cavos (Stranger)
04-24-03 20:13
No 429163
      tramadol  Bookmark   

Swim become each month from doc. prescribed his good 3 grams tramadol hcl.
Swimm like tramadol, but the tollerance become really great and now 3 gramms are good for only 4 good days.IS it possible to modify the tramadol hcl versus something better?
(Chief Bee)
04-24-03 21:22
No 429176
      Tramadol (Ultram) analogs  Bookmark   

Tramadol has no immediate useful analogs it can be made into. Its structure is pretty unique among opioids:
(Hive Bee)
04-25-03 01:31
No 429218
      I know a thing or two about opioids and indeed  Bookmark   

I know a thing or two about opioids and indeed it can't bee transformed into something more usefull frown.  Or mabey a transamination to a brand-new fentanyl compound, but I wouldn't bet my money on it for being active mad.
04-25-03 13:36
No 429315
      I have a file on my hd that describes an ...  Bookmark   

I have a file on my hd that describes an analouge of this without the methoxy group on the phenylring. It says it was as potent as hydrocodone (or was it hydromorphone? cant remember). Anyways, you can also make the N-benzyl,N-methyl analogue which was much more potent apparently. It can be made quite easy from cyclohexanone, by reacting it with formaldehyde and dimethylamine, and then with the bromobenzene gringard reagent.

So if there is some easy way to split of that methoxy group you would have a more potent compound.
04-25-03 17:48
No 429344
      The file
(Rated as: excellent)

It turns out the analogue without the methoxy group was actually as potent as hydromorphone (1-2mg or something). So it would be worth the work if one could find a way to remove that methoxy group...

Anyways, here is the file. It was written by someone at


I have here a tilidine-analogue synthesis in english.It is more potent than hydromorphone and it's very easy to make! Since you helped me alot I will post it for you. It goes like this:

A solution of 10g phenyl magnesium bromide is poured in ether.This solution was then added with cooling and stirring to a solution of 5g 2-dimethylaminomethyl-cyclohexanone. After addition of Grignard reagent it is refluxed for 15min. Then 75cc 2N hydrochloric acid is added slowly with stirring and cooling.The aqueous layer is separated off, made alkaline and the product extracted with ether. 2-(dimethylaminomethyl)-1-phenyl-cyclohexan-1-ol was obtained as colorles oil.108'-111;C/0,5mm.
2-dimethylaminomethyl cyclohexanone:This mannich base can be prepared easily. Mix 5g dimethylamine hydrochloride with 3g cyclohexanone in paraformaldehyde. Let stand over-night, then extract it with ether. The product is almost pure.
phenyl magnesium bromide: This can be purchased at most chemical companies. It can be prepared from 1,6g magnesium ribbon and 10g bromobenzene(or iodobenzene?).
You can use 2-(methylbenzylaminomethyl)-cyclohexanone hydrochloride to get a really strong analogue. This is made by the condensation of methylbenzylamine hydrochloride, paraformaldehyde and cyclohexanone the same way as the above compound.
04-25-03 19:24
No 429356
      Btw, as I didn't write that text I don't have...  Bookmark   

Btw, as I didn't write that text I don't have any refs for the info in it.

But now that I've had some time to think, I suspect that you may only have to cleave the ether to a hydroxy group to make tramadol more potent. The reasoning is that there are many opiod families that become more potent with a meta-hydroxygroup, morphine, ketobemidone and levorphanol. When you put on longer and longer alkyl groups on the hydroxy group, it then becomes less potent, for example morphine -> codeine -> ethylmorphine.

It should be easy to cleave the ether, just reflux tramadol in some HBr. You don't have to worry about other parts of the structure as in the codeine -> morphine synth.

If it becomes more potent, it should also be interesting to acetylate it and see if it becomes more potent (remember morphine -> heroin). This would also be interesting to try on ketobemidine and levorphanol.
(Hive Bee)
04-25-03 21:02
No 429377
      Great :-) . What an elegant synthesis.  Bookmark   

Great smile.  What an elegant synthesis.  How powerfull the analogue which is made from 2-(methylbenzylaminomethyl)-cyclohexanone + PhMgBr?  This is interesting smile.

Thanks Josef_k smile
04-26-03 12:12
No 429518
      reflux  Bookmark   

would be possible to reflux in the same way to cleave the etherwith with HCl (37%) instead of  HBr?
How long reflux, and how after reflux extracted?Acetylation with acetic acid or acetic anydride?
(Hive Bee)
04-26-03 16:34
No 429562
      >> would be possible to reflux in the...  Bookmark   

>> would be possible to reflux in the same way to cleave
>> the etherwith with HCl (37%) instead of  HBr?

Besides, I think a reflux in HBr will hurt the alcohol .

>> Acetylation with acetic acid or acetic anydride?

With the anhydride.
04-28-03 17:15
No 429997
      Tramadol CAN be demethylated
(Rated as: excellent)

Yes, it can be demethylated, but it isn't easy. It requires quite a few reagents, among them DIBALH. Check (German), pages 178ff.. Read Page 186f for acetylation of the demethyl-derivative. The document also mentions other interesting analogues, might be a source of inspiration? (abstract only), has some useful information, particularly considering the grignard-step.

Also, tricyclic Tramadol analogues:

Check for synthesis and analgesic activity.
(Hive Bee)
04-28-03 18:00
No 430006
      That was a interesting read. Thanks :-) .  Bookmark   

That was a interesting read.  Thanks smile.  They mention also the ED50 of tramadol in mice: 18 mg/kg.  This is rather high frown.
05-06-03 13:21
No 431711
      tramadol demethylation/acetylation
(Rated as: excellent)

That rating was kind of an incent to mesmile, so here's the translation of some of the more interesting parts (I carefully put things that were spread throughout the document together):

Preparation of Tramadol Freebase

10g Tramadol HCl (33.3 mmol) were suspended in a mixture of 16ml of DH2O + 12ml of CH2Cl2 and 4.4ml of 40% NaOH were added dropwise under stirring, which was continued for 30 min until all the solid reacted. The organic phase was removed and the aqueos phase extracted three times with CH2Cl2(33,3 ml, 1ml/mmol). The combined organic phases were dried over Na2SO4 and the solvent was removed with a rotavap, traces of solvent were removed under high vacuum. Beware of foaming caused by the vacuum, the mixture can be warmed if this is a problem. 7.0g (33.0 mmol, 99%) of the freebase were obtained.

Preparation of O-Demethyltramadol

5.2g (19.8mmol) of the freebase were dissolved in 9ml of absolute toluene and at RT there were added dropwise 40ml of 20% DIBALH in toluene (39.6mmol), causing an exothermic reaction and evolution of gas. Then, the mixture was refluxed for 15h. After cooling down to RT, the mixture was cooled with ice and 11.3ml EtOH were added, not allowing the temperature to rise above 15 C. Then, the mixture was stirred for 15 min. Then, again cooling with ice, 11.3ml of a 1:1 H2O/EtOH-mixture were added, again not allowing the temperature to rise aboce 15C. After that , the mixture was diluted with 20ml of toluene and stirred for an hour. The solid, that precipitated was filtered off and -- the mixture? I guess! -- extracted with five times its volume of EtOAc at 60C for 30 min. The combined organic phases were dried over NaSO4 and the solvent was removed under reduced pressure with a rotavap. There were obtained 4.592g (18.4 mmol, 93%) of a colorless oil, that crystalized (m.p. 139 C)

Acetylation of O-Demethyltramadol

To 2.490g of O-Demethyltramadol was added dropwise a mixture of acetic anhydride (1.318g, 12.9 mmol) and pyridine (0.08g, 1-0 mmol) in 40ml of CH2Cl2 and the mixture was stirred 2-3 days at RT. As soon as no educt could be detected (TLC), the mixture was stirred overnight with sat. NaHCO3 sol. to remove unreacted anhydride. After removing the organic phase, the aqueos phase was extracted three times with ether (26ml, 2ml/mmol). The combined organic phases were dried over Na2SO4 and the solvent was removed with a rotavap, traces of solvent were removed under high vacuum. After cleaning the product by column chromatography (EtOAc/MeOH 3:1 over silica, Rf(product)=0.26, Rf(educt)=0.10), 2.881g (9.9 mmol, 99%) of a white crystaline solid (m.p. 84 C) were obtained. Note: only the phenolic OH was acetylated.
(Chief Bee)
05-07-03 03:08
No 431809
      Potency?  Bookmark   

What is the potency of the acetyl analog?
05-07-03 18:44
No 431945
      more from German document  Bookmark   

Unfortunalety the German document is not very much oriented towards pharmacology, the acetyl-derivative is not mentioned in this regard. Yet, some more interesting information could be gathered:

(page 7) "Additionally the main metabolite O-demethyltramadol, formed in vivo by oxidative dealkylation, which has a much higher affinity to mu-opioidreceptors, contributes to the complex overall activity."

(page 8) "Systematically analyzing derivatives of tramadol, Grnenthal GmbH found out, that a m-hydroxy function on the aromatic ring leads to the greatest potency and that the dimethylamino-group is essential for agonist-activity." (I'd not believe the last a 100%, check out the tricyclic analogues document, piperidine might work?) "Variations of ring size showed that cyclohexane is optimal. The free hydroxy function on the quaternary center increases activity, while Cl and H reduce it, esterification fully abolishes it."

It is also stated (page 7) that the (-)-(1S,2S)-isomer is responsible for 5-HT and NA reuptake inhibition (I guess this isomer causes seizures, serotonergic syndrom and so onmad), while the (+)-(1R,2R)-isomer is responsible for the opioid effectstongue.
05-08-03 16:42
No 432145
      translated extracts from original article
(Rated as: excellent)

To get more details on the whole tramadol issue, a far journey was undertaken and a copy of the original article on tramadol by K. Flick, E. Frankus and E. Friedrichs, that appeared in Arzneimittel-Forsch./Drug.Res. 28(I), Heft 1a (1978), p. 107-113, was obtained.

Therein was found a wealth of information, first the most discouraging factsmad:

-N,N-Dimethyl is the ONLY substitution pattern that is active, this is simply the end of the road (N-Benzyl-N-Methyl is inactive, at least with m-OCH3 on the aromatic ring)
-Demethoxytramadol (unsubstituted aromtic ring) is less than one third as active as tramadol

The good newssmile:

-O-Demethyl is three times as active than tramadol p.o., while being only equally toxic

Other pharmacological facts:

-O-Ethyl is about equipotent to O-Methyl, O-Benzyl is only slightly less active
-Reduction of ring-size to cyclopentane almost abolishes activity, cycloheptane is about one third as active
-The 1,2-elimination products were at least equipotent to the parent compound


Mannich reaction

0.9 mol cycloalkane, 0.45 mol amine.HCl and 0.45 mol para-HCHO were suspended in 100 ml glacial acetic acid and, while stirring, heated to 95C. As soon as a clear solution resulted, heating was reduced and the solvent removed under vacuum. The residue was refluxed with 100 ml acetone for 10 min, filtered off, and washed with acetone. The raw hydrochloride, which was formed in 75-85% yield (based on amine) is pure enough for further use.

0.1 mol Mannich base.HCl were disolved in 30ml DH2O and 30 ml of ether were added. Vigorously stirring NaOH 30% were added until pH reached 12. The ether layer was quickly removed and the aqueous layer extracted several times with ether. The combined ether fractions were dried over Na2SO4 and fractioned in vacuum after removal of ether.

Sdp. of 2-dimethylaminocyclohexanone = 80C(12mm), yield 40%

Grignard reaction

To 0.1 mol Mg-turnings were added 10 ml dry THF. Mg was activated with 1,2-dibromoethane and the mixture warmed. 0.1 mol (substituted) bromobenzene in 50 ml THF were added, ensuring that there was no strong reflux -- add dropwise? --. Then, while cooling under ice, 0.1 mol of freshly distilled Mannich base in 20 ml THF were added dropwise. The mixture was stirred for 2-3 h. The Mg-salts were hydrolyzed with 100ml sat. NH4Cl sol. After drying over Na2SO4 and removal of ether the product was distilled under vacuum. To make the HCl salts 0.1 mol of distilled grignard base were dissolved in 100ml abs. EtOH and treated with the equivalent amount of HCl in ether. Upon cooling, if necessary adding more ether, the salts crystalized. Recrystalization was done by dissolving in EtOH/acetone 9:1 and adding ether until clouding started.

Yield of tramadol = 72%
sdp. of freebase = 147-156C(0.8mm)
mp. of HCl-salt = 159-164C

Yield of demethoxytramadol = 78%
sdp. of freebase = 120-125C(0.1mm)
mp. of HCl-salt = 183-185C

Removal of aromatic O-benzyl group

Dissolve benzyl ether in 95% EtOH, add Pd/C 5% and hydrogenate at ordinary pressure and RT until the calculated amount of H2 is absorbed.

Btw: acetyl analogue wasn't mentioned at all.
Well, all in all it seems doubtful if tramadol or any derivative is worth making. The legal status sure is a big plus, but otherwise...

Still thinking about the tramadol issue and re-reading the document, it was realized that some VERY interesting detail had slipped through the first few readings (yes, stupid!blush).

Preparation of the 1,2-unsaturated compound
0.1 mol of the grignard base (the ROMgBr salt resulting from the grignard reaction?) were refluxed for several hours with 250 ml of a 1:1 mixture of conc. HBr/GAA. Besides the 1,2 elimination of H2O, the ether group was also cleaved . The distillation residue of this reaction was dissolved in H2O and neutralized with NaHCO3-sol.. The neutralized solution was extracted several times with ether. The ether fractions were dried (the following should remethylate the phenolic OH, so one might want to skip it) and treated with CH2N2-sol. at RT. When no more gas was evolved, the reaction product was treated with gaseous HCl. The precipitated hydrochloride was recrystalized from AcOEt/naphta.

The 1,2-saturated compound is stated to have a less favorable therapeutic index, on the other hand o-demethyl has a more favorable one, what might arise from combining the two structural elements?

all values mg/kg mouse p.o.

            LD 50        ED 50           th. index
tramadol    395(369-423) 16.1(11.9-21.7) 24.5
delta-1,2   149(111-199) 11.1(7.0-17.7)  13.4
O-demethyl  387(288-520) 5.2(2.6-10.3)   74.5

unfortunately delta-1,2-O-demethyl isn't mentioned.