Introduction
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 same potency level as hydrocodone (Vicodin), or one half as potent as morphine.
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.
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.
Equipment and glassware:
- 1 L and 200 mL round bottom flasks;
- Reflux condenser;
- Magnetic stirrer with heating surface;
- Rotovap machine;
- Vacuum source;
- 1 L Buchner flask and funnel;
- 500 mL x2; 200 mL x2; 100 mL x2 Beakers;
- Hydrogen gas (H2) source;
- Glass rod;
- Conventional funnel;
- Filter paper;
- pH indicator paper;
- Flash chromatography kit with alumina oxide;
- Ice and oil baths;
- 1 L Separating funnel.
Reagents:
- 2-(1-Cyclohexadienyl)ethylamine 6.2 g;
- p-Methoxyphenylacetyl chloride 9.4 g;
- Phosphoryl chloride 3 g;
- Hydrobromic acid solution (HBr);
- Hydrochloric acid dilute solution (HCl);
- Caustic soda (NaOH) ~100 g;
- l-Tartaric acid - optional (if making levorphanol)
- Alternates (if not catalytically reducing as the last step; if desired):
- CH2O: Methylene oxide (alternate final procedure);
- Formic acid (alternate procedure, also);
- Phosphoric acid (alternate, also.);
- Benzene 130 mL;
- Petroleum ether;
- Methanol 100 mL;
- Distilled water;
- Anisole;
- 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);
- Sodium bicarbonate (NaHCO3) 5% solution, 200 milliliters;
- Raney nickel 1.5 g;
- Decolorizing carbon;
- Formaldehyde;
- Diethyl ether (Et2O);
(-)-3-Hydroxy-N-methylmorphinan:
Boiling Point: 401 °C at 760 mm Hg;
Melting Point: 198-199 °C;
Molecular Weight: 257.377 g/mole;
Density: 0.9711 g/mL;
CAS Number: 77-07-6.
Procedure
1. 6.2 g 2-(1-Cyclohexadienyl)ethylamine (1), which is placed in 1 L round bottom flask with 80 mL benzene, and then treated, in the presence of sodium bicarbonate (a 5% solution, 200 mL), with 9.4 g p-methoxyphenylacetyl chloride (2), in benzene. As this is done, the concoction is stirred and externally cooled (ice bath).
2. 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-cyclohexadienyl)ethyl-p-methoxyphenylacetamide (3), which is in the form of colorless scales, and melts at a temperature of 86-86.5°С, is obtained at a quantity of 12.5 g.
3. 3 g Of this substance, in a mixture with 3 g phosphoryl chloride (POCl3), and 50 mL benzene, is refluxed for 30 minutes in 200 mL round bottom flask and reflux condenser. The result is the formation of a solution reddish-yellow in color, plus the evolution of hydrogen chloride.
3. 3 g Of this substance, in a mixture with 3 g phosphoryl chloride (POCl3), and 50 mL benzene, is refluxed for 30 minutes in 200 mL round bottom flask and reflux condenser. The result is the formation of a solution reddish-yellow in color, plus the evolution of hydrogen chloride.
4. Rm must be cooled to r.t. 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.
5. Dissolve this in dilute hydrochloric acid aq. solution. Shake with benzene, and filter through filtration paper wetted with benzene.
6. Now, with external cooling and stirring, make this alkaline by careful addition of strong caustic soda (NaOH aq. Solution) in separating funnel. For this process, you need pH paper. Next, separate the layer of benzene, and dry, evaporating the benzene, in vacuo.
7. The red residue (4) is then dissolved in 50 mL of methanol. Reduce it over 1.5 g Raney nickel catalyst by hydrogen gas (H2).
5. Dissolve this in dilute hydrochloric acid aq. solution. Shake with benzene, and filter through filtration paper wetted with benzene.
6. Now, with external cooling and stirring, make this alkaline by careful addition of strong caustic soda (NaOH aq. Solution) in separating funnel. For this process, you need pH paper. Next, separate the layer of benzene, and dry, evaporating the benzene, in vacuo.
7. The red residue (4) is then dissolved in 50 mL of methanol. Reduce it over 1.5 g Raney nickel catalyst by hydrogen gas (H2).
8. Remove the Raney nickel by filtration, and remove the methanol by evaporation in vacuo.
9. Dissolve the residue in benzene. It may be purified by running through a chromatography column filled with alumina oxide. After evaporating the benzene solvent in vacuo, dissolve the yellow-colored and oily base in another 50 mL of methanol.
10. This is neutralized with hydrobromic acid (not too much, or it'll attack the phenolic-ester methoxy group, which remains for the time being) to pH 7, and evaporated in vacuo. The residue from this crystallizes when scratched with a glass rod.
11. Dissolve this, using small water amount (but enough). When heated to the point of boiling, add decolorized carbon. Then, filter off hot solution. This gives you a yield of 1.5 g of the compound 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroiso-quinoline hydrobromide (salt) (5), which is in the form of colorless prisms, and has a melting point of 197-198°С.
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:
9. Dissolve the residue in benzene. It may be purified by running through a chromatography column filled with alumina oxide. After evaporating the benzene solvent in vacuo, dissolve the yellow-colored and oily base in another 50 mL of methanol.
10. This is neutralized with hydrobromic acid (not too much, or it'll attack the phenolic-ester methoxy group, which remains for the time being) to pH 7, and evaporated in vacuo. The residue from this crystallizes when scratched with a glass rod.
11. Dissolve this, using small water amount (but enough). When heated to the point of boiling, add decolorized carbon. Then, filter off hot solution. This gives you a yield of 1.5 g of the compound 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroiso-quinoline hydrobromide (salt) (5), which is in the form of colorless prisms, and has a melting point of 197-198°С.
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:
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 (5) with formaldehyde (CH2O) and hydrogen gas (H2), or formic acid, resulting in 2-methyl substitution of the isoquinoline. Heat this with ten times (x10) its weight in phosphoric acid (specific gravity, 1.75, 88%) at 140-150°С for approximately 70 hours, or a bit longer. The resultant brown solution is ice-cooled (with water, and externally, as well), and carefully made alkaline, using the pH indicator phenolphthalein, 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 with anisole and dilute ethyl alcohol.
Racemorphan recrystallizing:
(Specifically, starting right where the paragraph before the last one left off)
In an extraction, shake out the freebase with diethyl ether, and then evaporate the ether in vacuo. The racemorphan is then sublimated in an oil bath at a temperature of 180 - 199°С, under 0.3 mm Hg 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.
In an extraction, shake out the freebase with diethyl ether, and then evaporate the ether in vacuo. The racemorphan is then sublimated in an oil bath at a temperature of 180 - 199°С, under 0.3 mm Hg 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.
Levorphanol
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. 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!
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!
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