4A-Aryl-cis-decahydroisoquinolines, such as N-phenethyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline, useful as analgesics.

BACKGROUND 
This invention concerns the discovery that a selected group of 
4a-aryl-cis-decahydroisoquinolines are useful as analgesics, many with 
little or no addictive properties. 
Boekelheide and Schilling, J. Am. Chem. Soc. 72, 712 (1950), disclosed the 
compound N-methyl-4a-phenyl-cis decahydroisoquinoline, (naming it 
"N-methyl-10-phenyldecahydroisoquinoline") and indicated that it had low 
analgesic activity. 
The present invention results from efforts to develop new compounds with 
high analgesic potency and low abuse liability. 
SUMMARY 
According to this invention there is provided novel compounds of formula I 
and their suitable pharmaceutical salts, processes for their manufacture, 
pharmaceutical compositions containing them, and methods of using them to 
produce analgesia in mammals. 
##STR1## 
where R.sub.1 is hydrogen; C.sub.1 -C.sub.6 alkyl; --CH.sub.2 Y where Y is 
C.sub.2 -C.sub.6 alkenyl or C.sub.2 -C.sub.6 alkynyl; 
--(CH.sub.2).sub.m 
##STR2## 
WHERE M IS 1 TO 4, X is Cl, Br, F, CF.sub.3, OCH.sub.3, CH.sub.3, 
isopropyl, --NH.sub.2, or --N(CH.sub.3).sub.2, a=0, 1 or 2; 
--(CH.sub.2).sub.m 
##STR3## 
--(CH.sub.2).sub.m 
##STR4## 
or cycloalkylmethyl of the formula --CH.sub.2 CH&lt;(CH.sub.2).sub.n, where 
n is 2-5; 
R.sub.2 is divalent oxygen (.dbd.O), 
##STR5## 
R.sub.3 is --OH, --OCH.sub.3, 
##STR6## 
or F; R.sub.4 is --H, --OH, --OCH.sub.3, 
##STR7## 
with the proviso that when R.sub.3 is --F, R.sub.4 must be --H. 
DETAILED DESCRIPTION 
Representative R.sub.1 groups are methyl, ethyl, propyl, butyl, hexyl, 
allyl (--CH.sub.2 CH.dbd.CH.sub.2), 2-butenyl, 3-butenyl, 4-heptenyl, 
3,3-dimethylallyl [--CH.sub.2 CH.dbd.C(CH.sub.3).sub.2 ], propargyl 
(--CH.sub.2 .tbd.CH), phenyl propargyl, heptynyl, benzyl, phenethyl, 
4-phenyl-n-butyl[--CH.sub.2 (C.sub.2).sub.3 C.sub.6 H.sub.5 ], 
cyclopropylmethyl [--CH.sub.2 CH&lt;(CH.sub.2).sub.2 ], cyclobutylmethyl 
[--CH.sub.2 CH&lt;(CH.sub.2).sub.3 ], cyclohexylmethyl [--CH.sub.2 
CH&lt;(CH.sub.2).sub.5 ], furylmethyl 
##STR8## 
2-furylethyl 
##STR9## 
2-thienylethyl 
##STR10## 
p-methylphenethyl 
##STR11## 
p-fluorophenethyl, 
##STR12## 
p-methoxyphenethyl 
##STR13## 
p-chlorophenethyl 
##STR14## 
p-aminophenethyl 
##STR15## 
p-dimethylaminophenethyl, and cinnamyl (--CH.sub.2 CH.dbd.CHC.sub.6 
H.sub.5). 
Representative Ar groups are 3-hydroxyphenyl, 3-methoxyphenyl, 
4-methoxyphenyl, 3-acetoxyphenyl, 2,3-dihydroxyphenyl, 
3,4-dimethoxyphenyl, 3,4-diacetoxyphenyl, 3-hydroxy-4-methoxyphenyl, 
2-methoxy-3-acetoxyphenyl, 3-fluorophenyl and 4-fluorophenyl. 
The 4a-aryl-cis-decahydroisoquinolines of formula I include various 
stereochemical isomers stemming from substitution at position 6, and from 
optical asymmetry of the whole structure. When monovalent R.sup.2 
substituents at position 6 are different (e.g., when 
##STR16## 
spatial considerations require the existence of axial and equatorial 
isomers. In the molecule as a whole, spatial considerations require the 
existence of d and l optical isomers. These are normally present as 
racemic mixtures which can be resolved by known methods (Eliel, 
Stereochemistry of Carbon Compounds, McGraw-Hill, 1962, p. 31). 
Pharmaceutically suitable acid addition salts of these compounds include 
those made with physiologically acceptable acids that are known in the 
art; such salts include hydrochloride, sulfate, phosphate, nitrate, 
citrate, maleate and the like. 
PREFERRED COMPOUNDS 
The analgesic compounds preferred because of their high level of activity 
are those where 
R.sup.1 is 
##STR17## 
X.dbd.H or CH.sub.3 with CH.sub.3 being more preferred; R.sup.2 is 
##STR18## 
being more preferred; R.sup.3 is m-OH or m-OCH.sub.3 ; and 
R.sup.4 is H. 
Most preferred because of their activity are 
N-(p-tolylethyl)-4a-m-hydroxyphenyl-6.beta.-cis-decahydroisoquinoline and 
N-(phenethyl)-4a-m-methoxyphenyl-cis-decahydroisoquinoline. 
Synthesis 
The multi-step processes of the invention start with 
2-cyano-3-aryl-3-carbalkoxymethylcyclohexenes which can be obtained 
according to procedures disclosed by Boekelheide and Schilling (loc. cit.) 
with respect to 2-cyano-3-phenyl-3-carbethoxymethylcyclohexene (cf, 
Example 1, Part A). Reaction of a 
2-cyano-3-aryl-3-carbalkoxymethylcyclohexene with hydrogen chloride in a 
lower alkanol such as ethanol forms a 
4a-aryl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (cf, Example 1, 
Part B). These 1,3-diketo-octahydroisoquinolines possess a conformational 
arrangement of the fused rings which requires formation of 
trans-decahydroisoquinoline structures when the 8,8a- double bond is 
converted to a single bond (cf, Example 1, Part D; Example 6, Part A). A 
key step in the invention is the novel isomerization of a 
1,3-diketo-trans-decahydroisoquinoline to the cis isomer in the presence 
of a relatively strong base (cf, Example 1, Part E; Example 4, Part A). 
The selection of specific preparational steps following the initial 
formation of a 1,3-diketo-1,2,3,4,4a,-5,6,7-octahydroisoquinoline depends 
upon the specific 4a-aryl-cis-decahydroisoquinoline derivative that is 
desired. The sequence involves at least three steps, A, B, and C, which 
are illustrated below. Compounds having no unsaturated carbon to carbon 
bonds in R.sup.1 (R.sup.1a in process steps) are prepared by steps A, B-1, 
and C. Compounds having saturated or unsaturated carbon to carbon bonds in 
R.sup.1 are prepared by steps A, B-2, and C. 
##STR19## 
R.sup.1a in path B-1 is the same as R.sup.1 except that it does not include 
unsaturated groups such as alkenyl or alkynyl. These groups appear to 
undergo reduction to alkyl, simultaneously with the reduction of the 8,8a 
bond, in going from compound (3) to compound (4). Thus to obtain compounds 
of formula I where R.sup.1 has alkenyl or alkynyl bonds, path B-2is 
followed. In this path the 8,8a bond of compound (2) is first reduced and 
then the resulting trans product (6) is reacted with R.sup.1 Br, R.sup.1 I 
or mesylates to form the cis product (5) in which R.sup.1 has alkenyl or 
alkynyl groups. Path B-2 includes the possibility of isolating the 
N-unsubstituted cis imide followed by normal N-alkylation with either a 
saturated or unsaturated R.sup.1 group. 
##STR20## 
In the foregoing formulas (1) through (8), the groups R.sup.1 have the 
values given previously. R.sup.5 is 
##STR21## 
R.sup.6 is C.sub.1 to C.sub.4 alkyl. Ar.sup.1 is 
##STR22## 
in which R.sup.7 is hydrogen, F or methoxyl; 
R.sup.8 is H or methoxyl; provided when R.sup.7 is F, R.sup.8 is H. 
In Step A reactant R.sup.6 OH, which is also the reaction medium, is 
generally used in excess, but to insure maximum yield it should be used in 
an amount of at least one mole per mole of cyanoester. Likewise, the HCl 
reactant can be used in excess but to insure maximum yield it should be 
present in an amount of at least one mole per mole of cyanoester. The 
reaction is run in the liquid phase under anhydrous conditions. The 
reaction temperature should be in the range of about 50.degree. to about 
120.degree. C. The reaction pressure is not critical, ordinarily being 
atmospheric for convenience, but should be consistent with achievement of 
the stated reaction temperature. 
In step B-1 for the conversion of (2) to (3), or in step B-2 for converting 
(6) to (5), any reactive alkylating agent can be used, such as hydrocarbyl 
iodide, bromide, mesylate, tosylate, azide, and the like. Alkyl iodides, 
bromides, mesylates, tosylates, and azides are included and the 
hydrocarbyl group corresponds to R.sup.1 in general formula I. Any base 
capable of extracting a proton from the imide is satisfactory. Exemplary 
are alkali metal hydrides (sodium hydride or potassium hydride) in aprotic 
media (dimethylformamide, hexamethyl phosphoramide, dimethylsulfoxide); 
alkoxides in aprotic or alcoholic solvents, as, for example, sodium 
ethoxide in ethanol and potassium t-butoxide in ethanol. Mesylates 
(Ms=mesyl group=methanesulfonyl group) are described in Fieser and Fieser, 
Advanced Organic Chemistry, 1961, pp. 292, 293 and 319. Hydrocarbyl 
bromides, iodides or mesylates are readily available, as indicated in the 
following table (Table I). 
In paths B-1 (4) to (5a) and B-2 (6) to (7) a relatively strong base, with 
or without an inert solvent, is used. Representative strong bases include 
alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, 
and lithium hydroxide; alkali metal alkoxides in which the alkoxide group 
contains 1-4 carbon atoms, such as sodium methoxide, potassium ethoxide, 
lithium propoxide, and the like. An inert solvent can be used if desired; 
included are lower alkanols, e.g., methanol, ethanol, t-butanol and the 
like. The reaction temperature can range from room temperature to reflux 
temperature of the reaction mixture. 
TABLE I 
______________________________________ 
R.sup.1 Source 
______________________________________ 
C.sub.1 to C.sub.6 Alkyl bromides 
Commercially available 
Alkenyl bromides Commercially available 
Propargyl bromides 
Commercially available 
3,3-Dimethylallyl bromides 
Commercially available 
Cyclohexylmethyl bromides 
Commercially available 
Benzyl bromides Commercially available 
Phenethyl bromides 
Commercially available 
4-Phenyl-n-butyl bromides 
Bugrova et al., Zh. obshch. 
Khim, 32, 3573 (1962) 
Cyclopropylmethyl bromides 
Kirmse et al., Ber., 99, 
2855 (1966) 
Cyclobutylmethyl bromides 
Krug et al., J. Am. Chem. 
Soc., 76, 3222 (1954) 
Cyclopentylmethyl bromides 
Smith et al., J. Org. Chem., 
21, 1448 (1956) 
2-Furylmethyl bromides 
Sharifkanov et al., Khim. 
Khim Technol (alma-ata) 
1971, 80 
2-Furylethyl mesylates 
Crossland and Servis, J. 
Org. Chem. 35, 3195 (1970) 
2-Pyridylethyl mesylates 
give Procedure for 
mesylates from alcohols 
2-Thienylethyl mesylates 
Substituted phenethyl mesylates 
" 
______________________________________ 
In the preparation of a 2-cyano-3-phenyl-3-carbalkoxymethylcyclohexene, the 
Boekelheide and Schilling procedure involves preliminary steps starting 
with cyclohexanone, as follows; 
a. Cyclohexanone.fwdarw.2-chlorocyclohexanone (Horning, Organic Syntheses, 
Coll. Vol. III, 1955, p. 188). 
b. 2-Chlorocyclohexanone.fwdarw.2-phenylcyclohexanone [Newman et al. J., 
Am. Chem. Soc. 66, 1551 (1944)]. 
c. 2-Phenylcyclohexanone.fwdarw.2-phenyl-2-carbethoxycyclohexanone [Newman 
et al., J. Am. Chem. Soc. 69, 942 (1947)]. 
d. 
2-Phenyl-2-carbethoxycyclohexanone.fwdarw.2-cyano-3-phenyl-3-carbethoxycyc 
lohexene. 
Final products corresponding to formula I contain certain groups R.sup.2 
which do not appear to be compatible with the chemistry of the process 
steps. The R.sup.5 groups, which are stable to the various process steps, 
are used in the process and at the end of the syntheses are converted to 
R.sup.2 groups. 
The preliminary steps above aid in producing various equivalents defined by 
the various values of Ar and R.sup.2 in general formula I through starting 
with appropriately substituted cyclohexanones in step (a) and with 
appropriately substituted arylmagnesium bromides as intermediates in step 
(b). Thus, 4-methylcyclohexanone and 4-methoxycyclohexane, which are 
commercially available, can be used as basic starting materials to produce 
compounds of formula I in which 
##STR23## 
respectively. 
The compounds of formula I in which R.sub.2 (R.sup.5 in the process 
description) is 
##STR24## 
serve as intermediates to compounds of formula I in which R.sup.2 had 
other values. The following table (Table II) shows the additional R.sup.2 
values and the known methods for obtaining them. 
TABLE II 
______________________________________ 
R.sup.2 Procedure 
______________________________________ 
##STR25## Demethylation of the methoxy compound 
##STR26## Acetylation of the hydroxy compound 
O Oxidation of the hydroxy compound 
##STR27## Reaction of the oxo compound with methyl- lithium 
##STR28## 
##STR29## 
##STR30## Reaction of the hydroxy compound with a strong chloridation 
agent, e.g., thionyl chloride. 
##STR31## Reaction of the oxo compound with sulfur tetraflouride 
[(Martin et al. J. Org. Chem. 27, 3164 (1962))] 
______________________________________ 
Likewise, the use of appropriately substituted phenyl bromides in the 
preparation of the arylmagnesium bromide Grignard reactant for step (b) 
leads to corresponding Ar groups (Ar.sup.1 in the process description) in 
the products of formula I. The following table (Table III) shows pertinent 
Ar.sup.1 groups with substituent R.sup.7 and R.sup.8 groups as defined 
above. 
TABLE III 
______________________________________ 
Ar.sup.1 Source 
______________________________________ 
##STR32## 
Bromides in which R.sup.7 is hydrogen, fluorine or methoxyl and 
R.sup.8 is hydrogen are commer- cially available. The bromide 
in which R.sup.7 is hydrogen and R.sup.8 is methoxyl is also 
commercially available. The bromide in which both R.sup.7 and 
R.sup.8 are methoxyl is obtainable by the method of Mason, J. 
Am. Chem. Soc. 69, 2241 (1947). 
##STR33## 
The bromides in which R.sup.8 and R.sup.7 are both methoxyl, 
and in which R.sup.8 is hydrogen and R.sup.7 is methoxyl or 
fluorine, are commercially available. The bromide in which 
R.sup.8 and R.sup.7 are combined to form dioxymethylene is also 
commercially available. 
______________________________________ 
Compounds in which Ar.sup.1 has methoxyl substituents (as in Table III) 
serve as intermediates to compounds of formula I in which Ar has hydroxyl 
or acetoxyl substituents by using methods for conversion of R.sup.5 groups 
to R.sup.2 groups as shown in Table II. This appears necessary since 
certain substituents such as OH have to be introduced at the end of the 
synthesis. Thus Ar.sup.1 contains a methoxyl, or "masked hydroxyl", which 
is subsequently converted to OH. 
Process steps A, B-1 and C are illustrated by Examples 1-3 and process 
steps A, B-2 and C are illustrated by Examples 4-7, etc. 
In the following illustrative examples all parts are by weight and 
temperatures are in degrees centigrade unless otherwise stated. The nmr 
spectra were at 60 H.sub.z and resonance positions are described as cps or 
in ppm from tetramethylsilane (tms).

EXAMPLE 1 
N-Methyl-4a-phenyl-cis-decahydroisoquinoline 
A. 2-Cyano-3-phenyl-3-carbethoxymethylcyclohexene 
##STR34## 
2-Carbethoxymethyl-2-phenylcyclohexanone (Boekelheide, et al., above) (90 
g., 0.346 mole), 200 ml of hydrogen cyanide and 12 drops of a saturated 
aqueous solution of potassium cyanide was stirred at 0.degree. C. 
overnight. Concentrated sulfuric acid (15 drops) was then added and the 
excess hydrogen cyanide evaporated. The crude cyanohydrin was taken up in 
ether and washed with cold 10% sulfuric acid solution, then dried with 
Na.sub.2 SO.sub.4 and evaporated. The residual oil was dissolved in 500 ml 
of pyridine and 100 ml of phosphorus oxychloride was added. The reaction 
mixture was stirred under nitrogen at reflux for 5 hours then allowed to 
stand at 25.degree. C. overnight. It was then carefully poured into a 
mixture of 2 liters of ice-water and 400 ml of concentrated hydrochloric 
acid and extracted with ether. The ether extract was washed with dilute 
hydrochloric acid, water and brine, then dried (Na.sub.2 SO.sub.4) and 
evaporated. The residual oil was distilled, yielding 45 g of pale yellow 
liquid, bp 135.degree. C. (0.20 mm), identified as 
2-cyano-3-phenyl-3-carbethoxymethylcyclohexene. 
Nmr (cdcl.sub.3): triplet at 64, 71, 78 cps, 3H (--OCH.sub.2 CH.sub.3); 
methylene envelope from 70-150 cps, ca 6H; singlet at 178 cps, 2H 
##STR35## 
quartet at 234, 242, 249, 256, 2H (--OCH.sub.2 CH.sub.3); triplet at 406, 
410, 414, 1H 
##STR36## 
singlet at 436 cps, 5H (aromatic H). IR (neat): 4.50.mu. (C.dbd.N); 5.5 
and 5.85.mu. (lactone impurity); 5.75.mu. (--CO.sub.2 --). 
B. 4a-Phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-Octahydroisoquinoline 
##STR37## 
The product of Part A (50 g), dissolved in a minimum amount of absolute 
ethanol, was added to 2.5 liters of absolute ethanol previously saturated 
with anhydrous hydrogen chloride. The solution was refluxed under nitrogen 
for 48 hours. It was then cooled and concentrated to about 300 ml on a 
rotary evaporator. On cooling, a white crystalline solid precipitated 
which was filtered, washed with cold ethanol, and dried to yield 25 g 
(56%) of 4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline, mp 
241.degree.-3.degree.. 
Anal. Calcd. for C.sub.15 H.sub.15 NO.sub.2 : C, 74.65; H, 6.26; N, 5.81; 
Found: C, 74.67; H, 6.25; N, 5.65. 
C. N-Methyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline 
##STR38## 
The product of Part B (7.20 g, 29.9 mmoles) in 50 ml of dry 
dimethylformamide was added to 1.58 g of a 55.5% suspension of sodium 
hydride in mineral oil (36.5 mmoles NaH), while the reaction mixture was 
maintained at 70.degree. C. under nitrogen. When evolution of hydrogen 
ceased (about 1 hour) the reaction mixture was cooled to 25.degree. C. and 
a solution of methyl iodide (8.52 g, 60 mmoles) in 20 ml of 
dimethylformamide was added dropwise. The mixture was then heated to 
90.degree.-100.degree. C. for 2 hours, after which it was cooled, poured 
into ice-water and extracted with ether. The ether was evaporated and the 
residue recrystallized from ethanol to yield 6.56 g (86%) of 
N-methyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline. 
Anal. Calcd. for C.sub.16 H.sub.17 O.sub.2 N: C, 75.27; H, 6.71; N, 5.49; 
Found: C, 75.22; H, 6.71; N, 5.71. 
Using an analogous procedure but substituting cyclohexylmethyl bromide for 
methyl iodide, 
N-cyclohexylmethyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquino 
line was prepared. Similarly, substituting cyclopropylmethyl bromide and 
cyclobutylmethyl bromide for methyl iodide, 
N-cyclopropylmethyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquin 
oline and 
N-cyclobutylmethyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquino 
line, respectively, were prepared. 
D. N-Methyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline 
##STR39## 
A mixture of the product of Part C (2.0 g, 7.85 mmoles), 175 ml of absolute 
ethanol, and 300 mg of 5% palladium on carbon was shaken under 40 psi of 
hydrogen for 24 hours. The catalyst was removed by filtration and the 
solvent evaporated from the filtrate. Recrystallization of the residue 
from ethanol gave 1.8 g (90%) of 
N-methyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline, mp 
151.degree.-153.degree. C. 
Anal. Calcd. for C.sub.16 H.sub.18 NO.sub.2 : C, 74.66; H, 7.44; N, 5.44; 
Found: C, 74.74; H, 7.66; N, 5.33. 
In an analogous procedure reduction of the 
N-hydrocarbyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinolines 
described in Part C, yielded 
N-cyclohexylmethyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline, 
N-cyclopropylmethyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline and 
N-cyclobutylmethyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline, 
respectively. 
E. N-Methyl-4a-phenyl-1,3-diketo-cis-decahydroisoquinoline 
##STR40## 
N-Methyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline (2.0 g) in 100 ml 
of methanol was treated with 400 mg of sodium methoxide and the mixture 
was refluxed for 30 minutes. It was allowed to stand overnight at 
25.degree., then poured into 1 N hydrochloric acid and extracted with 
ether. The ether extracts were washed successively with water and brine, 
then dried (MgSO.sub.4) and the ether evaporated to yield 1.9 g of an oil. 
NMR (CDCl.sub.3): methylene envelope from 70 to 140 cps (8H); singlet at 
177 cps (3H); multiplet at 145 to 205 cps (3H); singlet at 434 cps (5H). 
A small scale experiment (40 mg compound 1, 1 ml methanol and 10 mg sodium 
methoxide) conducted in an nmr tube, with spectra being taken at periodic 
intervals, clearly showed the gradual disappearance of the N-methyl 
resonance of the starting compound 1 and the appearance of a new N-methyl 
resonance due to the cis compound. The aromatic proton resonance pattern 
also underwent a change in the transition from trans to cis conformation. 
Accordingly, the oil mentioned above was considered to be 
N-methyl-4a-phenyl-1,3-diketo-cis-decahydroisoquinoline. 
F. N-Methyl-4a-phenyl-cis-decahydroisoquinoline 
##STR41## 
N-Methyl-4a-phenyl-1,3-diketo-cis-decahydroisoquinoline (1.9 g) in 75 ml of 
anhydrous tetrahydrofuran was treated with lithium aluminum hydride (2.0 
g) and refluxed overnight. The reaction was quenched by the successive 
addition of 2.0 ml of water, 2.0 ml of 15% sodium hydroxide and finally 
6.0 ml of water. The inorganic salts were filtered and washed well with 
ether. The combined filtrates were evaporated to yield 1.6 g of an oil 
which was evaporatively distilled, bp 125.degree. (0.05 mm), 
n.sub.D.sup.20 1.5514, and identified as 
N-methyl-4a-phenyl-cis-decahydroisoquinoline. 
______________________________________ 
Anal. Calcd. for C.sub.16 H.sub.23 N: 
C, 83.77; H, 10.10; N, 6.11 
Found: C, 83.74; H, 10.11; N, 6.07. 
83.41 10.11 
______________________________________ 
EXAMPLE 2 
N-Methyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
A. 2-Cyano-3-carbethoxymethyl-3-(m-methoxyphenyl)cyclohexene 
##STR42## 
A mixture of 2-carbethoxymethyl-2-(m-methoxyphenyl)cyclohexanone, Langlois 
et al., Tetrahedron 27, 5641 (1971), (25 g, 86.3 mmoles), 100 ml of 
hydrogen cyanide and 4 drops of a saturated aqueous potassium cyanide 
solution was stirred at 0.degree. C. under nitrogen, for 24 hours. After 
this time, 5 drops of concentrated sulfuric acid was added and the excess 
hydrogen cyanide evaporated. The residual oil was taken up in ether and 
washed with 10% aqueous sulfuric acid and then with brine, dried 
(MgSO.sub.4), and the ether evaporated. The crude cyanohydrin thus 
obtained was taken up in 175 ml of pyridine, 35 ml of phosphorus 
oxychloride was added, and the solution was stirred at reflux, under 
nitrogen, for 3 hours. It was then cooled and poured into a mixture of 500 
ml of ice-water and 100 ml of concentrated hydrochloric acid, and the 
resulting mixture was extracted with ether. After washing the ether 
extract with brine, drying and concentrating, 22 g of crude product was 
obtained. This was distilled by short path distillation to yield 16 g, bp 
166.degree. C. (0.5 mm). The infrared spectrum of this material indicated 
it to be 2-cyano-3-carbethoxymethyl-3-(m-methoxyphenyl)cyclohexene with a 
small amount of an impurity, probably a lactone, with bands at 5.50.mu. 
and 5.85.mu.. The material was considered of sufficient purity to carry it 
on to the next step. 
Anal. Calcd. for C.sub.18 H.sub.21 O.sub.3 N: C, 72.20; H, 7.07; N, 4.68; 
Found: C, 72.22, H, 7.13; N, 4.10. 
B. 4a-(m-Methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline 
##STR43## 
The product of Part A (16 g, 53.5 mmoles) dissolved in absolute ethanol was 
added to 1.5 liters of absolute ethanol previously saturated with 
anhydrous hydrogen chloride. The solution was refluxed, under nitrogen, 
for 48 hours and then allowed to stand at 25.degree. C. for 24 hours. It 
was concentrated on a rotary evaporator to about 500 ml, cooled in ice, 
and the resulting crystalline precipitate filtered to yield 8.0 g (55%) of 
4a-(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline, mp 
230.degree.-232.degree.. 
Anal. Calcd. for C.sub.16 H.sub.17 NO.sub.3 : C, 70.83; H, 6.31; N, 5.16; 
Found: C, 70.97; H, 6.33; N, 5.59. 
C. 
N-Methyl-4a-(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquin 
oline 
##STR44## 
The product of Part B (4.07 g, 15 mmoles) in 50 ml of dry dimethylformamide 
was added to a mixture of 790 mg of a 55% suspension of sodium hydride 
(18.1 mmoles of NaH) in mineral oil in 25 ml of dimethylformamide while 
the temperature of the reaction mixture was maintained at 
60.degree.-70.degree. C. under nitrogen. After the addition was complete, 
the reaction mixture was heated at 90.degree. C. for 2 hours, by which 
time evolution of hydrogen had ceased. It was then cooled to 30.degree. C. 
whereupon a solution of 4.25 g (30 mmoles) of methyl iodide in 10 ml of 
dimethylformamide was added dropwise. The mixture was heated at 
90.degree.-100.degree. C. for 2 hours, then cooled, poured into ice-water 
and extracted with ether. The ether extracts were washed with water, dried 
(MgSO.sub.4) and evaporated. The residue was recrystallized from ethanol 
to yield crystalline 
N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquin 
oline (3.8 g, 89%), mp 139.degree.-141.degree.. 
Anal. Calcd. for C.sub.17 H.sub.18 NO.sub.3 : C, 71.54; H, 6.71; N, 4.91; 
Found: C, 71.58; H, 6.93; N, 4.94. 
D. N-Methyl-4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline 
##STR45## 
The product of Part C (3.2 g, 11.21 mmoles), 100 ml of glacial acetic acid, 
50 ml of dioxane and 700 mg of 5% palladium-on-carbon were shaken under 40 
psi of hydrogen for 24 hours. The catalyst was then filtered off and 
washed well with dioxane, and the combined filtrate was concentrated to a 
clear oil, yield 3.2 g (99.4%). The product was pure 
N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline, as 
determined by thin-layer chromatography (20% ether-benzene on silica gel 
plates) and by its nmr spectrum. NMR (CDCl.sub.3): complex multiplet at 
50-150 cps from TMS (9H, --CH.sub.2 -- and 
##STR46## 
quartet at 148, 163, 173, 189 cps (2H, --CH.sub.2 --CO--); singlet at 180 
cps (3H, NCH.sub.3); singlet at 220 cps (3H, OCH.sub.3); multiplet at 
397-420 cps (4H, Ar-H). 
E. N-Methyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline 
##STR47## 
A solution of 
N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline (4.6 
g, 1.6 mmole) and sodium methoxide (1.84 g, 3.4 mmole) in 150 ml of 
methanol was stirred at room temperature under nitrogen for 20 hours. It 
was poured into 150 ml of ice-water and extracted with ether, and the 
combined extracts were washed with 3 N hydrochloric acid and sat. sodium 
bicarbonate, dried (Na.sub.2 SO.sub.4) and evaporated. The crude product 
was a white viscous oil (3.8 g). Thin layer chromatography on silica gel, 
eluting with 10% ether/benzene, showed a major spot (R.sub.f 0.31) and a 
minor component (R.sub.f 0.07). The major component, 
N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline, was 
clearly separated by preparative thick layer chromatography and isolated 
as a colorless oil. 
Nmr: 7.2 (q, J=8, 1H, Ar-H), 7.0-6.65 (m's, 3H, Ar-H), 3.76 (s, 3H, 
--OCH.sub.3), 3.0 (s, 3H, NCH.sub.3), 3.15-2.95 (m, 2H, --CH.sub.2 CO--), 
3.4-3.2 (br, m, 1H, 
##STR48## 
2.2-1.4 (m's, 8H --CH.sub.2 --). 
F. N-Methyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
##STR49## 
A solution of 
N-methyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline (3.8 g, 
1.3 mmoles) in 50 ml of dry tetrahydrofuran was added dropwise to a 
stirred suspension of 3.8 g of lithium aluminum hydride in 25 ml of 
tetrahydrofuran under nitrogen. When addition was complete, the reaction 
mixture was refluxed overnight, then cooled and excess hydride destroyed 
by dropwise addition of 3.8 ml of water, 3.8 ml of 3 N sodium hydroxide 
and 11.4 ml of water. The resultant white salts were filtered off and 
washed with ether. The organic solution was dried (Na.sub.2 SO.sub.4) and 
evaporated, leaving 2.5 g of an opaque oil. This was evaporatively 
distilled at 50.degree. at 0.3 microns Hg. The product was isolated as a 
colorless, viscous oil identified as 
N-methyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline, yield 2.38 g. 
HRMS: Calc. MW for C.sub.17 H.sub.25 NO: 259.1935 Measured: 259.1936 NMR: 
7.27 (t, J=8, 1H, Ar-H), 7.18-6.95 (m's, 2H, Ar-H), 6.73 (d.times.t, 
J=7.5, 2, 1H, Ar-H), 3.78 (s, 3H, --OCH.sub.3), 2.6-2.3 (sh, m, 4H, 
--CH.sub.2 --), 2.23 (s, 3H, --NCH.sub.3), 2.0-1.2 (m, 11H, --CH.sub.2, 
##STR50## 
EXAMPLE 3 
N-(4-Phenyl-n-butyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
A. 
N-(4-Phenyl-n-butyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquino 
line 
##STR51## 
N-(4-Phenyl-n-butyl)-4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquin 
oline (7) was prepared by substituting phenylbutyl bromide for the methyl 
iodide of step C of Example 2 and proceeding as in the subsequent steps of 
Example 2. 1.1 gram of the resultant compound (7) in 50 ml of methanol was 
treated with 400 mg of sodium methoxide and the solution stirred at 
25.degree. for 72 hours. It was then poured into water and extracted with 
ether. The organic extracts were washed successively with water, 3 N 
hydrochloric acid, saturated sodium bicarbonate and brine, and finally 
dried over anhydrous sodium sulfate. Evaporation of the ether gave 0.81 g 
of a clear oil whose nmr and ir spectra, being distinct from the trans 
starting material, identified it as the cis isomer. Thin-layer 
chromatography (silica gel, 10% ether-benzene) showed a single spot. 
B. N-(4-Phenyl-n-butyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
##STR52## 
N-(4-Phenyl-n-butyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinol 
ine (0.8 g) in anhydrous tetrahydrofuran was treated with 0.8 g of lithium 
aluminum hydride and refluxed overnight. The reaction mixture was worked 
up as indicated in Example 2-B to yield 0.7 g of an opaque oil which was 
evaporatively distilled, bp 80.degree.-90.degree., and identified as 
N-(4-phenyl-n-butyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline. 
EXAMPLE 4 
N-Phenethyl-4a-phenyl-cis-decahydroisoquinoline 
A. N-Phenethyl-4a-phenyl-1,3-diketo-cis-decahydroisoquinoline 
##STR53## 
A solution of 4a-phenyl-1,3-diketo-trans-decahydrosoquinoline (2.0 g, 8.22 
mmoles) from Ex. 6A in 35 ml of dry dimethylformamide was added dropwise 
to 375 mg of a 55% suspension of sodium hydride in mineral oil in 15 ml of 
dimethylformamide at 70.degree. C. The reaction mixture was heated at 
70.degree. C. until hydrogen evolution ceased. It was then cooled to 
10.degree. C. and a solution of 1.52 g (8.22 mmoles) of phenethyl bromide 
in 20 ml of dimethylformamide was added. The mixture was stirred for 24 
hours at 25.degree. C., then poured into water and extracted with ether. 
The resulting crude product from the ether extracts was chromatographed on 
100 g of Florisil and eluted with 4% acetone-hexane to yield 1.8 g (63.5%) 
of a clear oil, which was identified by nmr as 
N-phenethyl-4a-phenyl-1,3-diketo-cis-decahydroisoquinoline. 
Nmr (cdcl.sub.3): Complex multiplet at 80 to 140 cps from TMS (methylene H, 
9H); complex multiplet at 140 to 200 cps (4H, --CH.sub.2 CO and --CH.sub.2 
.phi.); multiplet at 220 to 243cps (2H, NCH.sub.2); multiplets at 420 to 
445 cps (10H, ArH). 
B. N-Phenethyl-4a-phenyl-cis-decahydroisoquinoline 
##STR54## 
The product of Part A (1.8 g, 5.19 mmoles) in 50 ml of sodium-dried 
tetrahydrofuran was treated with 2.0 g of lithium aluminum hydride, under 
nitrogen, and the mixture was stirred and refluxed for 24 hours. It was 
allowed to cool, then was treated successively with 2.0 ml of water, 2.0 
ml of 15% aqueous sodium hydroxide and 6.0 ml of water. The precipitated 
inorganic salts were filtered off and washed well with ether. The combined 
filtrates were dried over anhydrous potassium carbonate and concentrated 
to an oil. Evaporative distillation gave 1.4 g (87.5%) of 
N-phenethyl-4a-phenyl-cis-decahydroisoquinoline as a clear oil, bp 
160.degree. C. (0.002 mm). 
Anal. Calcd. for C.sub.23 H.sub.29 N: C, 86.44; H, 9.15; N, 4.39; Found: C, 
86.00; H, 9.11; N, 3.86. 
In place of phenethyl bromide in the preceding (Part A), p-bromophenethyl 
bromide, m-chlorophenethyl bromide, o-fluorophenethyl bromide, 
p-trifluoromethylphenethyl bromide, 2,4-dimethoxyphenethyl bromide, 
3,4-methylenedioxyphenethyl bromide, and 3,4-dichlorophenethyl bromide or 
corresponding mesylates can be employed to give the corresponding 
N-substituted-phenethyl-4a-phenyl-cis-decahydroisoquinoline. 
EXAMPLE 5 
N-Cyclopropylmethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
A. 
N-Cyclopropylmethyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinol 
ine 
##STR55## 
A solution of 2.0 g (7.3 mmoles) of 
4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline (Ex. 7A) in 50 
ml of anhydrous dimethylformamide was added to 35.1 mg of a 55% suspension 
of sodium hydride in mineral oil in 25 ml of dimethylformamide heated at 
70.degree.. Heating was continued for 45 minutes after the addition was 
complete after which time 1.09 g (8.1 mmoles) of cyclopropylmethyl bromide 
in 10 ml of dimethylformamide was added. The reaction mixture was heated 
at 80.degree. for 2 hours and allowed to stand at 25.degree. overnight. It 
was poured into water and extracted with ether. Evaporation of the ether 
gave an oil which showed one spot by thin-layer chromatography (silica gel 
plates, benzene solvent, R.sub.f 0.4, starting material had R.sub.f 0.07) 
and was identified by nmr as 
N-cyclopropylmethyl-4a(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoli 
ne. 
Nmr (cdcl.sub.3): multiplet at 5 to 22 cps (4H); methylene envelope at 
40-130 cps (9H); multiplets from 150-220 cps (5H); singlet at 227 cps 
(3H); multiplets at 400-445 cps (4H). 
B. N-Cyclopropylmethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
##STR56## 
The product of Part A (2.17 g, 6.6 mmoles) in 75 ml of sodium-dried 
tetrahydrofuran was treated with 2.2 g (58 mmoles) of lithium aluminum 
hydride, under nitrogen, and the mixture was stirred and refluxed for 24 
hours. It was then treated successively with 2.2 ml of water, 2.2 ml of 
15% sodium hydroxide and 6.6 ml of water. The inorganic salts were 
filtered and washed well with ether. The combined filtrates were 
evaporated and the residual 
N-cyclopropylmethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline (oil) 
evaporatively distilled, bp 125.degree. (0.005 mm). 
Nmr (cdcl.sub.3): methylene envelope at 5 to 160 cps from TMS (22H); 
singlet at 228 cps (3H); multiplets from 398 to 445 cps (4H). 
EXAMPLE 6 
N-Allyl-4a-phenyl-trans-decahydroisoquinoline 
A. 4a-Phenyl-1,3-diketo-trans-decahydroisoquinoline 
##STR57## 
4a-Phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (3.0 g, 12.45 
mmoles) from Ex. 1B was dissolved in 100 ml of glacial acetic acid and 50 
ml of dioxane. The catalyst, 5% palladium on carbon (700 mg), was added 
and the mixture was hydrogenated under 40 psi of hydrogen for 24 hours in 
a Parr shaker. The catalyst was then filtered off and the filtrate 
evaporated. The white crystalline 
4a-phenyl-1,3-diketo-trans-decahydroisoquinoline was recrystallized from 
ethanol, mp 180.degree.-182.5.degree.. 
Anal. Calcd. for C.sub.15 H.sub.17 NO.sub.2 : C, 74.05; H, 7.04; N, 5.75; 
Found: C, 74.30; H, 7.22; N, 5.55. 
B. N-Allyl-4a-phenyl-1,3-diketo-cis-decahydroisoquinoline 
##STR58## 
A solution of the product of Part A above (2.0 g; 8.23 mmoles) in 35 ml of 
dry dimethylformamide was added dropwise to 440 mg of a 55% suspension of 
sodium hydride in mineral oil in 15 ml of dimethylformamide at 70.degree. 
C. The reaction mixture was heated at 70.degree. C. until hydrogen 
evolution ceased (ca 1 hour). It was then cooled to 25.degree. C. and a 
solution of 1.01 g (8.35 mmoles) of allyl bromide in 15 ml of 
dimethylformamide was added. The mixture was heated at 
90.degree.-100.degree. C. for 2 hours, then cooled and poured into 
ice-water. Extraction with ether gave, after drying (K.sub.2 CO.sub.3) and 
evaporation of the ether, 2.5 g of crude product (oil). This material was 
chromatographed on 100 g of Florisil and eluted with 3-5% acetone-hexane 
to give 1.7 g (oil) of 
N-allyl-4a-phenyl-1,3-diketo-cis-decahydroisoquinoline, shown to be pure 
by thin-layer chromatography (20% ether-benzene with silica gel plates). 
In an analogous procedure, when propargyl bromide was substituted for allyl 
bromide, N-propargyl-4a-phenyl-1,3-diketo-cis-decahydroisoquinoline was 
obtained. 
C. N-Allyl-4a-phenyl-cis-decahydroisoquinoline 
##STR59## 
The product of Part B (1.7 g, 6.0 mmoles) in 50 ml of sodium-dried 
tetrahydrofuran was treated with 1.7 g (44.7 mmoles) of lithium hydride, 
under nitrogen, and the mixture was stirred and refluxed for 24 hours. It 
was allowed to cool and then was treated successively with 1.7 ml of 
water, 1.7 ml of 15% aqueous sodium hydroxide and 5.1 ml of water. The 
precipitated inorganic salts were filtered off and washed well with ether. 
The combined filtrates were dried over anhydrous potassium carbonate and 
concentrated to an oil. Evaporative distillation gave 1.0 g (65.5%) of 
N-allyl-4a-phenyl-cis-decahydroisoquinoline as a clear oil, bp 117.degree. 
C. (0.07 mm). 
Anal. Calcd. for C.sub.18 H.sub.25 N: C, 84.67; H, 9.86; N, 5.48; Found: C, 
84.30; H, 9.79; N, 5.11. 
Similarly, lithium aluminum hydride reduction of 
N-propargyl-4a-phenyl-1,3-diketo-cis-decahydroisoquinoline yielded 
N-propargyl-4a-phenyl-cis-decahydroisoquinoline. 
EXAMPLE 7 
N-allyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
A. 4a-(M-Methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline 
##STR60## 
A solution of 
4a-(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline 
(6.0 g) in 250 ml of glacial acetic acid was treated with 1 g of 5% 
palladium on carbon and the mixture hydrogenated under 40 psi of hydrogen 
for 24 hours in a Parr shaker. The catalyst was then filtered off and the 
filtrate evaporated. The residual 
4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline was 
recrystallized from ethanol, m.p. 189-190. 
______________________________________ 
Anal. Calcd. for C.sub.16 H.sub.19 NO.sub.3 : 
C, 70.31; H, 7.01; N, 5.12 
Found: C, 70.60; H, 7.01; N, 5.05 
70.46 7.02 5.13 
______________________________________ 
B. N-Allyl-4a-(m-methoxyphenyl)-cis-1,3-diketodecahydroisoquinoline 
##STR61## 
The product of Part A (4.5 g, 16.5 mmoles) in 70 ml of dry 
dimethylformamide was added dropwise to 880 mg of a 55% suspension of 
sodium hydride in mineral oil in 30 ml of dimethylformamide at 
70.degree.-80.degree.. The mixture was heated at 70.degree. and stirred 
for 1 hour. It was then cooled to 35.degree., whereupon allyl bromide 
(2.02 g, 16.7 mmoles) in 30 ml of dimethylformamide was added dropwise. 
After heating the reaction mixture at 90.degree.-110.degree. for 2 hours 
and allowing it to stand at 25.degree. overnight it was poured into 
ice-cold 1% hydrochloric acid and extracted with ether. The organic 
extracts were washed with water, brine, then dried (magnesium sulfate). 
Evaporation of the ether yielded 5.6 g of crude product which was 
chromatographed on 200 g of Florisil and eluted with 5% acetone-hexane to 
yield 4.0 g of 
N-allyl-4a-(m-methoxyphenyl)-cis-1,3-diketodecahydroisoquinoline (oil), 
which was evaporatively distilled, bp 160.degree. (0.05 mm). 
______________________________________ 
Anal. Calcd. for C.sub.19 H.sub.23 O.sub.3 N: 
C, 72.81; H, 7.40; N, 4.47 
Found: C, 72.62; H, 7.50; N, 4.48 
72.46 7.37 
______________________________________ 
Treatment of a sample of the allyl derivative prepared as above with sodium 
methoxide in methanol (both at room temperature and reflux) or with 
potassium t-butoxide in THF left it totally unchanged, confirming that the 
cis derivative has been formed initially. Also confirmed by spectral 
analysis. NMR: 7.2 (q, J=8, 1H, Ar-H), 7.05-6.75 (m, 3H, Ar-H), 5.9-5.3 
(m, 1H, --CH.dbd.), 5.1-4.5 (m, 2H, .dbd.CH.sub.2), 4.4-4.15 (m, 2H, 
n-CH.sub.2 -), 3.75 (s, 3H, --OCH.sub.3), 3.4-2.6 (m's, 3H, --CH.sub.2 CO 
and 
##STR62## 
2.1-1.4 (m, 8H, --CH.sub.2 --). 
C. N-allyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
##STR63## 
The product of Part B (4.0 g, 12.8 mmoles) in 75 ml of sodium-dried 
tetrahydrofuran was treated with 4.0 g (105 mmoles) of lithium aluminum 
hydride, under nitrogen, and the mixture was stirred and refluxed for 24 
hours. It was allowed to cool and then treated successively with 4.0 ml of 
water, 4.0 ml of 15% aqueous sodium hydroxide, and finally with 12.0 ml of 
water. The precipitated inorganic salts were filtered off and washed well 
with ether. The combined filtrates were dried over anhydrous potassium 
carbonate to yield, after evaporation of the ether, 3.27 g of 
N-allyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline (oil), which was 
evaporatively distilled, bp 150.degree. (0.05 mm). 
Nmr (cdcl.sub.3): complex multiplet at 70 to 190 cps from TMS (methylene H, 
17H); singlet at 234 cps (3H, OCH.sub.3); multiplets at 300-350 cps (vinyl 
H) and multiplets at 405 to 460 cps (aromatic H). 
Ir: 6.10.mu. (c.dbd.c); 6.25, 6.35.mu. (ar). 
EXAMPLE 8 
N-Allyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline 
##STR64## 
A. A solution of 880 mg (3.09 mmoles) of 
N-allyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline in 30 ml of 
methylene chloride was added in portions to an ice-cold solution of 0.6 ml 
of boron tribromide in 15 ml of methylene chloride. The reaction mixture 
was stirred at 0.degree. for 5 hours, then overnight at 25.degree.. 
Methanol (5 ml) was added and the solution was evaporated under vacuum. 
The residue was treated with 15 ml of 5 N sodium hydroxide and stirred for 
15 minutes. Ether (50 ml) was added and, after stirring for 2 hours, the 
layers were separated and the aqueous portion, after being further 
extracted with ether, was then saturated with carbon dioxide. The 
resulting mixture was extracted with ether and the ether extracts were 
washed with brine, then dried (K.sub.2 CO.sub.3) and evaporated to yield 
370 mg of a white foam. NMR spectra confirmed the loss of the O-methyl, 
identifying the product as 
N-allyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline. NMR: methylene 
envelope at 60-200 cps from TMS (17H); multiplets at 300-330 cps, singlet 
at 341 cps, multiplet at 395-450 cps. 
B. N-Allyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline (900 mg) and 
pyridine hydrochloride (5 g) were mixed and heated at 200.degree., under 
nitrogen, for 1 hour. The reaction was cooled and diluted with water, then 
extracted with ether. The aqueous portion was basified with potassium 
carbonate and extracted with ether. This ether extract was concentrated 
and the residue evaporatively distilled, bp, 250.degree. (2 microns); 
yield, 380 mg. 
Mass. Spec.: Calcd for C.sub.18 H.sub.25 NO: 271.1935: Found: 271.1884. 
EXAMPLE 9 
N-(3,3-Dimethylallyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
A. 
N-(3,3-Dimethylallyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquin 
oline 
##STR65## 
A solution of 4 g (14.7 mmoles) of 
4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 50 ml of 
anhydrous dimethylformamide was added dropwise to 700 mg of a 55% 
suspension of sodium hydride in mineral oil in 50 ml of dimethylformamide 
at 70.degree.. The reaction mixture was heated for 1 hour after the 
addition was complete and then cooled to 25.degree.. 3,3-Dimethylallyl 
bromide (2.37 g, 15.8 mmoles) in 10 ml of dimethylformamide was added 
dropwise and the solution stirred overnight at 25.degree.. After heating 
at 80.degree. for 1 hour it was poured into water and extracted with ether 
to yield 4.74 g of 
N-(3,3-dimethylallyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquin 
oline (oil), which was evaporatively distilled, bp 225.degree. (0.005 mm). 
______________________________________ 
Anal. Calcd. for C.sub.21 H.sub.27 O.sub.3 N: 
C, 73.86; H, 
7.97; N, 4.10 
Found: C, 74.48; H, 
7.25; N, 4.07 
74.40 7.88 
______________________________________ 
B. N-(3,3-Dimethylallyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
##STR66## 
A solution of 4.5 g (13.2 mmoles) of the product of Part A in 100 ml of 
sodium-dried tetrahydrofuran was treated with 4.5 g of lithium aluminum 
hydride and the mixture refluxed overnight. The reaction was quenched by 
adding, successively, 4.5 ml of water, 4.5 ml of 15% sodium hydroxide and 
finally 14.5 ml of water. The inorganic salts were filtered and the 
filtrate evaporated on a rotary evaporator to yield 
N-(3,3-dimethylallyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
(oil), which was evaporatively distilled, bp 125.degree. (0.005 mm). 
______________________________________ 
Anal. Calcd. for C.sub.21 H.sub.31 NO: 
C, 80.45; H, 
9.97; N, 
4.47 
Found: C, 80.51; H, 
10.31; N, 
4.56 
80.26 10.41 4.72 
______________________________________ 
EXAMPLE 10 
N-Cyclopropylmethyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline 
##STR67## 
N-Cyclopropylmethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline (1.52 g, 
5.1 mmoles) and pyridine hydrochloride (3.0 g, 26 mmoles) were mixed and 
heated with stirring under nitrogen at 190.degree. for 1 hour. When 
cooled, the mixture solidified and was dissolved in water and extracted 
with ether. The aqueous solution was basified to pH 8 with potassium 
carbonate and again extracted with ether. The combined extracts were dried 
(Na.sub.2 SO.sub.4) and evaporated, yielding 0.6 g of starting material. 
The aqueous layer was made strongly basic by adding additional potassium 
carbonate and again extracted with ether, and the extracts dried (Na.sub.2 
SO.sub.4) and evaporated. The residue was evaporatively distilled, 
yielding starting material (bp, 70.degree. at 0.002 mm) and 
N-cyclopropylmethyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline (bp, 
80.degree. at 0.002 mm), which formed a glass when cooled. 
Nmr (cdcl.sub.3): 7.3-6.85 (m, 3H), 6.8-6.5 (m, 1H), 2.9-2.1 (m, 7H), 
2.1-1.1 (m, 10H), 1.1-0.0 (m, 5H). 
EXAMPLE 11 
N-Cyclobutylmethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
A. 
N-Cyclobutylmethyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoli 
ne 
##STR68## 
A solution of 5.0 g (18.5 mmoles) of 
4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 125 ml of 
anhydrous dimethylformamide was added to a suspension of 1.35 g (28 
mmoles) of 50% sodium hydride in mineral oil (washed with pentane) in 60 
ml of anhydrous dimethylformamide heated at 50.degree. under nitrogen. The 
mixture was heated at 90.degree. for 2 hours, then cooled to 40.degree.. A 
solution of 6.05 g (37 mmoles) of freshly prepared cyclobutylmethyl 
mesylate (prepared according to the procedure of Crossland and Servis, J. 
Org. Chem. 35, 3195 (1970)) in 10 ml of anhydrous dimethylformamide was 
added and the reaction mixture heated at 90.degree. overnight. It was then 
cooled and poured into ice-water and extracted with ether. Evaporation of 
the ether gave an oil, identified as 
N-cyclobutylmethyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoli 
ne. 
Nmr (cdcl.sub.3): 7.4-6.6 (m, 4H); 4.3-3.7 (m, 2H); 3.8 (s, 3H); 3.1-2.8 
(m, 2H); 2.4-1.2 (m, 16H). 
B. N-Cyclobutylmethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
##STR69## 
The product of Part A (3.9 g, 11.4 mmoles) in 300 ml of sodium-dried 
tetrahydrofuran was added with stirring to a suspension of 4.0 g of 
lithium aluminum hydride in 100 ml of tetrahydrofuran under nitrogen, and 
the mixture was stirred at reflux for 20 hours. It was then cooled and 
treated successively with 4.0 ml of water, 4.0 ml of 3 N sodium hydroxide 
and 12.0 ml of water. The inorganic salts were filtered and washed with 
ether. The combined filtrates were evaporated, and the residual 
N-cyclobutylmethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline (oil), 
was purified by Preparative Thick Layer Chromatography (silica gel, ethyl 
acetate/methanol 99:1) and evaporative distillation, bp 70.degree. (0.001 
mm). 
Nmr (cdcl.sub.3): 7.4-6.6 (m, 4H); 3.8 (s, 3H); 2.7-2.2 (m, 8H); 2.2-1.2 
(m, 16H). 
Mass Spec.: Calcd for C.sub.21 H.sub.31 NO: 313.2404; Found: 313.2362. 
EXAMPLE 12 
N-Phenethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
A. N-Phenethyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline 
##STR70## 
A solution of 10.0 g (37 mmoles) of 
4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 250 ml of 
anhydrous dimethylformamide was added with stirring to a suspension of 2.8 
g (55.5 mmoles) of 50% sodium hydride in mineral oil (washed with pentane) 
in 125 ml of anhydrous dimethylformamide heated at 50.degree. under 
nitrogen. The mixture was heated at 90.degree. for 2 hours, then cooled to 
40.degree., at which time a solution of 14.0 g (74 mmoles) of phenethyl 
bromide in 20 ml of anhydrous dimethylformamide was added and the reaction 
mixture heated at 90.degree. overnight. The cooled solution was poured 
into ice-water and extracted with ether. Evaporation of the ether gave an 
oil which was purified by column chromatography (Silicar CC-7, eluting 
with acetone-benzene). The major fraction was identified as 
N-phenethyl-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline. 
Nmr (cdcl.sub.3): 7.2-7.0 (m 6H); 6.95-6.6 (m, 3H); 4.0-3.7 (m, 2H); 3.75 
(s, 3H), 3.2-2.8 (m, 3H); 2.8-2.35 (m, 2H), 2.0-1.3 (m, 8H). 
B. N-Phenethyl-(m-methoxyphenyl)-cis-decahydroisoquinoline 
##STR71## 
The product of Part A (5.0 g, 13.3 mmoles) in 200 ml of sodium-dried 
tetrahydrofuran was added to a stirred suspension of 5.0 g of lithium 
aluminum hydride in 80 ml of tetrahydrofuran under nitrogen, and the 
mixture was stirred at reflux for 20 hours. It was cooled and treated 
successively with 5.0 ml of water, 5.0 ml of 3N sodium hydroxide and 15.0 
ml of water. The inorganic salts were filtered and washed with ether. The 
combined filtrates were evaporated and the residual 
N-phenethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline (oil) was 
evaporatively distilled, bp 70.degree. (0.002 mm). 
Nmr (cdcl.sub.3): 7.21 (s, 5H); 7.3-6.88 (m, 3H); 6.8-6.55 (m, 1H); 3.79 
(s, 3H); 2.9-2.3 (m, 8H); 2.1-1.1 (m, 11H). 
______________________________________ 
Anal. Calcd. for C.sub.24 H.sub.31 NO: 
C, 82.47; H, 
8.94; N, 4.01 
Found: C, 82.21; H, 
9.06; N, 3.96 
82.25 9.04 3.98. 
______________________________________ 
EXAMPLE 13 
N-Phenethyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline 
##STR72## 
N-Phenethyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline (1.49 g, 4.28 
mmoles) was mixed with pyridine hydrochloride (3.0 g, 25.8 mmoles) and 
stirred under nitrogen for 1 hour while heating at 190.degree.. After 
cooling the solid mixture was dissolved in chloroform, and the chloroform 
solution was washed with water, dried (Na.sub.2 SO.sub.4) and evaporated. 
The residue was evaporatively distilled, bp 95.degree. (0.0002 mm), 
yielding a glass (mp 70.degree.-80.degree.) which was identified as 
N-phenethyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline, hydrochloride 
salt. 
Nmr (cdcl.sub.3): 7.17 (s, 5H),; 7.3-6.6 (m, 4H); 3.1-2.5 (m, 9H); 2.3-1.2 
(m, 10H). 
EXAMPLE 14 
N-(4-Phenyl-n-butyl)-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline 
##STR73## 
A solution of 0.88 g (2.34 mmoles) of 
N-(4-phenyl-n-butyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline in 100 
ml of methylene chloride was added with stirring to a solution of 0.45 ml 
(4.68 mmoles) of boron tribromide in 50 ml of methylene chloride at 
-78.degree. under nitrogen. After 1 hour, 10 ml of methanol was added and 
the methylene chloride was removed under vacuum. The residue was treated 
with 40 ml of 6N sodium hydroxide and then stirred as a two-phase system 
with 100 ml of ether. The residue from the ether extract was evaporatively 
distilled, and the glass obtained was identified as 
N-(4-phenyl-n-butyl)-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline, mp 
50.degree.-52.degree.. 
Nmr (cdcl.sub.3): 7.15 (s, 5H); 7.45-6.5 (m, 4H); 3.8-1.2 (m, 24H). 
Mass Spec.: Calcd for C.sub.25 H.sub.33 NO: 363.2560; Found: 363.2531. 
EXAMPLE 15 
N-(2-Furylethyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
A. 
N-(2-Furylethyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline 
##STR74## 
A solution of 5.0 g (18.5 mmoles) of 
4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 100 ml of 
anhydrous dimethylformamide was added to a stirred suspension of 1.4 g (28 
mmoles) of 50% sodium hydride in mineral oil (washed with pentane) in 75 
ml of anhydrous dimethylformamide heated at 50.degree. under nitrogen. The 
mixture was heated at 90.degree. for 2 hours, then cooled to 35.degree.. A 
solution of 7.1 g (37 mmoles) of freshly prepared 2-furylethyl mesylate 
(prepared according ot the procedure of Crossland and Servis, J. Org. 
Chem., 35, 3195 (1970)) in 10 ml of anhydrous dimethylformamide was added 
and the reaction mixture heated at 90.degree. overnight. It was the cooled 
and poured into ice-water, and extracted with ether. Evaporation of the 
ether gave an oil which was purified by column chromatography (Silicar 
CC-7, eluting with acetone-benzene). The major fraction was identified as 
N-(2-furylethyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline 
Nmr (cdcl.sub.3): 7.4-7.1 (m, 2H); 7.0-6.6 (m, 3H); 6.2 (m, 1H); 5.9 (m, 
1H); 4.2-3.3 (m, 1H); 3.77 (s, 3H); 3.2-2.2 (m, 7H); 2.0-1.1 (m, 7H). 
B. N-(2-Furylethyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
##STR75## 
The product of Part A (6.3 g, 17.2 mmoles) in 250 ml of sodium-dried 
tetrahydrofuran was added to a stirred suspension of 6.3 g of lithium 
aluminum hydride in 100 ml of tetrahydrofuran under nitrogen, and the 
mixture was stirred at reflux for 20 hours. It was then cooled and treated 
successively with 6.3 ml of water, 6.3 ml of 3N sodium hydroxide and 18.9 
ml of water. The inorganic salts were filtered and washed with ether. The 
combined filtrates were evaporated and the residual 
N-(2-furylethyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline was 
evaporatively distilled, bp 70.degree. (0.0005 mm). 
Nmr (cdcl.sub.3): 7.2 (m, 1H); 7.1-6.9 (m, 3H); 6.8-6.55 (m, 1H); 6.2 (m, 
1H); 5.95 (m, 1H); 3.77 (s, 3H); 2.8-2.3 (m, 9H); 2.0-1.3 (m, 10H). 
EXAMPLE 16 
N-(3,3-Dimethylallyl)-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline 
##STR76## 
N-(3,3-Dimethylallyl)-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline (1.2 
g) and pyridine hydrochloride (5 g) were heated under nitrogen, for 1 hour 
at 200.degree.. The reaction was worked up as in Example 8-B to give 400 
mg, bp 240.degree. (0.2 micron), of 
N-(3,3-dimethylallyl)-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline. 
Mass Spec.: Calcd for C.sub.20 H.sub.29 NO: 299.2248; Found: 299.2273. 
EXAMPLE 17 
N-methyl-4a-(p-fluorophenyl)-cis-decahydroisoquinoline 
A. 2-(p-fluorophenyl)-cyclohexanone 
##STR77## 
The Grignard reagent prepared by adding 210 g of p-fluorobromobenzene in 
800 ml. of anhydrous ether to 29.1 g of magnesium turnings in 50 ml. of 
ether was added, with cooling to keep the temperature of the reaction less 
than 15.degree. C., to a solution of 158.4 g of 2-chlorocyclohexanone in 
800 ml. of anhydrous benzene. The reaction was stirred at 25.degree. for 
18 hrs. then the ether was distilled off and the resulting benzene 
solution refluxed for 24 hrs. It was then poured into a mixture of 1 liter 
water and 200 ml. hydrochloric acid and extracted with ether. After 
evaporation of the ether the residue was distilled to yield 117 g (51%), 
b.p. 115 (0.2 mm). The material solidified on standing and was 
recrystallized from hexane, m.p. 56.degree.-59.degree. C. 
Anal. Calcd. for C.sub.12 H.sub.13 FO: C, 74.98; H, 6.82; Found: C, 74.24; 
H, 6.83. 
B. 2-(p-fluorophenyl)-2-carbethoxymethylcyclohexanone 
##STR78## 
The product of Part A (117 g) in 120 ml. of anhydrous tetrahydrofuran was 
added to sodium amide (from 14.7 g sodium) in 2000 ml. of liquid ammonia. 
The reaction was stirred for 90 minutes then 68 ml .alpha.-bromoethyl 
acetate was added over 45 min. The reaction was stirred for 3 hrs. then 
the ammonia was allowed to slowly evaporate. Methanol (100 ml.) and water 
(1000 ml.) were added to the residue. Extraction with ether yielded the 
product, which when distilled, gave 115.4 g (68%), b.p. 134 (0.25 mm). 
Anal. Calcd. for C.sub.16 H.sub.19 FO.sub.3 : C, 69.05; H, 6.88; Found: C, 
68.97; H, 6.95. 
C. 2-Cyano-3-(p-fluorophenyl)-3-carbethoxymethylcyclohexanone 
##STR79## 
The product from Part B (50 g) was reacted in the manner described in 
Example 1, Part A, with 200 g of hydrogen cyanide and 12 drops of 
saturated aqueous potassium cyanide. Reaction of the product of this 
reaction with phosphorous oxychloride in pyridine (as described in Example 
1, Part A) gave 2-cyano-3-(p-fluorophenyl)-3-carbethoxycyclohexene. Yield 
33 g, b.p. 160.degree. (0.35 mm). 
D. 4a-(p-fluorophenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-Octahydroisoquinoline 
##STR80## 
The product from Part C (75 g) was added to 500 ml. of anhydrous ethanol 
saturated with anhydrous hydrogen chloride and the mixture refluxed for 48 
hrs. The solution was then concentrated, cooled, and the white precipitate 
collected. 
Yield 32 g, m.p. 201-203. Anal. Calcd. for C.sub.15 H.sub.14 FNO.sub.2 : C, 
69.49; H, 5.44; N, 5.40; Found: C, 69.30; H, 5.27; N, 5.02. 
E. 
N-methyl-4a-(p-fluorophenyl)-1,3-diketo-1,2,3,4,4a,5,6,7,-Octahydroisoquin 
oline 
##STR81## 
The product of part D (20 g) in 150 ml of anhydrous dimethylformamide was 
added to 3.35 g of a 55% suspension of sodium hydride in mineral oil in 
100 ml. of dimethylformamide in the manner described in Example 1, Part C. 
Alkylation with 11.5 g of methyl iodide and workup (described in Example 
1, Part C) gave 
N-methyl-4a-(p-fluorophenyl)-1,3,-diketo-1,2,3,4,4a,5,6,7,-octahydroisoqui 
noline, 12 g, m.p. 124-128. 
F. N-methyl-4a-(p-fluorophenyl)-1,3-diketo-trans-decahydroisoquinoline 
##STR82## 
The product from Part E (12 g) in 150 ml. of ethanol and 50 ml. of glacial 
acetic acid was hydrogenated over 3 g of 5% palladium on carbon over 40 
psi of hydrogen in the manner described in Example 1, Part D to give, 
after column chromatography on 350 g of silicon CC-7 and elution with 
benzene, 9 g, m.p. 141-143. 
Anal. Calcd. for C.sub.16 H.sub.18 F No.sub.2 : C, 69.80; H, 6.59; N, 5.09; 
Found: C, 69.81; H, 6.54; N, 5.08. 
G. N-methyl-4a-(p-fluorophenyl)-1,3,-diketo-cis-decahydroisoquinoline 
##STR83## 
The product from Part F (2 g), 100 ml. of methanol and 400 mg of sodium 
methoxide was stirred at 25.degree. for 4.8 hrs. after initially heating 
to reflux. The mixture was then poured into dilute hydrochloric acid and 
extracted with ether to yield a clear oil, 2 g. 
NMR (CDCl.sub.3) methylenes appear as broad singlet centered at 100 cps 
(8H); singlet at 181 cps (N--CH.sub.3, 3H); multiplet plus quartet at 
177,183,186,190 cps (CH.sub.2 CO and CHCO, 3H); multiplet at 410 to 450 
cps (ArH,4H). 
H. N-methyl-4a-(p-fluorophenyl)-cis-decahydroisoquinoline 
##STR84## 
The product from Part G (2 g), 75 ml. of anhydrous tetrahydrofuran, and 2 g 
of lithium aluminum hydride were refluxed for 24 hrs. The reaction was 
worked up as described in Example 1, Part F to give 1.35 g, b.p. 
110.degree. (0.15 mm). 
Anal. Calcd. for C.sub.16 H.sub.22 FN: C, 77.69; H, 8.97; N, 5.66; Found: 
C, 77.55; H, 9.10; N, 5.63. 
By the above general procedure of Example 17 
N-phenethyl-4a-(m-fluorophenyl)-cis-decahydroisoquinoline can be obtained. 
EXAMPLE 18 
Salts of N-phenethyl-4a-m-methoxyphenyl-cis-decahydroisoquinoline 
When N-phenethyl-4a-m-methoxyphenyl-cis-decahydroisoquinoline is added to 
0.1 to 3 N hydrochloric acid a white solid is obtained which can be 
recrystallized from ethanol. This hydrochloride has m.p. 
220.degree.-222.degree. C. (decomp). 
When N-phenethyl-4a-m-methoxyphenyl-cis-decahydroisoquinoline is mixed with 
a slight molar excess of maleic acid in hot acetonitrile it forms the 
crystalline maleate salt on cooling, m.p. 167.degree.-168.degree. C. 
EXAMPLE 19 
Dextro-N-methyl-4a-phenyl-cis-decahydroisoquinoline 
A. laevo- and dextro-2-carboxymethyl-2-phenylcyclohexanone a-phenethylamine 
salt 
##STR85## 
1. 2-Carboxymethyl-2-phenylcyclohexanone (Boekelheide et al., above) (40 g, 
0.154 mole) obtained by alkaline hydrolysis of 
2-carbethoxymethyl-2-phenylcyclohexanone was dissolved in 140 ml of hot 
ethanol and treated with 27 g of (+)-.alpha.-phenethylamine. The mixture 
was allowed to slowly crystallize to yield 21.8 g of the l-salt, m.p. 
130.degree.-132.degree., [.alpha.].sub.D -94. A second recrystallization 
from ethanol yielded material with m.p. 137.degree.-139.degree., 
[.alpha.].sub.D.sup.25.degree. -142.degree.. Further recrystallizations 
did not change the optical rotation. 
2. The mother liquors from above were taken up in 6 N hydrochloric acid and 
the free acid extracted with ether. This material was dissolved in 
ethanol, treated with (-).alpha.-phenethylamine, and allowed to slowly 
crystallize. The white crystalline d-salt had m.p. 
136.degree.-137.5.degree., [.alpha.].sub.D.sup.25.degree. +141.degree.. 
B. laevo- and dextro-2-carboxymethyl-2-phenylcyclohexanone 
##STR86## 
1. A solution of the product of Part A-1 (14.0 g) in 250 ml of cold 6 N 
hydrochloric acid was extracted with ether and treated as above to yield 
9.6 g of the l-ketoacid m.p. 94.degree.-95.degree. 
[.alpha.].sub.D.sup.25.degree. -194 (c 1.04, CHCl.sub.3). 
2. A solution of the product of Part A-2 (15.9 g) in 250 ml of cold 6 N 
hydrochloric acid was extracted with ether. The ether extracts were dried 
with anhydrous magnesium sulfate, filtered and the ether evaporated to 
yield 10.0 g, of the d-ketoacid m.p. 94.degree.-95.degree., 
[.alpha.].sub.D.sup.25.degree. +193.degree. (c 1.03, CHCl.sub.3). 
C. laevo- and dextro-2-Carbethoxymethyl-2-phenylcyclohexanone 
##STR87## 
1. A solution of the product of Part B-1 (28 g) in 700 ml of ethanol 
containing 3 ml of concentrated sulfuric acid was refluxed in a soxhlet 
extractor apparatus with the thimble filled with 3 A molecular sieves. 
After refluxing for 24 hrs, excess potassium carbonate was added. The 
mixture was filtered and the solution evaporated. The residue was 
distilled to yield l-ketoester; a clear oil, b.p. 125.degree. (0.1 mm), 
[.alpha.].sub.D.sup.25.degree. -207.degree. (c 1.5, CHCl.sub.3). 
2. A solution of the product of Part B-2 (40 g) in 1000 ml of ethanol 
containing 8 ml of concentrated sulfuric acid was treated as above to 
yield, after distillation, the d-ketoester as a clear oil, b.p. 
125.degree. (0.1 mm), [.alpha.].sub.D.sup.25.degree. +234.degree. (c 1.00, 
CHCl.sub.3). 
D. laevo- and dextro-2-cyano-3-phenyl-3-carbethoxymethylcyclohexene 
##STR88## 
1. The product of Part C-1 (36 g, 0.138 mole), 200 ml of hydrogen cyanide 
and 12 drops of a saturated aqueous solution of potassium cyanide was 
stirred at 0.degree. overnight. Concentrated sulfuric acid was added and 
the excess hydrogen cyanide evaporated. The residue was taken up in ether, 
washed successively with 0.1 N sulfuric acid, and brine, dried (Na.sub.2 
SO.sub.4), and evaporated. The residual oil was dissolved in 250 ml of 
pyridine and 50 ml of phosphorous oxychloride was added. The reaction 
mixture was stirred, under nitrogen, at reflux for 5 hours, then allowed 
to stand at 25.degree. overnight. It was then poured into a mixture of 1 
liter of ice-water and 200 ml of concentrated hydrochloric acid, and the 
resulting mixture was extracted with ether. The ether extract was washed 
with dilute hydrochloric acid, water and brine, then dried (Na.sub.2 
SO.sub.4) and evaporated. The residual oil was distilled yielding 28 g of 
the l-cyanoester, b.p. 130.degree. (0.1 mm). 
2. The product of Part C-2 (35 g, 0.134 mole) was treated as above to 
obtain 25 g of the d-cyanoester, b.p. 130.degree. (0.1 mm). 
E. dextro- and 
laevo-4a-Phenyl-1,3-diketo-1,2,3,4a,5,6,7-octahydroisoquinoline 
##STR89## 
1. The product of Part D-1 (28 g), dissolved in 50 ml of absolute ethanol, 
was added to 600 ml of absolute ethanol previously saturated with 
anhydrous hydrogen chloride. The solution was refluxed under nitrogen for 
48 hours. It was then cooled and concentrated. A white crystalline solid 
precipitated which was filtered, then recrystallized from ethanol to yield 
12.0 g of the unsaturated d-imide, [.alpha.].sub.D.sup.25.degree. +219 (c 
1.00, CHCl.sub.3). 
2. The product of Part D-2 (17 g) in 40 ml of absolute ethanol was added to 
400 ml of absolute ethanol previously saturated with anhydrous hydrogen 
chloride, then treated as above to yield 8.9 g of the unsaturated l-imide, 
m.p. 169-170, [.alpha.].sub.D.sup.25.degree. -208 (c 1.20, CHCl.sub.3). 
In this example the sign of rotation changes in the ring-closing reactions. 
F. dextro- and 
laevo-N-methyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline 
##STR90## 
1. The product of Part E-1 (7.2 g, 29.9 mmoles) in 50 ml of dry 
dimethylformamide was added to 1.58 g of a 55.5% suspension of sodium 
hydride in mineral oil (36.5 mmoles NaH) in 50 ml of dimethylformamide, 
while the reaction mixture was maintained at 70.degree. under nitrogen. 
The mixture was stirred and heated at 70.degree. for 1 hour after the 
addition was completed, then cooled, and methyl iodide (8.5 g) in 20 ml of 
dimethylformamide was added dropwise. The mixture was heated at 90.degree. 
for 30 min. then allowed to stand overnight at 25.degree.. It was poured 
into water and extracted with ether. The ether extracts were dried 
(Na.sub.2 SO.sub.4) and evaporated and the residue recrystallized from 
ethanol to yield 6.17 g of the unsaturated d-N-methylimide, m.p. 
156.degree.-158.degree., [.alpha.].sub.D.sup.25.degree. +245.degree. (c 
1.25, CHCl.sub.3). 
2. The product of Part E-2 (8.94 g, 37.1 mmole) in 60 ml of 
dimethylformamide was added to 1.96 g of a 55.5% suspension of sodium 
hydride in mineral oil in 50 ml of dimethylformamide as above to yield, 
after recrystallization in ethanol, 6.0 g of the unsaturated 
1-N-methylimide, m.p. 149.degree.-153.degree., 
[.alpha.].sub.D.sup.25.degree. -258.degree.. 
G. dextro- and laevo-N-methyl-4a-phenyl-1,3-diketo-trans 
decahydroisoquinoline 
##STR91## 
1. A mixture of the product of Part F-1 (6.1 g, 23.9 mmole), 100 ml of 
glacial acetic acid and 2 g of 5% palladium on carbon was shaken under 40 
psi of hydrogen for 24 hours. The catalyst was removed by filtration and 
the solvent evaporated. Recrystallization of the residue from ethanol gave 
3.7 g of the trans saturated d-N-methylimide, m.p. 
189.degree.-191.degree., [.alpha.].sub.D.sup.25.degree. +81.degree.. 
2. The product of Part F-2 (6.0 g, 23.5 mmoles) was treated as above to 
obtain 4.0 g of the trans saturated 1-N-methylimide, m.p. 
159.degree.-160.degree., [.alpha.].sub.D.sup.25.degree. -72.degree. (c, 
1.02, CHCl.sub.3). 
H. Dextro-N-methyl-4a-phenyl-1,3-diketo-cis-decahydroisoquinoline 
##STR92## 
A mixture of 2 g of the product of G-1 above, 100 ml of methanol and 500 mg 
of sodium methoxide were refluxed for one hour then allowed to stand at 
25.degree. for 18 hrs. The reaction was worked up as described in Example 
1, Part E to give an oil which was used without further purification. 
I. d-N-methyl-4a-phenyl-cis-decahydroisoquinoline 
##STR93## 
The crude product from Part H (2 g), 100 ml of anhydrous tetrahydrofuran 
and 2 g of lithium aluminum hydride were refluxed under nitrogen for 24 
hrs. The reaction was quenched by the successive addition of 2 ml. of 
water, 2 ml. of 15% sodium hydroxide and 6 ml of water. The inorganic 
salts were filtered and the filtrate concentrated. The residue was 
evaporatively distilled to give a clear oil, b.p. 100.degree. (0.07 mm), 
[.alpha.].sub.365.sup.25.degree. +368.degree.. The picrate derivative was 
readily formed, m.p. 144.degree.-147.degree.. 
EXAMPLE 20 
N-(p-Tolylethyl)-4a-m-hydroxyphenyl-6.beta.-methyl-cis-decahydroisoquinolin 
e 
A. 2-Methoxyphenyl-4-methylcyclohexanone 
##STR94## 
4-Methylcyclohexanone (224 g, 2 moles) was added dropwise rapidly to a 
cooled, stirred suspension of 170 g (4 moles) of sodium amide in 2 l of 
tetrahydrofuran under nitrogen. After the addition was complete, the ice 
bath was removed and the mixture was heated at reflux until the evolution 
of ammonia ceased (.about.3 hours). While still at reflux, 142.5 g (1 
mole) of o-chloroanisole was added rapidly dropwise and the mixture was 
heated for an additional hour, until evolution of ammonia ceased. 
The red-brown reaction mixture was cooled in an ice bath and excess sodium 
amide was quenched by the dropwise addition of a saturated aqueous 
solution of ammonium chloride. The mixture was poured into 3 l ice water, 
extracted with ether and the combined extracts washed with 3 N HCl and 
saturated sodium chloride, then dried (Na.sub.2 SO.sub.4) and evaporated. 
The crude product was distilled under vacuum, bp 120.degree.-130.degree. 
at 0.15 mm Hg. 
Nmr (cdcl.sub.3): .delta. 7.2 (quartet, J=8, 1H), 6.9-6.6 multiplet (3H), 
3.78 (singlet, 3H), 2.7-1.5 (broad envelope, 8H), 1.1 (overlapping 
doublets, J=5.5, 3H). 
B. 2-m-Methoxyphenyl-2-carbethoxymethyl-4-methylcyclohexanone 
##STR95## 
A solution of 142 g (0.65 mole) of the product from part A in 200 ml ether 
and 130 ml benzene was added rapidly dropwise to a suspension of 39 g 
(0.71 mole) of sodium amide in 330 ml ether stirred under nitrogen at room 
temperature. After the addition was complete, the mixture was heated at 
reflux for 4 hours, then cooled to -30.degree. to -40.degree. C. in a Dry 
Ice/acetone bath. Ethylbromoacetate (115 g, 0.60 mole) was added dropwise 
using an addition funnel without a sidearm, keeping the temperature below 
-30.degree. C. during the addition. After stirring for one hour at 
-30.degree. C. the reaction was allowed to warm to room temperature and 
was stirred overnight, poured into ice water, extracted with ether and 
dried the extracts (MgSO.sub.4). The solvent was evaporated and the crude 
product distilled under vacuum, bp 130.degree.-145.degree. at 10 microns. 
Nmr (cdcl.sub.3): .delta. 7.3-6.6 (multiplet, 4H), 4.2-3.8 (multiplet, 2H), 
3.75 (singlet, 3H), 3.1-4.1 (broad envelope, 9H), 1.3-0.8 (multiplet, 6H). 
Ir: 3.4, 5.8, 6.2, 6.3, 6.7, 6.9, 7.0, 7.8, 7.9, 8.1, 8.4, 8.7, 9.6, 11.7, 
12.8, 14.3.mu.. 
c. 2-cyano-3-m-methoxyphenyl-3-carbethoxymethyl-5-methylcyclohexene 
##STR96## 
The product from part B (135 g) 300 ml of liquid hydrogen cyanide and 20 
drops saturated aqueous potassium cyanide were stirred under nitrogen and 
packed in an ice bath for 20 hours. Concentrated sulfuric acid (20 drops) 
was added and the excess HCN evaporated. The crude cyanohydrin was taken 
up in ether, washed with 10% sulfuric acid, dried (MgSO.sub.4) and 
evaporated. The residual oil was dissolved in 725 ml pyridine and 180 ml 
of phosphorous oxychloride was added. The solution was heated at reflux 
under nitrogen for 3 hours, cooled, poured into 4 l ice water containing 
500 ml conc. hydrochloric acid and extracted with ether. The ether 
extracts were dried (Na.sub.2 SO.sub.4) and evaporated. The product, a 
viscous oil, can be distilled by using a wiped-film Molecular Still 
(180.degree. at 3 microns) or a short path still (bp 
145.degree.-155.degree. at 3 microns). 
Nmr (cdcl.sub.3): .delta. 7.4-6.7 (multiplet, 5H), 4.1 (quartet, J=7, 2H), 
3.8 (singlet, 3H), 3.0 (multiplet, 2H), 3.2-2.5 (envelope, 7H), 1.25 
(triplet, J=7, 3H), 0.9 (multiplet, 3H). 
Ir: 3.4, 4.5, 5.55, 6.2, 6.3, 6.7, 6.9, 7.0, 7.3, 7.7, 8.0, 8.2, 8.5, 9.6, 
11.4, 12.8, 14.3.mu.. 
d. 
4a-m-Methoxyphenyl-6.beta.-methyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroiso 
quinoline 
##STR97## 
A solution of 112 g of the product from part C in 500 ml anhydrous ethanol 
was added to 2.5 l of anhydrous ethanol which had been saturated with 
anhydrous hydrogen chloride. The solution was heated at reflux under 
nitrogen for 3 days, then cooled to 0.degree. in an ice bath. The fine 
white precipitate which had formed was filtered, washed with cold ethanol 
and dried. mp 214.degree.-216.degree.. 
Nmr (dmso-d.sub.6): .delta. 10.4 (singlet, 1H), 7.4-6.6 (multiplet, 5H), 
3.65 (singlet, 3H), 3.7-3.5 (multiplet, 1H), 3.0 (broad singlet, 2H), 
2.3-1.2 (envelope, 5H), 0.8 (doublet, J=4.5, 3H) 
Anal. Calcd for C.sub.17 H.sub.19 NO.sub.3 : C, 71.56; H, 6.71; N, 4.91; 
Found: C, 71.90; H, 6.92; N, 4.94. 
E. 4a-m-Methoxyphenyl-6.beta.-methyl-1,3-diketo-trans-decahydroisoquinoline 
##STR98## 
A mixture of the product from part D (10.5 g), 400 ml glacial acetic acid, 
200 ml dioane and 2.0 g 5% palladium on activated carbon was shaken under 
1000 psi of hydrogen at 40.degree. C. for 6 hours. The catalyst was 
removed by filtration and the solvent evaporated from the filtrate. 
Recrystallization of the residue from ethanol yielded the product, mp 
201.degree.-202.degree. C. 
Nmr (dmso-d.sub.6): .delta. 10.6 (singlet, 1H), 7.4-6.7 (multiplet, 4H), 
3.72 (singlet, 3H), 3.0-26 (multiplet, 1H), 2.8 (singlet, 2H), 2.3-1.3 
(envelope, 7H), 0.3 (doublet, J=7, 3H). 
Anal. Calcd. for C.sub.17 H.sub.21 NO.sub.3 : C, 71.06; H, 7.37; N, 4.87; 
Found: C, 71.34; H, 7.50; N, 4.97. 
F. 
N-(p-Tolylethyl)-4a-m-methoxyphenyl-6.beta.-methyl-1,3-diketo-cis-decahydi 
oisoquinoline 
##STR99## 
To a suspension of 5.6 g (117 mmole) of sodium hydride in 200 ml anhydrous 
dimethylformamide, stirred at 40.degree. under N.sub.2, was added 20 g (70 
mmole) of the product from part E in 400 ml dry dimethylformamide. The 
mixture was heated to 90.degree. until the evolution of hydrogen ceased 
(.about.2 hr), then cooled to 30.degree.. A solution of 37.3 g (174 mmole) 
of the mesylate of 2-p-tolylethanol in 40 ml of anhy. dimethylformamide 
was added rapidly dropwise and the resultant solution was heated at 
90.degree. overnight. The reaction was cooled, poured into ice water and 
extracted with ether. The extract was dried (Na.sub.2 SO.sub.4), 
evaporated, and on standing crystallized. The crystalline mass was 
filtered, washed with ether and dried. mp 108.degree.-110.degree., single 
spot by TLC. 
220 hz NMR (CDCl.sub.3): .delta. 7.43 (triplet, J=8, 1H), 7.25-6.9 
(multiplet, 3H), 7.2 (doublet, J=6, 4H), 3.79 (triplet, J=8, 2H), 3.75 
(singlet, 3H), 3.25-2.9 (AB, 2H), 3.1 (doublet of multiplets, 1H), 2.44 
(triplet, J=8, 2H), 2.26 (singlet, 3H), 2.12 (multiplet, 1H), 1.95-1.55 
(multiplet, 4H), 1.25-1.0 (multiplet, 2H), 0.9 (doublet, J=6). 
G. 
N-(p-Tolylethyl)-4a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinoli 
ne 
##STR100## 
A solution of 21 g (0.05 mole) of the product from part F in 750 ml 
anhydrous tetrahydrofuran was added rapidly dropwise to a stirred 
suspension of 21 g (0.55 mole) of lithium aluminum hydride in 400 ml dry 
tetrahydrofuran, under nitrogen. The reaction mixture was heated at reflux 
overnight, then cooled and excess lithium aluminum hydride quenched by the 
dropwise addition of 21 ml water, 21 ml 3 N sodium hydroxide solution, and 
63 ml water. The inorganic salts were filtered, washed with ether and the 
filtrate dried (MgSO.sub.4) and evaporated. 
The product oil can be evaporatively distilled at 150.degree. at 3 microns; 
mp of hydrochloride salt 107.degree.-109.degree.. 
Nmr (cdcl.sub.3): 7.4-6.9 (multiplet, 3H), 7.08 (singlet, 4H), 6.75 
(multiplet, 1H), 3.8 (singlet, 3H), 2.9-1.0 (methylene envelope, 18H), 2.3 
(singlet, 3H), 0.8 (doublet, J=6, 3H). 
H. 
N-(p-Tolylethyl)-4a-m-hydroxyphenyl-6.beta.-methyl-cis-decahydroisoquinoli 
ne 
##STR101## 
A mixture of 16.9 g (44.8 mmole) of the product from part G and 67 g (0.58 
mole) of anydrous pyridine hydrochloride was heated at 195.degree. under 
nitrogen for 3 hours. The mixture was cooled, dissolved in methylene 
chloride and washed with water, saturated potassium carbonate solution, 
and dried (Na.sub.2 SO.sub.4). After removal of solvent the solid product 
was recrystallized from absolute ethanol. mp 150.degree.-152.degree. 
Anal. Calcd. for C.sub.25 H.sub.33 NO: C, 82.60; H, 9.15; N, 3.85; Found: 
C, 82.16, 82.17; H, 9.24, 9.09; N, 3.86, 3.93. 
Nmr (cdcl.sub.3): 7.3-6.5 (multiplet, 4H), 6.97 (singlet, 4H), 3.0-0.9 
(methylene envelope of multiplets, 18H), 2.25 (singlet, 3H), 0.8 (doublet, 
J=6, 3H). 
EXAMPLE 21 
N-(p-Tolylethyl)-4a-m-hydroxyphenyl-6.beta.-methyl 
cis-decahydroisoquinoline maleic acid salt 
##STR102## 
To a solution of 14 g (38.5 mmole) of the product from I-H in 70 ml of hot 
ethyl acetate was added 4.5 g (38.8 mmole) of maleic acid in 50 ml of hot 
ethyl acetate. The solution was cooled and the resultant crystalline salt 
was filtered and recrystallized from ethyl acetate; mp 
168.degree.-170.degree. 
Anal. Calcd. for C.sub.29 H.sub.37 NO.sub.5 : C, 72.62; H, 7.78; N, 2.92; 
Found: C, 72.83; H, 7.75; N, 3.06. 
220 nmr (dmso-d.sub.6): .delta. 7.25 (triplet, J=8, 1H), 7.15 (singlet, 
4H), 6.95-6.7 (multiplet, 3H), 6.1 (singlet, 2H), 3.5-1.5 (methylene 
envelope of many multiplets, 16H), 2.25 (singlet, 3H), 1.0 (multiplet, 
2H), 0.8 (doublet, J=6, 3H). 
EXAMPLE 22 
N-Cyclobutylmethyl-4a-m-hydroxyphenyl-6.beta.-methyl-cis-decahydroisoquinol 
ine 
A. 
N-Cyclobutylmethyl-4a-m-methoxyphenyl-6.beta.-methyl-1,3-diketo-cis-decahy 
droisoquinoline 
##STR103## 
To a suspension of 0.7 g (14 mmole) of sodium hydride in 40 ml anhydrous 
dimethylformamide, stirred at 40.degree. under nitrogen, was added rapidly 
dropwise a solution of 2.5 g (8.7 mmole) of 
4a-m-methoxyphenyl-6.beta.-methyl-1,3-diketo-trans-decahydroisoquinoline 
in 50 ml anhydrous dimethylformamide. The mixture was heated at 90.degree. 
for 3 hours, cooled to room temperature, and 2.85 g (17.4 mmole) of the 
mesylate of cyclobutanemethanol in 5 ml anhydrous dimethylformamide was 
added. The mixture was heated at 90.degree. overnight, cooled, poured into 
water and extracted with ether. The extract was washed with water, dried 
(Na.sub.2 SO.sub.4) and evaporated. The crude product oil was column 
chromatographed on Florisil and eluted with 2% acetone-benzene. 
Nmr (cdcl.sub.3): .delta. 7.4-7.0 (quartet, J=8, 1H), 7.0-6.6 (multiplet, 
3H), 3.75 (singlet, 3H), 3.7-3.0 (multiplet, 5H), 2.4-1.1 (envelope, 14H), 
0.9 (doublet, J=5, 3H). 
Ir: 3.4, 5.8, 6.0, 6.2, 6.3, 6.85, 6.9, 7.0, 7.2, 7.4, 7.5, 7.75, 7.9, 8.1, 
8.3, 8.5, 8.7, 8.9, 9.5, 11.7, 12.8, 13.6, 14.3.mu.. 
b. 
n-cyclobutylmethyl-4a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquino 
line 
##STR104## 
A solution of 2.3 g (6.47 mmole) of the product from part A in 100 ml of 
anhydrous tetrahydrofuran was added dropwise to a suspension of 2.3 g of 
lithium aluminum hydride in 65 ml dry tetrahydrofuran stirred under 
nitrogen. The suspension was heated at reflux overnight, cooled and excess 
reagent quenched by the dropwise addition of 2.3 ml water, 2.3 ml 3 N 
sodium hydroxide, 6.9 ml water. Filtration of the inorganic salts and 
evaporation of the filtrate yielded the product as a clear viscous oil. 
Nmr (cdcl.sub.3): .delta. 7.4-6.6 (multiplet, 4H), 3.8 (singlet, 3H), 
2.8-1.2 (envelope, 21H), 1.0 multiplet, 2H), 0.8 (doublet, J=6, 3H). 
Ir: 3.4, 6.2, 6.3, 6.7, 6.85, 6.9, 7.0, 7.8, 7.95, 8.1, 9.5, 12.9, 14.15, 
14.4.mu.. 
c. 
n-cyclobutylmethyl-4a-m-hydroxyphenyl-6.beta.-methyl-cis-decahydroisoquino 
line 
##STR105## 
A mixture of 1.7 g (5.2 mmole) of the product from part B and 6.0 g (52 
mmole) of anhydrous pyridine hydrochloride was heated under nitrogen at 
190.degree. for 3 hr, then cooled to room temperature. It was dissolved in 
chloroform, washed with water, dried (Na.sub.2 SO.sub.4) and the solvent 
evaporated. The crude product was dissolved in tetrahydrofuran and stirred 
with 3 N sodium hydroxide solution for 3 hours. Ether was added and the 
ether-tetrahydrofuran layer was washed with water, dried (Na.sub.2 
SO.sub.4) and evaporated. The oil was stirred with ether until a solid 
precipitate formed which was filtered and recrystallized from absolute 
ethanol, mp 148.degree.-150.degree.. 
Alternatively the product oil can be evaporatively distilled at 
170.degree.-180.degree. at 3 microns and the resultant glass 
recrystallized from ethanol. 
Nmr (cdcl.sub.3): .delta. 7.4-6.6 (multiplet, 4H), 2.8-1.2 (methylene 
envelope, 21H), 1.0 (multiplet, 2H), 0.8 (doublet, J=6, 3H). 
EXAMPLE 23 
N-Methyl-4a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinoline 
A. 
N-Methyl-4a-m-methoxyphenyl-6.beta.-methyl-1,3-diketo-cis-decahydroisoquin 
oline 
##STR106## 
To a suspension of 5.6 g (116 mmole) of sodium hydride in 320 ml of 
anhydrous dimethylformamide, stirred at 40.degree. under nitrogen, was 
added a solution of 20 g (69 mmole) of 
4a-m-methoxyphenyl-6.beta.-methyl-trans-decahydroisoquinoline in 400 ml 
dry dimethylformamide. The mixture was heated at 90.degree. for 3 hours, 
cooled to room temperature, and 19.8 g (139 mmole) of methyl iodide in 40 
ml dry dimethylformamide was added rapidly dropwise. The reaction mixture 
was heated at 90.degree. overnight, cooled, poured into ice water and 
extracted with ether. The extract was washed with water, dried (Na.sub.2 
SO.sub.4) and evaporated. The crude product oil was column chromatographed 
on silica gel, eluting with benzene and 1% acetone-benzene. TLC shows 
single spot. 
Nmr (cdcl.sub.3): .delta. 7.2 (quartet, J=8, 1 H), 7.0-6.6 (multiplet, 3H), 
3.78 (singlet, 3H), 3.2-2.9 (multiplet, 3H), 2.97 (singlet, 3H), 2.2-1.0 
(envelope, 7H), 0.9 (doublet, J=5, 3H). 
Ir: 3.35, 5.75, 5.95, 6.2, 6.3, 6.75, 6.8, 6.9, 7.65, 7.95, 8.6, 8.9, 9.5, 
12.8, 14.3, 14.7.mu.. 
b. n-methyl-4a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinoline 
##STR107## 
A solution of 11.3 g (37.5 mmole) of the product from part A in 400 ml 
anhydrous tetrahydrofuran was added dropwise to a suspension of 11.3 g 
(0.3 mole) of lithium aluminum hydride in 200 ml anhydrous 
tetrahydrofuran, stirred under nitrogen. The mixture was heated at reflux 
overnight, cooled, and excess reagent quenched by the dropwise addition of 
11.3 ml water, 11.3 ml 3 N sodium hydroxide solution, and 33.9 ml water. 
The inorganic salts were filtered off and the filtrate evaporated yielding 
the product as a clear viscous oil; mp of picrate (recrystallized from 
benzene) 162.degree.-164.degree. 
Nmr (cdcl.sub.3): .delta. 7.24 (quartet, J=8, 1H), 7.02 (multiplet, 2H), 
6.9-6.65 (multiplet, 1H), 3.85 (singlet, 3H), 2.1 (singlet, 3H), 2.9-1.0 
(envelope, 14H), 0.8 (doublet, J=6, 3H). 
Ir: 3.4, 6.2, 6.3, 6.75, 6.85, 6.9, 7.0, 7.8, 8.1, 9.5, 9.6, 12.9, 14.1, 
14.4.mu.. 
mass Spec. Calc. for C.sub.18 H.sub.27 ON: 273.2091; Found: 273.2106. 
EXAMPLE 24 
4a-m-Methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinoline 
##STR108## 
To a solution of 8.8 g (32.2 mmole) of 
N-methyl-4a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinoline in 70 
ml of methylene chloride, stirred at room temperature under nitrogen, was 
added a solution of 6.3 g (40.2 mmole) of phenylchloroformate in 20 ml of 
methylene chloride. The resultant solution was heated at reflux for 2.5 
hr, then stirred at room temperature overnight. The solvent was evaporated 
and the residual oil was heated at reflux in 100 ml of 5% sodium hydroxide 
solution under nitrogen for 30 minutes. After cooling the reaction was 
extracted with ether. The ether extracts were washed with 3 N hydrochloric 
acid to remove unreacted amine (1.5 g recovered), then dried and 
evaporated. 
The phenylurethane product was dissolved in 240 ml absolute ethanol and 50 
ml of 50% aqueous potassium hydroxide was added. The mixture was heated at 
reflux for 3 days under nitrogen, then cooled and ethanol removed under 
vacuum. The aqueous residue was extracted with ether and the ether extract 
was dried (Na.sub.2 SO.sub.4) and evaporated. The resultant oil was 
dissolved in 250 ml of 3 N hydrochloric acid, washed with ether, made 
strongly basic with 50% aqueous sodium hydroxide and extracted with ether. 
The ether extract was dried (Na.sub.2 SO.sub.4) and evaporated, yielding 
the product as a clear viscous oil. 
Nmr (cdcl.sub.3): .delta. 7.2 (quartet, J=8, 1H), 7.1-6.9 (multiplet, 2H), 
6.8-6.6 (multiplet, 1H), 3.8 (singlet, 3H), 3.1-0.9 (methylene envelope, 
15H), 0.8 (doublet, J=6, 3H). 
Ir: 3.0, 3.4, 6.25, 6.35, 6.7, 6.9, 7.8, 8.0, 8.1, 9.5, 12.8, 14.3.mu.. 
example 25 
4-a-m-Methoxyphenyl-cis-decahydroisoquinoline 
##STR109## 
To a solution of 4.2 g (16.2 mmole) of 
N-methyl-4a-m-methoxyphenyl-cis-decahydroisoquinoline in 100 ml benzene, 
stirred at room temperature under nitrogen, was added 11.2 g (81.1 mmole) 
anhydrous potassium carbonate and 5.2 g (24.5 mmole) of trichloroethyl 
chloroformate in 80 ml benzene. The resultant suspension was heated at 
reflux for 48 hours, cooled and diluted with 200 ml of ether. The organic 
solution was washed with water and 3 N hydrochloric acid and dried 
(Na.sub.2 SO.sub.4). Evaporation left an oil which was purified by column 
chromatography on silica gel eluting with benzene. 
A sample of the urethane product obtained (3.7 g, 8.8 mmole) was dissolved 
in 150 ml of methanol and stirred at room temperature. Zinc powder (2.86 
g, 44 mmole) was added and the suspension heated at reflux under nitrogen 
for 24 hours. The reaction was then cooled and the zinc filtered off. The 
filtrate was diluted with 3 N sodium hydroxide solution and extracted with 
ether. The ether extracts were dried (K.sub.2 CO.sub.3) and solvent 
evaporated. The product oil was evaporatively distilled at 110.degree. at 
0.5 microns Hg. 
Nmr (cdcl.sub.3): .delta. 7.4-6.6 (multiplet, 4H), 3.8 (singlet, 3H), 
3.0-2.7 (multiplet, 2H), 2.6-1.2 (methylene envelope, 12H). 
Ir: 3.4, 6.25, 6.35, 6.7-7.0, 7.8, 8.1, 9.5, 13.0, 14.3.mu.. 
example 26 
n-(p-Tolyethyl)-4a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinoline 
(same prod. as Example 20-G) 
A. 
N-(p-Tolyacetyl)-4a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinoli 
ne 
##STR110## 
To a solution of 3.8 g (14.7 mmole) of 
4-a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinoline in 120 ml of 
chloroform, stirred under N.sub.2 at 0.degree., was added 1.4 ml (17.6 
mmole) of pyridine and 3.0 g (17.6 mmole) of p-tolylacetic acid chloride 
in 5 ml chloroform. The solution was stirred at 0.degree. for 2.5 hr and 
then at room temperature for 2.5 days. The chloroform solution was poured 
into 120 ml of 3 N hydrochloric acid, separated, washed with saturated 
sodium bicarbonate solution, dried (Na.sub.2 SO.sub.4) and evaporated. The 
crude amide was column chromatographed on silica gel and eluted with 2-5% 
acetone-benzene. 
Nmr (cdcl.sub.3): .delta. 7.5-6.6 (multiplet, 4H), 7.13 (doublet, J=2, 4H), 
3.8 (singlet, 3H), 3.7 (doublet, J=2.5, 2H), 3.5-0.9 (methylene envelope 
of multiplets, 14H), 0.8 (doublet, J=5, 3H). 
Ir: 3.35, 6.05, 6.2, 6.3, 6.75, 6.9, 7.75, 7.95, 8.1, 9.0, 9.6, 12.9.mu.. 
b. n-(p-Tolylethyl)-4-a-m-methoxyphenyl-6.beta.-methyl-cis 
decahydroisoquinoline 
##STR111## 
To a suspension of 1.0 g (26 mmole) of lithium aluminum hydride in 40 ml 
anhydrous tetrahydrofuran, stirred under nitrogen, was added 2.7 g (6.9 
mmole) of the product from part A, and the suspension was heated at reflux 
overnight. It was then cooled and the excess lithium aluminum hydried 
quenched by the addition of 1 ml water, 1 ml 3 N sodium hydroxide solution 
and 3 ml water. The inorganic salts were removed by filtration and the 
filtrate was evaporated. 
NMR is the same as product from Example 20 G. 
EXAMPLE 27 
N-Phenethyl-4a-m-hydroxyphenyl-6.beta.-methyl-cis-decahydroisoquinoline 
A. 
N-Phenethyl-4a-m-methoxyphenyl-6.beta.-methyl-1,3-diketo-cis-decahydroisoq 
uinoline 
##STR112## 
To a suspension of 2.25 g (47 mmole) of sodium hydride in 130 ml anhydrous 
dimethylformamide, stirred at 40.degree. under N.sub.2, was added 8.0 g 
(28 mmole) of 
4a-m-methoxyphenyl-6.beta.-methyl-1,3-diketo-trans-decahydroisoquinoline 
in 160 ml of anhydrous dimethylformamide. The mixture was heated to 
90.degree. until the evolution of hydrogen ceased (.about.2 hr), then 
cooled to 30.degree.. A solution of 7.6 ml (55.7 mmole) of 
(2-bromoethyl)-benzene in 10 ml anhydrous dimethylformamide was added 
rapidly dropwise and the resultant solution was heated at 90.degree. 
overnight. The reaction was cooled, poured into ice-water and extracted 
with ether. The extract was dried (Na.sub.2 SO.sub.4), evaporated, and 
column chromatographed on Silicar CC-7 (silica gel) eluting with benzene 
and 2% acetone-benzene. 
Nmr (cdcl.sub.3): .delta. 7.4-6.6 (multiplet, 9H), 3.8 (triplet, J=7, 2H), 
3.7 (Singlet, 3H), 3.1-1.0 (multiplets, 12H), 0.88 (doublet, J=5, 3H). 
B. N-Phenethyl-4a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinoline 
##STR113## 
A solution of 7.0 g (17.9 mmole) of the product from part A in 300 ml 
anhydrous tetrahydrofuran was added rapidly dropwise to a stirred 
suspension of 7.0 g (183 mmole) of lithium aluminum hydride in 150 ml 
anhydrous tetrahydrofuran under nitrogen. The reaction mixture was heated 
at reflux overnight, then cooled and the excess lithium aluminum hydride 
quenched by adding successively 7 ml water, 7 ml 3 N sodium hydroxide, 21 
ml water. The inorganic salts were filtered, washed with ether, and the 
filtrate dried (MgSO.sub.4) and evaporated. The hydrochloride salt had mp 
of 118.degree.-120.degree.. 
Nmr (cdcl.sub.3): .delta. 7.3-6.8 (multiplet, 3H), 7.1 (singlet, 5H), 
6.8-6.6 (multiplet, 1H), 3.7 (singlet, 3H), 2.9-0.9 (multiplets, 18H), 0.8 
(doublet, J=5, 3H). 
Ir: 3.4, 6.2, 6.3, 6.7, 6.8, 6.9, 7.0, 7.75, 7.9, 8.1, 9.1, 9.5, 12.9, 
14.3.mu. 
c. n-phenethyl-4a-m-hydroxyphenyl-6.beta.-methyl-cis-decahydroisoquinoline 
##STR114## 
A mixture of 5.0 g (13.8 mmole) of the product from part B and 20 g (173 
mmole) of anhydrous pyridine hydrochloride was heated at 195.degree. under 
nitrogen for 3 hrs. The mixture was cooled, dissolved in methylene 
chloride and washed with water, saturated potassium carbonate and dried 
(Na.sub.2 SO.sub.4). After removal of solvent, the product was 
recrystallized from ethanol, mp 174.degree.-175.degree. 
Anal. Calcd. for C.sub.24 H.sub.31 NO: C, 82.48; H, 8.94; N, 4.01; Found: 
C, 82.11, 82.22; H, 8.91, 8.67; N, 4.10, 4.05. 
Nmr (cdcl.sub.3) .delta. 7.4-6.6 (multiplet, 9H), 3.0-0.9 (multiplets, 
18H), 0.8 (doublet, J=5, 3H). 
EXAMPLE 28 
N-(2-Furylmethyl)-4a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinoli 
ne 
A. N-(2-Furoyl)-4a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinoline 
##STR115## 
To a solution of 1.9 g (7.3 mmole) of 
4a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinoline in 60 ml of 
chloroform, stirred under nitrogen at 0.degree., was added 0.75 ml (9.4 
mmole) of pyridine and 0.9 ml (9.1 mmole) of 2-furoylchloride in 5 ml 
chloroform. The solution was stirred at 0.degree. for 2 hr and then at 
room temperature overnight. The chloroform solution was poured into 60 ml 
of 3 N hydrochloric acid, separated, washed with saturated sodium 
bicarbonate, dried (Na.sub.2 SO.sub.4) and evaporated. The crude amide was 
column chromatographed on silica gel eluting with benzene and 
ether-benzene mixtures. 
Nmr (cdcl.sub.3): .delta. 7.6-6.4 (multiplets, 7H), 3.8 (singlet, 3H), 
3.3-0.9 (multiplets 14H), 0.8 (doublet, J=6, 3H). 
Ir: 3.3, 5.7, 6.1, 6.3, 6.7, 6.9, 7.7, 7.9, 8.0, 8.4, 8.5, 9.0, 9.6, 9.85, 
13.2.mu. 
b. 
n-(2-furylmethyl)-4a-m-methoxyphenyl-6.beta.-methyl-cis-decahydroisoquinol 
ine 
##STR116## 
To a suspension of 0.5 g (13.1 mmole) of lithium aluminum hydride in 25 ml 
anhydrous tetrahydrofuran, stirred under nitrogen, was added 1.2 g (3.4 
mmole) of the product from part A, and the suspension was heated at reflux 
overnight. It was then cooled and the excess lithium aluminum hydride 
quenched by the addition of 0.5 ml water, 0.5 ml of 3 N sodium hydroxide 
and 1.5 ml water. The inorganic salts were filtered and washed with ether 
and the filtrate evaporated. The viscous oil product can be evaporatively 
distilled at 125.degree.-130.degree. at 3 microns. 
Nmr (cdcl.sub.3) .delta. 7.3-7.1 (multiplet, 2H), 7.0-6.85 (multiplet, 2H), 
6.85-6.55 (multiplet, 1H), 6.3-6.0 (multiplet, 2H), 3.8 (singlet, 3H), 3.3 
(multiplet, 2H), 2.8-0.9 (multiplet, 14H), 0.8 (doublet, J=6, 3H). 
Ir: 3.4, 6.2, 6.3, 6.7, 6.8, 6.9, 7.0, 7.5, 7.8, 7.95, 8.1, 8.7, 9.6, 9.9, 
13.0, 13.7, 14.1, 14.4.mu.. 
example 29 
n-cyclopropylmethyl-6-methyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
A. 
N-cyclopropylmethyl-4a-(m-methoxyphenyl)-6-methyl-1,3-diketo-cis-decahydro 
isoquinoline 
##STR117## 
N-Cyclopropylmethyl-4a-(m-methoxyphenyl)-6-methyl-1,3-diketo-trans-decahydr 
oisoquinoline (4.0 g, 11.7 mmoles), sodium methoxide (0.5 g) and 100 ml of 
methanol were heated to reflux for 18 hours. The mixture was cooled, 
concentrated on a rotary evaporator and diluted with water. The product 
was extracted with ether to yield, after evaporation of the ether, a 
viscous oil. This material was used in part B without further 
purification. 
B. 
N-cyclopropylmethyl-6-methyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinolin 
e 
##STR118## 
Product from Part A (3.0 g), tetrahydrofuran (75 ml) and lithium aluminum 
hydride (3 g) were refluxed for 18 hours. The mixture was cooled and 3 ml 
of water, 3 ml of 15% aqueous sodium hydroxide and 9 ml of water were 
added successively. The inorganic salts were filtered and the filtrate 
evaporated. The residual oil was evaporatively distilled to yield 2.8 g, 
bp 130.degree. (1.mu.). 
EXAMPLE 30 
N-cyclopropylmethyl-6-methyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline 
##STR119## 
N-cyclopropylmethyl-6-methyl-4a-(m-methoxyphenyl)-cis-decahydroisoquinoline 
(2.8 g) and anhydrous pyridine hydrochloride (12 g) were heated at 
190.degree. for 1 hour. The mixture was cooled, diluted with water, 
basified with potassium carbonate and extracted with methylene chloride. 
Evaporation of the methylene chloride gave a residue which was 
crystallized from ethyl acetate to yield 1.3 g, mp 
113.degree.-116.degree.. 
TABLE I 
______________________________________ 
PHYSICAL DATA 
##STR120## 
R X Physical Constant 
______________________________________ 
CH.sub.3 m-OH b.p. 145.degree.-155.degree. (0.5 .mu.) 
CH.sub.3 m-OCH.sub.3 
b.p. 120.degree. (0.3 .mu.) 
CH.sub.3 p-F b.p. 110.degree. (0.15 nm) 
CH.sub.2CHCH.sub.2 
m-OH b.p. 240.degree. (0.2 .mu.) 
CH.sub.2CHCH.sub.2 
m-OCH.sub.3 
b.p. 150.degree. (0.05 nm) 
CH.sub.2CHC(CH.sub.3).sub.2 
m-OH b.p. 240.degree. (o.2 .mu.) 
C.sub.5 H.sub.11 
##STR121## 
b.p. 100.degree.-105.degree. (1 .mu.) 
C.sub.3 H.sub.11 m-OCH.sub.3 
b.p. 70.degree. (1 .mu.) 
##STR122## m-OH b.p. 160.degree. (2 .mu.) 
##STR123## m-OCH.sub.3 
b.p. 120.degree. (1 .mu.) 
##STR124## m-OH b.p. 180.degree. (1 .mu.) m.p. 
79.degree.-81.degree. 
##STR125## m-OCH.sub. 3 
b.p. 130.degree.-135.degree. (0.5 .mu.) 
##STR126## m-OH b.p. 200.degree. (0.5 .mu.) m.p. 
78.degree.-80.degree. 
##STR127## m-OCH.sub.3 
b.p. 140.degree. (1 .mu.) 
##STR128## m-OCH.sub.3 
b.p. 125.degree. (0.3 .mu.) 
##STR129## m-OH b.p. 170.degree. (0.5 .mu.) 
##STR130## m-OH (HCl salt) 
b.p. 200.degree. (0.5 .mu.) 
##STR131## m-OCH.sub.3 
b.p. 150.degree.-156.degree. (0.5 .mu.) 
##STR132## m-OH b.p. 205.degree.-210.degree. (0.5 .mu.) 
##STR133## m-OCH.sub.3 
b.p. 120.degree.-130.degree. (0.5 .mu.) 
##STR134## m-OH b.p. 200.degree.-210.degree. (0.5 .mu.) 
##STR135## m-OCH.sub.3 
b.p. 140.degree.-145.degree. (0.5 .mu.) 
##STR136## m-OCH.sub.3 
b.p. 165.degree.-169.degree. (0.4 .mu.) 
##STR137## m-OCH.sub.3 
b.p. 155.degree.-160.degree. (0.5 .mu.) 
##STR138## m-OCH.sub.3 
b.p. 140.degree. (0.5 .mu.) 
##STR139## m-OH (HCl salt) 
m.p. 100.degree. (d) 
##STR140## m-OCH.sub.3 
b.p. 150.degree. (0.5 .mu.) 
##STR141## 
##STR142## 
b.p. 150.degree. (0.5 .mu.) 
##STR143## m-OCH.sub.3 
b.p. 150.degree. (0.4 .mu.) 
##STR144## m-OH b.p. 170.degree.-180.degree. (1.mu.) 
______________________________________ 
Dosage Forms and Use 
The analgesic agents of this invention can be administered to alleviate 
pain by any means that produces contact of the active agent with the 
agent's site of action in the body of a mammal. They can be administered 
by any conventional means available for use in conjunction with 
pharmaceuticals; either as individual therapeutic agents or in a 
combination of therapeutic agents. They can be administered alone, but are 
generally administered with a pharmaceutical carrier selected on the basis 
of the chosen route of administration and standard pharmaceutical 
practice. 
The dosage administered will, of course, vary depending upon known factors 
such as the pharmacodynamic characteristics of the particular agent, and 
its mode and route of administration; age, health, and weight of the 
recipient; nature and extent of symptoms, kind of concurrent treatment, 
frequency of treatment, and the effect desired. Usually a daily dosage of 
active ingredient can be about 0.01 to 100 milligrams per kilogram of body 
weight. Ordinarily 0.1 to 50, and preferably 1 to 25 milligrams per 
kilogram per day given in divided doses 2 to 4 times a day or in sustained 
release form is effective to obtain desired results. 
Dosage forms (compositions) suitable for internal administration contain 
from about 25 milligrams to about 75 milligrams of active ingredient per 
unit. In these pharmaceutical compositions the active ingredient will 
ordinarily be present in an amount of about 0.5-95% by weight based on the 
total weight of the composition. 
The active ingredient can be administered orally in solid dosage forms, 
such as capsules, tablets, and powders, or in liquid dosage forms, such as 
elixirs, syrups, and suspensions; it can also be administered 
parenterally, in sterile liquid dosage forms; or rectally in the form of 
suppositories. 
Gelatin capsules contain the active ingredient and powdered carriers, such 
as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium 
stearate, stearic acid, and the like. Similar diluents can be used to make 
compressed tablets. Both tablets and capsules can be manufactured as 
sustained release products to provide for continuous release of medication 
over a period of hours. Compressed tablets can be sugar coated or film 
coated to mask any unpleasant taste and protect the tablet from the 
atmosphere, or enteric coated for selective disintegration in the 
gastrointestinal tract. 
Liquid dosage forms for oral administration can contain coloring and 
flavoring to increase patient acceptance. 
In general, water, a soluble oil, saline, aqueous dextrose (glucose), and 
related sugar solutions and glycols such as propylene glycol or 
polyethylene glycols are suitable carriers for parenteral solutions. 
Solutions for parenteral administration contain preferably a water soluble 
salt of the active ingredient, suitable stabilizing agents, and if 
necessary, buffer substances. Antioxidizing agents such as sodium 
bisulfite, sodium sulfite, or ascorbic acid either alone or combined are 
suitable stabilizing agents. Also used are citric acid and its salts and 
sodium EDTA. In addition parenteral solutions can contain preservatives, 
such as benzalkonium chloride, methyl- or propyl-paraben, and 
chlorobutanol. 
Suppositories contain the active ingredient in a suitable oleaginous or 
water-soluble base. The oleaginous class includes cocoa butter and fats 
with similar properties; the water-soluble class includes polyethylene 
glycols. 
Suitable pharmaceutical carriers are described in Remington's 
Pharmaceutical Sciences, E. W. Martin, a standard reference text in this 
field. 
Useful pharmaceutical dosage-forms for administration of the compounds of 
this invention can be illustrated as follows: 
Capsules 
A large number of unit capsules are prepared by filling standard two-piece 
hard gelatin capsules each with 50 milligrams of powdered active 
ingredient, 110 milligrams of lactose, 32 milligrams of talc, and 8 
milligrams magnesium stearate. 
Capsules 
A mixture of active ingredient in soybean oil is prepared and injected by 
means of a positive displacement pump into gelatin to form soft gelatin 
capsules containing 50 milligrams of the active ingredient. The capsules 
are washed in petroleum ether and dried. 
Tablets 
A large number of tablets are prepared by conventional procedures so that 
the dosage unit is 50 milligrams of active ingredient, 7 milligrams of 
ethyl cellulose, 0.2 milligrams of colloidal silicon dioxide, 7 milligrams 
of magnesium stearate, 11 milligrams of microcrystalline cellulose, 11 
milligrams of cornstarch and 98.8 milligrams of lactose. Appropriate 
coatings may be applied to increase palatability or delay absorption. 
Injectable 
A parenteral composition suitable for administration by injection is 
prepared by stirring 1.5% by weight of active ingredient in 10% by volume 
propylene glycol and water. The solution is sterilized by filtration. 
Suspension 
An aqueous suspension is prepared for oral administration so that each 5 
milliliters contain 10 milligrams of finely divided active ingredient, 500 
milligrams of acacia, 5 milligrams of sodium benzoate, 1.0 grams of 
sorbitol solution, U.S.P., 5 milligrams of sodium saccharin, and 0.025 
milliliters of vanilla tincture. 
Injectable 
A parenteral composition suitable for administration by injection is 
prepared by dissolving 1% by weight of active ingredient in sodium 
chloride injection U.S.P. XV and adjusting the pH of the solution to 
between 6 and 7. The solution is sterilized by filtration. 
A standard procedure for detecting and comparing the analgesic activity of 
compounds in this series for which there is good correlation with human 
efficacy is the standard phenylquinone writhing test (PQW) modified from 
Siegmund, et al., Proc. Soc. Exp. Biol. Med. 95, 729 (1957). A test 
compound suspended in 1% methylcellulose was given orally to fasted (17-21 
hours) female white mice, 5-20 animals per dose in a double blind test. 
Aqueous (0.01% phenyl-p-benzoquinone) phenylquinone was injected 
intraperitoneally at 23 or 30 minutes later using 0.20 ml per mouse. 
Commencing at 30 or 37 minutes, respectively, after the oral 
administration of the test compound, the mice were observed for 10 minutes 
for a characteristic stretching or writhing syndrome which is indicative 
of pain induced by phenylquinone. The effective analgesic dose for 50% of 
the mice (ED 50) was calculated by the moving average method of Weil, 
Biometrics 8, 249 (1952). 
The following table shows the oral ED 50 dosages for analgesia (PQW test) 
of a number of compounds of the invention and several standard analgesics. 
TABLE II 
______________________________________ 
CIS-DECAHYDROISOQUINOLINE ANALGESICS 
##STR145## 
PQW 
ED.sub.50 
R X (mg/kg) 
______________________________________ 
CH.sub.3 m-OH 2.9 
##STR146## m-OCH.sub.3 14. 
##STR147## m-OH 20. 
##STR148## m-OCH.sub.3 18.5 
##STR149## m-OH 20. 
##STR150## m-OCH.sub.3 14.5 
##STR151## m-OH 21. 
CH.sub.3 p-F 26. 
CH.sub.2CHCH.sub.2 
m-OH 43. 
CH.sub.2CHC(CH.sub.3).sub.2 
m-OH 40. 
C.sub.5 H.sub.11 m-OCH.sub.3 20. 
##STR152## m-OCH.sub.3 33. 
##STR153## m-OH 28. 
##STR154## m-OCH.sub.3 [HCl salt] 
16. 
##STR155## m-OH [HCl salt] 
9.7 
##STR156## m-OCH.sub.3 11. 
##STR157## m-OCH.sub.3 15.1 
##STR158## m-OCH.sub.3 25. 
##STR159## m-OH [HCl salt] 
24. 
##STR160## m-OCH.sub.3 27. 
##STR161## 
##STR162## 27. 
STANDARD ANALGESICS ED.sub.50 (mg/kg) 
______________________________________ 
Morphine H.sub.2 SO.sub.4 
1.6 
Codeine H.sub.3 PO.sub.4 
8. 
Nalbuphine HCl 8.4 
Pentazocine HCl 57. 
Aspirin 109. 
______________________________________ 
The following table gives data for additional compounds of the invention. 
Table III 
______________________________________ 
Mouse ED.sub.50 mg/kg 
Compound of Analgesia 
Example (PQW)-Oral 
______________________________________ 
20-G 28; 22 
20-H 6.7; 2.6 
21 8.2; 3.4 
22-C 54 
23 3.5 
27-C 10.8 
28 61 
______________________________________