Author Topic: l-Dromoran (17-methylmorphinan-3-ol)  (Read 8693 times)

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  • Guest
l-Dromoran (17-methylmorphinan-3-ol)
« on: May 18, 2004, 05:41:00 PM »
Ok, so swim has read the synthesis of levorphanol posted by Dopaman and swim is curious.

A few stupid questions:

1. Suppose one has access to the necessary chemicals for synthesis, is the method Dopaman writes about, easily scalable (scaled upwards to say in the kilograms).

2. Will one need special equipment for scaling it up?

Please help!


  • Guest
Where can Swim look up Swiss patents for free?
« Reply #1 on: May 18, 2004, 06:08:00 PM »
Swim tried searching on the web for looking up the swiss patents regarding the substance but either got pay-sites, or sites with the title but not the patent.  Any suggestions.

P.S. - Please go easy on this newbie.


  • Guest
Swiss Levorphanol Patents
« Reply #2 on: May 18, 2004, 08:04:00 PM »

Patent CH254106

Patent CH252755

Patent CH253710

Edit: It seems like those links are acting up at the moment. If it doesn't work, try the URL format

instead (change the trailing numbers to access the other patents)


  • Guest
Thanks, but...
« Reply #3 on: May 19, 2004, 03:59:00 AM »
Swim doesn't know German.  Swim tried copying the text, but couldn't (to feed to a translator.)

Swim gathers that the Dopaman process is legit.

Please help, swim needs some assurance for scaling up.  Any caveats to watch out for, etc. Thanks.

P.S. - All theoretical, no one is planning on making ANYTHING.  Also, Rhodium, love you and your site.  I wish you good health and happiness.


  • Guest
Swim needs some sureity
« Reply #4 on: May 24, 2004, 07:10:00 PM »
Suppose swim wanted to make Levorphanol and had all the precursors... swim could probably do it following DopaMan's article on its synthesis. 

Swim's curiosity is this:  What if swim wanted to make 100 kilos of the thing.  Would it be difficult?  How would you scale up from 6.2 grams to say 6.2 kilograms?  Swim can't find pointers to this.  Example, refluxing, evaporation in vacuo on a larger scale.  Please help.


  • Guest
(flame deleted)
« Reply #5 on: May 25, 2004, 04:10:00 AM »
Appology accepted (sorry about the flame).

I wish you good luck with your book.

Now for scaling up, this is how things are usually been done.  First, research chemist optimize the synthetic pathway.  This is done on batches of 25 --> 500 milligram.  Special attention goes to using minimal amounts of solvents, using cheap precursors & devising a reaction scheme with a minimal number of (high yielding) steps.  Then, the optimized procedure is sent to the industrial chemist (mostly some engenieer) who designs a chemical reactor for the bulk synthesis.  It is possible for reaction conditions for being modified somewhat during the scale-up.  The work-up is usually different.  Techniques such a distillation are energy consuming (--> expensive) & not prefered on industrial scale.

Industrial chemistry is a hybrid of engenieering / economics / chemistry.


  • Guest
« Reply #6 on: May 25, 2004, 05:29:00 PM »
I promise, (not that it will mean anything to you), to NEVER make or SELL any (not even 1 mg) of opiods, or stimulants (unless coffee) or even Marijuana  to anyone.  I guess you won't believe me, but I am writing a action thriller novel (now in point form notes) and it includes clandestine labs, big-bad international conspiracies, etc.
I'm trying to follow Dan Brown(an author's) way of researching the material first.  If I said this upfront, I am sure I would have gotten skewed answers, so I didn't reveal it. 

Now, I don't think anyone will help me over here, so I'll have to keep taking my night-courses and talk to "chemists" who aren't into the scene, but I PROMISE, I will NEVER make and sell this or any illegal stuff to anyone. 

Take this post as you might.  Take care.

P.S. - If time permits, I'll get the web-site ready with some summaries of my new book.  Not that it means shit to you.  Oh yes, instead of the "Hive", the book's going to have the "Nest" and birds!  Get it?  The Bird of prey in Jungian archetype.  Ofcourse the characters are going to be more than a little crazy than what I've witnessed here.


  • Guest
I might as well explain the bird thing more:
« Reply #7 on: May 25, 2004, 05:44:00 PM »
Ancient Egypt Archetype, as described by the Merriam Webster Collegiate Dictionary states, “The original pattern or model of which all things of the same type are representations or copies”. The Egyptian model is considered an archetype because it set the groundwork for all religion. Egyptian mythology centers itself on nature, the earth, the sky, the moon, the sun and the stars. Another important figure in Egyptian mythology is the Nile River. The Nile River is said to manifest itself over the land of ancient Egypt and its people. The gods and goddesses of ancient Egypt are anthropomorphic; they contain the heads of birds and other animals. Many Egyptians deified the bird. This was because the bird was considered the hope of resurrection. Also, flight is considered to be a religious concept. In addition, the Egyptian archetype is a polytheistic model, containing almost two-thousand gods and goddesses. These gods represented hope and explanation. One of these gods, Re, is said to be the greatest god. Re, the god of sun and the creator god, is represented with the head of a falcon. Re is the most influential god because he is known as the god of creation.

So, now the bird (aka the chemists) are the creators, the ressurectors who give hope to the dead psyches of humans.  With LSD and whatnot.


  • Guest
Thanks Megatherium.
« Reply #8 on: May 25, 2004, 07:21:00 PM »
Now this was helpful.  :)

So, I'm learning a lot about "Chemical Process Design".

Again, forgive me when I ask stupid questions.  I don't want my book to sound outlandish by just making up stuff which would be purely impossible. 

Next thing, bug people on political conspiracy sites.  ;)


  • Guest
No problem
« Reply #9 on: May 25, 2004, 08:08:00 PM »
Now, in your book you have already 3 star players:
1) The geeky research chemist who works about 2 entire years optimizing a threesome of (high yielding) from scratch synthetic routes (his major find being of course a one pot procedure that simplifies several synthetic steps).
2) The evil industrial chemist, who sees which synthetic pathways can be scaled up with the best results
3) The crooked accountant, who launders all the money


  • Guest
« Reply #10 on: May 25, 2004, 10:39:00 PM »
Good ideas, but it will more be towards a young guy stumbling onto a massive conspiracy + religious archetypes + symbols + fate + eastern philosophy.  The protagonist started out being Chinese, but after advice from editors, he is "white". 

2 stupid questions:
1. Could someone with a Bachelors degree in Chemistry do the synthesis easily?
2. I've heard of people come up with better analogs.  So in theory (for a book atleast) it would be possible for the protagonist to "stumble" upon a better substance from some (not a lot) of experimentation?  Right?  Or can the process be only done in a high tech lab... Talking about morphinans.


  • Guest
Could someone with a Bachelors degree in ...
« Reply #11 on: May 26, 2004, 12:47:00 AM »
Could someone with a Bachelors degree in Chemistry do the synthesis easily?

Optimizing such a multi step from scratch synthesis is a task for an experienced organic chemist, not for a chem newbee like someone who just got his bachelors degree.

This is no kitchen chemistry, you know.


  • Guest
Thanks again!
« Reply #12 on: May 26, 2004, 05:29:00 AM »
Probably will change some of the premise.

Now, when looking and after using TFSE, it seems the precursors to levorphanol are strange.  What would they be normally used for?  Solvents?

Just so you all know, the reason I chose opiates and opiods is because of the Chinese Opium wars which plays an important role in the story.


  • Guest
Dromoran synth = tough
« Reply #13 on: May 31, 2004, 07:55:00 PM »
Pimpo has posted some info on morphinan synth and SARs, too. Humble Student should take a look at them.

I would definately agree with Megatherium's comment, morphinan synthesis is not for beginners. Making Cyclohexenylethylamine (CHEA) works well enough and this stuff can also be obtained commercially, but getting to the benzyl-octahydroisochinoline stage is difficult, even tough there are various routes from CHEA known. Although the literature states something different, SWIM has up to now always obtained only brownish sticky products that were impossible to clean up. Distillation at high vacuum or chromatography might be necessary.

A very interesting synth has been developed at Bayer which makes the benzyl-octahydroisoquinoline (to be more precise: a 10-oxy-decahydroisoquinoline, which can be considered as the corresponding hydrate and basically reacts like the octahydroisoquinoline) in one step from CHEA via a Pictet-Spengler synthesis. This means racemorphan from CHEA in 3 steps! Pimpo sees that there is significant interest in morphinans and some more excerpts from the literature will be posted this week.

A few things that have been learned so far:

When making Cyclohexenylacetonitrile according to 'Organic Syntheses':

-the benzene can be replaced by toluene
-the intermediate cyano-cyclohexylidene-acetic acid is more stable than one might conclude from the Org Syn article, so one can easily remove benzene/toluene AND excess cyclohexanone at this stage. This will make the final destillation of the product easier and ensures a clean good product
-50 - 60 % of water-white, completely clear product with characteristic intense rather agreeable smell, that contained no ketone according to dinitrophenylhydrazine test was consistently obtained

When making CHEA according to the Swiss article:

- the synth was downscaled to 15 - 30 g of nitrile
- only half the stated (downscaled) amount of ether was used
- no inert gas was used
- the final distillation must be conducted at as low temps as possible as CHEA is easily resinificated at this step
- only 1/4 to 1/3 yield of water-white to slightly yellow clear product was obtained, the rest probably sticking to the LiOH/Al(OH)3 sludge (extract this several times with ether!) or being resinificated during distillation
- adding a little hydroquinone to the CHEA/ether mix before distillation to retard decomposition proved useless and even worse the amine obtained turned red after a few days (formation of quinone?)
--> - CHEA must be made and treated carefully
    - LiAlH4 + ether + low yields = a lot of cost, therefore it might be worthwhile to buy CHEA, even though it is expensive


  • Guest
Thanks Pimpo
« Reply #14 on: May 31, 2004, 10:45:00 PM »
Thanks Pimpo.

I'm still trying to digest all that I am reading and have found that a lot of what I intended to add in the story is extremely wrong.  Anyway, I'm still learning.

I have a synthesis of 1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-
octahydro-isoquinoline from p-methoxy-benzyl bromide and (5,6,7,8) tetrahydroisoquinoline methiodide.  I'm not sure as to whether it is already in the hive, so I am asking as to whether you would be interested in looking at it and should I post it here?



  • Guest
Question Pimpo
« Reply #15 on: June 01, 2004, 01:07:00 AM »
I'm still working on getting my hands on the above mentioned synthesis, but the person I have asked for hasn't replied yet.

Anyway, if I am reading this right, are you saying that once 1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-
octahydro-isoquinoline is synthesized, it is easy to produce levorphanol?


  • Guest
Here it is:
« Reply #16 on: June 02, 2004, 02:53:00 AM »
Ok, before I get tongue lashed for the synthesis, it was given to me by a Swiss friend who was in the business.  I got a hold of him through people I have come to know during my research.  Anyway, he told me that this is a well known synthesis (even in some books) and is extremely easy.

Everyone, Rhodium, Magetherium, Pimpo, Ning, etc.  Please comment on this.

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) and cool to 0-3 C.  275
parts of (5,6,7,8) 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 phenolphthalein, 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%. 

So there, this is what I am contributing to the Hive.  I hope Megatherium still doesn't consider me to be some greedy people destroying scum.  If I were really interested in becoming a drug dealer, I would have:
a) Kept the synthesis to myself, OR
b) started dealing heroin, which is apparently plentiful in the USA. (Quick money for a known product and no need to work up my puney brain on synthesis of exotic chemicals.)


  • Guest
discussion + article
« Reply #17 on: June 02, 2004, 11:48:00 AM »
Sorry HumbleStudent for me taking somewhat long to reply  :) .

Thanks for posting the above synth, I read about this, too, but didn't really consider it worthwhile posting, mainly because of the difficulty making the 5,6,7,8-tetrahydroisochinoline (reaction with POCl3 at elevated temperature + pressure involved, synth can be found at: R. Grewe + A. Mondon, Chem. Ber. 81, 279 (1948)). Also again a very good = very expensive pump is needed for cleanup and catalytic hydrogenation is utilized. Furthermore p-MeOPhMgX (the grignard reagent used here) is rather too reactive causing the grignard-reaction to give worse yields than with ordinary PhMgX. Therefore the method is considered to be more suitable for (only) N-substituted morphinans, which haven't been investigated thoroughly enough in my oppinion.

So here are the translated excerpts concerning the Pictet-Spengler synthesis:

- Unfortunately the exact reference was lost, but the article by Hans Hennecka (Bayer Research Laboratories) is from 1953, starting at page 110. The journal, I think, is Angewandte Chemie.

starting from p. 126:

'4. Synthesis of 3-Hydroxy-N-methyl-morphinan

p-Methoxyphenyl-glycidic acid methyl ester (XXXVIII) [of course the 2,3-substituted compound, note that the methyl ester is formed]

To synthesize this glycidic acid ester it is not necessary to work in ether with sodium [31], dry sodium methylate or with sodamide. Rather it is possible, as already R. B. Loftfield described, to effect the condensation of anisic aldehyde with chloroacetic acid [ethyl] ester in methanolic sodium methylate solution. To compensate for the accompanying side reaction of formation of methoxy acetic acid [methyl/ethyl?] ester [Trying to use bromoacetic acid ethyl or methyl ester instead of the chloro compound resulted in complete failure of the reaction. SWIM supposes that with the more reactive bromo compound this side reaction becomes the main reaction, as sodium bromide is immidiatelly formed upon dripping the aldehyde/ester mix into the methanolic solution. The bromoacetic acid ethyl ester is a terrible lachrymator and a carcinogen anyway!], 1 1/2 mol each of chloroacetic acid [ethyl] ester and sodium methylate is used per mol of anisic aldehyde.

A sodium methylate solution containing 69 g (3 gramm atom) sodium (prepared by dissolving 70 g sodium in 1 L methanol and titration after filtration through glass filter) is cooled to - 10 °C and treated within 5 - 6 hours with moderate stirring with a mixture of 272 g (2 mol) freshly distilled anisic aldehyde and 326 g (3 mol) of acid free chloroacetic acid [ethyl] ester. A nearly colorless to slightly yellow paste, that can still be stirred well is formed. After completing the addition stirring is continued for 2 hours at - 10 °C and the mixture is allowed to stand overnight without renewing the cooling. The next morning the mix is slightly acidified by addition of little GAA and the paste is transfered to 6 L of H2O that has been slightly acidified with GAA. After standing 1/2 h the crystal solid is filtered with suction, washed with water and air-dried. Yield 360 - 390 g, 86.5 - 93.7 % of theoretical yield, mp. 60 - 62 °C; the ester can be distilled at high vacuum without decomposition, bp. 145 °C / 0.7.

[elemental analysis omitted]

1-p-Methoxybenzyl-10-hydroxy-decahydro-isoquinoline (XXXIII)

a) with p-Methoxyphenyl-acetaldehyde bisulfite compound

[omitted, worse yields and more hassle than b)]

b) with p-Methoxybenzyl-glycidic acid [methyl] ester

In 20,145 L of dil. aq. HCl, containing 3.95 mol of HCl, 465 g (3.72 mol) of cyclohexenylethyl amine is dissolved, 774 g p-methoxyphenyl-glycidic acid methyl ester is added and stirred for 48 h at 80 - 90 °C until CO2 evolution ceases. pH of solution: 3 - 4. After cooling down, the solution is decanted from a small amount of tarry residue and the now colorless solution is clarified by stirring with a little bit of animal charcoal, filtrated and the now clear solution is overlayed with a little bit ether and base is set free with conc. K2CO3 solution. The, at first oily, deposit soon solidifies to fine, nearly colorless crystals that mainly collect at the interface of the ether layer. The thereby obtained raw 1-p-methoxybenzyl-10-hydroxy-decahydro-isoquinoline is filtered with suction after 2 h standing, washed with water and then with a little bit of ether and dried. Raw yield 413 g, 40.3 % of theoretical yield. After recrystallization from dil. methanol (1800 ml MeOH, 2000 ml H2O) 373 g of mp. 152 °C is obtained. Identical with the product from a) by mp. and mixed mp.

1-p-Methoxybenzyl-N-methyl-10-hydroxy-decahydro-isoquinoline (XXXV)

A solution of 20 g XXXIII in 100 ml of technical formic acid (ca. 84 %), prepared in the cold, is treated with 8 g of 30 % formaldehyde solution and heated for 12 h on a water-bath after standing for 2 h. The excess formic acid is evaporated i. v., the residue is dissolved with water, the base set free with K2CO3 solution and the oil that deposits is dissolved with ether. The oily base that is obtained upon evaporating the ether can be distilled at high vacuum. Bp. 160 - 165 °C / 0.01; highly viscous oil, that crystalizes upon dissolving in little pet ether. mp. 65 - 66 °C, picrate mp. 153 - 156 °C (from MeOH).

[elemental analysis info omitted]

1-(p-hydroxybenzyl)-N-methyl-delta 9, 10-octahydro-isoquinoline (XXXVII)

11.1 g 10-hydroxy-precursor (XXXV) is boiled in 100 ml constant boiling HBr for 20 min, until the evolution of gas is finished. Upon pouring the cooled down solution into ice water a stiff paste deposits that becomes crystalline upon standing. It is filtered with suction, washed with a little bit of ice water and recrystallized from MeOH/ether. Thereby 3.7 g of the hydrobromide of XXXVII with mp. 235 - 237 °C is obtained.

[elemental analysis info omitted]

Gives no [mp] depression with the salt of equal constitution from Schnider & Grüssner [15].

3-Hydroxy-N-methyl-morphinan (XXIX)

150 g XXXV is dissolved in 1500 ml of constant boiling HBr (d = 1.49 - 1.50) and boiled for 6 h. Then excess HBr is evaporated from the slightly yellow solution i. v. at 60 - 80 °C, the syrup obtained is dissolved in 300 ml hot methanol and the thereby obtained solution is diluted with 3 L H2O with stirring. Benzene-[1-]butanol 1 : 1 is added on top in a sep funnel and the base is set free with conc. NH3 and the voluminous non-crystalline deposit is driven over into the benzene-butanol layer, which can easily be done. The layer is removed, the aqeous phase is again extracted with benzene-butanol and the pooled extracts are washed first with water and then with conc. NaCl solution, filtrated through a double filter and then the solvents are evaporated i. v. at 50 - 60 °C. The remaining syrup, which contains crystals, is boiled in 150 ml methanol until all syrupy substance has been dissolved. The colorless crystals obtained upon cooling down are filtered with suction, washed with little methanol and then with ether. Raw yield 41.2 g, 31 % of theoretical amount; mp. 250 - 251 °C (from methanol).

Identical by mp. and mixed mp. with the 3-hydroxy-N-methyl-morphinan obtained by Schnider & Grüssner [15]

The dark brown mother liquor of 3-hydroxy-N-methyl-morphinan is boiled down to a syrup i. v. at 40 - 50 °C and vigorously shaken with 500 ml ether in a flask until a fine, seemingly still amorphous, separation of the syrup has been effected. After prolonged standing in a sealed flask a light brown crystalline precipitate is formed, which is filtered with suction and washed with ether. Raw yield 38 g; mp. 187 - 193 °C. By careful fractionating crystallization from methanol 20 - 25 g of pure compound with mp. 197 - 198 °C can be obtained [this isomer of unclear constitution is stated to be ineffective as an analgesic!]

[15] O. Schnider, A. Grüssner, Helv. chim. Acta 32, 821 (1949).
[31] ethyl ester: K. W. Rosenmund, H. Dornsaft, Ber. dtsch. chem. Ges. 52, 1740(1919); see also DRP. 591 452 (21. 3. 1930) I. G. Farbenindustrie AG'

Sounds sweet, eh ;D ? Hard to say, how well the conversion from octahydro-isoquinoline/10-hydroxy-decahydroisoquinoline to morphinan really works, but it does look possible! The Pictet-Spengler route seems to be perhaps the most elegant and promissing one, IMHO. This field takes a lot of dedicated and frustration resistant work, but it might be worth the fuss in the end :P .


  • Guest
« Reply #18 on: June 02, 2004, 06:22:00 PM »
Thanks Pimpo,

But am I reading it right?
"In 20,145 L of dil. aq. HCl, containing 3.95 mol of HCl, 465 g (3.72 mol) of cyclohexenylethyl amine is dissolved, 774 g p-methoxyphenyl-glycidic acid methyl ester is added and stirred for 48 h at 80 - 90 °C until CO2 evolution ceases. "

20,145L ?!?


  • Guest
differing US/european decimal notation
« Reply #19 on: June 02, 2004, 07:02:00 PM »
I believe this is just a confusion due to differing US/european decimal notation. The volume they refer to is just a little over 20 L, not 20 m3.