Hello People!
A crazy friend of mine has telepatically indicated to me that although
he loves all sorts of opioid analgesics, he cant find any substantial info
on benzomorphans on The Hive. Since there havent been too many
discussions on opioid analgesics recently, he decided to start a little
discussion on these interesting benzomorphan type opiate analoges.
Pentazocine and cyclazocine, the 2 most well known benzomorphans
are both mixed opioid agonist-antagonists (thus comes the belife that
benzomorphans do not cause opiate addiction) and especially the latter
one has some sort of halucinogenic activity.
Here are some links to the pharmacology of these compounds:
http://www.cpdd.vcu.edu/97pdf/mclaughlin.pdf
http://www.acnp.org/g4/GN401000168/CH164.html
http://www.google.co.hu/search?q=cache%3Ax1GQY0AJg_wJ%3Awww.rpi.edu/~wentmp/Brochure_homepage-3.pdf+%22current+medicinal+chemistry+research%22+and+%22Agents+to+treat+cocaine+and+heroin+addiction%22&hl=hu&ie=UTF-8&inlang=pl
Well the part this wacky paraphenomenal friend is most interested in is :
THE SYNTHESES
Benzomorphans are triciclic analoges of morphine. Since the aromatic ring is alvais present in one of the precursors, only 1 or 2 cyclisation steps are needed per procedure.
US 5,354,758
This is probably the simplest synthesys of benzomorphans. The starting material
is 3,4-Luthidine, available from larger chem suppliers. Though the procedure involves
a grignard, there is only one cyclisation step (that of the cyclohexane ring), making
the procedure quite simple. It leads to N substituted (N-Me in this case) benzomorphan
analoges. Yealds are high except for the final, cyclisation step.
EXAMPLES
Example 1
Synthesis of 2,5,9-trimethyl-6,7-benzomorphan ((.+-.)-IIId-5
As shown in Scheme 2 (in FIG. 2), a solution of 100 g of 3,4-dimethylpyridine in 800 ml of acetone was added dropwise to
57.27 mL of methyl iodide. The reaction mixture was stirred at room temperature for 18 hrs. The solid was collected by
filtration and washed with cold ether. After drying under vacuum, there was obtained 202 g of 1,3,4-trimethylpyridinium
iodide. The subsequent Grignard reaction was conducted under standard conditions to afford an unstable intermediate that
was utilized immediately.
To a solution of 3.02M of benzylmagnesium chloride (2M solution) in THF was added portionwise 300 g (20 g portions) of
1,3,4-trimethylpyridinium iodide. The reaction mixture was stirred at room temperature for 18 hrs. The THF was evaporated
at reduced pressure, and the resulting residue was poured into iced saturated NH.sub.4 Cl. The mixture was extracted with
ether and the ether solution washed with additional saturated NH.sub.4 Cl. The ether solution was dried over magnesium
sulfate and evaporated to dryness at reduced pressure to afford 338 g of crude 2-benzyl-1,3,4-trimethyl-1,2-dihydropyridine.
The Grignard diene intermediate was then efficiently reduced to the corresponding
2-benzyl-1,3,4-trimethyl-1,2,5,6-tetrahydropyridine analog. To a solution of the crude dihydropyridine product in 2.0 L of
100% ethanol was added portionwise 37.8 g of NaBH.sub.4. The reaction mixture was refluxed for 2 hrs and then cooled to
room temperature. The reaction mixture was quenched by the slow addition of concentrated HCl until a pH of 2 was
maintained. The ethanol was evaporated at reduced pressure, the resultant residue was dissolved in ether and water. The
aqueous phase was separated and brought to pH 11 by the portionwise addition of solid NaOH pellets. The aqueous phase
was extracted with ether. The ether solution was dried over MgSO.sub.4 and evaporated to dryness at reduced pressure to
afford 200 g of crude 2-benzyl-1,3,4-trimethyl-1,2,5,6-tetrahydropyridine (59% yield).
The cyclization of the tetrahydropyridine proceeded smoothly in 48% HBr. A solution of 195 g of
2-benzyl-1,3,4-trimethyl-1,2,5,6-tetrahydropyridine in 2500 mL of 48% HBr was heated to slightly below reflux for 48 hrs.
The reaction mixture was poured into H.sub.2 O and extracted with ether. To the aqueous solution was added slowly NaOH
pellets to pH 11. The aqueous solution was then extracted with ether. The ether solution was dried over MgSO.sub.4 and
evaporated to dryness at reduced pressure to afford 185 g of crude material. The crude product was purified by vacuum
distillation to obtain 69.8 g of 2,5,9-trimethyl-6,7-benzomorphan ((.+-.)-IIId-5) (36% yield).
.sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta.7.0-7.30 (m, 4H aromatic), 2.4 (s, 3H, N--CH.sub.3), 1.38 (s, 3H, C.sub.5
--CH.sub.3), 0.85 (d, J=7 Hz, C.sub.9 --CH.sub.3) .