The disclosed invention is to a compound of the formula: ##STR1## in which R.sup.2 is lower alkyl. These compounds are useful in the preparation of N-substituted-14-hydroxy-3-substituted morphinan derivatives which have been found to possess potent narcotic agonist or antagonist activity.

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 
##STR2## 
and the diols resulting therefrom having the formulas 
##STR3## 
Nothing in this paper describes, anticipates or teaches the preparation of 
the 9,10-diols in which the N-methyl is H, or an alkanoyl as described 
herein. Furthermore, it is significant that the authors' goal was to 
synthesize 14-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. Chem. 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 
##STR4## 
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 
A new process for the preparation of compounds having the formula 
##STR5## 
wherein R.sup.2 is H or (lower)alkyl; or an acid addition salt thereof 
from the starting material 
2-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline is disclosed. 
This invention relates to a new and novel synthesis of 
14-hydroxy-3-substituted morphinan derivatives having the formula 
##STR6## 
in which R.sup.2 is H or (lower)alkyl; which compounds are further 
transformable into the compounds having the formula 
##STR7## 
in which R.sup.1 is cyclopropylmethyl and cyclobutylmethyl and R.sup.2 is 
H or (lower)alkyl; or a pharmaceutically acceptable salt thereof. 
Drug abuse by thrill-seeking youth or by people looking for an escape from 
the realities of everyday life has become more and more common place 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 XXI and XX 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 I by their total synthesis from the 
readily available starting material. 
The compounds of the instant invention have the basic morphinan nucleus 
which is numbered and represented by the following plane formula: 
##STR8## 
Although there are three asymetric 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 (13) and 8 (14) bonds 
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: 
##STR9## 
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 XX and XXI of the instant invention are prepared by a total 
synthesis comprising 5 steps. The synthesis is efficient and appears 
commercially feasible. The process is outlined in Chart I 
##STR10## 
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. 
Compound XXI is readily converted to compound XX or compound L by the 
processes and examples found in U.S. Pat. No. 3,819,635, which issued June 
25, 1974. 
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. 
A preferred embodiment of the present invention is the process for the 
preparation of compounds having the formulas 
##STR11## 
wherein R.sup.2 is (lower)alkyl; which process consists of the step of 
treating the compound having the formulas 
##STR12## 
in which R.sup.2 is (lower)alkyl and R is H or a radical of the formula 
##STR13## 
wherein X is H, CF.sub.3, --OR.sup.3 or R.sup.3 in which R.sup.3 is 
(lower)alkyl or a radical having the formula 
##STR14## 
wherein n is an integer of 0 to 5, R.sup.4 and R.sup.5 are alike or 
different and each is H, Cl, Br, F, CF.sub.3, NO.sub.2, OH, (lower)alkyl 
or (lower)alkoxy with a strong acid to produce the compounds having the 
formulas XX and XXI. 
A more preferred embodiment is the process of preparing compound XX, which 
process consists of the consecutive steps of 
A. treating the compounds having the formulas 
##STR15## 
in which R.sup.2 is (lower)alkyl with phosgene in the presence of a 
tertiary amine to produce the compounds having the formulas 
##STR16## 
in which R.sup.2 is as defined above; and 
B. heating compounds VIa and VIb with a strong acid to produce the compound 
XX. 
A most preferred embodiment is the process for the preparation of the 
compound having formula XX in which R.sup.2 is methyl, which process 
comprises the steps of 
A. treating the compound having the formula 
##STR17## 
with a slight molar excess of phosgene in the presence of at least a two 
molar excess of a tertiary amine selected from the group consisting of 
triethylamine, pyridine, trimethylamine, dimethylaniline and 
N-methylpiperidine in tetrahydrofuran at a temperature in the range of 
about -15.degree. C. to +35.degree. C. to produce the compounds having the 
formulas 
B. heating compounds VI' in polyphosphoric acid for at least 72 hours to 
produce compound XX in which R.sup.2 is methyl. 
Another preferred embodiment is the process for the preparation of the 
compounds having the formulas XX and XXI, which process comprises the step 
of treating the compounds having the formulas 
##STR18## 
in which R.sup.2 is (lower)alkyl and R is trifluoroacetyl, 
carbo(lower)alkoxy or formyl, with a strong acid to produce the compounds 
having the formulas XX or XXI. 
A most preferred embodiment is the process for the preparation of compounds 
XX and XXI in which R.sup.2 is methyl, which process comprises the step of 
treating the compounds having the formulas 
##STR19## 
in which R is formyl, carbomethoxy or trifluoroacetyl with polyphosphoric 
acid or phosphoric acid with the aid of heat to produce the compounds XX 
and XXI in which R.sup.2 is methyl. 
A preferred embodiment of the present invention is the compound having the 
formula 
##STR20## 
in which R.sup.2 is (lower)alkyl. 
A most preferred embodiment is the compound having the formula 
##STR21## 
A preferred embodiment of the present invention is the compound having the 
formula 
##STR22## 
wherein R.sup.2 is (lower)alkyl, R is H or a radical of the formula 
##STR23## 
wherein X is H, CF.sub.3, --OR.sup.3 or R.sup.3 in which R.sup.3 is 
(lower)alkyl or a radical having the formula 
##STR24## 
wherein n is an integer of 0 to 5, R.sup.4 and R.sup.5 are alike or 
different and each is H, Cl, Br, F, CF.sub.3, NO.sub.2, OH, (lower)alkyl 
or (lower)alkoxy. 
Another preferred embodiment of the present invention is the compound 
having the formula 
##STR25## 
in which R.sup.2 is (lower)alkyl. 
A most preferred embodiment is the compound having the formula 
##STR26## 
Another preferred embodiment is the compound having the formula 
##STR27## 
in which R.sup.2 is (lower)alkyl, R is a radical of the formula 
##STR28## 
wherein X is H, CF.sub.3, --OR.sup.3 or R.sup.3 in which R.sup.3 is 
(lower)alkyl or a radical of the formula 
##STR29## 
wherein n is an integer of 0 to 5 and R.sup.4 and R.sup.5 are alike or 
different and each is H, Cl, Br, F, CF.sub.3, NO.sub.2, OH, (lower)alkyl 
or (lower)alkoxy. 
A more preferred embodiment is the compound having the formula 
##STR30## 
in which R is a radical having the formula wherein X is H, CF.sub.3 or 
OR.sup.3 in which R.sup.3 is (lower)-alkyl. 
A most preferred embodiment is the compound having the formula 
##STR31## 
Another preferred embodiment is the compound having the formula 
##STR32## 
in which R.sup.2 is (lower)alkyl and R is H or a radical having the 
formula 
##STR33## 
wherein X is H, CF.sub.3, --OR.sup.3 or R.sup.3 in which R.sup.3 is 
(lower)-alkyl or a radical of the formula 
##STR34## 
wherein n is 0 to 5 and R.sup.4 and R.sup.5 are alike or different and 
each is H, Cl, Br, F, CF.sub.3, NO.sub.2, OH, (lower)alkyl or 
(lower)alkoxy. 
A more preferred embodiment is the compound having the formula 
##STR35## 
in which R is a radical of the formula 
##STR36## 
wherein X is H, CF.sub.3 or OR.sup.3 in which R.sup.3 is (lower)alkyl. 
A most preferred embodiment is the compound having the formula 
##STR37## 
A more preferred embodiment is the compound having the formula 
##STR38## 
in which R.sup.2 is (lower)alkyl. 
A most preferred embodiment is the compound having the formula 
##STR39## 
The term strong acid as used herein includes, but is not limited to, 
polyphosphoric acid, phosphoric acid, sulfuric acid, orthophosphoric acid, 
pyrophosphoric acid and mixtures thereof, and the like. 
EXPERIMENTAL 
All temperatures are expressed in degrees Centigrade unless otherwise 
stated. IR means infrared spectrum, NMR means nuclear magnetic resonance 
spectrum.