Process for the preparation of 14-hydroxymorphinan derivatives

N-substituted-14-hydroxy-3-substituted-morphinan derivatives have been found to possess potent narcotic agonist or antagonist activity. In particular, the compound N-Cyclobutylmethyl-3,14-dihydroxymorphinan has been found to possess potent agonist/antagonist activity as a non-narcotic analgesic. A new and efficient total synthesis of these compounds is described herein from the starting material 2-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline.

DESCRIPTION OF THE PRIOR ART 
1. U.S. Pat. No. 3,775,414 describes a process for the preparation of the 
identical compounds prepared by the process claimed herein. 
2. U.S. Pat. No. 3,819,635 describes another process for the preparation of 
the identical compounds prepared by the process claimed herein. 
3. Onda et al, Chem. Pharm. Bull. 21, 2359-2365 (1973) report the 
epoxidation of 
1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline to 
produce the two epimeric epoxides 
##STR1## 
and the diols resulting therefrom having the formulas 
##STR2## 
Nothing in this paper describes, anticipates or teaches the preparation of 
the 9, 10-diols in which the N-methyl is alkanoyl as described herein. 
Furthermore, it is significant that the author's goal was to synthesize 
4-hydroxymorphinans via these diol intermediates and that they failed in 
their attempts, whereas the instant inventors have succeeded. 
4. Schnider and Hellerback, Helv. Chim. Acta., 34, 2218-2222 (1951) 
describe the preparation of morphinans from the same starting materials as 
used in the instant invention. Nothing is taught or suggested that 
14.beta.-hydroxymorphinans could be prepared via this route. 
5. Schnider, Brossi and Vogler, Helv. Chim. Acta., 37, 710-720 (1954) 
further describe the preparation of 14-deoxymorphinans from the same 
starting materials as used in the instant invention. Again, nothing is 
taught or suggested that 14.beta.-hydroxymorphinans could be prepared via 
this route. 
6. Schnider and Hellerback, Helv. Chim. Acta. 33, 1437-1448 (1950) describe 
the preparation of 14-deoxymorphinans from the same starting materials as 
used in the instant invention. Again, nothing is taught or suggested that 
14.beta.-hydroxymorphinans could be prepared via this route. 
7. U.S. Pat. No. 3,919,237 reports the cyclization of compounds having the 
formulas 
##STR3## 
and derivatives thereof into isomorphinans and morphinans using boron 
trifluoride and a proton/hydronium ion donor as the cyclization catalyst. 
None of the compounds so produced have a 14.beta.-hydroxy substituent. 
SUMMARY OF THE INVENTION 
This invention relates to a new process for the preparation of compounds 
having the formula 
##STR4## 
in which R.sup.2 is H or (lower)alkyl; or an acid addition salt thereof 
from the starting material 
2-(p-alkoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline. 
COMPLETE DISCLOSURE 
This invention relates to a new and novel synthesis of 
N-substituted-14-hydroxy-3-substituted-morphinans having the formula 
##STR5## 
in which R.sup.2 is H or (lower)alkyl and R is cyclobutylmethyl or 
cyclopropylmethyl. 
Drug abuse by thrill-seeking youth or by people looking for an escape from 
the realities of everyday life has become more and more commonplace in our 
present society. One class of widely abused drugs are the narcotic 
analgetics such as codeine, morphine, meperidine, etc. It is because of 
the high addictive potential of these agents that much time and money are 
being expended by the pharmaceutical industry and by governments to try 
and discover and develop new nonaddicting analgetics and/or narcotic 
antagonists. 
It was an object of the present invention to develop a method of synthesis 
for the above-described compounds L that would not be dependent upon opium 
alkaloids as starting materials and yet would be commercially feasible. 
The objectives of the present invention have been achieved by the process 
of preparing the compounds of Formula L by their total synthesis from the 
readily available starting material 
2-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoqinoline. 
The compounds of the instant invention have the basic morphinan nucleus 
which is numbered and represented by the following plane formula: 
##STR6## 
Although there are three asymmetric carbons (asterisks) in the morphinan 
molecule, only two diastereoisomeric (racemic) forms are possible, because 
the iminoethano system, attached to position 9 and 13, is geometrically 
contained to a cis-(1,3-diaxial)-fusion. These racemates can, therefore, 
differ only at the junction of rings B and C--in other words, in the 
configuration of carbon 14. The only variable will be the cis and trans 
relationship between the 5 (13) and 8 (14) bonds (Analgetics, Ed. George 
de Stevens, Academic Press, New York, p. 137 (1965)). 
When in the compounds of the present invention, the 5 (13) and 8 (14) are 
cis to each other, we have compounds commonly designated as "morphinans". 
The use of a graphic representation of a "morphinan" is meant to include 
the dl racemic mixture and the resolved d and l isomers thereof. 
The "morphinan" compounds of the present invention can each exist as two 
optical isomers, the levorotatory and dextrorotatory isomers. The optical 
isomers can be graphically illustrated as: 
##STR7## 
The present invention embodies all of the morphinan isomers including the 
optical isomers in their resolved form. 
The optical isomers can be separated and isolated by fractional 
crystallization of the diastereoisomeric salts formed, for instance, with 
d- or l-tartaric acid or D-(+)-.alpha.-bromocamphor sulfonic acid. The 
levorotatory isomers of the compounds of the present invention are the 
most preferred embodiments. 
For the purpose of this disclosure, the term "(lower)alkyl" is defined as 
an alkyl radical containing 1 to 6 carbon atoms. "(Lower)alkenyl" is 
defined as a hydrocarbon radical of 3 to 7 carbons containing one double 
bond. The term "(lower)acyl" is an acyl radical of 2 to 6 carbon atoms, 
e.g., acetyl, propionyl, isobutyryl, etc. The term "pharmaceutically 
acceptable acid addition salt" is defined to include all those inorganic 
and organic acid salts of the compounds of the instant invention, which 
salts are commonly used to produce nontoxic salts of medicinal agents 
containing amine functions. Illustrative examples would be those salts 
formed by mixing the compounds of Formula I with hydrochloric, sulfuric, 
nitric, phosphoric, phosphorous, hydrobromic, maleic, malic, ascorbic, 
citric or tartaric, pamoic, lauric, stearic, palmitic, oleic, myristic, 
lauryl sulfuric, naphthalenesulfonic, linoleic or linolenic acid, and the 
like. 
The compounds LV and LX of the instant invention are prepared by a total 
synthesis comprising 5-6 steps. The synthesis is efficient and appears 
commercially feasible. The process is outlined in Chart I. 
##STR8## 
For the purpose of this disclosure the term "inert organic solvent" means 
an organic solvent that does not participate in the reaction to the extent 
that it emerges unchanged from the reaction. Such solvents are methylene 
chloride, chloroform, dichloroethane, tetrachloromethane, benzene, 
toluene, ether, ethyl acetate, xylene, tetrahydrofuran dioxane, 
dimethylacetamide, and the like when an acid halide is employed. When an 
alkylation reaction is being performed, the inert solvent used may also 
include (lower)alkanols such as methanol, ethanol, n-propanol, isopropanol 
and the like. 
The term "organic tertiary amine" means a tertiary amine commonly employed 
as a proton acceptor in alkylation and acylation reactions. Such amines 
are tri(lower)alkylamines, e.g., trimethylamine, triethylamine and the 
like, pyridine, dimethylaniline, N-methylpiperidine, and the like. 
The compounds N-cyclopropylmethyl-14.beta.-hydroxy-3-methoxymorphinan, 
N-cyclobutylmethyl-14.beta.-hydroxy-3-methoxymorphinan, 
N-cyclopropylmethyl-3,14.beta.-dihydroxymorphinan and 
N-cyclobutylmethyl-3,14.beta.-dihydroxymorphinan are known and described 
in the processes and examples of U.S. Pat. No. 3,819,635, which issued 
June 25, 1974. 
A preferred embodiment of the present invention is the process for the 
preparation of the compound having the formula 
##STR9## 
wherein R.sup.2 is H or (lower)alkyl and R is cyclopropyl or cyclobutyl; 
which process consists of the consecutive steps of 
A. treating the compound having the formula 
##STR10## 
in which R.sup.2 is (lower)alkyl and R is cyclopropyl or cyclobutyl with 
borane followed by an acid catalyst to produce the compound having the 
formula 
##STR11## 
in which R.sup.2 are R are as defined above; and when desired 
B. cleaving the R.sup.2 O-ether function of compound LV by methods known to 
the art. 
A preferred embodiment of the present invention is the process for the 
preparation of compounds having the formulas 
##STR12## 
wherein R.sup.2 is H or (lower)alkyl and R is cyclobutyl or cyclopropyl; 
which process consists of the consecutive steps of 
A. treating the compound having the formula 
##STR13## 
in which R is cyclopropyl or cyclobutyl and R.sup.2 is (lower) alkyl with 
an excess of borane followed by an acid selected from the group consisting 
of phosphoric, orthophosphoric, pyrophosphoric, polyphosphoric, boron 
trifluoride etherate, and mixture thereof to produce the compound having 
the formula 
##STR14## 
in which R.sup.2 is (lower) alkyl; and when desired 
B. cleaving the R.sup.2 O ether functin of compound LV by methods known to 
the art to produce the compound having the formula 
##STR15## 
in which R is cyclopropyl or cyclobutyl; and when desired 
C. converting compound LX to a nontoxic pharmaceutically acceptable acid 
addition salt thereof by methods known in the art. 
A more preferred embodiment of the present invention is the process for the 
preparation of compounds having the formula 
##STR16## 
in which R.sup.2 is H or CH.sub.3 and R is cyclopropyl or cyclobutyl; 
which process consists of the consecutive steps of 
A. treating the compound having the formula 
##STR17## 
in which R is cyclopropyl or cyclobutyl with a slight molar excess of 
borane followed by a large excess of concentrated acid selected from the 
group consisting of phosphoric acid, polyphosphoric acid, orthophosphoric 
acid, boron trifluoride etherate and mixtures thereof pyrophosphoric acid 
with the aid of heat in the range of about 35.degree. C. to 55.degree. C. 
to produce the compound having the formula 
##STR18## 
in which R is as defined above; and when desired 
B. treating compound LV with NaSC.sub.2 H.sub.5, hydrobromic acid, boron 
tribormide or pyridine hydrochloride to produce the compound having the 
formula 
##STR19## 
in which R is cyclopropyl or cyclobutyl; and when desired, 
C. converting compound LX into a nontoxide pharmaceutically acceptable acid 
addition salt thereof by methods known in the art. 
The most preferred embodiment of the present invention is the process for 
the preparation of the compound having the formula 
##STR20## 
in which R.sup.2 is H or CH.sub.3 ; which process comprises the 
consecutive steps of 
A. treating the compound having the formula 
##STR21## 
with borane in about a 1:1 molar ratio of borane: VIb in the presence of a 
large excess of anhydrous phosphoric acid with the aid of heat in the 
range of about +40.degree. C. to about +50.degree. C. until the 
cyclization is essentially complete to produce the compound having the 
formula 
##STR22## 
and when desired 
B. treating compound LVb with NaSC.sub.2 H.sub.5, hydrobromic acid, boron 
tribromide or pyridine hydrochloride to produce the compound having the 
formula 
##STR23## 
and when desired 
C. converting compound LXb into a nontoxic pharmaceutically acceptable acid 
addition salt thereof by methods known in the art. 
A preferred embodiment of the present invention is the compound having the 
formula 
##STR24## 
in which X is carbonyl (.dbd.O) or H.sub.2, R.sup.2 is (lower)alkyl of 1 
to 5 carbon atoms and R is cyclopropyl or cyclobutyl. 
A further preferred embodiment is the compound having the formula 
##STR25## 
in which X is carbonyl (.dbd.O) or H.sub.2 and R is cyclopropyl or 
cyclobutyl. 
A most preferred embodiment is the compound having the formula 
##STR26## 
Another preferred embodiment is the compounds having the formulas 
##STR27## 
in which R.sup.2 is (lower)alkyl of 1 to 5 carbon atoms and R is 
cyclopropyl or cyclobutyl. 
A more preferred embodiment is the compounds having the formulas 
##STR28## 
in which R is cyclopropyl or cyclobutyl. 
A most preferred embodiment is the compounds having the formula 
##STR29## 
The 9,10-diol compounds of the present invention are capable of existing in 
different conformations, e.g., 
##STR30## 
and the four optical isomers thereof. In the synthetic scheme of this 
process, it is thought that the major product obtained by the opening of 
the 9,10 epoxide group of compounds IIIb and IVb possesses 9.alpha., 
10.beta.-diol functions (trans-diols). However, it is thought that some of 
all the various possible conformations exist in the reaction mixture. The 
applicants consider all the various diols to be a part of the instant 
invention and they are so included by reference in the structure 
illustrated as follows: 
##STR31##

EXPERIMENTAL 
All temperatures are expressed in degrees Centigrade unless otherwise 
stated. IR means infrared spectrum, NMR means nuclear magnetic resonance 
spectrum. 
EXAMPLE 1 
(.+-.)-2-Cyclobutylcarbonyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydrois 
oquinoline (IIb). 
To a stirred and cooled (ice-bath) solution of 
dl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline I (9.77 g., 
37.7 mmol) and triethylamine (4.04 g., 40 mmol) in dichloromethane (80 ml) 
was added dropwise a solution of cyclobutylcarbonyl chloride (4.76 g., 40 
mmol) in dichloromethane (20 ml). The reaction mixture was then washed 
with water followed by diluted hydrochloric acid and brine. The organic 
layer was dried and concentrated in vacuo to give 12.8 of racemic IIb as 
an oil. Molecular weight calculated for C.sub.22 H.sub.29 NO.sub.2 : 339. 
Found (mass spectrometry): 339. 
The (+)-IIb was obtained in a similar procedure from (-)-Ib; 
[.alpha.].sub.D = +145.degree. (C, 0.1; CHCl.sub.3). 
A sample for analysis was distilled at 190-200/0.3 mm. 
Anal. calc'd, for C.sub.22 H.sub.29 NO.sub.2 : C, 77.84; H, 8.61; N, 4.13. 
Found: C, 77.58; H, 8.69; H, 4.38. 
EXAMPLE 2 
(.+-.)-2-Cyclobutylcarbonyl-9,10-epoxy-1-(p-methoxybenzyl)-perhydroisoquino 
lines (IIIb and IVb). 
To a cooled (ice-bath) stirred solution of racemic IIb (12.8 g) in 
dichloromethane (100 ml) was added in several portions m-chloroperbenzoic 
acid (6.92 g. of 80% purity) and the mixture was left at room temperature 
for 16 hours. Fifteen ml. of 1M NaHSO.sub.3 in water was added to the 
solution and shaken vigorously. The mixture was then treated with 
saturated sodium bicarbonate solution with agitation until the evolution 
of CO.sub.2 ceased. The methylene chloride phase was collected, washed 
with water and dried over anhydrous sodium sulfate. Filtration and 
evaporation of the methylene chloride gave 13.2 g of a 4:1 mixture of 
racemic IIIb and IVb as an oil. 
Molecular weight calculated for C.sub.22 H.sub.29 NO.sub.3 : 355. Found 
(mass spectrometry): 355. 
A mixture of (+)-IIIb and (+)-IVb, an oil was obtained from (+)-IIb; 
[.alpha.].sub.D = +82.degree. (C, 0.1; CHCl.sub.3). 
A sample for analysis was distilled at 200 - 205/0.5 mm. 
Anal. calc'd. for C.sub.22 H.sub.29 NO.sub.3 : C, 74.33; H, 8.22; N, 3.94. 
Found: C, 74.13; H, 8.40; N, 3.76. 
A sample of pure IIIb was obtained by column chromatography (silica 
gel-ether) as white solid; m.p. 109.degree.-110.degree. (from ether); 
[.alpha.].sub.D = +70.5 (C.05, CHCl.sub.3). 
EXAMPLE 3 
(+)-2-Cyclobutylcarbonyl-9.alpha.,10.beta.-dihydroxy-1.beta.-(p-methoxybenz 
yl)-perhydroisoquinoline (Vb). 
To a cooled (ice-bath) solution of a mixture of racemic IIIb and IVb (1.7 
g.) in THF [Tetrahydrofuran, 25 ml] was added 15% aqueous perchloric acid 
(20 ml) and the mixture allowed to stand at room temperature for 16 hours. 
It was then treated with an ice-cold solution of sodium carbonate (30 ml 
of 10% solution) and extracted with benzene (2 .times. 20 ml). The extract 
was dried and evaporated in vacuo to give an oil, which crystallized from 
ether. There was obtained 920 mg. of racemic Vb as white solid: m.p. 
135.degree. - 137.degree.. Recrystallization from ether gave an analytical 
sample; m.p. 148.degree.-150.degree. C. 
Anal. Calc'd. for C.sub.21 H.sub.31 NO.sub.4 : C, 70.75; H, 8.37; N, 3.75. 
Found: C, 71.12; H, 8.16; N, 3.97. 
The optically active Vb was obtained similarly from pure (+)-IIIb as white 
solid, m.p. 130.degree.-132.degree. from ocetonitrile, [.alpha.].sub.D = 
-4.0 (C, 0.4, CHCl.sub.3). 
EXAMPLE 4 
(+)-2-Cyclobutylmethyl-9.alpha.,10.beta.-dihydroxy-1.beta.-(p-methoxybenzyl 
)-perhydroisoquinoline (VIb) 
To a boiling solution of lithium aluminum hydride (300 mg) in THF (8 ml) 
was added dropwise a solution of 920 mg of racemic Vb in THF (20 ml) and 
the mixture was heated under reflux for 3 hours. After cooling, the excess 
lithium aluminum hydride was decomposed by the careful addition of about 
0.5 ml of water, followed by filtration and evaporation in vacuo to give 
800 mg. of racemic solid VIb; m.p. 120.degree.-122.degree. C. 
Molecular weight calculated for C.sub.22 H.sub.33 NO.sub.3 : 359. Found 
(mass spectrometry): 359. 
The optically active VIb was similarly obtained from (-)-Vb; m.p. 
136.degree. C., 137.degree. C. from 2-propanol; [.alpha.].sub.D = 
-42.degree. (C, 0.53; CHCl.sub.3). 
Anal. Calc'd. for C.sub.21 H.sub.33 NO.sub.3, C, 73.50; H, 9.25; N 3.90. 
Found: C, 73.25; H, 9.49; N, 3.90. 
EXAMPLE 5 
(.+-.)-N-Cyclobutylmethyl-14.beta.-hydroxy-3-methoxymorphinan (LVb) 
To a cooled (ice-bath) solution of VIb (800 mg) in benzene (10 ml) was 
added 1M borane solution in THF (2.2 ml) and the mixture concentrated in 
vacuo. To the solid borane complex was added phosphoric acid (16 g., 
anhydrous) and the mixture was heated at 45.degree. for 16 hours. It was 
then treated with water (60 ml) and concentrated ammonium hydroxide (24 
ml) and extracted with benzene (2 .times. 20 ml). The benzene extract was 
dried and concentrated in vacuo to give 600 mg. of crude racemic LVb as an 
oil. This was dissolved in acetone and treated with dry hydrogen chloride 
solution in ether to give 500 mg of solid hydrochloride salt of LVb; m.p. 
248.degree.-250.degree. C. Reported m.p.: 248.degree.-250.degree. C. The 
optically active LVb was similarly obtained purified as free base by 
recrystallization from methanol; m.p. 82.degree.-84.degree. C. 
[.alpha.].sub.D = +81.0 (C, 0.7; MeOH). 
If (+)-I is utilized as starting material, then the end product LVb would 
be levorotatory. 
EXAMPLE 6 
(.+-.)-2-Cyclopropylcarbonyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroi 
soquinoline (IIc) 
Substitution in the procedure of example 1 for the cyclobutylcarbonyl 
chloride used therein of an equimolar quantity of cyclopropylcarbonyl 
chloride produces the title product IIc. 
EXAMPLE 7 
(.+-.)-2-Cyclopropylcarbonyl-9,10-epoxy-1-(p-methoxybenzyl)-perhydroisoquin 
olines (IIIc and IVc) 
Substitution in the procedure of example 2 for the racemic IIb used therein 
of an equimolar quantity of IIc produces the title compounds IIIc and IVc. 
EXAMPLE 8 
(.+-.)-2-Cyclopropylcarbonyl-9.alpha.,10.beta.-dihydroxy-1.beta.-(p-methoxy 
benzyl)perhydroisoquinoline (Vc) 
Substitution in the procedure of example 3 for the racemic IIIb and IVb 
used therein of an equimolar quantity of IIIc and IVc produces the title 
compound Vc. 
EXAMPLE 9 
(.+-.)-2-Cyclopropylmethyl-9.alpha.,10.beta.-dihydroxy-1.beta.-(p-methoxybe 
nzyl)perhydroisoquinoline (VIc) 
Substitution in the procedure of example 4 for the racemic Vb used therein 
of an equimolar quantity of Vc produces the title compound VIc. 
EXAMPLE 10 
(.+-.)-N-Cyclopropylmethyl-14.beta.-hydroxy-3-methoxymorphinan (LVc) 
Substitution in the procedure of example 5 for the racemic VIb used therein 
of an equimolar quantity of VIc produces the title product LVc. 
EXAMPLE 11 
(.+-.)-2-Cyclobutylmethyl-9.alpha.,10.beta.-dihydroxy-1.beta.-(p-methoxyben 
zyl)perhydroisoquinoline (VIb) 
To a cooled (ice-bath) stirred solution of racemic IIb (12.8 g) in 100 ml 
of formic acid, was added in several portions a slight molar excess of 
performic acid. The mixture was heated at 40.degree.-50.degree. C. for 
several hours and cooled to room temperature. Fifteen ml. of 1M 
NaHSO.sub.3 in water was added and shaken. The solution was diluted with 5 
to 8 volumes of water and extracted with several 100 ml portions of 
methylene chloride. The methylene chloride extracts were combined, washed 
with water and then treated with saturated sodium bicarbonate solution 
until the evolution of CO.sub.2 ceased. The methylene chloride solution 
was collected, dried over anhydrous Na.sub.2 SO.sub.4, filtered and 
evaporated in vacuo to yield a mixture of product which was directly 
reduced as in example 4 to give VIb after crystallization from propanol; 
m.p. 120.degree.-122.degree. C.