dioulasso (Stranger)
06-05-03 10:12
No 438007
      Benzomorphans  Bookmark   

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:




Well the part this wacky paraphenomenal friend is most interested in is :


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.


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) .
06-05-03 10:25
No 438011
      benzomorphans  Bookmark   

US 6,136,980

This is a bit more complicated procedure. It has already been posted by pHarmacist:
Post 391724 (pHarmacist: "Just for fun!", Novel Discourse)

It is a rather valuable method since the final product is the N unsubstituted norbenzomorphan.
Let me note that this procedure features a Dieckmann condensation w/ 95% yeald. This one w/ K-t-BuO is thus much higher yealding than those taking use of NaH or Na-EtO (for the prepn of you know which compounds).
This might be due to the large scale nature of the procedure.

US 4,425,353

If only N substituted analoges are needed than the procedure from US 6,136,980 can be simplified by substituding the folloving reaction in from the 6th reaction step. This way no Me(Ph)3PBr is needed.


(a) 5-hydroxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphan-hydrochloride

A mixture of 59.5 g (0.2 Mol) 2-(4-methoxybenzyl)-1,3,3-trimethyl-4-piperidone hydrochloride and 53.8 g (0.4 Mol) of
aluminium trichloride in 54 g nitrobenzene and 1500 ml of dry benzene are boiled under reflux for 1 hour. After cooling the
reaction mixture is extracted with 750 ml 4 N sodium hydroxide solution, the temperature being maintained below 35.degree.
C. The organic phase is separated and extracted with 750 ml 1 N hydrochloric acid. The acid aequeous phase is rendered
alkali by the addition of 100 ml 25% ammonia and extracted three times with 250 ml chloroform. The collected chloroformic
phases are dried with sodium sulphate and evaporated under reduced pressure. The residue, 46.7 g, is converted into the
hydrochloride by reaction with isopropanol/HCl and crystallized from a mixture of methanol and ethylacetate. 44.6 g of the
title compound are obtained, m.p. 233.degree.-236.degree. C. (with decomposition)[url]http://
06-05-03 10:27
No 438012
      benzomorphans  Bookmark   

US 4,268,673

The starting material for this rather tedious procedure is the product from the 1st reaction step in US 6,136,980.
In contrast to the other methods, in this procedure the cyclohexane ring cyclisation is folloved by the piperidine ring cyclisation. Thus the amine has to be protected by a p-toulesulphonyl groop all along.


Methyl 2,2-dimethyl-4-(p-methoxyphenyl)-3-(p-toluenesulphonamido)butyrate

To a solution of 251 g of methyl 3-amino-2,2-dimethyl-4-(p-methoxyphenyl)butyrate and 121 g of triethylamine in 750 ml of
chloroform, there is added, with mechanical stirring and cooling with ice water, a solution of 210 g of p-toluenesulphonyl
chloride in 500 ml of chloroform. After completion of the addition, which is carried out at such a rate that the temperature of
the reaction mixture does not exceed 25.degree. C., stirring is continued for 1.5 hours. Then the solution is washed with
water, dilute hydrochloric acid and again with water, subsequently. After drying, the organic solvent is stripped off in vacuo.
The residue is treated with ether, resulting in the crystallization of the title compound.

White crystals, melting point 126.degree.-127.degree. C. Yield 85%.


Methyl 2,2-dimethyl-4-(p-methoxyphenyl)-3-(N-methyl-p-toluenesulphonamido)butyrat e

A solution of 405 g of methyl 2,2-dimethyl-4-(p-methoxyphenyl)-3-(p-toluenesulphonamido)butyrate in 1800 ml of dry
dimethylformamide is added to a mechanically stirred suspension of 52.8 g of sodium hydride in 320 ml of the same solvent.
After the reaction mixture has been heated at 80.degree. C. for 1 hour it is cooled when 93 ml of methyl iodide is added.
After an additional period of heating (under reflux) the mixture, after being cooled, is poured into plenty of water. A white
crystallisate separates. After filtration and drying it melts at 132.degree.-134.degree. C. Yield 96%.


2,2-Dimethyl-4-(p-methoxyphenyl)-3-(N-methyl-p-toluenesulphonamido)butyric acid

A solution of 418 g of methyl 2,2-dimethyl-4-(p-methoxyphenyl)-3-(N-methyl-p-toluenesulfonamido)butyrate in 2350 ml of
ethanol is mixed with a solution of 248 g of potassium hydroxide in 370 ml of water. After boiling the mixture for 4 hours it is
cooled and acidified by the addition of 6 N hydrochloric acid.

The title compound separates as white crystals melting at 175.degree.-176.degree. C. Yield 96%.


2,2-Dimethyl-4-(p-methoxyphenyl)-3-(N-methyl-p-toluenesulfonamido)butyryl chloride

A mixture of 283 g of 2,2-dimethyl-4-(p-methoxyphenyl)-3-(N-methyl-p-toluenesulfonamido)butyric acid, 1500 ml of dry
benzene and 430 ml of thionyl chloride is boiled for 3 hours. After removal of volatile material by evaporation in vacuo, the
residue is taken up in toluene and the solvent is evaporated in vacuo. This procedure is repeated twice whereafter
crystallization of the initially oily product is accomplished by treatment with ether, melting point 110.degree.-111.degree. C.


3,4-Dihydro-2,2-dimethyl-7-methoxy-3-(N-methyl-p-toluenesulfonamido)-1(2H)- naphthalenone

To a cooled (with ice water) and stirred solution of 256 g of
2,2-dimethyl-4-(p-methoxyphenyl)-3-(N-methyl-p-toluenesulfonamido)-butyryl chloride in 1500 ml of dry benzene 195 g of
aluminium chloride is added rather rapidly. The mixture is stirred at room temperature for an additional 25 minutes and then
poured on to a mixture of ice and 950 ml of concentrated hydrochloric acid. After stirring the mixture at room temperature for
30 minutes the organic layer is separated whereas the aqueous layer is shaken twice with benzene. The combined organic
solutions are washed twice with water and again twice with an aqueous solution of potassium carbonate whereupon, after
drying, the whole is concentrated in vacuo. The residue is taken up in ether which brings about the crystallization of the title
product. White crystals melting at 119.degree.-120.degree. C. Yield 82%.


2,2-Dimethyl-1-ethinyl-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1,2,3,4 -tetrahydro-1-naphthol

A suspension of 100 g of lithium acetylide-ethylenediamine in 1400 ml of dry tetrahydrofuran is saturated with acetylene. To
this suspension, which is mechanically stirred and flushed continuously with acetylene, there is added a solution of 230 g of
3,4-dihydro-2,2-dimethyl-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1(2H )-naphthalenone in 650 ml of dry
tetrahydrofuran. The addition takes some 20 minutes, the temperature of the mixture being kept at 25.degree.-30.degree. C.
After elapse of an additional 30 minutes the reaction mixture is poured into a solution of 160 g of ammonium chloride in 1500
ml of water. The products of the reaction are extracted from the mixture by means of shaking with chloroform. The
chloroform layer is washed with dilute hydrochloric acid and again twice with water. After being dried the organic solution is
evaporated in vacuo, leaving a residue which is dissolved in ether. From this solution the product separates as white crystals
melting at 148.degree.-150.degree. C. Yield 90%.


2,2-Dimethyl- 7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1,2,3,4-tetrahydro-1-vinyl-1- naphthol

A mixture of 205 g of 2,2-dimethyl-1-ethinyl-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1,2,3,
4-tetrahydro-1-naphthol, 0.8 g of 0.5% palladium on calcium carbonate, 0.8 g 5% palladium on charcoal and 1000 ml of
ethyl acetate is submitted to hydrogenation at atmospheric pressure and room temperature. After the absorption of 1200 ml of
hydrogen the catalysts are removed by filtration. The solution is concentrated by evaporation in vacuo of most of the solvent,
whereafter the product crystallizes as white crystals melting at 152.degree.-154.degree. C. Yield 95%.


2,2-Dimethyl-1(2-hydroxyethylidene)-7-methoxy-3-(N-methyl-p-toluene-sulphon amido)-1,2,3,4-tetrahydronaphthalene

A stirred mixture of 149 g of 2,2-dimethyl-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1,2,3,4-tetrahyd
ro-1-vinyl-1-naphthol, 1200 ml of dioxane and 1380 ml of 0.5 N sulphuric acid is heated until, after 40 minutes, a
temperature of 90.degree. C. is reached. The mixture is kept at that temperature during 2.5 hours whereafter it is cooled and
extracted three times with chloroform. The chloroform solution is washed with plenty of water and then, after being dried,
evaporated in vacuo. The residue is dissolved in acetone. From this solution the product separates as white crystals melting at
142.degree.-144.degree. C. Yield 70%.



2,2-Dimethyl-1-(2-hydroxyethyl)-7-methoxy-3-methylamino-1,2,3,4-tetrahydron aphthalene hydrochloride

A solution of 121.5 g of 2,2-dimethyl-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1-[2-(tetrahydro
-2-pyranyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene in 300 ml of absolute ether and 5 ml of dry dioxane is added dropwise to
1500 ml of liquid ammonia which is stirred mechanically. At the same time small pieces of sodium (total amount 30 g) are
added. After completion of the addition, which takes some 2 hours, the colourless reaction mixture is diluted cautiously with
200 ml of ether whereafter 15 g of ammonium chloride is added and the ammonia is allowed to evaporate. Then water is
added and the aqueous layer separated from the organic one. The aqueous solution is shaken twice with ether and the
combined organic solutions are extracted with an excess of dilute hydrochloric acid. The acidic aqueous solution is heated on
a steambath during 1.5 hours. After cooling, the basic reaction product is set free by the addition of 4 N sodium hydroxide
and gathered by extraction with ether. The ethereal solution is dried and evaporated. The product is converted into the
hydrochloride by means of ethanolic hydrogen chloride. The crystalline precipitate which is formed has a melting point of
240.degree.-244.degree. C. It is not a single isomer but mixed with a lower melting one. Accordingly, from the mother liquor
more soluble and lower melting (205.degree.-210.degree. C.) crystallisates can be obtained. No special attempts are made to
achieve a separation of the isomers. The total yield is 76%.
06-05-03 10:28
No 438013
      continued  Bookmark   


2,2-Dimethyl-1-(2-hydroxyethyl)-7-methoxy-3-methylamino-1,2,3,4-tetrahydron aphthalene hydrochloride

This compound, described already in Example 12, can be prepared in exactly the same way as described in that example if
one starts from 2,2-dimethyl-1-(2-hydroxyethyl)-7-methoxy-3-(N-methyl-p-toluenesulphonamid
o)-1,2,3,4-tetrahydronaphthalene (cf. Example 11). In this case, however, a 2-pyranyloxy group is absent and accordingly
the saponification procedure (heating the aqueous acidic solution on a steambath) is not necessary.

In this case the total yield is 73%.


2,2-Dimethyl-1-(2-hyroxyethyl)-7-methoxy-3-methylamino-1,2,3,4-tetrahydrona phthalene hydrochloride

This compound, described already in Examples 12 and 13, can also be prepared as described in Example 13, however,
starting from 2,2-dimethyl-1-(2-hydroxyethylidene)-7-methoxy-3-(N-methyl-p-toluenesulfon
amido)-1,2,3,4-tetrahydronaphthalene. In this case, both the reduction of the olefinic double bond and the reductive cleavage
of the p-toluenesulphonamido group are effectuated by the sodium metal dissolving in liquid ammonia. The endpoint of the
reduction is reached if the blue colour persists for some 15 minutes. In this case again, a mixture of two stereoisomers is
obtained, the total yield being 87% of crystalline hydrochloride.


2'-Methoxy-2,9,9-trimethyl-6,7-benzomorphan hydrochloride

A mixture of 41 g of 2,2-dimethyl-1-(2-hydroxyethyl)-7-methoxy-3-methylamino-1,2,3,4-tetrahydro naphthalene
hydrochloride, as prepared in Example 12, 200 ml of chloroform and 90 ml of thionylchloride is refluxed during 1.5 hours.
The mixture is concentrated in vacuo and then diluted with toluene. The toluene is evaporated in vacuo and this procedure of
dissolving in toluene and evaporation of the solvent is repeated once. The residue is finally dissolved in chloroform. From this
solution a quantity of 18.5 g of a crystalline hydrochloride separates. It melts at 255.degree.-258.degree. C. and is the
diastereoisomer of the starting compound having the substituents at posititons 1 and 3 in a trans relation (for convenience
called "trans halide"). The mother liquor of the crystallizate is shaken with a solution of sodium carbonate in water, and after
being dried stripped from solvent in vacuo. The residue is dissolved in petroleum ether (boiling range 40.degree.-60.degree.
C.) and this solution is filtered over aluminium oxide. After evaporation of the petroleum ether, the remaining basic material is
dissolved in acetone and converted into the hydrochloride by the addition of ethanolic hydrogen chloride. Again the crystals
which appear first belong to the "trans halide" but, after their removal by filtration, the desired compound can be secured as a
crystalline hydrochloride melting at 235.degree.-238.degree. C. The yield is 33%. The same yields are obtained if the starting
material is prepared according to either example 12 or 13. But if, instead, the starting compound is obtained as described in
example 14 the yield of the benzomorphan is 60%. In this case apparently the ratio between the cis and the trans halide is
more favourable.

Examples 9-11 are not featured for reasons explained in Examples 14-15.

US 4,166,174

Finally, just to show how many different procedures are there for prepareing benzomorphans, her is this one starting from an unique precursor.


(1) 2-(4-Methoxyphenyl)-2-methylpropanal-1 (70 g) and urethane (73 g) were dissolved in benzene (500 ml), and after the
addition of 1 ml of boron trifluoride etherate, the mixture was refluxed for 5 hours with a reflux condenser equipped with a
water separater. After cooling, the reaction mixture was washed several times with water and then two times with a saturated
sodium bicarbonate aqueous solution and dried over potassium carbonate. After removal of benzene, the residue was
recrystallized from chloroformhexane to obtain 108 g of 1,1-bis(ethoxycarbamino)-2-(4-methoxyphenyl)-2-methylpropane as
colorless needles.

(m.p.: 127.degree.-128.degree. C.).

Analysis: Calcd. for C.sub.17 H.sub.26 O.sub.5 N.sub.2 : C, 60.34; H, 7.74; N, 8.28 (%). Found: C, 60.13; H, 7.85; N,
8.34 (%).

(2) The resulting 1,1-bis(ethoxycarbamino)-2-(4-methoxyphenyl)-2-methylpropane (67.2 g) and boron trifluoride etherate
(30 ml) were dissolved in dried benzene (500 ml). Isoprene (15 g) dissolved in 50 ml of dried benzene was added dropwise
to the solution over one hour while mildly refluxing and the mixture was refluxed for 3 hours while stirring. After cooling, the
reaction mixture was washed several times with water and then washed two times with a saturated sodium bicarbonate
aqueous solution and dried over potassium carbonate. After removal of benzene, the residue was further distilled under
reduced pressure to obtain 49 g of 1-ethoxycarbonyl-1,2,3,6-tetrahydro-2-[1-(4-methoxyphenyl)-1-methylethyl]-
4-methylpyridine as a light yellow syrup.

(b.p.: 158.degree.-160.degree. C./0.5 mmHg).

Analysis: Calcd. for C.sub.19 H.sub.27 O.sub.3 N: C, 71.89; H, 8.57; N, 4.41 (%). Found: C, 71.95; H, 8.85; N, 4.60

(3) 1-Ethoxycarbonyl-1,2,3,6-tetrahydro-2-[1-(4-methoxyphenyl)-1-methylethyl]- 4-methylpyridine (3.17 g) dissolved in 10
ml of dried tetrahydrofuran was added dropwise to a suspension of 0.9 g of lithium aluminium hydride in 5 ml of dried
tetrahydrofuran while stirring under cooling with ice and then the mixture was refluxed for 30 minutes. After cooling,
water-containing ether (150 ml) and then 10 ml of a 30% sodium hydroxide aqueous solution was added dropwise to the
mixture while stirring under cooling with ice. An diethyl ether-tetrahydrofuran layer was decanted and combined with the
diethyl ether portions with which the remaining matter had been washed. The combined liquid was dried over potassium
carbonate, stripped of the solvent and distilled under reduced pressure to obtain 2.1 g of
1,2,3,6-tetrahydro-2-[1-(4-methoxyphenyl)-1-methylethyl]-1,4-dimethylpyrid ine as a colorless viscous mass.

(b.p.: 115.degree.-117.degree. C./0.4 mmHg).

Analysis: Calcd. for C.sub.17 H.sub.25 ON: C, 78.71; H, 9.72; N, 5.40 (%). Found: C, 78.81; H, 10.14; N, 5.45 (%).

(4) A mixture of 2.6 g of 1,2,3,6-tetrahydro-2-[1-(4-methoxyphenyl)-1-methylethyl]-1,4-dimethylpyrid ine, 30 ml of 47%
hydrobromic acid and 10 ml of acetic acid was refluxed for 12 hours while stirring. After cooling, the reaction mixture was
made alkaline with concentrated ammonia water under cooling and then extracted with chloroform. The extract was washed
with water, dried over sodium sulfate, stripped of chloroform and recrystallized from chloroform-hexane to obtain 2.0 g of
1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-1,1,3,6-tetramethyl-3-benzazoc ine as pale orange cubes.

(m.p.: 182.degree.-184.degree. C.).

Analysis: Calcd. for C.sub.16 H.sub.23 ON: C, 78.32; H, 9.45; N, 5.71 (%). Found: C, 78.44; H, 9.49; N, 5.61 (%).

(5) The resulting product in the form of free base was dissolved in diethyl ether and to the solution was added a saturated
hydrogen chloride in diethyl ether to render the precipitation in the form of its hydrochloride. The precipitated crystals were
recovered by the filtration and then recrystallized from methanol-ethyl ether to obtain reddish brown prisms.

(m.p.: 270.degree.-272.degree. C.).

Analysis: Calcd. for C.sub.16 H.sub.24 ONCl: C, 68.19; H, 8.58; N, 4.97 (%). Found: C, 67.89; H, 8.73; N, 4.94 (%).

The aforementioned spooky friend wishes all who are interested to contribute further procedures for benzomorphan synthes.
Also he would be wery happy if people with greater pharmacological knowledge would help him put together some sort of pharmacological profile for the warious benzomorphan analoges especilly the newer norbenzomorphan derivants.

Edit: Whoops! Sorry for posting so much. If it is too much I will delete the quotations.