levorphan synthesis - possible other precursors or methods?

stooge · Thu Feb 17, 2005 12:34 am

Hi there,

swim was always fascinated by levorphan (although he never tried it) besides of fentanyls, but the precursors used in the synth (from rhodiums site) below seem to be very hard to get or produce to him, even if the synth itself seems not to be too hard.

may there be any other possible precursors for this or home usable methods to produce the named/other precursors?!? swim'd very much estimate any suggestion/hint/thought/and so on ...

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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 methedrine.

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Web Bilder Groups Verzeichnis News
Erweiterte Groups-Suche
Einstellungen
Groups Suchergebnis 13 für levorphan

Suchergebnis 13
Von:Lamont Granquist (lamontg@u.washington.edu)
Betrifft:chemistry: levorphanol
Dies ist der einzige Artikel zu diesem Diskussionsthema
View: Original Format
Newsgroups:alt.drugs
Datum:1994-05-30 05:38:04 PST

More copyright violations of Loompanics Books. I'll be getting that catalog
of theirs up on my WWW site shortly to assuade my guilty conscience...

I have *zero* comments on the process involved, indeed i've yet to read
through it all...

A small section out of _Recreational Drugs_ by Professor Buzz:

Dromoran (Sometimes called Methorphinan or 3-Hydroxy-N-Methyl-Morphinan)

This drug is quite easily synthesized, yet it contains the same
numbering system as morphine, which is considerably harder to synthesize.
Although Dromoran lacks the oxygen bridge, the Alicyclic double bond, and
the alcoholic hydroxyl of morphine it is still 4-5 times more powerful, as
well as longer acting. The average dose is 1-3 mg intramuscularly
injected. Dromoran has less than one half the addiction liability of
morphine and is, therefore, used almost exclusively for severe injuries,
amputations , etc. The incredible feeling of well-being it produces is
accompanied by addiction, so it cannot be used regularly. It also has no
marked hypnotic effect, so it may be taken and enjoyed without drowsiness
or reduced clarity of thought. The drug is wel l tolerated and does not
depress blood pressure or cause other circulatory disturbances. The
effects begin after ten minutes and continue for nine to thirteen hours
with a minimal dose.

This first formula is a street method, but I am sure it was taken
from the Swiss patents 252,755 and/or 254,106. You should always look up
all references, even though I know that this method does work and I have
double checked all the figures.

Prepare a Grignard reagent from 325 parts (as usual all parts
refer to parts by weight) of p-methoxy-benzyl bromide in 800 parts of
absolute ether with 40 parts thin clean magnesium (unlike THCs, different
Grignard reagents cannot be substituted here) an d cool to 0-3 C. 275
parts of (5,6,7, Cool

tetrahydroisoquinoline methiodide are added in small
portions. This mixture is allowed to stand for one hour at 0 C and
saturate with ammonium chloride after pouring onto cracked ice, then
basify with ammonia by a dding in small portions and checking pH often.
Separate the ether solution and extract the base with hydrochloric acid.
The acid solution is basified with ammonia and extracted with ether, the
ethereal solution is dried in the usual manner. Remove the ether by
evaporation in vacuo with gentle heating, or distill it out at a low
temperature in the next step. Distill with 0.2 mmHg of vacuo, collecting
the fraction at 149 to 154 C to get the desired base.

The above base is catalytically hydrogenated (platinum oxide seems
to work the best) to 1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-
octahydro-isoquinoline. This is separated from the catalyst and purified
by distilling under 0.2 mmHg of vacuum, collect ing the fraction at
138-142 C. Heat at 150 C for three days with ten times its weight of
phosphoric acid (specific gravity 1.75). The resulting brown solution is
cooled with ice (in water and externally) and made alkaline to the
indicator phenolphthalei n, by carefully adding ammonia. The free base is
then shaken out with ether (this is an extraction) and the ether is
removed by evaporation in vacuo. Purify the Dromoran by sublimation on an
oil bath, at 180-199 C with 0.3 mmHg of vacuo and recrystalliz e once with
anisole, or recrystallize twice with anisole after evaporating the ether.
Yield: about 30-35%. To get the hydrochloride form, or the sulphate,
etc., use any of the above methods for isomethorphinan, amidone, etc.

Dromoran JOC, 24, 2043 (1950)

This method is more modern than the last and it gives details for
making a lower starting material, eliminating the need for purchasing
(5,6,7, Cool

tetrahydroisoquinoline methiodide.

6.2 g of 2-(1,4-cyclohexadienyl)ethylamine in 80 ml of benzene is
treated with p-methoxyphenylacetyl chloride (9.4 g in benzene) in the
presence of sodium bicarbonate (200 ml of a 5% solution) with stirring and
external cooling. An oily amide results, w hich solidifies (crystallizes)
upon scratching the flask with a glass rod (see crystallization in the
equipment chapter). Recrystallize from a mixture of n-hexane and benzene
to get colorless scales that melt at 86-86.5 C. Yield of this
N-2(1,4-cyclohex adienyl)ethyl-p-methoxyphenylacetamide is 12.5 grams or
92%.

A mixture of the above amide (3 g), phosphoryl chloride (3 g) and
50 ml of benzene is refluxed for 30 minutes creating a reddish-yellow
solution and evolution of hydrogen chloride. Cool, add enough petroleum
ether to give a reddish precipitate, which is separated by filtration,
after allowing to stand long enough to make sure no more precipitation
will occur. Dissolve the precipitate in dilute hydrochloric acid, then
shake with benzene and filter through a benzene wetted filter paper. Make
the filtrat e alkaline by carefully adding a strong caustic soda solution
with external cooling and stirring. Separate the benzene layer and dry,
evaporate the solvent (benzene) under vacuo in a hydrogen atmosphere.
Dissolve the red residue in 50 ml of methanol and reduce over 1.5 g of
Raney nickel (see reductions chapter for complete information, then work
in 1.5 g of catalyst). The catalyst is removed by filtration and the
solvent by evaporation in vacuo. The residue is dissolved in benzene and
purified by runn ing through an alumina filled chromatography column.
Evaporate the benzene in vacuo and dissolve the resulting yellow, oily
base in methanol (50 ml), neutralize with hydrobromic acid, and evaporate
in vacuo. The residue crystallizes on scratching with a glass rod. Use a
minimum amount of water to dissolve, upon boiling, add decolorizing carbon
and filter off hot to get 1.5 g of the hydrobromide salt of
1-p-methoxybenzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline as colorless
prisms, mp: 197-198 C.

The above quinoline can be converted in several ways to Dromoran.
The process given below methylates it at the same time as the reduction
takes place and is a superior operation.

Reduce the quinoline catalytically in the presence of
formaldehyde. Most any of the general methods of catalytic reductions
found in the reductions chapter will work fine, as long as you remember to
use formaldehyde.

Another method is to proceed after the Raney Nickel reduction like
this: filter the catalyst off and purify as above. React the product with
CH2O and hydrogen or HCO2H to get the 2-Me derivative, which is heated
with H3PO4 at 140-150 C for 70 hours. Note: HCO2H is a strange way to
say formic acid.

[From _The Merck Index_ Eleventh Edition] slighty abbreviated

Levorphanol. 17-methylmorphinan-3-ol; (-)-3-hydroxy-N-methylmorphinan;
levorphan; lemoran; Ro 1-5341. C17H23NO; mol wt. 257.38. Orally active
synthetic morphine analog. Preparation of racemate from 2-methyl-1-
benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline: Grewe, Naturwiss. 33, 333
(1946); Angew. Chem. A59, 198 (1947); Grewe, Mondon, Ber. 81, 279 (1948);
Swiss pat. 280,674 (1952 to Hoffman-LaRoche), C.A. 47, 7554 (1953).
Preparation of isomers: Schnider, Grussner, Helv. Chim. Acta. 34, 2211
(1951); Vogler, U.S. patent 2,744,112 (1956 to Hoffman-LaRoche). Absolute
configuration: Corrodi, et al., Helv. Chim. Acta. 42, 212 (1959).
Analgesic activity and toxicity data: L.O. Randall, G. Lehmann, J.
Pharmacol. Exp. Ther. 99, 163, (1950). HPLC determination in plasma: R.
Lucek, R. Dixon, J. Chromatog. 341, 239 (1985). Clinical pharmokinetics:
R. Dixon et al., Res. Commun. Chem. Pathol. Pharmacol. 41, 3 (1983).
Crystals, mp 198-199 C.
Tartrate dihydrate, C21H29NO72H2O, Ro 1-5341/7, Dromoran,
Levo-Dromoran. Crystals, mp. 113-115 C (when anhydrous, mp 206-208 C).
pH of a 0.2% aq solution 3.4 to 4.0. One gram dissolves in 45 ml water,
in 110 g alcohol, in 50 g ether.
dl-Form, racemorphan, methorphinan. Crystals from anisole and dil
alcohol, mp. 251-253 C.
dl-Form Hydrobromide, C17H24BrNO, NU-2206. Crystals, mp 193-195.
Sol in water; sparingly sol in alcohol. Practically insoluble in ether.
LD50 i.v. in mice: 41 mg/kg (Randall, Lehmann).
d-Form, Ro 1-6794, dextrorphan. Crystals, mp 198-199 C.

[From 48th edition Physicians Desk Reference]

Equianalgesic Dose (mg)
Name IM PO
-------------------------------------------------------------------------
morphine 10 60
hydromorphone (Dilaudid) 1.5 7.5
methadone (Dolophine) 10 20
oxycodone (Percocet) 15 30
levorphanol (Dromoran) 2 4
oxymorphone (Numorphan) 1 10 (PR)
heroin 5 60
meperidine (Demerol) 75 --
codeine 130 200
-------------------------------------------------------------------------
Note: All IM and PO doses in this chart are considered equivalent to 10 mg
of IM morphine in analgesic effect. IM denotes intramuscular, PO oral,
and PR rectal.

--
Lamont Granquist (lamontg@u.washington.edu)
"And then the alien anthropologists - Admitted they were still perplexed - But on eliminating every other reason - For our sad demise - They logged the only explanation left - This species has amused itself to death" -- Roger Waters

©2004 Google

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Dope_Amine · Wed Jun 01, 2005 4:13 pm

Many find DopaMan's method unattractive due to the precursors. So Dopey decided to try the swiss patent only to find that there was a MAJOR solubility problem concerning quartenary amine salt during the grignard step where it was supposed to be reacted in ether. So, she triend THF only to find the results similarly dissappointing (like yield almost nothing!). Years later, she felt a bit better when she read in Opioid Analgesics, chemistry & receptors, that this solubility issue was exactly what made the grignard and thus over-all synth so low yielding. Seeing as how it was a patent, she had always wondering if it were missing crucial details. Opioid Analgesics is very essential reading for any serious dope-bee. Alas, I will have to buy another copy sometime soon.

I wrote this post b4 with much more detail to reaction conditions and everything referenced and then when I pressed "submit" the next page wouldn't load and I was quite pissed. So I'm not going to be as detailed this time around (and I'm going to remember to highlight and copy b4 submitting). Great detail and all references will be given in the formal write-up which is to be released in the next coming weeks. This took a fair amount of library research to reach the goal: An improved, alternative, facile, high yielding route to levorphanol!

1. Formation of Reissert compound: isoquinoline (easy to make if one has access to phenethylamine) or 5,6,7,8-tetrahydroisoquinoline, or even 3,4,5,6,7,8-hexahydroisoquinoline is stirred with AlCl3, TMSCN, and DCM and then benzoylchloride is added dropwise, yielding the 1-cyano-N/2-benzoyl derivative after 4 hours with slight heating or 3-5 days, then water is added, more stirring, breif extraction and washing with HCl and NaOH and rapid re-xtalization from ether (88% yield!)

2. alkylation at C1 and hydrolysis: TEBA Chloride, 50% aq. NaOH, p-meo-benzyl chloride and then above material is added and all is stirred together for 2 hours, thus alkylating. Hydrolysis occurs to some extent if temp is not controlled to 30 deg C during stirring. It might be possible to reflux rxn mixture to remove cyano and benzoyl groups. The safe way to ensure hydrolysis is to extract product and reflux for 6 hours in a solution of KOH/95% EtOH/H20 .54/30/4 to get 1-(p-meo-benzyl)-whatever-hydro-isoquinoline (alkylation 80%, hydrolysis quantitative)

3. Formation of quaternary salt: Dissolve above material in DCM or chloroform and add MeI dropwise with stirring. Experience with non-alkylated regular 5,6,7,8-tetrahydroisoquinoline says that this material will likely crash out of solution and also likely to be hydroscopic. (>95%)

4. Reduction of all double bonds except 9,10: if using tetrahydro or hexahydro, then all one would need is NaBH4. If using regular ol' isoquinoline, then CTH w/ Pd/C and potassium formate or triethylammonium formate should do the trick. (either should be high-yielding for the experienced chemist)

5. Grewe Cyclization/demethylation: Last step to product just like in the patent!

I've got multiple ref's for each step. Anyone wanna tell me how to upload PDF's? Again, a detailed write-up is in the works and it will also compare differences between using 5,6,7,8-tetrahydro versus regular isoquinoline for the starting material. I'm just terrible at holding out on an exciting topic.

One item I'm quite curious to research on is the N-phenethyl deriv. of levorphanol. Sounds supa-fun to me but I wonder if quaternization with phenethyl bromide would reduce the yield in the next step. Hmmm.....

C-ya laterz.

stratosphere · Sun Jun 05, 2005 12:31 pm

the write up involves a very long synthesis and is more of a how to, then a whats going on, and i had a hard time following the chemistry, but from shulgrins site i got a very abbreviated explanation of the process .

"It has been synthesized from a benzylisoquinoline (with a planar structure) by a process known as Grewe's cyclization (from the 1950's !) to give the corresponding morphinan (with a three dimensional structure). The isoquinoline is 1,2,3,4,5,6,7,8-octahydro-1-(4-methoxybenzyl)isoquinoline (there is just one residual double bond at the fusion position of the two rings of the isoquinoline) is converted into the N-formyl derivative, cyclized to the N- formyl normorphinan, and the formyl group reduced to an N-methyl group, to give 3-methoxy-17-methylmorphinan, or Racemethorphan"

and to keep it short are there any possible natural sources for the benzylisoquinine so that most of the steps could be skipped and proceed directly to the grewe cyclization?
benzylisoquinines occur in many plant species.

stooge · Sun Jun 05, 2005 3:23 pm

Hey! IndoleAmine - that would be great!!! I already gave up all hope as this is way beyond my present abilities- really looking forward to hear from you again! (*drool*)

stratosphere, all plant sources i found are from "The Simple Plant Isoqinolines":

Isoquinoline
Leucoline
2-Benzazine

Cistanche salsa (Orobanchaceae)
Nicotinia tabacum cv (Solanaceae)
Papaver somniferum (Papaveraceae)
Spigelia anthelmia (Loganiaceae)
(*woah - always been dreaming to get something usable from tobacco - i guess the extraction would not be so easy?!? or ... ?)

1-Methyl-1,2,3,4-tetrahydroisoquinoline

Pachycereus weberi (Cactaceae)

1-Benzylisoquinoline

Thalictrum spp. (Ranunculaceae)

Hope this helps? I will search myself a little for this plants, maybe there is one somewhere where it would work ...

Thanks, greets

Lief · Sun Jun 05, 2005 6:58 pm

stooge · Sun Jun 05, 2005 10:56 pm

Sounds good, but there are lots of threads saying it's impossible to get levorphan from DXM.
not that i could judge ...
IF possible swim'd be of course VERY interested Smile

Stinging_Nettle · Mon Jul 18, 2005 4:41 am

There is a good book by Daniel Lednicer that has a levophanol synthesis in it. I can't pin-point it at this time although I will say that his version was different to that posted on Rh.ws

stooge · Mon Jul 18, 2005 2:46 pm

Hm, yes, sounds like he wrote some pretty interesting books - i guess it will be one of these, or ... ?

-Central Analgetics (Chemistry & Pharmacology of Drugs S.)
-The Organic Chemistry of Drug Synthesis

Only thing is, the prices are heavy ...

Stinging_Nettle · Mon Jul 18, 2005 9:45 pm

i dont expect you to fork out money on that scale for a couple of books.
if you are enthusiastic enough maybe there is a way that you can get access to a university library and some how get the journal articles to the relevent syntheses?

stooge · Mon Jul 18, 2005 10:43 pm

yes ... of course, you are right - the easiest solutions are always overlooked by swim ...
Thanks!
(btw.: anyone ever thought about tilidine? very nice stuff also)

Fentasies · Wed Jul 20, 2005 5:24 am