CA1110243A - 2,5-methanobenzo [5] quinoline-3-carboxylate esters - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Lower-alkyl 1-R1-3R5CO-4a.alpha.-R3-5a-R4-6-R2"-7-R2-8-R2'-9-R2'''-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3-carboxylates, useful as intermediates for the preparation of 3-R1-6(eq)-R4-7-R2"-8-R2-9-R2"-10-R2'''-11(ax)-R3-11(eq)-CH2CH2COR5-2,6-methano-3-benzazocines. useful as analgesics and narcotic antagonists, are prepared by carbox-ylation of an appropriate 1-R1-3-COR5"-4a.alpha.-R3-5.alpha.-R4-6-R2"-7-R2-8-R2'-9-R2'''-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo[g]quinoline.

Description

.
.

This application is dividcd out o~ our co- -- pendin~ App3.ication 286:,972.

This invention relates to lower-alkyl 3-acyl-. o~tahydro 2,5-methanobenzo[g]quinoline-3-carboxylates, useful :: 5 as intermediates for the preparation of ll(eq)-(2-acylethyl)-2,6-.~ methano-3-benzazocines, ~hich in.turn are uselul as analgesicsand analgesic antayonists and to the preparat on of sai~
benzazocines from said carboxylates.
United S~ates Patent No. 3,932,422 describes certa.in 10 3-acyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinolines useful as intermediates for the-preparation of 1,2,3,-4,5,6-hexahydro-ll(eq)-(2-acylethyl)-2,6-methano-3-benæazocines.
Even under the most favorable reaction condi~ions, however, the prior method produces, as a side produc~, substantial quantities .: 15 of 2-substituted-1,2,3,4,4a,5,10,10a-octahydro-3,5-e~henobenzo[g]-quinolines, thus appreciably diminishing the yield of the main product, the 2,6-methano-3-benzazocines.
The invention relates to certain lower-alkyl l-Rl-3-R5co-4a~-R3-s~-R4-6-R2"-7-R2-~-R2~-9-R2~ 2~3~4~4 lO,lOa-octahydro~2,5-methanobenzo[g]quinoline-3-carboxylates, which are useful as intermediates for the preparation of certain hexahydxo-2,6-methano-3-benzazocines.
More specificaily, this invention provide.~ valuable intermediates having the formula:

~k 29t3 .
, . .
: . . R2"' Rl .~ ~, ~ r~,COOAlk R2 ~ ~ORs ~` R2l- R4 R3 .. ~I
which can be designated lower-alkyl l-Rl-3-RsCO-4a~-R3-5~-Rq-6-R2"-7-R2-8-R2'-9-R2' "-1,2,3,4,4a,5,10,10a-octahydro-2,5-.. methanobenzo[g]quinoline-3-carboxylates and, which are useful , in the preparation of 3-Rl-6(eq)-R4-7 R2"-8-R2-9-R2'-1-R2'''-. ll(ax)-R3-ll(eq)-cH2CH2CoRs-2,6-methano-3-benzazocines having : the formula:
. R2''' R2' /~N-Rl :. R2 ~ ~ ~ R5 R2~ R4 3 ... II
wherein, in both Formulas I and II:
Rl is hydrogen, lower-alkyl, lower~alkenyl, lower-alkynyl, halo-lower-alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, 2- or : 3-furylmethyl, or such 2- or 3-furylmethyl substituted on the unsubstituted ring carbon atoms by from one to three methyl groups, phenyl-lower-alkyl, or phenyl-lower-alkyl substituted . 15 in the phenyl ring by from one to two members of the group consisting of halogen (including bromine, chlorine and fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, amino, lower-alkanoylamino or a single methylenedioxy attached to adjacent carbon atoms;
R2, R2', R2" and R2''' are each hydrogen, or three of them are hydrogen and the fourth is halogen (including bromine, .
chlorine or fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, .'. '~ ' .

24~1 lower-alkoxy, lower-alkylmercapto, trifluoromethyl, nitro, amino, lower-alkanoylamino, lower-alkoxycarbonylamino or phenyl, or two of the adjacent such groups together are methylenedioxy;
R3 is hydrogen or lower-alkyl;
R4 is hydrogen, lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkyl-sulfinyl-lower-alkyl, phenylthio-lower-alkyl, phenyl-sulfinyl-lower-alkyl, lower-alkenyl or halo-lower-alkyl, or R3 and R4 together are divalent lower-alkylene, -~CH2)n~, where n is one of the integers 3 or 4;
R5 is lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkoxy-lower-alkyl, lower-alkoxy, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3-furyl, 2- or 3-furyl-(CH2)m, where m is an integer from 2 to 4, or such 2- or 3~furyl or 2- or 3-furyl-(CH2)m substituted on the unsubstituted ring carbon atoms by from one to three methyl groups, phenyl, phenyl-(CH2)m, or phenyl or phenyl-(CH2)m substituted in the phenyl ring by from one to two members of the group consisting of halogen (including bromine, _~ chlorine and fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, amino, lower-alkanoylamino or a single methylenedioxy attached to adjacent carbon atoms; and Alk is lower-alkyl.
As used herein, the terms lower-alkyl or lower-alkoxy mean saturated, acyclic groups which may be straight or branched containing from one to about seven carbon atoms as exemplified by methyl, ethyl, propyl, isopropyl, butyl, non-adjacent t-butyl, methoxy, ethoxy, propoxy, isopropoxy or t-butoxy.
As used herein, the terms lower-alkenyl, halo-lower-~ .

:
1~ 229L3 alkenyl and lower-alkynyl represent monovalent groups of rom three to seven carbon atom-~ containing one double or triple bond as illustrated, for e~ample, by l-propenyl, 2-butenyl,.
4-pentenyl, 3-methyl-2-butenyl, 1-methyl-2-propenyl, 2-methyl-

2-propenyl, 2-propynyl, 2-butynyl, 4-pentynyl, 2-hexynyl and the like. The term halo-lower-alkenyl includes, for example, . 3-chloro-2-propenyl, 3-bromo-2-propenyl, 3,3-dichloro-2-propenyl, 3-bromo-2-methyl-2-propenyl and tne like.
As used herein, the term cycloalkyl means saturated carbocyclic groups containing fxom three to seven ring carbon : . . atoms as illustrated, for example, by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclobutyl, 4-ethylcyclohexyl and t~e like.
As used herein, the term lower-alkanoyl means such groups derived from saturated, aliphatic monocarboxylic acids having from one to four carbon atoms, as illustrated, for - example, by formyl, acetyl, propionyl, butyryl, isobutyryl and the like.
_~ The above-mentioned United States Patent describes a process for preparing compounds of Formula I~ which comprises heating a l-Rl-3-Rs'CO-4a~-R3-5~-R4-6-R2"-7-R2-8-R2 -9 R2 -1,2,-

3,4,4a,5,10,10a-octahydro-2,5-methanobenzo~g]quinoline of Formula Ia below with formic acid in an inert organic solvent or with a benzyl-di~ r-alkylammonium formate or a tri-lower-alkylammonium formate. The products of Formula IIa are produced by ring opening of the starting material of Formula Ia by rupture of the bond indicated by the letter (b). The method however also produces, by rupture of the bond indicated by (a) followed by recyclization of the Rs'CO carbonyl group to the nitxogen : 30 atom, significant amounts of 1-Rl-2-R5'-4a~-R3-S~-R4-6-R2"-7-R2-~5-.
,: .
8-R2'-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo~g]qUinolineS
of Formula III, thus diminishing the yield of the main product of Formula IIa. The two transformations are represented by the reaction sequence:- .
R.l R2~ Rl~ R2' ~ ~ ~ ~ R5' S 1~

IIa ~ / III
\
~ ' , ' \ ~' - IRl (a) R2- I ~ `(b~

R2" R4 Ia where Rl, R2, R2 , R2 , R3 and R4 have the meanings given above, and R5' is hydrogen, lower-alkyl, phenyl or phenyl-lower-alkyl.
. . The compounds of Formula II can be produced in high yield, without the formation of side products represented by Formula III, by heating the novel ~-keto esters of Formula I
with formic acid in an inert organic solvent or with a benzyl-di-lower-alkylammonium formate or a tri-lower-alkylammonium formate, usually at a temperature in the range from 120-150C. The reaction results in simultaneous ring opening between the 2- and 3-ring . carbon atoms of the com2Ounds of Formula I and hydrolysis and decarboxylation of the 3-carbo-lower-alkoxy group, COOAlk.

Suitable solvents are toluene, xylene or mesitylene. A preferred :- -6-~ .
. ~ .

4 3 ~olvent med$um i3 formlc acid in me~itylene.
-A further advantage of the use of the ~-keto esters of Formula I, rather than the ocmpounds of Formula Ia, i9 that use of the latter require~ a reaction time in the order of days5 ln some ca~es up to 8iX day~, wherea~ the ~-keto ester~ of Formula I usually require reaction ~imes in the order of minuto~
or hours, reaction ln most ca~es being complete in four ~o 8iX
: hour~ using formic acid in me~itylene a~ 601vent or in nine to - thirteen minutes using trimethylammonlum ~ormate at 145C. In : 10 all case3, the cour~e of the reaction i~ routinely followed by sampl$ng the reaction mixture onto thin layer chromatogr~phy plat~s and notlng the di~appearance, with increasing reaction tlme, o~ zon~s attributable to start~ng material.
The compound~ o~ Formula I are prepared by reacting lS a l-Rl-3-Rs~CO-4~-R3-5~ R4-~-R2"~7~2-B-R~ -9-R2 -1,2,3,4,4a,

5,10,10a-octAhydro-2,5-me~hanoben~o[g]quinoline o~ ~ormula ~b with ~n alk~li metal amid~, ~or examp~e ~odamide or lithium dli~opropylami~ nYan inert organic ~ol~ent,and reacting the alkali m~tal ~alt thus ~ormed with an appropriate acyl halide~
Rs"'-CO-X~s low~r-alkyl halo ~ormate when ~5 "' i8 lower alkoxy) ~ccordlng to the ~ollowiny reaction sQ~uences - 12''' 1l R2 ~ ~1) M-N~B
R2 ~ R5" (2) X~X~Rs R2ll R4 R2" ' ll R2 ~ ~OOAlk C0~5 . . R2 ~4 : _7_ I

.. , 29~3 ;, .
where Rl, R2, R2 ~ R2 , R2' ", R3, R4 and Alk have the meanings given above, R5" and R5" ' have the same meanings as Rs except Rs''' must represent lower-alkoxy when R5" is not lower-alkoxy, X is halogen and M-N=B is an alkali metal tM) amide (N=B). The ~- 5 reaction is preferably carried out at a temperature from about -10C. to about -70~C. Suitable solvents are tetrahydrofuran, diethyl ether or dioxane.
The starting materials of Formula Ib and methods for their preparation are disclosed in United States Patent 3,932,422.
As indicated above, the steric configurations of the 3-acyl group (COR5") in the compounds of Formula Ib and of the 3-acyl (R5CO) and 3-carbo-lower-alkoxy groups (COOAlk) in the ~-keto esters of Formula I are not known with absolute certainty.
~owever, insofar as the structures of the 2,6-methano-3-benza-zocineb of Formula II (which are prepared from the ~-kG~o esters of Formula I) are concerned, the question of the steric con-figuration at the 3-position of the compounds of Formula I is moot, because the asymmetry at the 3-position is destroyed on conversion of the compounds of Formula I to the compounds of Formula II. Compounds of Formula I having both possible steric cpnfigurations at the 3-position are fully operable for the pre-paration of the compounds of Formula II. In any e~ent, acylation or carboxylation of the COmpounds of Formula Ib followed by ring opening and decarboxylation gives, in each case, a single, clean product of Formula II.
- The compounds of this invention can exist in stereo-chemically isomeric forms, that is, optical isomers and geometric isomers. If desired, the isolation or the production of a parti-cular stereochemical form can be accomplished by application of . .

- ' .

general principles known in the prior art. In the nomenclature employed for the compounds of Formula II, herein, "ax" stands for axial and "eq" for equatorial, and the configurations are given with reference to the hydroaromatic ring.
S Thus, the 6(eq~, ll(ax) compounds of Formula II

.'~' ' .
.~
.

, _g_ ~a .

' - ' . ' are in the cls configuration, whereas the 6(eq), ll(eq) compounds are in the trans configuration.
In the nomenclature employed for the compounds of formulas I, Ia, Ib, Ic and III, again configurations are given S with reference to the hydroaromatic ring, and the designation '~' indicates the cis configuration relative to the 2,5-methano bridge of the compounds of formula I or the 3,5-etheno bridge of the compounds of formula III. Conversely, the designation ''~C'' indicates the trans configuration relati.ve to the same groups.
The structures of the compounds of this invention were established by the modes of synthesis, by elementary analyses and by infrared and nuclear magnetic resonance spectra. The course of reactions and homogeneity of the products were routinely ascertained by thin layer chromatography.
The manner and process of making and using the inven-tion, and the best mode contemplated of carrying out this invention, will now be described so as to enable any person-skilled in the art to which it pertains to make and use the same.
The melting points are uncorrected unless noted otherwise.
A. Prep~ration of Lower-alkyl 3-R5CO-Octahydro-2,5-methano-! benzo~g~quinoline-3-carboxylates of Formula I
1- By acylation of the corresponding lower-alkyl 3-carboxylate ~ Example 1 A. To a solution of S0 ml. (0.12 mole) of 2.4N n-butyl lithium in hexane was added, over a period of about thirty minutes - while maintaining the temperature at 0DC., a solution of 13.1 g.
~0.13 mole) of redistilled diisopropylamine in 110 ml. of dry tetrahydrofuran. The mixture was then cooled to -60C., and a :

' _ __ _ . . _ ... . , . . . . , . . _ _ , . .
; solution of 34.3 g. (0.1 mole) of ethyl 7-methoxy-1,4a~C,S~-trimethyl-1,2,3,4,4a,5,IO,lOa-octahydro-2,5-methanobenzo[g]quino-line-3-carboxylate in 110 ml. of tetrahydrofuran was added over a two hour period. The solution was then treated, over a period S of about thirty minutes while cooling at -60~c., with a solution of 18.8 g. (0.13 mole3 of redistilled hexanoyl chloride in 110 ml.
~ , of *etrahydrofuran. The clear reaction mixture was poured into 500 ml. of aqueous sodium bicarbonate, extracted with two 100 ml.
portions of ether, and the combined ether extracts were washed once with brine and then dried over sodium sulfate and evaporated to dryness leaving 44 g. of an oil which solidified on standing.
The residue was recrystallized from hexane to give 27.5 g. (63%3 -of ethyl 3~ oxohexyl)-7-methoxy-1,4a~C,5~-trimethyl-1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzotg~qulnoline-3-carboxylate, m.p. 117-120C.
Following a procedure similar to that described above, the following compounds of formula I were similarly prepared:
B. EthYl 7-methoxy-1,4a~C,5~C-trimethyl-3-(4-methyl-1-oxo-pentyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo~g]quino-line-3-carboxylate (22.8 g., 43%, m.p. 97-100C. from pentane) prepared by reaction of 40.5 g.-(0.12 mole) of ethyl 7-methoxy-1,4a~,5~C-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo[g~quinoline-3-carboxylate with 0.13 mole of lithium di-isopropylamide followed by reaction of the resulting salt with 17.5 g. I0.13 mole) of 4-methylpentanoyl chloride;
C. Ethyl 7-methoxy-l,S~C-dimethyl-3-(l-oxopent~ 1,2,3,4,4a,5, lO,lOa-octahydro-2,5-methanobenzo~]quinoline-3-carboxylate ~5.2 g., 27~, m.p. 87-92~C., from pentane) prepared by reaction of ~5 0 g. (0.046 mole3 of ethyl 7-methoxy-1,5~C-dimethyl-1,2,3,4, .

~' ' ' .

4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylat:e with 0.047 mole of lithium dii~opropylamide followed by reaction of the resulting salt with 5.7 g. (0.046 mole) of pentanoyl chloride.
Following a procedure similar to that described in Exampie 1 above, the following compounds of formula I listed in Table l are similarly prepared. The melting point and solvent used for crystallization are given in the column headed "m.p. (C.)!Solv.".
Table 1 Example 1 5 R2/R2"R2',~R2 R3/R4 % Yiéld So~v.
_ _ 1 D ~ CH3 CH30 H CH3 C2H5 109-111 (CH2)2CH3 H - H CH3 62 hexane CH2CH(CH3)2 H H CH3 44 hexane 2CH3 H . CH3 53 hexane . ~ G CH3 CH30 H H . C2H5 120-123 CH3 H H CH3 28 ethanol 2)3CH3 H H CH3 28 pentane 1 I CH3 CH30 H CH3 C2H5 117.5-119 ~CH2)3scH3 H H . CH3 59 hexane lJ CH3 CH30 H CH3 C2H5 120-122 CH3 H H CH3 40 benzene/hexane lK CH3 CH30 H H C2H5 106-108 (CH2)4CH3 H H CH3 39 ethanol . lL CH3 CH30 H CH3 C2H5 117-123 (CH2)2c6H5 E H CH3 Sl ethanol lM C6H5CH2 H H CH3 C2H5 oil (C~2)4CH3 H H CH3 78 -:~ - 12 -zg~ ' . rrable 1 (con~'d) , R /R R /R " R '/R '" R /R Alk/ m.p.(C.)/
Example 1 5 2 2 2 2 3 4 % Yield Solv.
: _ .
: - lN 6 5 2 CH30 H CH3 C2H5 123-125 . CH3 H H 3 hexane lP 6 5 2 CH30 H CH3 C2H5 oil t-C4Hg H H CH3 2 . lQ C6H5CH2 CH30 H CH3 C2H5 oil (CH2)4CH3 H 3 1R C6H5CH2 CH30 H CH3 C2H5 oil (CH2)3CH3 H H CH3 37 ; lS C6H5CH2 CH30 H ., CH3 C2H5 oil (CH2)5CH3 H H CH3 80 - lT CH3 CH30 H CH3 C2H5 86-87 (CH2)5CH3 H H CH3 7 ethanol : lU 3 5CH2 CH30 H CH3 C2H5 89-91 - (CH2)3CH3 II H CH3 36 pentane lV C6}5CH2 CH30 H CH3 C2H5 oil (CH2)2CH(CH3)2 H CH3 46 lW CH3 CH~0 H H C2H5 oil (CH2)5CH3 H 3 lX CH3 CH30 H C2II5 oil (CH2)2CH3 H H CH3 64 - lY CH3 CH30 H CH3 C2H~ oil ~ cycl~pentyl(CH2)2 H H CH3 100 (crude) .: lZ CH3 CH30 H CH3 C2H5 oil cyclopropyl(CH2)2 H H CH3 60 lAA CH3 CH30 H H C2H5 90.5-93.5 (CH2)2CH(cH3)2 H CH3 62 ethanol lAB CH3 - CH30 H CH3 C2H5 93.0-95.5 ~CH2)3CH3 H H CH3 16 ethanol lAC CH3 CH30 H CH3 C2H5 142-144 2-furyl H H CH3 26 acetone lAD CH3 3 CH3 C2H5 121-123 2-furyl-(CH2)2 H 3 hexane .
.: - 13 -~i .
,.

1~ 7Z4~
Table 1 (cont'd) _ 5 R /R " R '/R2"' R3/R~ ~ Yleld Solv.

lAE CH3 H H H C21l5 cyclohexyl H H . CH2CH20CH3 lA~ CH3 H H H C H
cyclohexyl-CH2 H H CH2CH2SC6}I5 lAG 6 5 2 H H .CH3 C2H5 cyclopropyl H CH30 CH3 lAH CH3 H H H C2H5 . cyclopropyl-CH2 H H CH2CH2soc6 5 lAJ CH3 H H H C2H5 C6HS H H CH=CH2 lAK H H H CH3C2H5 2-furyl-(CH2)2 CH30 ~I CH3 : lAL H H H CH32 5 3-furyl-(C~2)2 H CH30 3 .:. lA~. CH2CH=CH2 H H CH3C2H5 5-CH3-3-furyl-(CH2)3 H H C~3 lAN CH2CH=C~CH3)2 H H CH3 C2H5 -~ (CH2)4cH3 H H CH2CH20H
lAP CH2C-CH H H CH3C2H5 (CH2)4CH3 H H CH3 lAQ C4H7CH2 H H CH3C2 5 (CH2)4CH3 H H CH3 .. lAR 3-furyl-CH2 H H CH3C2H5 - . ~CH2)4CH3 H H CH3 .
2-By carboxylation of the corresponding 3-carboxylates or 3-R5"C0 ketones i i _ . . - - . . .-- . . , 24~;~

Exam~le 2 ,.
A- A solution of 0.055 mole of lithium diisopropylamide in 60 ml. O r tetrahydrofuran ~as prepared from butyl lithium and diisopropylamine using the procedure described in Example 1 above. The solution thus prepared was cooled to -75C. and treated with a solution of 17.1 g. (0.05 mole) of ethyl ` 7-methoxy-1,4a~C,5~-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxyla~e added over a period of about thirty minutes while maintaining the tem~eratu-^e at -75C. The solution was then tîeated dropwise over a period of one hour at -75C. with a solution of 5.4 g. (0.05 mole) of ethyl chloroformate in 80 ml. o tetrahydrofuran. The mixture was stlrred for one hour, then poured into 400 ml. of aqueous sodium bicarbonate and worked up in the same manner as described in lS Example 1 to give 9.7 g. of cruda material which was recrystallize from pentane to give 6.3 g. (30%) of diethyl 7-methoxy-1,4a~,5DC
trimethyl-l ! 2, 3, 4, 4a~5~10~10a-octahydro-2~5-methanobenzG[y]-quinoline-3,3-dicarboY.ylate, m.p. 8g-91~C.
Following a procedure similar to that described . 20 above, using an appropriate 3-R5"CO-1,2,3,4,4a,5,1~,10a-octa-hydro-2,5-methanobenzo[g]quinoline of formula Ib and ethyl chloro-formate in the presence of diisopropylamide, the following com-pounds o~ formula ~ are similarly prepared.
Table 2 25Example 1~ 5 R2/R2 R2'/R2''l R3/R4 Alk . .
2i B CH3 H Cl C2H5 2 C CH3 H Br H C2H5 ~ ' ' .

Ll.!~24~

Table 2 (cont'd) Example l/ 5 R2/R2 R2'/R2 ~ R3/R4 Alk 2 D CH3 H F H C2~5 - CH3 H . H 3 . 5 2 B CH3 H CF3 H C2H5 ~: 2 G CH3 H H H C2H5 2 H C~13 -OCH20- H C2H5 C~13 H H CH3 ;:: - 2; I CH3 H H H . C2H5 . . CH3 H H CH2CH2Cl 2J 3 , 2 3 C2H5 ... . .
' 2K 3 H H (CH2)~ C2H5 2L cyclohexyl CH3S H H C2H5 I M . 4 BrC6H4CH2CH2 CH30 H H C2H5 - 4 C~C6H4CH2CH2 CH3CONH H H C2H5 : 25 2P C6H4CH2CH2 C2H50CONH H C2 5 2Q 3 6 3CH2c~I2 H H H C2H5 CH3 H. H CH3 .
. . - 16 -.. ~, ,,,,,, ~

2~3 Table 2 (cont'd) Example 1/ S R2/R2 R2 /R2 R3/R4 Alk 2S 3,4 (CH30)2C6H3CH2CH2 H H H C2~15 ~ CH3 H H CH3 - 5 2T 4-CH3SC6H4cH2cH2 H H ' C2H5 2U 3-CF3C6H4CH2cH2 H H C2H5 2W 3,4-OCH20C6H3CH2CH2 H H ~ C2H5 2Y CH3 H H ~ C2~I5 B. Conversion of the Compounds of Formula I to ll(eq)-CH2C,H2-COR5-2 ! 6-methano-3-benzazocines of Formula II
~s ~
A. A solution of 10 g. (0.023 mole) of ethyl 3-(1-oxohexyl)-7-methoxy-1,4a~C,5~C-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methan~benzo~g]quinoline-3-carboxylate in 475 ml. of mesitylene and 35 ml. of 97~ formic acid was heated under reflux for seventeen and a half hours. The solvent was removed in vacuo, and the residue was treated with aqueous sodium bicarbonate and ether. The ether extracts were dried over anhydrous magne-sium sulfate and then treated with ethereal hydrogen chloride.
The material which separated was collected and recrystallized from acetone to give two crops, totalling 6.5 g. (69~), of . - 17 -.
8-methox~-3,6(e~),11tax)-trimethyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxooct~1)-2,6-methano-3-benzazocine hydrochloride, m.p. 213-215C.
Following a procedure similar to that described in Example 3 above, usiny an appropriate lower-alkyl 3-R5CO-'A 1,2,3,~,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate of formula I in refluxing mesitylene/97~ formic acid, the following 1,2,3,4,5,6-hexahydro-ll(eq)-CH2CH2COR5-2,6-methano-3-benzazocines of formula II were similarly prepared.
~. 8-Methoxy-3,6(e~),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-ll(e~)-(3-oxo-6-methylhept~1)-2,6-methano-3-benzazocine hydro-- chloride (4.2 g., 38%, m.p. 228-232~C. from acetone) prepared by refluxing 12 g. (0.027 molé) of ethyl 7-methoxy-1,4a~,5~-trimethyl-3-(4-methyl-1-oxopentyl)-1,2,3,4,4a,5,10,10a-octa- -hydro-2,5-methanobenzo[g]quinoline-3-carboxylate in a solution o~ 500 ml. of mesitylene and 35 ml. of 97% formic acid for twenty-one hours and isolating the product in the form of the hydrochloride salt.
Following a procedure similar to that described in Example 3 above the following 1,2,3,4,5,6-hexahydro-ll(eq)-CH2CH2CORS-2,6-methano-3-benzazocines of formula II were prepared by heating an appropria~e lower-alkyl 3-R5CO-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate in xefluxing mesitylene/97% formic acid. The reaction time and ~ yield are given in the last column. In each instance, R2', R2" and R2"' are hydrogen, and unless noted otherwise, melting points are given for the free bases.

Table 3 Time (Hrs.)/
30Example Rl/~5 ~2 R3jR4 m-p.()C.)/Solv. % Yield - 3 C CH3 CH30 H 182-185 (a) 24 (CH2)3CH3 CH3 acetone 23 ~ D CH3 CH30 CH3 98-99 22 - (Cl~2)2cH3 CH3 hexane 70 ,!
,~

- l L~243 ' ' -.

: Table 3 (cont'd) . Example Rl/R5 R2 3 4 m p.(C.)/Solv ~ ye,e(drs.
... ..
3, E CH3 CH30 CH3 95-97 24 : CH2CH(CH3)2 CH3 pentane 60 :: 5 3, Y CH3 CH30 CH3 100-103 (c) 24 C2H5 CH3 ethanol 63 G CH3 CH30 H 175-179(b) 22 CH3 CH3 acetone/ether 70 : 3 H C3H5CH2 CH30 CH3 219-220(b) 21 ~CH2)3CH3 CH3 acetone/ether 67 .. . 3 I, CH3 CH30 - CH3 163-165 (d) 24 : . (CH2)3SCH3 CH3 acetone/ether 89 3~ CH3 CH30 CH3 176-179 (b) 19 CH3 CH3 acetone/ether 58 - 15 3K CH3 CH30 H 127.5-130 (e) 24 ~CH2)4CH3 CH3 ethanol 63 3L CH3 CH30 CH3 176-179 (e) 17 ( 2)2C6H5 CH3 acetone 37 :- 3M 6HSCH2 H CH3 190-193 (b) 80 (C~2?4cH3 CH3 acetone/ether 39 3N C6H5CH2 CH 0 CH oil - 20.5 CH3 C~3 56 3P C H CH CH30 CH3 214-217 (b) 6.75 (CH2)4CH3 CH3 acetone/ether 28 226-228 (b) 20 - (CH2)3CH3 CH3 acetone/ether 56 . 3R C6H5CH2 CH30 CH3. 219-221~(b) 28 : (CH2)5CH3 . CH3 acetone~ether 69 3S CH3 CH30 CH3 178-182 (b) ' .20 (CH2)5CH3 CH3 ether . 84 ~',';1'~';~4,;~ 4~ ,,"ilt',~ Table 3 (cont'd) Time(Hrs.)/

Example Rl/R5 R2 R3/~4 m.p.~C.)/Solv. %-Yield 3~ C6H5C~2 C~3O CH3 221-225C. (b) 24 , tCH2)2C~(c~3)2 CH3 acetone/ether 36 3U C~3 CH30 H oil 24 - (CH2)2CH3 CH3 67 3V ' CH3 CH30 CH3 220-222 (b) 15 , cyclopentyl(CH2)2CH3 ethanol/ether 48 3W ' ' CH3 C~3O CH3 224-225 (b) 24 cyclopropyl(CH2)2CH3 ethanol/ether 20 3X CH3 ' CH30 H 131-135 (c) 16 (CH2)2CH(c~3)2 CH3 methanol 5 3Y CH3 CH30 CH3 209-212 (b) 21 (CH2)3CH3 ~ CH3 acetone/ether46 ,~a) Picrate salt (b) Hydrochloride salt (c) Methanesulfonate melts 215-220 - (d) Methanesulfonate salt (e) p-Toluenesulfonate salt .,; ' ' . ~ , .
A. To a solution of 30 ml. of trimethylammonlum formate (prepared by addition of two parts of trimethylamine to five , 5' parts of 97% formic acid) heated to 100C. was added'8.3 g.
`, (0.02 mole) of diethyl 7-methoxy-1,4a,5a-trimethyl-1,2,3,-4,4a,5, lO,lOa-octahydro-2,5-methanobenzo[g]quinoline-3,3-dicarboxylate ,,~described above in Example 2),, and the mixture was'heated to boiling for fifteen minutes. The mixture was then poured ~ onto ice, basified with excess sodium hydroxide and extracted with ether. The ether extracts were washed once with brine, dried over magnesium sulfate and taken to dryness to give

6.5 y. of a colorless oil which was recrystallized from hexane to give 3.8 g. ~55%) of ethyl 3-[8~methoxy-3,6(eq),11~ax)-.. . . .
' ' -,20 -, " ' ' ' , .

, trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-ll(eq)-yl]propionate, m.p. 91-93C.
Following a procedure similax to that described in above, using an appropriate lower-alkyl 3-R5CO-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate of formula I in trimethylàmmonium formate, the following 1,2,3,4,5,6-hexahydro-ll(eq)-CH2C~2COR5-2,6-methano-3-benzazocines of formula II were similarly prepared.
B. 8-Methoxy-3,6(eq),11(ax)-trimeth~l-1,2,3,4,i,6-hexah~dro-ll(eq)-[3-oxo-3-(2-furyl)propyl]-2,6-methano-3-benzazocine (1.5 g., 10%, m.p. 119-122C from acetone) prepared by heating 20.5 g. (0.04 mole) of ethyl 7-methoxy-1,4a~,5~-trimethyl-3-~2-furoyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g~-guinoline-3-carboxylate in 60 ml. of a solution of trimethyl-ammonium formate to boiling for twelve minutes and isolating the product in the form of the free base.
C. 8-Methoxy-3,6(e~),11(ax)-trimeth~l-1,2,3,4,5,6-he ll(eq)-[3-oxo-5-(2-furyl)pentyl]-2,6-methano-3-be_zazocine (0.600 g., 71%, m.p. 144-149C. from acetone/e~her) prepared by heating 1.0 g. (0.0022 mole) of ethyl 7-methoxy-1,4a~,5~-trimethyl-3-[3-(2-furyl)-1-oxopropyl]-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate in 10 ml.
of a solution of trimethylammonium formate to boiling for - ten minutes and isolating the product in the form of the free base.
Examples 5A-5AT
Following a procedure similar to that described in Example 3 using an appropriate lower-alkyl 3-R5CO-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate ~f formula I, the .

``` lll~Z~3 ;,, ' ' fol1owing ll(eq)-cH2cH2co~5-2~6-methano-3-be~zazocines of formula II are prepared.
Table S

Example Rl/R5 R2/R2 R2'/~2 R3/R4 t-C4H9 H H CH3 (CH2)3CH3 H H CH3 (CH2)5 3 H H CH3 cyclohexyl H H CH2CH20CH3 5E CH3 H . H H
cyclohexyl-CH2 ~ H -CH2CH2SC6H5 5F . C6H5CH2 H H CH3 cyclopropyl H CH30 CH3 cyclopropyl-CH2 H H CH2C 2 6 5 5H CH3 H . H ~ H
C6H5 H, H -CH-CH2 5J H H H . CH3 2-furyl-(CH2)2 CH30 H CH3 -furyl-tCH2~2 H CH30 CH3 5L CH2CH=CH2 H H CH3 5-CH3-3-furyl-(CH2)3 H H CH3 5M CH2CH=C(CH3)2 H H . CH3 lCH2j4C~3 H H CH2CH20H
.

(CH2)4CH3 H H CH3 (CH2)4CH3 H H CH3 ' . ~ '' ' ~
:

24;~
, Table 5 (contrd) Example R1/R5 R2/R2" R '/R "' R /R
5Q 3-furyl-CH2 H H CH3 (CH2)4c~3 H H CH3 - 5R CH3 H Cl H

5S CH3 H Br H

5U 3 c~3 H

. CH3 H H CH3 : 5Y CH3 H H H
CH3 H H CH2CH2Cl 5z CH3 H H
. CH3 H H
: 5AA CH3 H H ~, ~ 4 ~ 5AB . cyclohexyl CH3S H H
,. CH3 H H CH3 5AC 4-BrC6H4CH2CH2 CH30 H H

5AD 4.ClC6H4CH2c 2 3 H

5AE 4-FC6H4CH2cH2 C2H50CONH H H
: CH3 H H CH3 - .,.

24~
:.' ' "` ' Table 5 (cont'd) R /R R /R " i~2'/R2 R3/R4 ~xample 1 5 2 2 5AF 4 Cl 3 3 6 3 2 2 H H
. CH3 H H CH3 5AG 3-CH3C00C6H4CH2C~2 H ~l C~3 H H C~3 5AH 3,4-(CH30)2C6H3C~2C~2 H
CH3 ~ H CH3 :: 5AJ 4-CH3SC6~4cH2cH2 H H

5AK . 3-CH3C6H4CH2cH2 H H
CH3 H H C~3 SAL 3-CH3CO~HC6H4cH2cH2 H
CH3 X ~ CH3 . - 5AM . 3~4-ocH2oc6H3cH2cH2 H H H
; CH3 H H CH3 .

C. Comparison of Claimed and Prior Methods The superior overall yield obtained in the lnstant process for the preparation of 3-benzazocines of formula II
in comparison with the process of the prior method disclosed in Japanese Provisional Patent Publication ~o. 160,275 (and U.S. Patent 3,932,422) is demonstrated by the following descriptions which compare the stepwise and overall yields obtained in the preparation of 8-methoxy-3,6(eq),11(ax)-tri-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine via the i.nstant process through the intermediate ethyl 7-methoxy-1,4a~,5~-trimethyl-3-(1-oxoethyl)-1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo~g]quinoline-3-carboxylate .' ~ ' ' .

` `` 1~1~243 formula I and via the prior art process through the inter-~ediate 7-methoxy-1,4a,5a-trimethyl-1,2,3,4,4a,5,10,10a-octa-hydro-2,5-methanobenzo[g)quinoline-3-carboxylic acid and 7-methoxy-1,4aa,5a-trimethyl-3-(1-oxoethyl)-1,2,3,4,4a,5,10,10a-~ctahydro-2,5-methanobenzo[g]quinoline of formula Ic (R5" is ~H3) from a common starting material, ethyl 7-methoxy-1,4a~,5a-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanoben~o[g~-~uinoline-3-carboxylate, of formula Ib. ~he procedures are illustrated by the reaction sequences:

. ' ' .
: .

~ , . . .

. , , ' " .

; ~ Step lB ~ ~
CU~ ~ COOC2H5 CH3O ~ ~3 OOH

; ~ tep lA ~ ¦ Step 2B-CH3 , CH3 C~3~ ~ ~ COCH3 ~ CH ~ 1 3~oc~3 \ Step 2A . / Step 3B
.' ' \~ I~ .

C~3 ~ C~3 . ~H3 3 O

A. ~he Claimed Process (Step lA) A solution of 0.127 mole of lithium diiso-propylamid-e in 150 ml. o~ tetrahydrofuran was prepared using the procedure described above in Example 1. The soIution thus prepared was cooled to -70C. and treated over a period of two hours with stirring with a solution of 40.4 g. (0.118 mole) of ethyl 7-methoxy-1,4a~,5~C-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzolg~quinoline-3-carboxylate in 200 ml. of tetra-hydrofuran. ~hen addition was complete, the mixture was stirred for an additional thirty minutes and then treated with stirring . -26-Z4~

over a period of one hour with a solution of 9.9 g. ~0.127 mole) of acetyl chloride in 150 ml. of tetrahydro~uran while maintain-ing the temperature at -70C. The reaction mixture was then worked up in the manner described above in Example 1, and the crude product recrystallized from hexane to give 18.2 g. (40~) of ethyl 7-methoxy-1,4~,5~C-trimethyl-3-(1-oxoethyl)-1,2,3,4, 4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate, m.p. 120-123~C.
(Step 2A) A solution o~ 1.23 g. (0.0032 mole) of the latter in 22 ml. of mesitylene and 81.8 ml. of 97% formic acid was heated under reflux for nineteen hours and then wor~ed up in the manner described above in Example 3. The product was isolated in the form of the free base to give 0.36 g. (36%) of 8-methoxy-3,6(e~),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocir.e, m.p~ 67-69C. (14% ov~rall y.teld rom the oxigilal starting material).
. B. The Prior Process (Step lB) A solution of 10.0 g. (0.029 mole) of ethyl

7-methoxy-1,4ao~,5OC-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5~methanobenzolg]quinoline-3-carboxylate in 100 ml. of ethanol and 50 ml. of water containing 2 g. (0.05 mole) of sodium hydroxide was heated under reflux for about sixteen hours and then concentrated to a small volume. The residue was diluted with about 20 ml. of water, and the pH was adjusted to about - 25 6.5-7.0 with dilute hydrochloric acid. The mixture was diluted with 200 ml. o~ ethanol, filtered, and the filtrate taken to dryness in vacuo. After drying the residue by repeated concen-tration from bolling benzene and toluene, the product was crystallized from acetonitrile to give 7.9 g. (`~ 100%) of 7-methoxy-1,4a~G 5dC-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-~ methanobenzo~ uinoline-3-carboxylic acid, m.p. 118-121C.

Z~3 (Step 2B) A solu~ion of 3.15 g. (0.010 mole) of the latter in 50 ml. of anhyarous t~trahydrouran was trca~ed drop-.
wise ~ith stirring under a nitrogen atmosphere with 20 ml.
(0.020 mole) of a 1.7 molar solution of me~hyl lithiun. The mixture was stirred for about thirty minutes c~nd then poured into a solu~ion containing 10 y. of a~r,onium chloric'e in 100 ml.
of ~ater The mixture ~;as extrac~ed t~ice with eth~r, the et~er extracts dried over masnesium sulfate and taken to dr~ness to give 1.4 g. of a brown oil which was extracted with boiling pentane to give 0.5 g. (16~) 7-methoxy-1,4~;5~-trimethyl-3~ oxoethyl)-1,2,3,4,4a,5,10,10a-octa ~ inolihe.
.
The aqueous layer remaining after extxaction of the crude product : \
with ether was saturated with solid sodium hydroxide, and the oil which separated was dissolved in water, acidified strongly lS and the solid which separated was collected, dried and converted to the hydrochloride salt to give 2.2 g. (0.0062 mole) of the hydrochloride salt (m.p. 295-297C.) of-the startin~ carboxylic acid. The corrected yield for the reaction based on the reco~ered starting material is thus 42%.
.. ~ -~ 20 (Step 3B) A solution of 1.0 g. (0.0032 mole) of ~he .
7-methoxy-1,4a~,5~-tximethyl-3-(1-oxoethyl)-1,2,3,4,4a,5,10, lOa-octahydro-2,5-methanobenzo[g]quinoline obtained in step 2 above was heated in a solution of 22 ml. of mesitylene and 1.8 ml.
of formic acid for a total of sixty-seven hours, the course of the reaction being followed from time to time by thin layer chromatography. The reaction mixture was worked up in the manner described above in Example 3 to give 60 mg. (6~) of 8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine, m.p. 62-65C. The overall yield from the original starting material was 2.5% based on recovered start-ing material in step 2.

~7i ,~

-z~3 .

- The above compounds of Formula II wherein R5 is lower-a].kylthio-lower-alkyl, lower-alkoxy-lower-alkyl, lower-alkoxy, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3-furyl, 2- or 3-furyl-~cH2)ml where m is an integer from 2 to 4,or such 2- or 3 furyl or 2- or 3-furyl-(CH2)m substituted on the unsubstituted ring carbon atoms by from one to three methyl groups ~ and Rl, R2, R2 I R2 ~ R2 ' 3 4 . defined above are novel.
,` , .
' .

' .

. , .
. .

'

Claims (13)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the Formula I

...I

wherein:
R1 is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, halo-lower-alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3-furylmethyl; or such 2- or 3-furyl-methyl substituted on the unsubstituted ring carbon atoms by from one to three methyl groups, phenyl-lower-alkyl, or phenyl-lower-alkyl substituted in the phenyl ring by from one to two members of the group consisting of halogen, lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, amino, lower-alkanoyl-amino or a single methylenedioxy attached to adjacent carbon atoms;
R2, R2', R2", and R2''' are each hydrogen, or three of them are hydrogen and the fourth is halogen, lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, nitro, amino, lower-alkanoyl-amino, lower-alkoxycarbonylamino or phenyl, or two of the adjacent such groups together are methylenedioxy;
R3 is hydrogen or lower-alkyl;
R4 is hydrogen, lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkyl-sulfinyl-lower-alkyl, phenylthio-lower-alkyl, phenyl-sulfinyl-lower-alkyl, lower-alkenyl or halo-lower-alkyl, or R3 and R4 together are divalent lower-alkylene, -(CH2)n-, where n is one of the integers 3 or 4;
R5 is lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkoxy-lower-alkyl, lower-alkoxy, cycloalkyl, cyclo-alkyl-lower alkyl, 2- or 3-furyl, 2- or 3-furyl-(CH2)m, where m is an integer from 2 to 4, or such 2- or 3-furyl or 2- or 3-furyl-(CH2)m substituted on the unsubstituted ring carbon atoms by from one to three methyl groups, phenyl, phenyl-(CH2)m, or phenyl or phenyl-(CH2)m sub-stituted in the phenyl ring by from one to two members of the group consisting of halogen, lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, tri-fluoromethyl, amino, lower-alkanoylamino or a single methylenedioxy attached to adjacent carbon atoms and A1K
is lower-alkyl which comprises reacting a compound having the formula ...Ib with an alkali metal amide and reacting the alkali metal salt thus formed with a compound having the Formula R5''' CO-X, wherein R1, R2, R2', R2", R2''', R3 and R4 are as defined above; R5" and R5''' have the same meanings as R5 above, except that R5''' must represent lower-alkoxy when R5" is not lower-alkoxy; and X is halogen.

2. A process according to claim 1, wherein in the starting compound R1 is lower-alkyl or cycloalkyl-lower-alkyl; R2 is lower-alkoxy; R2', R2" and R2''' are each hydrogen; and R4 is lower alkyl.

3. A process according to claim 1, for preparing ethyl 3-(1-oxohexyl)-7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-1,2,3,4,4a,5,10, 10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate wherein ethyl 7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-1,2,3,4,4a,5,10, 10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate is reacted with lithium diisopropylamide and the resulting salt is reacted with hexanoyl chloride.

4. A process according to claim 1, for preparing ethyl 7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-3-(4-methyl-1-oxo-pentyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]
quinoline-3-carboxylate wherein ethyl 7-methoxy-1,4a.alpha., 5.alpha.-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo[g]quinoline-3-carboxylate is reacted with lithium diisopropylamide and the resulting salt is reacted with 4-methylpentanoyl chloride.

5. A process according to claim 1, for preparing ethyl 7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-3-(4-methylmercapto-1-oxobutyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo [g]quinoline-3-carboxylate wherein ethyl 7-methoxy-1,4a.alpha., 5.alpha.-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo[g]quinoline-3-carboxylate is reacted with lithium diisopropylamide and the resulting salt is reacted with 4-methylmercaptobutyryl chloride.

6. A process according to claim 1, for preparing ethyl 7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-3-(1-oxoethyl)-1,2,3, 4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate wherein ethyl 7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-1, 2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate is reacted with lithium diisopropylamide and the resulting salt is reacted with acetyl chloride.

7. A process according to claim 1, for preparing ethyl 7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-3-(3-phenyl-1-oxopropyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline 3-carboxylate wherein ethyl 7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate is reacted with lithium diisopropylamide and the resulting salt is reacted with 3-phenylpropionyl chloride.

8. A process according to claim 1, for preparing ethyl 3-(3-cyclopentyl-1-oxopropyl)-7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo [g]quinoline-3-carboxylate wherein ethyl 7-methoxy-1,4a.alpha., 5.alpha.-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo[g]quinoline-3-carboxylate is reacted with lithium diisopropylamide and the resulting salt is reacted with-3-cyclopentylpropionyl chloride

9, A process according to claim 1, for preparing ethyl 3-(3-cyclopropyl-1-oxopropyl)-7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo [g]quinoline-3-carboxylate wherein ethyl 7-methoxy-1,4a.alpha., 5.alpha.-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo[g]quinoline-3-carboxylate is reacted with lithium diisopropylamide and the resulting salt is reacted with 3-cyclopropylpropionyl chloride

10. A compound of the Formula I as defined in claim 1 or 2 when prepared by the process according to claim 1 or 2, respectively, or by an obvious chemical equivalent thereof

11. Ethyl 3-(1-oxohexyl)-7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo [g]qulnoline-3-carboxylate, ethyl 7-mothoxy-1,4a.alpha.,5.alpha.-trimethyl-3-(4-methyl-1-oxopentyl)-1,2,3,4,4a,5,10,10-octahydro-2,5-methano-benzo[g]quinolinoe-3-carboxylate or ethyl 7-methoxy-1,4a.alpha., 5a-trlimethyl-3-(4-methylmercapto-1-oxobutyl)-1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate when prepared by the process according to claim 3,4 or 5, respectively, or by an obvious chemical equivalent thereof.

12. Ethyl 7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-3-(1-oxoethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate, ethyl 7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-3-(3-phenyl-1-oxopropyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate or ethyl 3-(3-cyclopentyl-1-oxopropyl)-7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-1, 2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate when prepared by the process according to clalm 6,7, or 8, respectively,by or by an obvious chemical equlvalent.

13. Ethyl 3-(3-cyclopropyl-1-oxopropyl)-7-methoxy-1,4a.alpha.,5.alpha.-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate when prepared by the process according to claim 9, or by obvious chemical equivalent thereof.