more potent levorphanol. (Still checking on this one part of the procedure, but it should work just fine.) Alternates (if not catalytically reducing as the last step; if desired): CH2O: Methylene oxide (alternate final procedure). I think, but I'm not sure, that this might be carcinogenic, if taken internally, or your skin is exposed to a lot of it, so don't be jerkin' off while you're handling it (salami must be slapped before hand or afterward!) Formic acid (alternate procedure, also). This is apparently not something that you want in your lungs! Watch out for toxic fumes, and other such shit! Phosphoric acid: (alternate, also.) Be wary of these kinds of acids! They can be pretty dangerous! Solvents: Benzene: 130 ml, at least (remember, this is highly toxic, and a carcinogen, if inhaled, or spilled on or taken into your body, so make sure it is completely evaporated each and every time it is used, and have proper(!) damn ventilation. Don't leave this in your final product if you care at all about your health, or the health of whomever is going to be consuming it. Better smell the product (not too deeply) at the end to make sure that there isn't contamination. Petroleum ether: look for directions in Rhodium's archive. Methanol (very toxic; make sure all is evaporated): 100 milliliters+ at least, preferably more for ready use. Purified water (highly toxic; just kidding!): any supermarket; even bottled water would probably do. If you use plain ol' bottled water, you should drink seven to eight glasses a day : ). Anisole: (if desired) for crystallization, assuming it's racemorphan hydrobromide. (May be a useful thing for you.) Vodka, Everclear, or denatured ethanol(this last one being toxic): (if desired) for making a dilute solution for crystallizing of final product (of racemorphan especially). Catalysts: Sodium bicarbonate (baking soda--duh!): 5% solution, 200 milliliters--this one's so easy it actually hurts: any supermarket has powdered baking soda. Measure out and make your own solution. Raney nickel: I'm sure this is fairly easy to come by, say, at chemical supply houses, or in catalogues. It may be even easier to get than that. You need to know how to accomplish a reduction with this substance. Decolorizing carbon (sufficient for procedure given). Formaldehyde: for the end reduction, assuming you're doing it that way. (Not for use in marachino cherries, as the old wives' [piece o'] tale goes.) Method of catalytically reducing a quinoline. There are a number of acceptable methods, which apply to many compounds. The methods applicable aren't specifically for isoquinoline compounds necessarily. They are general catalytic reduction methods. If synthesizing racemorphan/levorphanol, you should probably know one of these already, anyway. Synthesis directions: One starts out with 6.2 grams 2-(1,4-cyclohexadienyl)ethylamine, which is placed in 80 ml benzene, and then treated, in the presence of sodium bicarb. (a 5 per cent solution, 200 ml), with p-methoxyphenylacetyl chloride, in benzene. As this is done, the concoction is stirred and externally cooled. The chemical it yields is an oily amide, crystallizing if scratched with a glass rod. Now, recrystallize this from a mixture of n-hexane, and benzene. The chemical, N-2-(1,4-cyclohexadienyl)ethyl-p-methoxyphenylacetamide, which is in the form of colorless scales, and melts at a temperature of 86-86.5 degrees Celsius, is obtained at a quantity of 12.5 grams. Three Grams of this substance, in a mixture with 3 g. phosphoryl chloride, and 50 ml benzene, is refluxed for 30 minutes. (TV time; better set your egg timer(!)--it's not just for eggs, you know. Can you picture watching Matlock while synthesizing narcotics?) The result is the formation of a solution reddish-yellow in color, plus the evolution of hydrogen chloride. This must be cooled. Then, add petroleum ether - enough so that there is produced a reddish precipitate. By allowing this time to stand, make sure that no more will precipitate (that the precipitation process is finished with), then separate the precipitate by filtration. Dissolve this in dilute hydrochloric acid solution. Shake with benzene, and filter through filtration paper wetted with benzene. Now, with external cooling and stirring, make this alkaline by careful addition of strong caustic soda. For this process, you will, of course, need pH paper, available at some pool supply stores, or in some catalogues. Potentially, you might use the effective boiled red cabbage pH indicator technique (aren't vegetables cool?! Underrated, I think!). Next, separate the layer of benzene, and dry, evaporating the benzene, in vacuo, within a hydrogen atmosphere. The red residue is then dissolved in 50 ml of methanol. Reduce it over 1.5 g. Raney nickel catalyst. Remove the Raney nickel by filtration, and remove the methanol by evaporation in vacuo. Dissolve the residue in benzene. It may be purified by running through a chromatography column filled with alumina. After evaporating the benzene solvent in vacuo, dissolve the yellow-colored and oily base in another 50 ml of methanol. This is neutralized with hydrobromic acid (not too much, or it'll attack the phenolic-ester methoxy group, which remains for the time being), and evaporated in vacuo. The residue from this crystallizes when scratched with a glass rod. Dissolve this, using little water (but enough). When heated to the point of boiling, add decolorized carbon. Then, filter off while hot. This gives you a yield of 1.5 grams of the compound 1-p-methoxy-benzyl-1,2,3,4,5,6,7,8-octahydroiso-quinoline hydrobromide (salt), which is in the form of colorless prisms, and has a melting point of 197-198 degrees Celsius. This isoquinoline product is then converted, in one of several ways, to racemorphan (levorphanol+dextrorphan). Other methods may be discovered that work well, but this is probably the best method, as it methylates the compound at the same time as the reduction is going on: reduce the quinoline catalytically, in the presence of formaldehyde, by one of a number of acceptable methods (general catalytic reduction - many will work with a semi-complex, cyclic aryl-amine like this). Just be sure to remember to use formaldehyde! Otherwise, use another method. Another, different, way of finishing the process is as follows: After the Raney nickel reduction, separate the product from the catalyst, purifying as previously outlined. Now, react your product with CH2O and hydrogen, or formic acid, resulting in 2-methyl substitution of the isoquinoline. Heat this with ten times its weight in phosphoric acid (specific gravity, 1.75) at 140-150 degrees Celsius for approximately 70 hours, or a bit longer. (This would be a a good time to restock your reagents or solvents, in case there isn't a good sci-fi marathon on television. Or grab a Hustler or a Penthouse, some Jergen's hand lotion, and some Puff's Plus, at 7-Eleven.) The resultant brown solution is ice-colled (with water, and externally, as well), and carefully made alkaline, using the pH indicator phenolphalein, with ammonia. See below at crystallization, as it very specifically applies here. Assuming you are keeping the product at the racemorphan stage, and crystallizing, you can do this well with anisole and dilute ethyl alcohol. Here is one method for recrystallizing: (Specifically, starting right where the paragraph before the last one left off) In an extraction, shake out the freebase with diethyl ether ("duh--what other kind would one use," you ask, right?), and then evaporate the ether in vacuo. The racemorphan is then sublimated on an oil bath at a temperature of 180-199 degrees Celsius, plus 0.3 mmHg, vacuo. You may recrystallize this once, from anisole (and dilute ethanol, maybe?). You may also, after evaporating the ether, recrystallize twice using the anisole, or that and dilute ethyl alcohol upon second recrystallization(?). The most soluble salt of racemorphan is apparently that of the hydrobromide, but one may also use the hydrochloride, or apparently even the sulfate (would one be able to create this salt before recrystallizing, I wonder? It would sure be helpful). You might check on the sulfate viability, though, to be sure. Couldn't hurt. However, if one desires the twice-as-potent and less toxic (as if the first were even anywhere close to being as toxic as even a martini) compound levorphanol (the pure opioid, from this racemic mixture of an opioid and an agent affecting NMDA receptors, which is dextrorphan, as previously mentioned) optical resolution with l-tartaric acid should furnish levorphanol tartrate, which may be separated from the remaining dextrorphan base. The dextrorphan may also be saved, and made into the hydrobromide salt for use as a ketamine-like dissociative and psychotomimetic, at much higher doses than those at which racemorphan is active at as an opioid analgesic. I would actually not recommend this final step (resolution), even though I think levorphanol is one of the greatest opioids of all time, as it may reduce yields to perform the optical resolution, and it really isn't worth the extra effort, as you simply only have to make the dose of racemorphan twice that of what the levorphanol would be (check up top for my instructions). It's not significantly more toxic, or anything, so I would really encourage you to keep the racemorphan as-is. It's still some seriously potent shit! More powerful than heroin: but don't expect it or levorphanol to produce any quick rush or flash of euphoria, like heroin, fentanyl, or morphine, though they do produce a rush when snorted or injected, and (no matter how they're taken), both racemorphan and levorphanol actually end up producing a more steady state of, and even stronger sense of euphoria than even morphine or Demerol. They are highly euphoric, but it takes a bit of time: about 30 to 45 minutes or more for the major effects to start, when taken orally; or about five minutes for this after injection (around fifteen minutes after snorting), so don't take more if you think it's not working(!), because it will! A peak is reached at about one-and-a-half (even two) hours (and then the peak lasts for hours and hours). The peak after injection is about one hour; or an hour and fifteen minutes after insufflation. Whether racemorphan or levorphanol is used, it is crucial that one has a scale with the ability to measure accurately down to 1 to 2 milligrams. Taken by mouth, 3 to 4 mg of levorphanol is a very potent dose. Take it from someone who has had a lot of personal experience (pharmaceutically produced levorphanol) with this wonderful, yet seriously potent compound. Racemorphan is basically half as potent. If injected, both substances are about twice as effective as they are orally. Be warned! These are highly potent narcotic-analgesics! Properties and data Levorphanol tartrate: 17-methylmorphinan-3-ol, or l-3-hydroxy-N-methyl-morphinan, has the empirical formula C17H23NO, and a molecular weight of 257.38. A highly active mu-opioid orally, it is approximately equipotent with Dilaudid (hydromorphone) when injected. One mg Levorphanol tartrate equals 0.58 mg levorphanol base. Levorphanol tartrate dihydrate: 17-methylmorphinan-3-ol hydrogen tartrate (1:1) dihydrate; C17H23NO-C4H6O6-2H2O. Crystals melt at 113-115°C. Racemorphan (d,l-form; half dextrorphan) hydrobromide, crystals from anisole and dilute alcohol. Melting point 198-199°C. Good luck! Be careful! This is a habit-forming and controlled substance that is scheduled (C-II; Schedule II) alongside morphine and stimulants like cocaine and methamphetamine.