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 facts
:
-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 news
:
-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
Experimental:
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 95°C. 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 = 80°C(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 = 147-156°C(0.8mm)
mp. of HCl-salt = 159-164°C
Yield of demethoxytramadol = 78%
sdp. of freebase = 120-125°C(0.1mm)
mp. of HCl-salt = 183-185°C
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!
).
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.
