CA1089859A - Preparation of 2-azabicyclo [2.2.2]-oct-5-enes - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
6(eq)-R4-1,2,3,4,5,6-Hexahydro-3-R1-11(ax)-R3-11(eq)-CH2Z-2,6-methano-3-benzazocine, useful as analgesic age?ts and narcotic antagonists, and 1-R1-2-Q-4?-R3-5?-R4-1,2,3,4,4a,5,10,-10a-octahydro-3,5-ethano- (and 3,5-ethano) benzo[g]quinolines, use-ful as analgesic agents, the former being prepared by heating, with formic acid in an organic solvent or with certain ammonium formates in the absence of a solvent, certain 1,2,3,4,4a,5,10,10a-octahydro-2,5-methanovenzo[g]quinolines, the latter being prepared by acid catalyzed cyclization of a 3-benzyl-2-azabicyclo[2.2.2]oct-5-ene.

Description

1¢~ D.N. 7198A

This invention relates to ll(eq)-substituted-2,6-methano-3-benzazocines useful as analgesics and narcotic antagonists.

2,6-Methano-3-benzazocines substituted in the ll-posi-tion with a lower alkyl group are known (See for e~ample United States Patent 2,924,603, patented February 9, 1960). Moreover, it is known tha~ compounds in the 6,14-endo-etheno and ethano-tetrahydrothebaine and 6,14-endo-etheno- and ethanotetrahydroori-pavine series having ketone, carbinol or lower-alkenyl groups at the 7-position thereof have unusual analgesic potency relative to morphine. lSee Bentley et al., J. Am. Chem. Soc. 89, 3267-3292 (1967)]. Consequently there has been much interest in the field of analgesics in incorporating the ketone, carbinol or lower-alkenyl function present in the latter series at the ll-position of 2,6-methano-3-benzazocine;type analgesics, but all ~ynthetic efforts in this direction have previously been unsuccessful.
The invention relates to certain 7-R2"-8-R2-9-R2'-6-~eq)-R4-1,2,3,4,5,6-hexahydro-3-R~ ax)-R3-ll(eq)-CH2Z-2,6-methano-3-benzazocines, where Z i9 a ketone, carbinol or lower-alkenyl function and Rl, R2, R2', R2", R3 and R4 are hydrogen, lower al~yl or other organic groups more specifically defined hereinafter, which are useful as analgesics and narcotic antagon-iQts. Said compounds can be depicted by the general Formula I:

R ~ ~ ~ 1 Ri' R4 ...I
~ he invention also relateQ to certain 6-R2"-7-R2-8-R2'-l-Rl-2-Q-4aa-R3-Sa-R4-1,2,3,4,4a,5,10,10a-octahydro-3~5-etheno-tand 3,5-ethano-1 benzotg~quinolines~ where Q is H2, oxo or certain organic groups more ~peclfically defined here~nafter, which are useful as analges~c agent9.
The invention further relates to certain 6-R2"-7-R2-8-- 1 - ~e 1~9~

R2'-1-Rl-3-Y-4ao~-R3-5a-R4-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzolg]quinoline~, where Y i9 certain oxygenated functions more ~pecifically defined hereinafter which are useful as inter-mediates for the preparation of the above-de~cribed hexahydro-2,6-methano-3-benzazocines, certain species being also useful a8 analgesic agents.
~he invention further relates to certain 2-Rl-3-(4-R2-

3-R2'-5-R2"-benzyl)-4-R3-5-R4-7-Y'-2-aZabicYClo[2.2-2]0Ct~5~
ene~, where Y' i8 carboxy, cyano, carbo-lower-alkoxy or lower alkanoyl, which are useful as intermediates for the preparatlon of the above descriked octahydro-2,5-methanobenzotg1quinol$nes and hexahydro-2,6-methano-3-bensazocines.
n 7 R2 8 R2-9-R2 -6~oq)-R4-l,2,3,4,5,6-heXa-hydro-3-R~ ax)-R3-ll~eq)-C~2Z-2,6-methano-3-benzasocines can be prepared by heating with formic acid in an inert organlc solv-ont or with a bonzyl-dl-lower-alkyl-ammonium formate or a tri-lower-alkylammonium formate certain 6-R2n-7-R2-8-R2'-l-Rl-3-Y-4aa-R3-Sa-R4-l,2,3,4,4a,5,lO,lOa-octahydro-2,5-methanobenzo~g]-qulnoline-. Sald proaoss als~ prepares certaln 6-R2"-7-R2-8-R2'-l-Rl-2-Q-4a~-R3-5-R4-l,2,3,4,4a,5,lO,lOa-octahydro-3,5-etheno-benzo[g]quinol~nes.
2 8 R2 9 R2 -6~eq)-R4-l,2,3,4,5,6-hoxahydro-3-Rl-ll~ax)-R3-ll~eq)-CH2Z-2,6-methano-3-benzazocine~ of Formula I and other novel lntermediates u~oful ln their preparation can be obtained according to the invention by novel reactions, includ-ing molecular rearrargements involving novel intormedlate~, according to tho generai reaction ~equence as follows:

1R~89859 ~R

+ ~

4 VII
VIII
~ H2~' Rl 1 b IRl ~11 S~' ~\8 i8 H, Y i8 COR5) IV ¦
IIIa tQ i9 RS) \ ~Rl ~ R2~ [,H

A R2--~ R8 II R2~Y

TR (R8 i8 H) I (Z 1~ Y 18 ~H) I~

I (Z l~ ~CH~H) I ~Z i~ R5R~) H H

h3 R3 R4 ~

IV (R~ H; Y~ is OOORg~ IV H

R n R lH] R2~ R4 IIIa (Q i~l H2; Rl i8 H) \ IIIa ~R~ H, Q i8 COII~) 7~ ~
2 ~ ~H~ Q

IIIb IIIa ~Q i~l H2) ~

7L ' ~Q

IIIa -` 1089~

In accordance with the present invention there is provided a process for preparing a compound of the formula ~Rl ~ ~ IV

which comprises react$ng a oompound of the formula R ~ ~1 R ~ VIII

with CH2~CHY', wherein Rl is hydrog~n, low~r-alkyl, lower-alk-nyl, lower-alkynyl, halo-lower-alkenyl, cycloalkyl, cycloalkyl-low~r-alkyl, 2- or 3-furylm thyl, or such 2-or 3-furylm-thyl substituted on tho ~nsubstituted ring carbon atoms by from one to thr~o methyl groups, phsnyl-lo~ r-alky1, or phenyl-lower-alkyl substltut~d in the ph nyl ring by from on~ to two members of the group con-~l-tlng of halogen, low~r-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, amino, low r-alkanoylam$no or a singl- m thyl-n dioxy attachea to ad~ac-nt carbon atomss R2 and R2' are each hydrogen, or on of th~m 18 hydrog n and the oth~r 18 halog-n, lower-alkyl, hydrexy, lower-alkanoyloxy, lower-alkoxy, lower-alkylm~rcapto, trifluoromethyl, nltro, am$no, lower-alkanoyl-umlno, lower-alkoxycarbonylam$no or ph nyl, or R2 and R2' g th~r ar- methyl-n dloxy~ R3 is hydrQgen or lower alkyl;
R~ 1- hydrog n, low r-alkyl, low-r-alkoxy-lower-alkyl, hy~roxy-low r-alkyl, lower-alkylthlo-lower-alkyl, lower-alkyl~ulf$nyl-lower-alkyl, ph nylthlo-lower-alkyl, phenyl-rul~lnyl-low-r-alkyl, low r-alkenyl or halo-lower-alkyl, or R3 and R4 together are divalent lower-alkylene, -(CH2)n~, where n i8 3 or 4; and Y' i~ carboxy, cyano, carbo-lower-alkoxy, COQ-lower-alkylene-cycloalkyl, COO-lower-alkylenephenyl or lower alkanoyl -4a-.

J

~0 8 ~ the 7 ~2 8-R2-9-~2~-6(eq)-R4-l~2~3~4~s~6-hexa-hydro-3-Rl-ll(ax) -R3-11 (eq)-CH2Z-2,6-methano-3-benzazocines hav-ing the Formula I are prepared via any of ~everal method~ from iate 6 R2 7-R2-8-R2'-l-Rl-3-y-3-R8-4a~-R3-s~-R4-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzotg]quinollnes of Formula II, which them~elves are obtained from tho 2-Rl-3-(4-R2-3-R2'[or R2l~]-benzyl)-4-R3-5-R4-7-yl-2-~zA~icyclol2 2~2loct

5-enes of Formula IV which, in turn, are preparoa according to ~tandard procedures by reaction of a Grign~rd reagent dsrlvod from a 4-R2-3-R2'(or R2")-ben~yl halide of Formula VI with a 3-R3-4-R4-1-Rl-pyr~dinium halide of Formula VII and roaction of g ~4 R2 3-R2 lor R2"]-benzyl)-3-R3-4-R -1 2 dl hydropyridine of Formula VIII with a dienophile, CH2-CHY' Th-

6-R2 ~7-R2-8-R2l-l-Rl-2-Q-4a~-R3-5~-R4-l~2~3~4~4a~5~lor hydro-3,5-othenobenzo[g]quinolines of Formula IIIa are obtained along wlth certain compounds of Formula I from the compounas of ~ormula II where Y is COR5 and R8 is hydrogen, and tho compounds of Formula lIIa are also obtainable by rearrang~ment of a 3-~4-R2-3-R2'tor R2~]-bonzyl)-4-R3-s-R4-2-azabicyclot2 2 21oct-5-ene-

7-carboxyll¢ acid est-r of Formula IV to a l-R3-2-(4-R2-3-R2'-tor R2~]-benzyl)-8-lower-alkylla-ne-3-azabicyclot3 3 1] non-6-on-4-one of Formula V and oyclization of th- lattor to a 6-R2 n _7_ R2-8-R2l-2-oxo-4a~t-R3-5~-R4-l~2~3~4~4~s~lo~loa-octahydro-3~s-oth~nob-nzo[q]quinolin- ha~ing the Formula lIIa The compound-of Formula IIIa can be catalytically reducoa to tho 6-R2~-7-R2-

8-R2'-1-Rl-2-Q-4sx-R3-5~-R4-1,2,3,4,4a,5,10,10a-octahydro-3,5-thanobonzotg]quinolino~ of Formula IIIb In the flnal products and ~ntorm diato~ doplct-d ln th- abo~Q reaction sequonce~
Rl i8 hydrogen, lowor-alkyl, lower-alkonyl, low r-alkynyl, halo-low-r-alk-nyl, cycloalkyl, cycloalkyl-low r-alkyl, 2- or 3-furylmethyl, or ~uch 2- or 3-furylmethyl substitut-a on tho unJub~tituted ring aarbon atoms by from one to three mothyl 5_ i~89t~9 group~, phenyl-lower-alkyl, or phenyl-lower-al~yl ~ubstitut~d in the phenyl ring by from one to two members of the group con~ist-ing of halogen (including bromine, chlorine and fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmer-capto, trifluoromethyl, amino, lower-alkanoylamino or a ~ingle methylenedioxy attached to adjacent carbon atom~;
R2, R2' and R2" are each hydrogen, or two of them are hydrogen and the third is halogen ~including bromino, chlorine or fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, nitro, amlno, lower-alkanoylamino, low~r-alkoxycarbonylamino or phenyl, or R2 and R2' or R2 and R2" together are methylenedioxy;
R3 i8 hydrogen or lower-alkyl;
R4 i~ hydrogen, lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkylthlo-lower-alkyl, lower-alkyl-sulfinyl-lower-alkyl, phenylthlo-lower-alkyl, phenylsulfinyl-lower-alkyl, lower-alkenyl or halo-lower-alkyl, or R3 and R4 together are divalent lower-alkylene, -~CH2)n-, where n 1~ 3 or 47 R4' 1~ hydrogen or lower alkyl;
Z 1~ one of the groups -C~COR5, -C-C~ 5 or a group of tho formula -C~ - C - OR7 where R5 and R6 are the same or different hydrogen,-lower-alkyl, phenyl or phenyl-lower-alkyl;
R7 is hydrogen, lower-alkanoyl, benzoyl or benzoyl sub-~tituted by from one to three mombers of tho group consistlng of lower-alkyl, lower-alkoxy, hydroxy, halo (including chlorino, bromine and fluorine) or tri~luoromethyl;

.. . . . . . . . .

- 16389~9 R8 is hydrogen or lower-alkyl;
Rg i~ lower-alkyl, cycloalkyl-lower-alkyl or phenyl-lower-alkyl;

Q is oxo ~=o), H2, < , ~ or lower-alkyl phenyl H
\ lower-alkylphenyl;
Y is carboxy, cyano, carbo-lower-alkoxy, COR5, COO-lower-alkylene-cycloalkyl, COO-lower-alkylene-phenyl, or a group of the formula:

0 Y ~ i8 carboxy, cyano, carbo-lower-alkoxy, COO-lower-alkylene-cycloalkyl, COO-lower-alkylene-phenyl or lower alkanoyl;
and Hal is halogen.
As used heroin, the terms lower-alkyl or lower-alkoxy mean saturated, acyclic group~ which may be straight or branched oontaining from one to about seven carbon atoms as exemplified by methyl, ethyl, propyl, i~opropyl, butyi, non-ad~acent t-butyl, methoxy, ethoxy, propoxy, isopropoxy, or t-bu~oxy.
As used herein, the terms lower-alkenyl, halo-lower-alkenyl and lowor-alkynyl reprosent monovalent groups of from throe to ~even carbon atoms containing one double or triplo bond as illu~tratod, for example, by l-proponyl, 2-butonyl, 4-pontenyl, 3-methyl-2-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-propynyl, 2-butynyl, 4-pentynyl, 2-hexynyl, and the l~ke. ~he term halo-lower-alk-nyl lncludes, for example, 2-chloroethenyl, 2-bromoethenyl, 3,3-dichloro-2-propenyl, 1-bromo-2-methylprop~nyl, and the lik-.`
As u d hereln, the torm cycloalkyl means saturated c rbocyclic groups containlng from throe to six ring carbon atoms as illu~trated, for example, by cyclopropyl, cyclobutyl, .

-- ~... .. ;., . - . , cyclopentyl, cyclohexyl, 2-methylcyclobutyl, 4-ethylcyclohexyl, and the like.
As used herein, the term lower-alkanoy~ means such groups derived from saturated, aliphatic monocarboxylic acid~
having from one to four carbon atoms, as illustrated, for example, by formyl, acetyl, propionyl, butyryl, isobutyryl, and the like.
As used herein, the term lower-alkylene meanq a saturated, divalent raaical, which can be straight or branched, and having from one to ~our carbon atoms, as illustrated, for example, by methylene 1-CH2-], 1,2-ethylene ~-CH2CH2-1, 7,3-propylene [-CM2CH2CH2-], 1,2-~1-methylethylene)[-CH~CH3)CH2-], 1,4-butylene [-CH2CH2CH2CH2-], and the like.
~.s determined by standard pharmacological test pro-cedures to be described hereinafter, the compounds of Formula I
and certain specie~ of Formula II have been found to have useful analge~ic activity, and as disclosed following Example 38~ infra, some compounds of Formula I have also been found to have useful narcotic antagonist activity. The compounds of Formula I are thus useful as analgesic agents and narootic antagonist9, and certain species of Formula II are useful a~ analgesic agents.
The compounds of Formula III have also been found to have analge~-ic actlvity and are thus useful as analgesic agents.
In ac~ordance with the above general de~cription, the 7-R2"-8-R2-9-R2'-6~eq)-R4-1,2,3,4,5,6-hexahydro-3-Rl-ll(ax)-R3-ll(eq)-C~2Z-2,6~methano-3-benzazocineR of Formula I where Z i8 I~COR~ or C~ ~ 1' 2' R2 ~ R2 ~ R3, R4, R5, R6 and R
R8 ~8 have the meanings given above are prepared by heating, with formic acid in an organic solvent, for example, toluene, xylene or mesitylene, or with a benzyl-dl-lower-al~ylammonium or a tri-lower-alkylammonlum formate, a 6-R2-7-R2-3-R2'-1-Rl-3-Y-3-R8-4ad~R3-5o~R4-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[glqu~noline of Formula II where R8 i8 hydrogen and Y is either COR5 (to give the 108~9 compounds of Formula I where Z is CH2COR5) or the group:

where R7 is hydrogen (to give the compounds of Fon.lula I where ,R5 Z is CH=C~ ). A preferred solvent is mesitylene. The compound~
of Formula II where Y is COR5 or the group where R7 is hydrogen are thus intermediates for preparing the compounds of Formula I where Z is, respectively, the groups ,R5 -CH2COR5 or -CH=C\
The compounds of Formula I where Z is -CHCOR5 , where R8 i~ lower-alkyl, are prepared by treatment of the compound~ of Formula IIB, where R8 is hydrogen and Y is a proton activating group~ i.e., an ester or keto (COR5) group, with a strong base, for example a lithium di-lower-alkylamide, a preferred base being lithium di-isopropylamide, and roaction of the re~ulting lithium salt with a iower-alkyl ester of a strong mineral acid, for ex-ample, a lower-alkyl halide or a di-lower-alkyl sulfate. The ester or keto group Y in the compoùnds of Formula IIA thus obtain-ed can then be converted to other groups, for example -C-OR7 , before conversion of the latter to the compound of ~!s , Formula I where Z is -7H-I-OR7 and R8 18 lowsr-al~yl by heating the compounds of Formula II whero R8 is lower-alk~l with`formic _9 _ J8~SS~
acid in an organic solvent or with a benzyl-di-lower-alkyl-ammonium or tri-lower-alkylammonium formate as described above.
As indicated in the above reaction sequence, alkyla-tion of the compounds of Formula IIB via the lithium salt results in epimerization of the Y group. The group Y in the compounds of Formula IIB as obtained by cyclization of the compounds of Formula IV normally possess the ~-configuration, i.e., the group Y is cis to the 2,5-methano bridge (vide infra), but alkylation of the compounds of Formula IIB via the lithium salt results in compounds where the group Y is in the a-configuration (trans to the 2,5-methano bridge), and the R8 lower-alkyl group is in the ~-configuration. In fact, the compounds of Formula IIA where R8 is hydrogen and the Y group is in the a-configuration can be prepared from the ~-Y compounds (Formula IIB) by treatment first with a strong base and then with acid. In view of the fact then that either of the groups Y and R8 in the compounds of Formulas IIA and IIB, respectively, can occupy either the a or the ~ con-figuration, the compounds of Formula~ IIA and IIB can be generally repre~ented by the formula:

~ ~

R " R ...II
wherein R8 can be lower-al~yl only in the ~-configuration.
~he compounds-of Formula I where Z is the group:

where R7 is hydrogen and R5, R6 and R8 have the meanings given above are prepared from the corresponding compounds where Z i8 the group -I-C~ 5 by hydroxylation of the latter, for example, with concentrated sulfuric acid and hydrolysis of the re~ulting hydrogen sulfate ester. The compounds of Formula I where Z is the group -C=C~ are thus intermediates for the carbinols of ¦8 R6 Formula I.
The compounds of Formula I where Z is the group where each of R6 and R7 is hydrogen and R5 and R8 have the mean-ings given above are prepared by selective reduction of the corresponding compounds where Z is -CHCOR5. When R5 is hydrogen, the selective reduction i5 carried out with an alkali metal aluminum hydride in an inert organic ~olvent such as dioxane, tetrahydrofuran or diethyl ether at temperatures in the range from about 0C. to 100C. When R5 is lower-alkyl, phenyl or phenyl-lower-alkyl, the reduction i8 carried out with an alkali metal borohydride in an inert organic solvsnt, for example lower-alkanols, ~uch as methanol, ethanol or isopropanol.
The compounds of Formula I where Z i8 f R5 and R6 are each lower-alkyl, phenyl or phenyl-lower-alkyl, R7 is hydrogen and R8 is hydrogen or lower-alkyl are prepared by reaction of the corresponding compounds where Z is -f coR5, where R5 is lower-alkyl, phenyl or phenyl-lower-alkyl with one molar equivalent of an appropriate organo lithium, R6Li, where R6 ha~
the meaning given above. The reaction i9 carried out in an inert organic solvent ~uch as benzene or toluene. In this manner com-pounds where R5 and R6 are either the same or different lower-alkyl, ?~'3 phenyl or phenyl-l~wer-alkyl groups can be prepared depending upon the identity of the R5 group and the choice of the particular organo lithium.
The compounds of Formula I where Z is -CH ~ F - OR7 , R5 and R6 are each hydrogen or the same or different lower-alkyl, phenyl or phenyl-lower-alkyl, R8 has the meanings given above, and R7 is lower-alkanoyl, benzoyl or substituted-benzoyl are pre-pared by esterification of the corresponding compounds where R7 is hydrogen, for example with an appropriate acid halide, anhydr-ide or other acylating agent. The reaction is advantageously carried out using an appropriate acid halide in a pyridine solv-ent which serves as an acid acceptor to take up the hydrogen halide split out during the course of the reaction.
The compounds of Formula I where Rl is lower-alkenyl, lower-alkynyl, halo-lower-alkenyl or 2- or 3-furylmethyl (or such 2- or 3-furylmethyl substituted by from one to three methyl groups) are advantageously prepared from the corre~ponding com-pounds where Rl is hydrogen by reaction of the latter with an appropriate lower-alkenyl halide, lower-alkynyl halide or halo-lower-alkenyl halide, a~ the case may be, in an inert organic solvent, for example a lower-alkanol, acetone or dimethylform-amide (hereinafter designatQd DM~), in the presence of an ac~d-acceptor, for example, an alkali metal carbonate or bicarbonate.
A preferred solvent is DMF.
The compounds of Formula I where R2, R2', or R2" is lower-alkanoyloxy are advantageou~ly prepared from the correspond-ing compound~ where R2, R2' or R2" i~ hydroxy by esterification with an appropriate lower-alkanoyl hal~de in the presence of pyrid~ne.
The compounds of Formula I where R2, R2' or R2" is 10~ 3 amino are prepared by hydrolysis of the corresponding compounds where R2, R2' or R2" is lower-alkanoylamino or lower-alkoxycarb-onylamino by heating the latter in aqueous alkali.
Alternatively, the com~ounds of Formula I where R2, R2' or R2" is amino are prepared by reaction of the compounds of Formula I where Z is -CH-COR5 and Rl is hydrogen with nitric acid in glacial acetic acid. The reaction is carried out at tempera-tures from 0 to 5C. The resulting nitro compound is then alkylat-ed as desired in the manner described above to prepare compounds where Rl has the other various meanings given above, and in a final step, the nitro group is reduced to the corresponding amino group by either catalytic means, for example with hydrogen over palladium-on-charcoal, or by chemical means, for example by iron and hydrochloric acid or by tin and hydrochloric acid.
As indicated in the reaction sequence qhown above, the 2 R2 8 R2 1 R1~2~Q~4a~~R3-S~-R4-1,2,3,4,4a,5,10,10a-octahydro_ 3,5-ethenobenzo~q7quinolines of Formula IIIa where Q is H2~
H < or ~ are produced lower-alkyl, phenyl lower-alkylphenyl along with the compounds of Formula I (where Z is -CH2COR5) when the compounds of Formula II where Y is COR5 and R8 is hydrogen are heated with formic acid in an organic solvent or with a benzyl-di-lower-alkylammonium formate or a tri-lower-alkylammonium formate as described above. When the benzazocines of Formula I are the desired product, it is preferred to carry out the reaction in mesitylene u3ing a concentration of 0.05 molar in st~ing material of Formula II and 1.0 molar in formic acid. This mixture gives a reaction temperature at reflux of about 120C. and affords the benzazocines of Formula I and the benzo~g~quinolines of Formula IIIa in a ratio of from 2:1 to 3:1. By progressively decrea~ing the formic acid concentration, successively higher boiling mixtures are produced, which result in production of progressively increased relative amounts of the benzo~g~quinolines. Thus at formic acid concentrations of 0.5 molar and 0.15 molar(and 0.05 m~lar in sta~ing 1(~8~5~material), the benzo/g~quinolines and benzazocines are produced in ratios of about 2:1 and 7:1, respectively. Similarly, by u~ing a ratio of 1 mole of starting material to 5 moles of, respective-ly, benzyldimethylammonium formate or trimethylammonium formate or triethylammonium formate and heating the mixture (in the ab~ence of any organic solvent) at 150C. for about fifteen minutes, a mixture of benzotg~quinoline and benzazocine is pro-duced in ratios of 10:1, 3:1 and 20:1, respectively.
The two transformations thus take place simultaneously under the given conditions and are best seen by reference to the reaction sequence:
Rl 2 ~ N-Rl R2 ~ N ~ Q
~ CH2CH(Rg)COR5 R2 ~ ~R3 R ~ "R8 R " ~ R2 4 I (Z Ls -C -COR5~ ~ IIIa R ' ~ ~ -~b) R2" ~4 3 R8 Il ~Y is COR5) ere Rl~ R2~ R2 ~ R2 ~ R3 ! R4~ Rs~ R8 and Q have the meaning8 given above. It will be seen from the above that the compound~
of Formula I result by rupture, under the reaction conditions, of bond (b) in the compounds of Formula II, whQrQas the compounds of Formula IIIa re~ult when bond (a) i8 broken, followed by ring clo~ure between the nitrogen atom and the carbonyl group of the COR5 moiety.

1~85~SS

The compounds of Formula IIIa, where Q is oxo (=0), Rl is hydrogen and R4 is lower-alkyl are prepared by reaction of a 3-(4-R2-3-R2'[or R2~]-benzyl)-4-R3-5-R4-7-yl-2-azabi-cyclot2.2.2]-oct-S-ene of Formula IV, where R~ hydrogen and Y' i9 COORg with an alkali metal lower-alkoxide in a lower-alkanol solvent at a temperature in the range from 20 to 80C. followed by heating the resulting l-R3-2-~4-R2-3-R2'tor R2"]-benzyl-8-lower-alkylidene-3-azabicyclo[3.3.l]-non-6-en-4-one of Formula V, with a mineral acid. The method i8 represented by the reaction sequences:

R2~_ _(C) OO-Rg R
H
Z ~3 4' R2 ~f 2 R~ IIIa As indicated, the rearrangement of the compounds of Formula IV to the compounds of Formula V takes place by cleavage of the bond designated (c) in Formula IV, cyclization of the e~ter group, COORg, to the nitrogen atom with formation of the lactam, shift of the endocyclic double bond and generation of an exocyclic double bond with loss of a proton from the R4 lower-alkyl group. ~t will also be seen from the abo~e-depicted re-action sequence that cyclization of the compounds of Formula V
to the compounds of Formula III can take place either at the 1-or the 6-position of the benzyl group to give rise to compounds of Formula IIIa where the R2' (or R2") group occupie~ either the 6- or 8-position of the latter.
Furthermore, it will also be appreciated that the cyclization affords the compounds where both the R3 and R4 groups are in the a-configuration, i.e. trans to the 3,5-etheno bridge ~vide infra).
The compounds of Formula IIIa where Q i8 H2 and Rl is hydrogen are prepared by reduction of the corre~ponding compounds where Q i8 OXO (=O) with an alkali metal aluminum hydride. The reaction takes place in an organic solvent inert under the condi-tions of the reaction, for example diethyl ether, dibutyl ether, tetrahydrofuran, dioxane and the like, at a temperature in the range from 20C. to 100C.
The compounds of Formula lIIa where Rl is other than hydrogen are advantageously prepared by reaction of the compounds where Rl i~ hydrogen with an appropriate lower-alkyl, lower-alkenyl, lower-alkynyl, halo-lower-alkenyl, cycloalkyl, cyclo-alkyl-lower-alkyl, 2- or 3-furylmethyl (or 2- or 3-furylmethyl ~ub~tituted by from one to three methyl groups), phenyl-lower-alkyl or sub~tituted-phenyl-lower~alkyl ester of a strong mineral acid, such as e~ter~ of hydrochloric, hydrobromic or sulfuric acid. ~he reaction is preferably carried out in the presence of an acid-acceptor, for example an alkali metal carbonate or bi-~16-carbonate, and in an inert organic solvent such as methanol,ethanol, acetone, isopropanol and the like.
The 6-R2 ~7-R2-8-R2'-1-Rl-2-Q_4a~_R3_5~_R4_1,2,3,4,_ 4a,5,10,10a-octahydro-3,5-ethano~enzo[g]quinolines of Formula IIIb are prepared by catalytic reduction of the corresponding 3,5-etheno compounds of Formula IIIa with hydrogen over a palladium-on-charcoal catalyst using an inert organic solvent, for example methanol, ethanol or isopropanol.
2 2 8 R2 ~1~Rl~3~~Y-4a~-R3-sd~R 1 2 3 4a,5,10,10a-octahydro-2,5-methanobenzolg]quinolines of Formula II
which, as described above, serve as key intermediates for the preparation of the final products of Formulas I, IIIa and IIIb are in turn prepared as follows:
The compounds of Formula II where Y is carboxy, cyano, carbo-lower-alkoxy, COR5 where R5 is lower-alkyl, COO-lower-alkyl-ene-cycloalkyl or COO-lower-alkylene-phenyl are prepared by the acid catalyzed cyclization of an appropriate 2-Rl-3-(4-R2-3-R2'-lor R2"]-benzyl)-4-R3-5-R4-7-Y'-2-azabicyclo{2.2.21oct-5-ene of Formula IV. The reaction is carried out by adding the starting material of Formula IV to the acid and either allowing the reaction mixture to stand at a temperature in the range from about 0C. to about 10C. or heating to about 100C.` Preferred acids are hydrofluoric`acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like. A particularly preferred acid is hydrofluoric acid.
A~ in the case of the cyclization of the compounds of Formula V to the compounds of Formula IIIa, cyclization of the compounds of Formula IV to the compounds of Formula II can take place at either the 1- or the 6-position of the benzyl group to produce compounds of Formula II where the R2' (or R2") group occupies either the 6- or the 8-position of the latter. And furthermore, a~ in the cyclization of the compounds of Formula to the compounds of Formula IIIa, cyclization of the compounds 1~8~of Formula IV to those of Formula II affords the compounds where both the R3 and R4 groups are in the ~-configuration, i.e., trans to the 2,5-methano bridge.
Moreover, during the course of the cyclization reaction, various ester or ether groups, [e.g., compounds where Y' in the compounds of Formula IV or Y in the compounds of Formula II is an ester group or either of R2, R2' or R2" is, for example, lower-alkoxy] are often cleaved to the respective carboxylic acid or the phenolic compound, particularly when the reaction mixture 0 i8 heated using, for example, hydrobromic acid. In such cases the products must be re-esterified or realkyla~ed using standard procedures, if the ssters or the ethers are the desired product.
This circumstance is readily obviated, if desired, by use of hydrofluor~c acid as the acid catalyst which only requires a re-action temperature of around 0-10C. Under these mild conditions, e~ter and ether groups remain unchanged during the reaction.
The above described method for the preparation of com-pounds of Formula II i8 particularly advantageous for the prepara-tion of compounds of Formula II where Y i8 carboxy, cyano, carbo-lower-alkoxy, COR5 where R5 i8 lower-alkyl, COO-lower-alkylene-cycloalkyl or COO-lower-alkylene-phenyl. The compounds of Formula II where Y is the group ~5 where R5, R6 and R7 have the meanings given above are advantageou~-ly prepared from the compounds of Formula II where Y has the other meanings gi~en above by methods involving various transformations of the Y group as carboxy, carboxylic acid ester or COR5 a~ de-Qcribed above ~n connection with the preparation of the compounds of Formula I.
The compounds of Formula II where Y is carboxy, cyano, carbo-lower-alkoxy or a group of the formula:
~18-lV~ 5~

where one or both of R5 and R6 i5 hydrogen or lower-alkyl, and R7 has the same meanings as in Formula I can be ~onverted to the compounds of Formula II where Y is a COR5 group by simple chem-ical transformations such as hydrolysis of a nitrile or ester to the carboxylic acid, or saponification of an ester of an hydroxy-methyl-bearing compound (R5, R6 and R7 are hydrogen) and oxida-tion of the hydroxymethyl group to the carboxylic acid.
The acid ~Y is carboxy) or the ester (Y is carbo-lowar-alkoxy, C00-lower-alkylene-cycloalkyl, C00-lower-alkylene-phenyl) can then be reacted with two moles of an appropriate organo lithium, R5Li, to produce the compounds where Y i9 COR5. Com-pound~ of Formula II where R7 and one of R5 and R6 is hydrogen and the other is lower-alkyl, phenyl or phenyl-lower-alkyl can likewise be converted to the compounds where Y is COR5 by oxida-tion. The compounds of Formula II where Y has the above-indicat-ed meanings are thus also useful as intermediates for preparing the compounds of Formula II where Y is COR5, which in turn are useful as intermediates for the preparation of the compounds of Formula I.
~h~ compounds of Formula II where Y i~ the group ~5 where R5 and. R6 are hydrogen, lower-alkyl, phenyl or phenyl-lower-alkyl and R7 is hydrogen, which as indicated abovs ars intermediates for preparing the compounds of ~ormula 1, are pre-pared by saponification of the corresponding compounds where R7 i~ lower-alkanoyl, benzoyl or substituted-benzoyl. The compound~
of Formula II where R~ is lower-alkanoyl, benzoyl or substituted-benzoyl are thus intermediates for the compounds where R7 is hydrogen. The ester forms are useful compound~ for purification of the carbinols and serve as intermediates for the latter.
The compounds of Formulas I or II where Rl is benzyl can be catalytically debenzylated to give the corresponding com-pounds where Rl is hydrogen. The latter can then be realkylated with an appropriate alkylating agent to give other different com-pounds where Rl has the meaning~ given above. Reduction i~
carried out in an inert organic solvent, for example ethanol, isopropanol, and the like, and at pressures from 40 to 100 pound~
0 p~ R. i. A preferred catalyst is palladium-on-charcoal. The alkyl-ation of the compounds of Formula II where Rl is hydrogen is carried out in an inert organic solvent, for example acetone, ethanol or DMF, and in the presence of an acid-acceptor, for example alkali metal carbonates or bicarbonates.
Finally the 2-Rl-3-(4-R2-3-R2'~or R2"]-benzyl)-4-R3-S-R4-7-Y'-2-azabicyclot2.2.2]oct-5-ene~ of Formula IV, which ~erve as intermediates for the preparation of the ~ey intermediates of Formula II are themselves prepared by reaction of a Grignard re-agent derived from a 4-R2-3-R2'(or R2")-benzyl halide of Formula VI with an appropriate 3-R3-4-R4-1-Rl-pyridinium halide of Formula VII followed by Diels-Alder conden~ation of the resulting 2-~4-R2-3-R2'[or R2'~]-benzyl)-3-R3-4-R4-1~2-dihydropyridine of Formula VIII with an appropriate dienophile, CH2-CHY'.
The reaction with the Grignard reagent is carri~d out at a temperature in the range from 0C. to 25C. in an inert organic solvent, for example aiethyl ether, tetrahydrofuran or dibutyl ether and is effected by addition of a solution of the Grignard ~o a suspen~ion of the quaternary salt in the roaction ~olvent. The resulting dihydro compound of Formula VIII is gen-erally not isolated and purified, but rather is carried forward directly to the next ~tep involving reaction with the dienophile without further purification. The reaction of the dihydro com-pounds of Formula VIII with the dienophile can either be carried ~20--` 1089~
out in an excess of the latter as a solvent or in an inert organic solvent such as benzene, toluene or xylene. Reaction is prefer-ably carried out at the reflux temperature of the mixture.
The 3-R3-4-R4-pyridines, from which the quaternaries of Formula VII are prepared, and also the 4-R2-3-R2'(or R2")-benzyl halides, from which the Grignard reagents are prepared, are known classes of compounds.
Due to the presence of a basic amino grouping, the free base forms represented by Formulas I, II, IIIa, IIIb and IV above react with organic and inorganic acids to form acid-addition salts.
The acid-addition salt forms are prepared from any organic or in-organic acid. They are obtained in conventional fashion, for instance either by direct mixing of the base with the acid or, when this is not appropriate, by di3solving either or both of the base and the acid separately in water or an organic solvent and mixing the two solutions, or by dis~olving both the base and the acid together in a solvent. ~he resulting acid-addition salt iB
isolated by filtration, if it i~ insoluble in the reaction medium, or by evaporation of the reaction medium to leave the acid addi-tion salt as a residue. The acid moieties or anions in these saltforms are in themselves neither novel nor critical and therefore can be any acid anion or acid-like substance capable of salt form-ation with the base.
Representative acids for the formation of the acid-addition salts include formic acid, acetic acid, i~obutyric acid~.
alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tannic acid, glutam-ic acid, tartaric acid, oxalic acid, pyromucic acid, citric acid, lactic acid, glycolic acid, gluconic acid, saccharic acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, sallcylic ac~d, 3,5-dinitrobenzoic acid~ anthranilic acid, cholic acid, 2-pyridinecarboxylic acid, pamoic acid, 3-hydroxy-2-naphthoic acid, picric acid, quinic acid, tropic acid, 3-indoleacetic acid, 1q)8~barbituric acid, sulfamic acid, methanesulfonic acid, ethanesulf-onic acid, isethionic acid, benzenesulfonic acid, ~-toluenesulf-onic acid, butylarQonic acid, methanephosphonic acid, acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromie acid, hydriodic acid, perchloric acid, nitric acid, ~ulfuric aeid, phosphoric acid, arsenic acid, and the like.
All of the acid-addition salts are useful as ~ources of the free base form~, by reaction with an inorganie base. It w~ll thu~ be appreciated that if one or more of the characteristics, such as solubility, molecular-weight, physical appearanee, tox-icity, or the like of a given ba~e or acid-addition ~alt thereof render that form unsuitable for the purpose at hand, it can be readily converted to another, more suitable form. For pharma-ceutical purposes, acid-addition salts of relatively non-toxie, pharmaceutically-acceptable acids, for example hydrochloric aeid, laetie aeid, tartarie aeid, and the like, are of course employed.
The compound~ of this invention can exist in stereo-ehemieally isomerie forms, that is, optieal isomers and geometrie isomers. If desired, the isolation or the produetion of a parti-eular stereoehemieal form ean be aeeomplished by applieation ofthe general prineiples known in the prior art. In the nomencla-ture employed for the compounds of Formula I, herein, "ax" ~tands for axial and "eq" for equatorial, and the configuration~ are given with referenee to the hydroaromatie ring. Thus, the 6(eq), ll(ax) compound~ of Formula I are in the eis eonfiguration, whereas the 6~eq), ll~eq) eompounds are in the trans eonfiguration.
In the nomeneiature employed for the eompounds of Formulas II, IIIa and IIIb, again eonfiguration~ are given with referenee to the hydroaromatie ring, and the designation "B" in-dieate~ the ei~ eonfiguration relative to the 2,5 methano bridgeof the eompound~ of Formula II or the 3,5-ethano tor 3,5-etheno) bridge of the eompounds of Formulas IIIa and IIIb. Conver~ely, the designation "~" ind$eates the tran-q eonfiguration relative to 1[)8'~the same groups.
In standard pharmacological test procedures, the com-pounds of Formulas I, IIIa and IIIb and the acid-addition salts thereof have been found useful as depressants of the central nervous system, and more particularly have been found useful as analgesics and as an~agonists of strong analgesics such as phenazocine, meperidine and morphine. In addition, particular species of the compounds of Formula II have been found useful as analgesics.
The compounds of Formulas I, II, IIIa and IIIb can be administered in the same manner as known analgesics and antagon-ists of strong analgesics, i.e., parenterally or orally in any of the conventional pharmaceutical forms, as for instance solu-tions, suspensions, tablets, capsules, and the like.
As described above and as will be seen hereinbelow, many of the species of Formulas I, II, IIIa, IIIb and IV are readily interconvertible by simple and well-known reactions such as reduction, oxidation, hydrolysis, esterification, etheri-fi¢ation, and the like, so that they are also useful as inter-mediates for each other.
The useful properties of the compounds of this inven-tion were demonstrated by standard pharmacological procedures readily carried out by technicians having ordinary skill in pharma-cological test procedures, 80 that the actual determination of the numerical biological data definitive for a particular test compound can be ascertained without the need for any extensive experimentation.
The test procedures used to determine the analgesic and analgesic antagonist activities of the compounds of the in-vention have been described in detail in the prior art and areas follows: the acetylcholine-induced abdominal constriction test, which i8 a primary analgesic screening test designed to measure the ability of a test agent to suppress acetylcholine--" lV8~59 induced abdominal constriction in mice, described by Collier et al., Brit. J. Pharmacol. Chemotherap. 32, 295 (1968); a modi-fication of the anti-bradykinin test, which is also a primary analgesic screening procedure, described by Berkowitz et al., J. Pharmacol. Exp. Therap. 177, 500-508 (1971), Blane et al., J. Pharm. Pharmacol. 19, 367-373 (1967), Botha et al., Eur. J.
Pharmacol. 6,312-321 (1969) and Deffenu et al., J. Pharm. Pharma--col. 18, 135 (1966); the phenyl-~-quinone-induced writhing test, also a primary analgesic screening test, designed to measure the ability of a test agent to prevent phenyl-P-quinone-indueed writhing in mi~e, described by Pearl and Harris, J. Pharmacol.
Exptl. Therap. 154, 319-323 (1966); the rat tail fliek radiant thermal heat analgesie (agonist) test deseribed by D'Amour and Smith, J. Pharmacol. Exptl. Therap. 72, 74 (1941) as modified by Bass and VanderBrook, J. Am. Pharm. Agsoe. Sci. Ed. 41, 569 (1956); and the phenazocine antagonist test, whieh is designed to measure the ability of a test agent to antagonize the effset of phenazoeine in the above-indieated rat tail fliek respon~e te~t, deseribed by Harris and Pierson, J. Pharmaeol. Exptl.
Therap. 143, 141 (1964).
The struetures of the eompounds of this invention were e~tabli~hed by the modes of synthesis, by elementary analyses and by ultraviolet, infrared and nuelear magnetie resonanee speetra. The course of reaetions and homogeneity of the produets were aseertained by thin layer ehromatography.
The manner and proeesg of making and using the inven-tion, and the best mode eontemplated by the inventor of earrying out this invention, will now be deseribed so as to enable any person skilled in the art to whieh it pertains to make and u9e the same. The melting points are uneorreeted unle~s noted other-~ wise.

-`` lU~

Preparation of Intermediates A. A solution of 76 g. (0.6 mole) of benzyl chloride in 450 ml. of diethyl ether was added to a mixture of 14.6 g. (0.6 moles) of magnesium turnings in 150 ml. of dry ether at such a rate as to maintain gentle reflux. The resulting solution was then added by filtration through glass wool to a su~pension of 75 g. (0.3 mole) of 4-ethylpyridine methiodide in 150 ml. of ether. The mixture was stirred for three hours at room tempera-ture, poured into a mixture of ice/water containing ammoniumchloride, and the organic layer was separated, dried, filtered, and diluted with ether to a volume of 900 ml.
The solution containing l-methyl-2-benzyl-4-ethyl-1,2-dihydropyridine was divided into three 300 ml. portions, and each portion was evaporated to dryness, di~solved, respectively, in 200 ml. portions of benzene, toluene and xylene, and the three separate solutions treated with 22 ml. of ethyl acrylate and re-fluxed overnight. The solutions were each allowed to cool, dlluted with diethyl ether and extracted with 150 ml. of lN hydro-chloric acid. The combined extracts were washed once with di-ethyl ether, then basified with 15 ml. of conoentrated ammonium hydroxide and the mixtures each extracted with 150 ml. of diethyl ether. The extracts of the three samples afforded, respectively, 18.2 g~, 20.0 g. and 19.3 g. of product as oils. The three samples were dissolved in diethyl ether and acidified with ethereal hydrochloric acid to give a total of 32.2 g. of ethyl-2-methyl-3-benzyl-5-ethyl-2-azabicyclo[2.2.2~oct-S-ene-7-carboxyl-`
ate hydrochloride, m.p. 189-191C.
~ollowing a procedure similar to that described in Example lA, using either benzene, toluene or xylene as ~olvent, an appropriate 4-R2-3-R2'-benzylmagnesium chloride of Formula VI, an appropriate 3-R3-4-R4-1-Rl-pyridinium halido of Formula VII
and an appropriate dlenophlle, CH2-CHY', the following 2-Rl-3-~25-(4-R2-3-R2'-benzyl)-4-R3-5-R4-7-Y'-2-azabicyclo~2.2,2]oct-5-enes of Formula IV ~re prepared. Unless noted otherwise, the products were isolated and characterized in the form of the hydrochloride salt. The anion of the quaternary of Formula VII is given in parentheses along with the weight of VII used.
Here and elsewhere throughout this specification in subsequent tables, the weights of starting materials (S.M.) and products (Prod.) are given in grams in the appropriate columns hea~ed "Wt. _ ", and melting points of the final products, to-gether with the solvent of recrystallization, are given in thelast column.
Where weights of only one of several reactants are given, the weights of such other reactants can be calculated on a proportionate molar basis from the amounts used in the example reerred to for the preparative procedure employed. In some instance~, the products were neither characterized nor purified, either by di~tillation or recrystallization, but rather were used directly in the next step as isolated from the reaction mixture.
The particular form of the starting material or product, whether base or salt, is specified along with the weights by`use of designation~ such as "base", "HCl", "HBr", etc. to indicate that the weights are given, respectively, for the free base or the hydrochloride, hydrobromide, etc. salts.
~E la Ekam~le Rl/Y' R2/R2' R3/R4 Wt VII~Wt.IV m ~.(C.)~Solv.
lB C~HcCH2 H H 23.4 (Cl-) 196-199 C~0~2H5 H C2H5 15.3 ethan~Vether lC C6HS~H2 CH3O H 117 ~Cl-l 183-186 COCC2Hs H C2H5 76 ethanoVether lD CH3 CH30 H 124 ~~~ 202-204 CCCC2H5 H C2H5 76 ethanoVether l$ CH3 H H 117 trl 237-238 COOC2H5 H ~H3 57 ethanol/ether lF C6HSCH2 H H 109.9 (Cl-) 215-217 COOC2Hs H CH3 114.9 ethanol/ether 85~85~

Example Rl~YI R2~R2 R3/R4 Wt.VII/Wt.IV m P.tC-)/Solv.
lG C6H5 H H 117 (Cl-) 106-111 (a) CO~H3 H C2H5 43-7 ethanol lH C6H5CH2 CH30 H 154 (Cl-) 216-219 COCC2Hs H CH3 120 ethanol/ether lJ CH3 H CH3 75.9 (I-¦ 168-170 CCCH3 H C2H5 26.8 ethanol/ether lK CH3 H CH3 50 (I ) 174 COCH3 H CH3 19.3 ethano Vether lL CH3 H CH3 37.4 (I ) 240-241 Ob) CN H CH3 17 ethanol lM CH3 ~H30 H 165 (I ) 200-202 (c) COCCH3 H CH3 58.8 ethano Vacetone lN C6H5CH2 H H 165 (Cl-) 165-170 (d) CCCH3 H CH3 123.1 ethanoVether lP CH3 H H 27.9 ~I-) 146-149 COOC2H5 H CH2CH2OCH3 6.4 ethanol/ether lQ C3H5-CH2(e) H H 11.6 (Br~) 230 COCC2Hs H CH3 8. 6 ethanol lR CH3 H H 184 (I-) 171-174 COCC2H5 H C3H7 71.3 ethanol/ether lS C6H5CH2 ~H30 H 112 (Cl-) 125-130 oo~H3 H CH3 64.5 ethan~l/ether lT C6H5C 2 H CH3 11.7 (Cl-) 218-220 aOOC2Hs(g) H CH3 6.1 ethanoVether lU C6H5~H2 CH30 CH3 157 (Cl ) 146 o~CH3 H CH3 15.3 ethanol/ether lV C6HscH2 CH30 H 165 (Cl-~ 122-127 CCCH3 H C2H5 105.3 acetone lW C6H5CH2 H CH3 238 (I-) 166-168 CO~H3 H C2H5 36.3 ethano Vether lX C6H5CH2 H CH3 46.8 (Cl ) oil lY CH3 H H 40.0 ~I-) 127-129 ~f) CCCC2H5 H ~H2CH2SC6H5 37 aoebone lZ C6HSCH2 H C2H5 172 (I-) 204-208 COOC2H5 H CH3 54 ethano VethPr l~A CH3 H CH3 149 188-190 a~C2H5 H C2H5 109 ethar~ol/et~r . .

- lV~39~jg Example Rl~Y' R2~R2~ R3/~4 Wt vlI/wt.rv m p.(C.)/Solv.
lAB CH3 CH30 CH3 148 186-188 CCCC2H5 H C2H5 46 ethanol/ether lAC C6H5~H2 H CH3 33.9 214-217 COOC2H5 C2H5 5~5 ethanol/ether lAD CH3 H H 94 167-169 COCC2H5 H H 2.7 ethanol/ether lAE C6H5~H2 H H 25.3 201-203 COCC2H5 H H 0.9 ethanol/o &
lAF CH3 H CH3 50 215-218 COCC2H5 H CH3 27.5 ethano Vether lAG C6H5CH2 CH3O CH3 200 188-195 COCC2H5 H CH3 31.5 (a) Free base.

Cb) Hydkochloride hemiethanolate.
tc) The corre~ponding ethyl ester l~dr~oride prepared similarly using ethyl acrylate as the dienoF~hile has m.p. 205-206C. (from ethanol).
he f~eo base has m.p. 118-120 (fr~m is~pr~s~ol).
(e) C~yclcprq?yl~thyl.
~) QKalate.
(g) q~ car~lic acid (47 g.), m.p. 191-196C. (free base), was prepared by ~ponification of the ester (58.5 g.).
EXAMPLE lAH
A solution of 21.1 g. (0.05 mole) of the ethyl 2,3-di-benzyl-5-ethyl-2-azabicyclol2.2.2]oct-5-ene-7-carboxylate hydro-chloride described above in Example lB was dissolved in a 801u-tion of 100 ml. of lN sodium hydroxide and 100 ml. of ethanol, and ths solution was heated and stirred under reflux for four 30 hours. The ethanol was then removed in vacuo, the m$xture diluted with water and then acidified with glacial acetic acid. Extrac-tion of the mixture with chloroform afforded 21.1 g. of a gummy material which was dissolved in methanol and treated with an ex-cess of methane~ulfonic acid. Tho solid which qeparated on dilu-tion wlth diethyl ether was collected to give lS.l g~ of 2,3-di-benzyl-S-ethyl-2-azabicyclol2.2.2]oct-5-ene-7-carboxylic acid -2a-- lU1~9~S9 methanesulfonate, m.p. 220-222C.
EXAMPLE lAJ
A solution of 10 g. (0.02 mole) of ethyl 2-benzyl-3-(4-methoxybenzyl)-5-methyl-2-azabicyclo[2.2.2]oct-5-ene-7-carb-oxylate hydrochloride described above in Example lH in 100 ml.
of absolute ethanol was reduced with hydrogen over 1.0 g. of 10~ palladium-on-charcoal, and when reduction was complete, the catalyst was removed by filtration and the filtrate taken to dryness. The residue was recrystallized from ethanol/ether to give 7.0 g. of ethyl 3-(4-methoxybenzyl)-5-methyl-2-azabicyclo-12~2~2]oct-5-ene-7-carboxylate hydrochloride, m.p. 173-175C., which on further recrystallization gave material having m.p.
177-179C.
Following a procedure similar to that described in Example lAJ above, the following compounds of Formula IV were prepared, where in each case Rl, R2, R2' and R2" are hydrogen;
R4 i8 CH3 and Y' is COOC2H5. Both compounds were isolated and characterized as the hydrochloride salt.
TABLE lb 20Example R3 Wt.S.M./Wt.Prod. m.p.(C.)/Solvent .
lAX CH3 42.6 223-226 24.2 ethanol/ether lAL H 34.0 160-162 20.1 acetone Following a procedure similar to that described in Example lA, using an appropriate 4-R2-3-R2'-benzylmagnesium chloride of Formula VI, an appropriate 3-R3-4-R4-1-Rl-pyridinium halide of Formula VII and methyl vinyl ~etone as dienophile, the following 2-Rl-3-(4-R2-3-R2'-benzyl)-4-R3-5-R4-7-CH3CO-2-azabi-cyclo[2.2.2]oct-5-enes of Formula IV are prepared, where Y' in each case is COCH3.

108~S~

TABLE lc Example Rl R2/R2 R3/R4 lAM CH3 H H
Cl CH3 lAN CH3 H H
Br CH3 lAP CH3 H H

lAQ CH3 H H

lAR CH3 H H

lAS CH3 H6H~ cHH3 lAT CH3 CH2~o CH3 lAU CH3 H H

lAV CH3 H H
H CH2CH2Cl lAW CH3 H (CH2) lAX CH3 H (CH2) lAY C6Hll HH3S CH3 lAZ 4-BrC6H4CH2cH2 CHH30 CH3 lBA 4-ClC6H4CH2cH2 CH3CONH CH3 lBB 4-FC6H4CH2cH2 H2H50CONH CH3 lBC 4 Cl 3 CH3C6H3CH2CH2 H CH3 lBD 3-CH3C00C6H4cH2cH2 H CH3 lBE 3,4-(CH30)2C6H3cH2cH2 H ` H

lBF 4-CH3SC6H4CH2cH2 HH CH3 lBG 3-CF3C6H4CH2cH2 HH CH3 1~8~

Example Rl R2/R2 R3/R4 lBH 3-CH3CONHC6H4cH2cH2 H CH3 lBJ 3,4-~CH20C6H3CH2cH2 H CHH3 lBK CH3 H H
H CH2CH2ScH3 A. A mixture of 12.3 g. (0.035 mole) of the ethyl 2-methyl-3-benzyl-5-ethyl-2-azabicyclot2.2.2]oct-5-ene-7-carboxylate bydro-chloride, de~cribed above in Example lA, in 125 ml. of 48% aqueou~
hydrobromic acid was stirred under reflux for twenty-four hours and cooled. The solid which separated was collected to give 8.4 g. of l-methyl-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo[g]quinoline-3~-carboxylic acid hydrobromide, m.p. 290-293C., which on recrystallization from water gave material having m.p.
295-299C.
Following a procedure similar to that described in Example 2A, using an appropriate 2-R1~3-(4-R2-3-R2'-benzyl)-4-R3-5-R4-7-Y'-2-azabicyclo[2.2.2]oct-5-ene of Formula IV, the following 7-R2-8-R2'-1-Rl-3~-Y-5a~-R3-~X-R4-1,2,3,4,4a,5,lO,lOa-octahydro-2,5-methanobenzo[g]quinolines of Formula II are prepar-ed, where R2', R2" and R8 in eaeh ease are hydrogen. The eyellza-tion ean be carried out using hydrofluorie acid at 0-15C., eon-centrated ~ulfurie aeid at ambient temperature, or hydrobromic aeid in glacial aeetie ac~d at reflux temperature. The part~-cular acid used to promote reaction in each ca~e i8 identified below by the de~ignations HF, H2804 and HBr, as the ea~e may be.
Unless noted otherwi~e the product~ were isolated aQ the hydro-ehloride salts.

~31-1"'~8~8S9 TABLE 2a ExamPle Rl/y R2 R3/R4 Wt IV/Wt.II m.p.(C.)/Solv.
2B C6HSCH2 H H 42.6 258-260 B r CCOH (a) C2H5 11.5 ethanol/ether 2C CH3 HO H 58.1 293 (c) HBr COOH (b) C2H5 30.2 H20 2D CH H H 50 269 (c) HBr ~ H (a) CH3 36.7 ethanol/ether 2E C6H5CH2 H H 10 109-111 (d) H2S04 COCH3 C2H5 7.1 methanol HF COOC2H5 CH3 7.3 aoe tone 2G CH3 H CH3 10 99-103 (d) H2go4 COCH3 - C2H5 3-7 hexane 2H CH HO (e) H 45.0 283-284 HBr ~ H3 CH3 17.6 ethanol 2J CH B H 88.4 228-229 FRr ~ C2H5 C3H7 23.3 iscpropanol 2K C~H~CH2 CH~O H `5.0 126-12g (d) HF C~C~3 CH3 2.6 ethanol 2L CLH CH2 CH30 H 176 88-90 (d) HF ~ 3 C2H5 43.2 ethanDl 2M CH CH30 H 153.7 101-102 (d) HF ~ 2H5'f' CH3 94.6 ethyl acetate 2N C~HsCH2 H CH3 200 207-209 HF C~CC2H5 CH3 167 ethanol/ether 2P C6H5CH2 CH30 CH3 4.3 125-126 (d) HF CCCH3 CH3 3.2 ethanol 2Q CdH CH2 H CH 79.2 95-98 (d) HF ~3 C2~5 29.3 ethanol 2R 4H5~H2. CH3O H 0.5 244-246 HF CCOC2Hs C2H5 0.25 eth3nol/ether 2S C6HsCR2 - H H 66 200-203 HF COCC2Hs CH3 53 ethuxiL/ether 2r C6H~CH2 H H 10 136-138 (d) H2S04 COCH3 ~ C83 3 ethanol 2U CH H H 1.0 189-191 HF ~2Hs CH2C~20~H3 0.85 eth2ox~L~ether Z~ CH H H 10 185-189 HF ~2H5 CH2CH2SC6H5 5.6 aoetone aw CH H CH 11.1 225-227 HF ~C2H5 CH3 9.2 acebone

9~.~9 ExamPle Rl~Y R2 R3/R4 Wt.lV/Wt.II m.P. (C.)/Solv.
2X CH3 H CH 10.9 202-205 H2S04 COCC2H5 C2~5 5~9 acetrnitile/ether 2Y ChH CH2 H CH 33.7 82-83 (d~
H2S04 C~CC H C2~5 21.4 hexane 2Z C6H5CH2 H C2Hs 75 213-215 H2S04 COOC2H5 CH3 29 ethanoVether 2AA ChHSC~2 CH30 CH3 314.5 94-95 ~d) HF C~CC2H5 CH3 137.9 ~a) Starting material was the ethyl ester.
nb) Starting material was the methoxy ether/ethyl ester.
(c) Hydrobromide salt.
(d) Free base.
(e) Starting material was the methoxy ether~methyl ester.
(f) 100 g. of the ester was sapcnified with aqueous alkali and the prcduct isolated as the free base to give 55.7 g. of the corre~x~ng ca~x~ylic acid, m.p. 195-197C. (ao~nitrile).
EXAMPLE 2A~
A solution of 4.2 g. (0.01 mole) of ethyl 1-methyl-5~-[2-(phenylthio)ethyl]-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo~g]quinoline-3p-carboxylate described in Example 2V in 80 ml.
of glacial acetic acid was treated with 1.4 ml. of 30% aqueous hydrogen peroxide, allowed to stand at ambient temperature for one hour and fifteen minutes and then concentrated to dryness in vacuo at 40C. The residue was partitioned between dilute -sodium hydroxide and methylene dichloride and the organic layer ~eparated, dried and taken to dryness to give 5.0 g. of ethyl 1-methyl-5d-[2-~phenylsulfinyl)ethyl]-1,2,3,4,4a,5,10,10a-octa-hydro-2,5-methanobenzo~g]quinoline-3p-carboxylate as an oil.
The latter (14.0 g., 0.032 mole) was distillea under reduced pre~sure, and the fraction boiling at 122-156C./0.03-0.11 mm. was collected ~7 g.) and chromatographed on silica in a 6:4 solution of hexanetether~ The column was eluted until the yellow color passed throug~, and the next 550 ml. was collected separately and taken to dryness to give 6.4 g. of a gum whic~
was dissolved in anhydrous ether and diluted with ethere~l hydro-- l~J~ 9 gen chloride. The solid which separated was collected and dried to give 3.8 g. of ethyl 1-methyl-5~-vinyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3~-carboxylate hydrochlor-ide, m.p. 241-243C.
The latter (2.1 g., 0.006 mole) was converted to the free base which was dissolved in 15 ml. of tetrahydrofuran and treated with 15.6 ml. of a lM solution of diborane in tetrahydro-furan. The solution was stirred for an hour and a half, poured into 10 ml. of ice water, the mixture basified with 3.6 ml. of 3N sodium hydroxide and treated with 2.2 ml. of 30~ hydrogen peroxide. After stirring for an hour, the mixture was filtered, diluted with water, extracted with ether and the ether extracts extracted with dilute hydrochloric acid. Isolation of the basic product from the aqueous acid medium in the usual manner by basifying and extraction with ether and conversion of the product to the hydrochloride salt gave ethyl l-methyl-5~-(2-hydroxyethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzolg~quinoline-3~-carboxylate hydrochloride, m.p. 212-216C. (from acetone).
Following a procedure ~imilar to that de~cribed in Example 2A, using an appropriate 2-Rl-3-(4-R2-3-R2'-benzyl)-4-R3-5-R4-7-Y'-2-azabicyclo[2.2.2~oct-5-ene of Formula IV and hydro-fluoric asid at 0-15C., the following 7-R2-8-R2'-1-Rl-3~-Y-4a~-R3-50~-R4-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]~uinol-ines of Formula II, when R2" and R8 in each ca~e are hydrogen, are prepared.
Table 2b Example Rl/y R2/R2- R3~R4 CO~H3 H ~ CH3 2AF cyclopropyl-CH2 H H

C~CH3 Cl CH3 Example Rl~.y ~2/R2 R3/R4 COCH3 Br CH3 2AL c~3 H H

2AM CH~ C H5 H
COCH3 H6 ~ CH3 COCH3 b CH3 COCH3 H CH2CH2Cl 2AR CH3 H ,~
COCH3 H (CH2) CO~H3 H (CH2) 2A~ C6Hll CH3S H

2AU 4-BrC6H4CH2cH2 HH3o cHH3 2AV 4-ClC6H4CH2cH2 CH3CONH CH3 2AW CoFCH6H4CH2CH2 H2H50CONH CH3 2AX 4-Cl-3-CH3C6H3CH2CH2 H CH3 2AY 3-CH3COOC6H4CH2cH2 H HCH3 2AZ 3,4-(CH30)2C6H3cH2cH2 HH cHH3 2BA 4-CH3SC6H4CH2cH2 H H

28B 3-CF3C6H4CH2cH2 H CHH3 29D 3,4-0 ~ H3CH2CH2 H H

COCH3 H CH2CH2ScH3 Cyclization of 2,5-dimethyl-3-(3-methylbenzyl)-7-acetyl-2-azabicyclo[2.2.2]oct-5-ene, described in Example lAR, in the presence of hydrofluoric acid at 0-15C. using a procedure similar to that described above in Example 2A affords 1,5~,6-tri-methyl-3~-acetyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo-~g]quinoline.

A sol~tion containing 21.3 g. (0.05 mole) of ethyl 1~ 2,3-dibenzyl-5-ethyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate hydrochloride (described in Example 1~) in 200 ml. of ethanol was reduced over 2.1 g. of palladium-on-charcoal u~ing the pro-cedure described above in Example lAJ. There was thus obtained 18 g. of ethyl 3-benzyl-5-ethyl-2-azabicyclo~2.2.2]oct-5-ene-7-carboxylate which, without further purification, was dissolved in 170 ml. of 48% hydrobromic acid and heated under reflux for about eight hours. The crude product obtained was recrystalliz-ed from water to give 9.4 g. of 5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3~-carboxylic acid hydro-bromide, m.p. >310C.

A. A mixture of 48.3 g. (0.13 mole) of 1-methyl-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzolg]quinoline-3~-carboxylic acid hydrobromide ~described in Example 2A) in 48a ml. of absolute ethanol was treated with anhydrous hydrogen chloride until all material had dissolved. ~he solution was re-fluxed for three hours, taken to dryness, and the ~olid residue was par~itioned between dilute ammonium ~x~ide and diethyl ether. The ether layer was separated, combined with additional ether wa~hes of the aqueous layer, and the combined organic ex-tracts dried and evaporated to dryness. The resulting solid residue was dissolved in ethanol and treated with ethereal hydro-gen chloride to give 39.3 g. of ethyl 1-methyl-5~-ethyl-1,2,3,4,-5~

4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3~-carboxylate hydrochloride, m.p. 244-246~C.
Following a procedure similar to that described in Example 4A, using an appropriate 7-R2-8-R2'-1-Rl-4aoc-R3-5~-R4-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3~
carboxylic acid hydrobromide of Formula II and an appropriate lower-alkanol, the corresponding lower-alkyl esters of Formula II given in Table 4 below are prepared, where R2" and R8 in each case are hydrogen. Unless noted otherwise, melting points are

10 given for the free base form.

Exa~le R~y R2/R2~ R3/R4 ~cAcid/Wt.Pmd. mp.(C.)/Solv.
4B CH H H 10.3 129-133 ~L3 H CH3 5 me~hanol 4C H H H 11.2 245-246 ~a) ~OC2H5 H C2H5 8.0 ethanol/ether 4D CH H0 H 10.0 190-193 ~H3 H C2H5 5~4 ethyl acetate/
he~c3ne 4E ~H~CH2 H 03 18-1 (b) a~oc H H CH3 (a) Hydr~oride salt (b) ~t isolated but treated further in Exan~le 6D. Acid (50.3 g.) cbta~n~ by ~aponificaticn of 77.9 g. of callpour~ of Exanple 2N.
EX~LE 5 A solution of 53.7 g. (0.15 mole) of 1-benzyl-3~3-acetyl-5~t-methyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo[g]quinoline (described in Example 2R) in 250 ml. of 48S
aqueous hydrobromic acid was warmed on a steam bath for two 30 hours and then filtered and cooled. The solid which had pre-cipitated was collected and recrystallized from water to givo 10.3 g. of l-benzyl-3l5-acetyl-50t-methyl-7-hydroxy-1,2,3,4,4a,5,-lO,lOa-octahydro-2,5-methanobenzolg]quinoline hydrobromide, m.p.
192-197C.

A. A solution of 21.7 g. ~0.06 mole) of 1-benzyl-3~-acetyl-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinol-ine (described in Example 2E) in 100 ml. of ethanol was made acidic with aqueous hydrochloric acid, and the solution was re-duced with hydrogen over 2.0 g. of 10% palladium-on-charcoal at room temperature using a Parr shaking apparatus. ~hen reduction was complete, the catalyst was removed by filtration, the fil-trate concentrated to dryness in vacuo, and the residue recrystal-lized from isopropanol to give 14.4 g. of 3~-acetyl-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydro-chloride, m.p. 240-241C.
Following a procedure similar to that described in Example 6A, using an appropriate 7-R2-8-R2'-1-benzyl-3p~Y-4a~-R3-5d-R4-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline of Formula II, the corresponding debenzylated compounds of Formula II in Table 6 below are prepared, where Rl, R2" and R8 in each case are hydrogen. The compounds were prepared from, and isolat-ed as, either the hydrobromide, the hydrochloride or the free base as indicated.

EenPle Y R2/R2 R3~R4 Wt.S.M.~Wt.Prod. m p.(C.)~Solv.

6B COCH3 HD H 8.2 (HBr) 247-248 H CH3 4.8 ~HBr) aoetonitrile 6C COOC2B5 H CH3 42.6 (HCl) 213-216 H CH3 26.4 (HCl) ethanoVether - 6D OX~3H7 H CH3 (a) 213-215 H CH3 13.6 (HCl) acetonitrile 6E COO~2H5 H CH 16.1 ~se) 226-229 H C2~5 9.0 (HCl) ethanol/ether 6F COOC2H5 H H 18.8 ~se) 213-214 H CH3 11.9 (HCl) ethanol/ether 6G COCC2H5 H CqH5 22.0 (HCl) 150-151 H C~3 12.6 ~) ether 6H aXX~3(b) H CH3 15.0 ~e) ~) 221-223 H CH3 7.5 OE~l) ethanol/ether 6J COX2H5 CH30 CH3 21.0 ~se) 202-203 H CH3 14.2 ~1) acetone/ether 6X aX~2H5 HO(c) CH3 21.0 nx~e) 185-187 H CH3 8.0 ~x~e) ethyl acetabe ~38-- lV~S5 Table 6 (continued) (a) Reaction carried out on product of Example 4E
without isolation of the latter.
(b) Prepared by saponification of 61.1 g. of the compound of Example 2N (36.9 g. of free base of the carboxylic acid, m.p. 178-185C. ob-tained) and re-esterification of the acid with methanol. Debenzylation carried out on the pro-duct directly without isolation.
(c) The crude product, without isolation, was cleaved with boiling 48~ hydrobromic acid using the pro-cedure described in ~xample 5.

A. A mixture of ~.0 g. (0.017 mole) of ethyl 5d-ethYl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzotg]quinoline-3~-carboxylate hydrochloride ~described in Example 4C), 2.8 g.
(0.17 mole) of cyclopropylmethyl bromide and 1.4 g. (0.017 mole) of sodium bicarbonate in 40 ml. of DMF was stirred and refluxed for three hours, and then evaporated to drynes~ in vacuo. $he residue was partitioned between water and diethyl ether, the ether layer was washed with water, dried, charcoaled and filter-ed, and the filtrate was diluted with ethanol and acidified with ethereal hydrogen chloride. The solid which separated was collec-ted and recrystallized from ethanol/ether to give 4.4 g, of ethyl l-cyclopropylmethyl-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3~-carboxylate hydrochloride, m.p.
215-217C.
Following a procedure similar to that described in Example 7A, using an appropriate alkylating agent and an appropri-3~ ate 3~-Y-4a~,R3-5~-R4-1~2~3~4~4a~5~10~10a-octahydro-2~5-methano-benzolg]quinoline, the following compounds of Formula II in Table 7 were prepared, where in each case, unless noted otherwi~e, R2 R2', R2N and R8 are each hydrogen. The form of the starting mate-rials and the products, whether free base or a particular salt form is indicated in each case.

--` 1089~3 Example Rl/y R3/R4 Wt S.M./Wt.Prod. m p. (C.)/Solvent 7B cyclopropyl-cH2 H 27.6 ~HCl) 202-204 COCH3 C2H5 24.1 (HCl) ethanoVether 7C C6H~CH2CH2 CH3 11.3 tbase) 173-174 C00~2H5 CH3 5 9 (CH3S03H) ethyl aoetate/ether 7D C2H5 CH3 11.0 (HCl) 218-219 COCC2H5 CH3 7.4 (HCl) aoetone 7E n-c3H CH3 11.0 (HCl) 210-213 CCOC2~5 CH3 8.7 (HCl) aoetone 7F n-C4Hg CH3 11.0 (HCl) 213-216 CCCC H CH3 7.2 (HCl) ~r~tone 7G n-C~H CH3 11.0 (HCl) 200-203 COCC ~ CH3 7.8 (HCl) aoetone 7H CH CH=CH CH 6.0 ~baæ) 120-123 ~ 2H5 2 CH3 5.3 (HCl) aoetone 7J CH~CH=C~CH3)2 CH 8.6 (base) 196-199 CO~C2H5 CH3 7.8 (HCl) aoetcne 7K cycloproPyl-cH2 CH3 7. 5 (base) 213-215 COOC2H5 CH3 6.2 (HCl) aoetone 7L CH~C=CH CH3 7. 5 (b2se) 184-186 CO~C2H5 CH3 5~ 8 (HCl) ethano Vether 7M cyclobutyl-CH2 CH3 6 . 6 tbase) 217-219 CCOC2H5 CH3 1.2 ~HCl) aoebone 7N 3-furyl-CH CH3 7~5 Oba~e) 213-215 COOC2H5 2 CH3 5'5 (HCl) ethanol 7P CH (a) CH3 27.6 (bace) 235-238 ~ 2HS CH3 14.5 (HCl) ethanol/ether 7Q C~ ta) ~) CH3 9 0 (base) 200-202 ~ 2HS CH3 2.7 (HCl) aaebone/ether 7R C~ (a) (c) CH3 20.5 ~x~e) CO~C2H5 ~H3 16.2 ~ase) (a) Prep~ by w~ng the 8t~ing mat~rial of FwoNla II with a m~lar excess each of formic acid and 37~ aq~us fo~d~b.
tb) Prcduct is ethyl 1,3 ~4a~5dLtetramethyl-1,2,3,4,4a,5,10,10a-oo~ kr~2,5 mstnax~rzo[g~quinoline,3~,cL*Yxylate prq~sd from the 3 ~ yl-3~-u~*~xylate described in Example 17.
(c) R2 is CH30.

A. A mixture of 18.0 g. (0.05 mole) of ~-ethyl-1,2,3,4,4a,-S,lO,lOa-octahydro-2,5-methanobenzo[g~quinoline-3~-carboxylic acid hydrobromide (described in Example 3), 20.4 g. (0.11 mole) of phenylethyl bromide and 13.5 g. tO.16 mole) of sodium bicarbonate --~0--8~9 in 200 ml. of DMF was stirred under reflux for four hours, and then worked up in the manner described above in Example 7A. The crude product was converted to the hydrochloride salt which was recrystallized from isopropanol to give 4.4 g. of 2-phenylethyl 1-(2-phenylethyl)-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo~g]quinoline-3~-carboxylate hydrochloride, m.p. 237-238~
B. Following a procedure similar to that described in Example 8A, 20.5 g. ~0.058 mole) of 5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3~-carboxylic acid hydro-bromide (described in Example 3) was reacted with 19.8 g. (0.12 mole) of cyclopropylmethyl bromide in the presence of ~odium bi-carbonate, and the product converted to the hydrochloride salt which was recrystallized from ethanol/ether to give 6.6 g. of cyclopropylmethyl l-cyclopropylmethyl-~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3~-carboxylate hydrochlor-ide, m.p. 184-187C.

A. A solution of 0.035 mole of ethyl 1-methyl-5d-propyl-1,2,3,4,4a,5,10,1Oa-octahydro-2,5-methanobenzolg]quinoline- ~ -carboxylate (obtained from 14.4 g. of the corresponding hydro-chloride described above in Example 2J) in diethyl ether was added in a fine stream to 81 ml. of a 2.16M solution ~0.175 mole) of methyl lithium in diethyl ether. When addition was complete, the mixture was stirred for about thirty minutes, allowed to stand overnight, and then poured into an ice/aqueous ammonium chloride mixture. The ether layer was separated, the aqueous layer washed with diethyl ether, and the combined organic extracts washed with saturated brine, dried, filtered and concentrated to dryne~s.
The residue was dissolved in ethanol/ether, and the solution acidified with ethereal hydrogen chloride. The solid which ~epa-rated was collected and recrystallized from ethanol/ether to give 2.5 g. of 1-methyl-3~ ~2-hydroxy-2-propyl)-~-propyl-l,2,3,4,4a,-5,10,1Oa-octahydro-2,5-methanobenzo~g]quinoline hydrochloride, m.p. 257-258C.
Following the procedure similar to that described in Example 9A, using an appropriate lower-alkyl 7-R2-8-R2'-1-Rl-4a~-R3-5~-R4-1,2,3,4,4a,5,10,10a-octahydro-2,5-met~anobenzo[gl-quinoline-3~ carboxylate of Formula II described in ExampleQ 4A, 4B, 4D, 8A, 2M, 7A and 2N, respectively, and methyl lithium, the following compounds of Formula II in Table 9, where in each case Y i8 C(CH3)20H and R2" and R8 are hydrogen, are prepared. In each case, the weights of starting materials are given for tho free base form, and unless noted otherwise, melting point-~ of the products are given for the hydrochloride salt.

Example Rl R2/R2' R3/R4 Wt S.M.~Wt.Pmd. m p.(C.)/Solv.
9B CH3 H H 15.7 275 H C2H5 6.9 ethanol H CH3 12.2 e~oVether 9D CH3 HO H 12.9 272 H C2H5 8.1 ethanoVether 9E C6HsCH2CH2 H H 8.2 248-248.5 H C2H5 3.9 ethanoVether 9F CH3 CH30 H 25 126-127 ~a) H CH3 22.1 hexane 9G C3H5-CH2 (b) H H 6.1 256 H C2H5 4 5 e~nol/ether 9H H (c) H CH3 13.7 152-153 (a) H CH3 4.4 isq~pyl ~ats/-he~e (a) Free base.
b) Cyclopropylmethyl.
(c) Pr~k~t debenzylated without i olation using the prooxble of Example 6A.

A. To a suspen~ion of 44.1 g. ~0.16 mole) of 1-methyl-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]qulnoline-3~-carboxylic acid ~from the hydrobromlde described in Example 2A) in 390 ml. of diethyl ether was added in a fine stream 230 ml.

11)~3'3~(0 5 mole) of a 2.16M solution of methyl lithium in diethyl ether. When addition was complete, the mixture was stirred for three hours, poured into an ice/aqueous ammonium chloride solu-tion, and worked up in the manner described in Example 9A.
There was thus obtained 32.8 ~. of product as an oily crude base, 3.3 g. of which was converted to the hydrochloride salt. The latter was recrystallized from methanol/diethyl ether to give 2.3 g. of 1-methyl-3 ~ acetyl-5~ethyl-1,2,3,4,4a,5,10,10a-octa-hydro-2,5-methanobenzo[g]quinoline hydrochloride, m.p. 191C.
Following a pxocedure similar to that described in Example lOA, using an appropriate 7-R2-8-R2'-1-Rl-4a~-R3-5~-R4-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g~quinoline-3~ carboxylic acid of Formula II described in Examples 2A, 2C and 2M and an appropriate organo lithium, R5Li, the following com-pounds of Formula II in Table lOa are prepared, where in each case R2" and R8 are hydrogen. The form tsalt or base) of the starting material i~ given in each case in parentheses along with the weight of starting material, and, of course, salt forms were converted to the free base before reaction with the organo lithium. The melting points for the compounds of Examples lOB
and lOD are given for the hydrochloride salts and for the free base of the compounds of Examples lOC and lOE.
E~n~le R1~0~5 R2/R2 R3/R4 Wt S.M./Wt.Prod. m p.(C.)/Solv.
lOB CH H H 12.1 tbase) 190-191 ~ 3H7 H C2H5 8.0 tHCl) ~qYx~nl Vether lOC CH HO H 36 tHBr) 201-204 ~ 3 H C2H5 18.9 t~a~e) DMF/H20 lOD CH H H 8.6 tba9e) 200-202 ~ 6H5 H C2H5 6.4 (HCl) ethanol/ether lOE CH CH3O H 18 ~base) 65-67 ~ 5Hll H CH3 6.3 n~e) ethanol lCF C~HeCH2 H CH3 59~8 ~xse) a~c~3 H C~3 55~3 ~e) lOG CH (a) CH~O CH3 27.8 ~xse) 130 )2 H CH3 2.3 ~1) acetone/ether ~a) P xX~ct isclated was result of reaction of ~h~e mDle~ of amyl lithium per ~le of carboxylic acid, i.e., 1,4a~,5q~trin~ yl-7-methoxy-3~-t6-hydrcxy-6-undRcyl)-1,2,3,4,4a,5,10,1Qa-octahydrn-2,5-methanobenso[g]quinoline h~nxdhloride.

10~9~

Following a procedure similar to that described in Example lOA, using an appropriate 7-R2-8-R2'-1-Rl-4a~-R3-5~-R4-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3 carboxylic acid ~prepared by alkaline saponification of the corresponding esters described in Examples 2V and 2AB) and methyl lithium, the following compounds of Formula II in Table lOb are prepared where, in each case, Y is COCH3 and R2" and R8 are each hydrogen.
TABLE lOb 10Example R1 R2/R2 R3/R4 lOH CH3 H H
H CH2CH2Sc6H5 lOJ CH3 H H

lOK CH3 H H
H CH=CH2 lOL CH3 H H

A. A solution of 2.8 g. (0.01 mole) of 1-methyl-3~-acetyl-~X-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinol-ine (from the hydrochloride described in Example lOA) in 25 ml.
of diethyl ether was added dropwise to a solution of 40 ml.
(O.032 mole) of a 0.8M solution of propyl lithium in diethyl e~her. When addition was complete, the mixture was allowed to ~tand for one hour, poured into an ice/aqueous ammonium chloride solution and worked up in the manner described in Example 9A
The product thus obtained was converted to the hydrochloride salt which was recrystallized from ethanol/ether to give 1.2 g. of 1-methyl-3~-(2-hydroxy-2-pentyl)-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydrochloride, m.p. 227-230C. ~de~lgnated i~omer A).
B. ~he compound, l-meth~l-3~-~2-hydroxy-2-pentyl)-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzotg~quinoline, m,p. 103-105C. (from hexane) (the hydrochloride ~alt ~how~ m.p.

- lV8~

263-265C., from isopropanol/DMF), isomeric in the configuration of the 3~B-(2-hydroxy-2-pentyl)group with isomer A above and designated isomer B, was prepared in a similar fashion by reac-tion of l-methyl-3~-butyryl-5~-ethyl-1,2,3,4,4a,5,10,10a-octa-hydro-2,5-methanobenzo[g]quinoline (from the hydrochloride salt described in Example lOB) with methyl lithium.
Following a procedure similar to that described in Example llA, using an appropriate 7-R2-8-R2~ Rl-3~B-acetyl-4a~-R3-5d-R4-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzolg~quinol-10 ine deqcribed in Examples 2G and 2K, respectively, and methyl lithium, the following compounds of Formula II in Table II are prepared where, in each case, Y is C (CH3)20H and R2" and R8 are both hydrogen. All melting points are for the hydrochloride salts.

EK~nple Rl R2/~2 R3/~ ~c S.M./Wt.Pmd. m.P.(C.)/Solv.
llC CH3 H CEI 5.0 ~a~e) 247-248 H C2~5 4.4 ethanol/ether llD C6EI5CH2 C~I30 H 15.0 (base) 236-237 H ~H3 12.2 ethanoVether D~E 12 A. A solution of 0.076 mole of ethyl l-methyl-50~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3 carboxylate (obtained from 26.7 g. of the hydrochloride salt described in Example 4A) in 250 ml. of anhydrous diethyl other was added in a fine stream to a stirred suspension of 2.9 g.
(0.076 mole) of lithium aluminum hydride in 125 ml. of diethyl ether. When addition was complete, the mixture was stirred for about one hour, treated dropwise with 5.8 ml. of water, stirred 30 for an additional ten minutes, and then filtered through filter aid. The filter cake was washed with several portions of diethyl ether, and the combined filtrates were evaporated to dryness to give 20.8 g. of the product in the form of the free base, 7.0 g.
of which was dissolved in 35 ml. of ethanol and acidified with .

~ 9~9 ethereal hydrogen chloride. The solid which separated wa~ col-lected and recrystallized from ethanol/diethyl ether to give 7.6 g. of 1-methyl-3~-hydroxymethyl-5~-ethyl-1,2,3,4,4a,5,10,lOa-octahydro-2,5-methanobenzo[g]quinoline hydrochloride m.p. 273-278C.
Following a procedure similar to that described in Example 12A using the ethyl l-methyl-4a~ -dimethyl-1,2,3,4,4a,-5,10,10a-octahydro-2,5-methanobenzo~g]quinoline-3~ and 3~
carboxylates described in Examples 7P, 2W and 7Q, respectively, there was obtained the following compounds of Formula II where in each instance Rl, R3 and R4 are each CH3 and R2, R2' and R2 n are each hydrogen. The products were isolated and characterized as the hydrochloride salts.

Example Y/R8 Wt.S.M./Wt. Prod. m P.(C.)/Solv.
12B o~-CB20H 10.5 (base) 245-247 H 7.5 ethanol~ether 12C ~-CH20H 13.4 (base) 270-274 H 10.6 ethanol/ether 12D ~-CH20H 3.8 (base) 232-234 ~-CH3 2.5 ethanol/ether A. A ~olution of 8.5 g. (0.3 mole) of 1-methyl-3~-acetyl-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzotg~quinol-ine hydrochloride ~described in Example lOA) in 135 ml. of othanol was addod in a fine stream to a solution of 1.2 g. (0.03 mole) of sodium borohydride in 25 ml. of ethanol. When addition was complete, the mixture was stirred for four and one half hours and then deoanted from the precipitated solids. The liquid lay-r was evaporated to drynes~, the residue dissolved in dilute hydro-chloric acid and the solutio~ basified with concentratod ammoniu~
hydroxide. Extraction of the mixture with diethyl ether afford-d 7.5 g. of crude base which was converted to the hydrochloride salt to give 3.3 g. of 1-methyl-3~-(1-hydroxyethyl)-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzotg]quinoline hydro-- lV89~9 chloride, m.p. 305-307C.
~ ollowing a procedure similar to that described in Example 13A, using the ethyl l-Rl-4a~-R3-5~-R4-7-R2-1,2,3,4,4a,-5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3~ carboxylates described in Examples 2M and 2N, respectively, there was obtain-ed the following compounds of Formula II where R2', R2" and R8 in each case is hydrogen. The compounds were prepared from the free bases and the products isolated and characterized either as the free base or the hydrochloride salt as indicated.

E~mPle R ~ R2 R3/R4 Wt S.M./Wt.PIcd. m p.(C.)/Solv.
133 CH3 CH30 H 25.0 264-268 CH2oH CH3 21.4 ~Cl) e~ Vether 13C H H CH3 15.2 165-166 CH20H CH3 3.7 (base) i~x~yl aoetate/-h~
E~E 14 A. A solution of 4.8 g. (0.018 mole) of 1-methyl-3~-hydroxymethyl-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo[glquinoline hydrochloride (described in Example 12A) in 50 ml. of pyridine was treated with 4.8 g. (0.02 mole) of 3,4,5-trimethoxybenzoyl chloride, the solution heated on a ~team bath for ~ix and one half hours and then allowed to ~tand overnight.
The solid material which had ~eparated was collected and re-crystallized from ethanol/ether to give 7.1 g. of l-methyl-~ -~3,4,5-trimethoxybenzoyloxymethyl)-5~-ethyl-1,2,3,4,4a,5,lO,lOa-octahydro-2,5-methanobenzolg]quinoline hydrochloride m.p. 247-249C.
9. Following a procedure ~imilar to that described in Example 14A, using 7.9 g. (0.029 mole) of the 1-methyl-3~-hydr-oxym~thyl-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo-[g~quinoline described in Example 12A and 80 ml. of propionic anhydride, and isolation of the product in the form of the hydro-chloride salt, there was obtained 3.9 g. of 1-methyl-3~-propionyl-oxymethyl-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanoben20-1'~3898~9 [g]quinoline hydrochloride, m.p. 264-266C. tfrom ethanol/ether).
Following a procedure similar to that de~cribed in Example 14A using the l-methyl-3~-hydroxymethyl-~-ethyl-1,2,3,4,-4a,5,10,lOa-octahydro-2,5-methanobenzo[g]quinoline described in Example 12A and an appropriate acid chloride in the presence of pyrldine, the following compounds of Formula II described in Table 14 are prepared where, in each instance, Rl is CH3; R2, R2', R2", R3 and R8 are hydrogen; R4 is C2H5; and Y is CH20R7.

Example R7 14C 4-C~3C6H4CO
14D 4 ~C6 4CO
14E 3-ClC6H4CO
14F 3-BrC6H4CO

ExAMæLE lS
A. A aolution of 427 g. (0.97 mole) of ethyl 2-benzyl-3-(4-methoxybenzyl)-S-methyl-2-azabicyclo[2.2.2]oct-S-ene-7-carb-oxylate hydrochloride (described in Example lH) wa~ dissolved in 1800 ml. of ethanol and reduced in two portion~ with hydrogen over 10 g. of palladium-on-charcoal. The product was worked up in the manner described above in Example lAJ to give 273 g. of ethyl 3-(4-methoxybenzyl)-S-methyl-2-azabicyclol2.2.2]oct-S-ene-7-carboxylate.
The latter was dissolved in 700 ml. of dry ethanol, and the solution added to a solution of 11 g. (0.48 mole) of aodium dissolved in 2 liters of dry ethanol. ~he resulting solu-tion wa~ stirred and refluxed for seventy-two hours, treated with 39 ml. of glacial acetic acid, cooled to room temperature and filtered through filter aid. The solution wa~ evaporated to dry-ne~s, the solid residue was refluxed with ethyl acetate, the mixture was filtered, and the filtrate diluted with hexane to give one crop of 75 g. of product, m.p. 130C. The filtrate,on extraction with dilute mineral acid, evaporation to dryness and recrystallization of the residue from ethyl acetate/hexane gave an additional 23 g. of product (total yield 98 g.), 2-(4-methoxybenzyl)-8-methylene-3-azabicyclo[3.3.1~non-6-en-4-one. A small sample, recrystallized twice from ethyl acetate/-hexane, gave material having m.p. 132-133C.
B. Following a procedure similar to that described in Example 15A, catalytic debenzylation of the ethyl 2,3-dibenzyl-5-methyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate hydrochloride described in Example lF and base catalyzed rearrangement of the resulting ethyl 3-benzyl-5-methyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate affords 2-benzyl-8-methylene-3-azabicyclo~3.3~1]-non-6-en-4-one.

8~ 9 Example 16 To a solution of 0.15 mole of sodium ethoxide (prepared by dissolving 3.5 g. of ~odium in 250 ml. of absolute ethanol) was added 28.5 (0.095 mole) of ethyl 4a~,5-dimethyl-1,2,3,4,4a,5,10,10a octahydro-2,5-methanobenzo[g]-qllinoline-33-carboxylate (described above in Example 6C), and the solution was stirred and refluxed for about eight hours, then neutralized by the addition of 8.6 ml.
of glacial acetic acid, evaporated to dryness, and the residue dissolved in 200 ml. of water and 200 ml. of dilute hydrochloric 10 acid. The aqueous ~olution was washed twice with ether,basified by the addition of about 30 ml. of concentrated ammonium hy~x~ide, and extracted twice with ether. The combined ether extracts, on washing with water, then with saturated sodium chloride, drying filtering and evaporation to dryness, afforded 23.8 g. of a ~p which was dissolved in absolute ethanol, and treated with e~ lic hydrogen chloride. The solid which separated wa~ removed by flltration, and the filtrate evaporated to drynes~ to give a res1due which was dissolved in 200 ml. of water. The sQlution was wa~hed once with ether, then basified by the addition of 20 concentrated ammonium hydroxide, and extracted two times with diethyl ether. The ether extracts on wa~hing, drying, filtering and evsporation to dryness afforded 19.0 g. of a ~olid which was di~solved in 100 ml. of ethyl acetate and treated with a solution of 12.1 g. of p-toluene~ulonio acid monohydrate in 200 ml. of ethyl acetate. There was thus obtained a solid which was recrystallized from ethanol/ether to give 7.0 g. of ethyl 4a,-Sa-dlmethyl-1,2,3,4,4a,5,10,10a-ootahydro-2,5-methanobenzo[g]
quinoline-3a-carboxylate p-toluenesulfonate, m.p. 216-220C.
Example 17 To a solution of 30 ml. of 2.0M butyl lithium in hexane wa~ added with cooling in an external ice bath a solution of 8.4 g. of cyclohexyliaopropylamine ~0.06 mola) in 45 ml. of pentane. When addition was complete, the solution was evap~rated 13~8~3~'3 to dryness, and the resulting gum was dissolved in 60 ml. of tetrahydrofuran and the solution cooled to -70C. with a dry ice/acetone bath. The solution was then treated with a solution of 11.7 g. of ethyl 1-benzyl-4a ~,5~-dimethyl-1,2,3,4,4a,5,10,lOa-octahydro-2,5-methanobenzo~quino~ine-3~-carboxylate (described in Example 2N) in 120 ml. of tetrahydrofuran. When addition waQ
complete the solution was stirred at -70C. for about thirty minutes, allowed to warm to -20C., and then treated with a solution of 12.8 g. (0.09 mole) of methyl iodide in 120 ml. of dimethylsulfoxide. mhe solution was stirred at ambient temperature for one hour and then poured into one liter of cold water and extracted three times with 200 ml. of ether. The ether extracts on washing with water and brine and evaporation to dryness afforded 17.5 g. of a yellow oil which was chromatographed in 10% ether/-hexane on a column of 2kg. of silica. The product was eluted with 10% ether/hexane, the first 4.7 liters of eluate being dis-carded. The next two liters were combined and evaporated to dry-ne~s to give 3.13g. of crude ethyl 1-benzyl-3 ~ ,4a~,5 ~ -trimethyl-1,2,3,4,4a,5,10,10a- octahydro-2,5-methanobenzo~quinoline-3-carboxylate.
The latter was dissolved in 200 ml. of absolute ethanol containing 0.7 ml. of concentrated hydrochloric acid, 0.5 g. of 10% palladium-on-charox~ -~as added, and the mixture was reduced under about 50 p.s.i. of hydrogen using the procedure de~cribed above in Example 6A. The product was converted to the methane-sulfonate salt which was recrystallized from ethanol~ether to g~ve 2.0 g, of ethyl 3~,4a ~,5~ -trimethyl-1,2,3,4,4a,5,10,10a-octa-hydro-2,5-methanobenzo~g~quinoline-3~-carboxylate methanesulfonate, m.p. 225-229C
Reaction of the above-described ethyl l-benzyl-3 ~
4aoL,5 ~-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo~7quinoline-3-carboxylate with one mole of methyl 3~'3 lithium using the procedure described in Example lOA affordsl-benzyl-3~-acetyl-3~,4a~,5-trimethyl-1,2,3,4,4a,5,10,10a-octa-hydro-2,~-meth~nobenzo~g~quinolinè.
Preparation of Final Products Example 18 A. A solution of 11 g. (0.039 mole) of 1-methyl-3~ -acetyl-5~-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo-~g~quinoline hydrochloride (described in Example lOA) in 20 ml.
of a solution prepared by adding 89 ml. of trimethylamine to 94 ml. of formic acid was stirred and heated under reflux for about 15 minutes. The mixture was allowed to cool, diluted with 100 ml. of water and washed with 50 ml. of diethyl ether.
The aqueous layer was basified with 15 ml. of concentrated ammonium hydrox~ide and extracted twice with diethyl ether. The combined organic extracts, on washing once with water, drying and concentration to dryness, afforded 10 g. of a solid residue which was dissolved in about 30 ml. of absolute ethanol, the solution acidified with 13 ml. of ethereal hydrogen chloride, and diluted to 250 ml. with additional ether. The solid which ~eparated was collected, washed, and set aside. (See Example 31A).
The filtrate was washed with dilute ammonium hydroxide, dried, filtered and taken to dryness to give 3.1 g. of residue which was dissolved in diethyl ether and acidified with ethereal hydrogen chloride. The gummy, semi-crystalline material which separated was recrystallized from ethanol/ether to give 0.8 g.
of 6~eg)-ethyl-1,2,3,4,5,6-hexahydro-3-methyl-ll(eq)-(3-oxo-butyl)-2,6-methano-3-benzazocine hydrochloride, m-p- 192-196C-B. An alternative method for the preparation of the compounds of Formula I from the compounds of Formula II is illustrated by the following procedure:
A mixture of 10.0 g. (0.03 mole) of 1-methyl-3~-acetyl-5~-ethyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo~g~quinoline described in Example lOC in 675 ml. of - l~J~ 3 mesitylene and 25 ml. of formic acid was stirred and refluxed for about eight hours while adding additional formic acid from time to time in order to maintain the pot temperature at 117-119C.
The mixture was then cooled, extracted with dilute hydroc~loric acid and the acid extracts washed first with diethyl ether, then basified with ammonium hydroxide and extracted once again with ethyl acetate. The organic extracts, on washing with brine, drying and evaporation to dryness, afforded 8.4 g. of solid which was recrystallized from ethyl acetate to give 3.7 g. of 6(eq)-ethyl-1,2,3,4,5,6-hexahydro-3-methyl-8-hydroxy-ll~eq)-(3-oxobutyl)-2,6-methano-3-benzazocine, m.p. 190-192C.
Following a procedure similar to that described in Example 18A or B above, using an appropriate 7-R2-8-R2'-1-Rl-3-COR5-4~-R3-5~-R4-1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo ~ ~quinoline of Formula II, the following 8-R2-9-R2'-6(eq)-R4-1,2,3,4,5,6-hexahydro-3-Rl-ll(ax)-R3-ll(eq)-(oxo-lower-alkyl)-2,6-methano-3-benzazocines of Formula I in Table 18a are prepared, where R2" and R8 in each case are both hydrogen.
The particular procedure used, that ~f Example 18A or 18B, is indicated by the letter designation (A) or (B), respectively, below the Example number. Unless noted otherwise, products were isolated as, and melting points recorded for, the free base form.
Table 18a Example Rl/CH2Z R2/R2' R3/R4 Wt. II/Wt. T m p.(C.)/Solv.
18C CH3 H CH3 10 (base) 207-208 (a) (A) CH2CH2cOcH3 H (a) ethanol/ether 18D C3H5-CH2(c) H H 16 (base) 206-208 (b) (B) CH2CH2COCH3 H C2H5 7.8 (base) ethanol/ether 18E C6H5CH2 `CH30 H 18.8 (base) 104-106 (B) - CH2cH2cocH3 H CH3 7.2 (base) ethanol 18F C6H5CH2 CH30 H 39 (base) 122-125 (8) 2C 2CO H3 C2H5 10.6 (base) ethanol Table 18a (cont'd) Example R1~2Z R2/R2' R3/R4 Wt.II/Wt.I m.p.(qC.)~k~v.
18G C6H5CH2 C~30 CH3 19.5 (base) 132-135 (B) CH2CH2COCH3 H CH3 11.5 (base) ethanol 18H CH3 CH30 H 4.9 ~base) 132-134 (B) CH2CH2C0C5Hll H CH3 3~3 (salt) ethanol/ether 18J C6H5CH2 H CH3 55.3 (base 229-232 (B) CH2CH2COcH3 H CH3 37.7 (HCl) ethanol/ether (a) p-~oluenesulfonate hemihydrate (b) Hydrochloride (c) Cyclopropylmethyl (d) p-Toluenesulfonate Following a procedure similar to that described in Example 18A or 18~ above, using an appropriate 7-R2-8-R2'-1-Rl-3~ -lower-alkanoyl-4a~-R3-54~R4-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo/g/quinoline of Formula II, there are obtained the following 8-R2-9-R2'-6~eq)-R4-1,2,3,4,5,6-hexahydro-3-R
ll(ax)-R3-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocines of Formula I in Table 18b, where in each case R2" and R8 are both hydrogen.
Table 18b 8xample Rl/cH2Z R2/R~' R3~R4 CH2CH2cocH3 H CH3 18M C~HsCH2 H H
CH2CH2COcH3 H CH3 18N C6HsCH2 H0 H
CH2CH2COcH3 H CH3 CH2CH2COC3H~ H C2H5 18Q C6Hll CH3S H

1~8~9 Table 18b (cont'd) Example Rl/CH2z R2/R2' R3/R4 _ 18R 4-BrC6H4CH2cH2 CH30 H

18S 4-clc6H4cH2cH2 CH3CONH H

18T 4 Fc6H4cH2cH2 C2H50CONH H
CH2CH2COcH3 H CH3 18U 4 Cl 3 CH3C6H3CH2CH2 H H

18V 3-CH3COOC6H4cH2cH2 H H

18W 3,4-(CH30)2C6H3CH2cH2 H H

18X 4-CH3SC6H4CH2cH2 H H

18Y 3-CF3C6H4CH2CH~ H H
CH2CH2C~CH3 H CH3 18Z 3-CH3CONHC6H4cH2cH2 H H

18AA 3,4-~CH20C6H3CH2cH2 H H

lOAB 3 . H H
2 2 CH3 Cl CH3 18AC C~3 H H
CH2CH2COCH3 ~r c~3 18~F CH3 H H

Table 18b (cont'd) Example Rl/CH2z R2/R2' R3/R4 18AH CH3 2~ H
CH2CH2cOcH3 ~ CH3 CH2CH2COCH3 H CH2CH2Cl 18AL CH3 H (CH2)3 ~
CH2CH2cOcH3 H
18AM CH3 H (CH2)4 =

CH2CH2cOc6H5 H C2H5 18AQ c~3 H H
CH2CH2COCH3 H CH2CH2Sc6H5 CH2CH2COCH3 CH2CH2SOC6Hs CH2CH2COCH3 H CH~CH2 CH2CH2cOcH3 . H CH2CH2SCH3 2 2 3 H CH2CH2OH . `
Example l~AV
Heating the 1,5~6-trimethyl-3~-acetyl-1,2,3,4,4a,5, lO,lOa-octahydro-2,5-methanobenzo~quinoline d-scribed in Example 2BF with formic acid in mesitylene u~ing the procedure described aboYe in Example 18B affords 3,6'eq),7-trimethyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine.

Heating the l-benzy~ -acetyl-3~4ac~5~-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline de~-cr~bed in Example 17 with formic acid in mesitylene using the pro-cedure described abo~e in Example 18B affords 3-benzyl-ll(ax),6~eq)-dimethyl-1,2,3,4,5,6-hexahydro-ll(eq)-(2-methyl-3-oxobuty~-2,6-methano-3-benzazocine.

A. A solution of 27.0 g. (0.072 mole) of 3-benzyl-8-methoxy-6(eg)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (described in Example 18E) was dissolved in 250 ml. of 48% hydrobromic acid and the mixture heated under reflux for about eleven hours. The mixture was concentrated to a small volume _ vacuo, diluted with 100 ml. of water, conc~ntrated again, and finally boiled with about 50 ml. of isopropanol. The solid which separated was collected and dried to give 23 g. of 3-benzyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-~3-oxobutyl)-2,6-methano-3-benzazocine hydrobrQmide, m.p. 156-165C.
B. Similarly ~repared was 3,6(eq)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-ll(eq)-~3-oxooctyl)-2,6-methano-3-benz-azocine ~1.8 g., m.p. 107-109C. from ethanol) by reaction of 4.0 g. of the 3,6teq)-dimethyl-8-methoxy-1,2,3,4,5,6-hox~hydro-ll(eq)-~3-oxooctyl)-2,6-methano-3-benzazocine p-toluenesulfonate described in Example 18H w~th 20 ml. of 48% hydrobromic acid.

A. A ~olution of 23.1 g. (0.05 mole) of 3-benzyl-8-hydroxy-6teq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-t3-oxobutyl)-2,6-methano-3-benzazocine hydrobromide (describQd in Examplo l9A) in 150 ml. of DM~ was reduced with hydrogen over 1.0 g.
of 10% palladium-on-charcoal using the procedure de~cribod above in Example 3. ~he product obtainod wa~ recrystallized from ethanol to give 16.1 g. of 8-hydroxy-6-(eq)-methyl-1,2,3,-4,5,6-hexahydro-ll(eq)-~3-oxobutyl)-2,6-methano-3-benzazocine hydrobromide, m.p. 235-237C. (from ethanol).
B. In a similar fashion 21.2 g. of 3-benzyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (described in Example 18E) was reduced with hydrogen over palladium-on-charcoal, and the product isolated in the form of the hydrochloride salt to give 11.4 g. of 8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-~3-oxobutyl)-2,6-methano-3-benzazocine hydrochloride, m.p. 189-193C. (from ethanol).

A. A mixture of 11.4 g. (0.03 mole) of 8-hydroxy-6(eq)-methyl-1~2~3~4~5~6-hexahydro-ll(eq)-(3-oxobutyl)-2~6-methano-3-benzazocine hydrobromide (described in Example 20A), 5.4 g. of sodium bicarbonate and 5.2 g. (0.04 mole) of cyclopropylmethyl bromide in 150 ml. of DMF was heated under reflux for about nine hours and then concentrated to a small volume in vacuo. The residue was par~itioned between ammonium hydroxide and ethyl ace-tate, the organic layer separated, and the aqueous layer extracted wlth additional portions of ethyl acetate. The combined extracts were washed once with water, then with brine, dried, filtered and taken to dryness to give 12.1 g. of crude product which was con-verted to the hydrochloride salt. The latter was recrystallized once from acetonitrile and once from ethanol/ether to give 5.2 g.
of 3-cyclopropylmethyl-8-hydroxy-6(eq)-methyl-1, 5, 3,4,5,6-hexa-hydro-ll~eq)-(3-oxobutyl)-2,6-methano-3-benza ~ ine hydrochloride, m.p. 147-154C.
B. Following a procedure similar to that described in Example 21A, 3-cyclopropylmethyl-8-methoxy-6~eq)-methyl-1,2,3,-4,5,6-hexahydro-ll~eq)-(3-oxobutyl)-2,6-methano-3-benzazocine ~12.9 g.) was prepared by reaction of 15.0 g. ~0.04 mole) of 3-methoxy-6teq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-~3-oxobutyl)-2,6-methano-3-benzazocine (described in Example 20B) with cyclo-propylmethyl bromide in the presence of sodium bic~rbonate in DMF.

lU~
, C. 3,6(eq)-Dimethyl-8-hydroxy-1,2,3,4 5,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine p-tolu~nesulfonate (9.9 g.
m.p. 199-201C. (from ethanol), was prepared by reductive alkyl-ation of 11.4 g. of 8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine hydrobromide (des-cribed in Example 20A) with formaldehyde and triethylamine over palladium-on-charcoal i~l ethanol under about 5Q p.s.i. of hydrogen using the procedure described in Example 38.
D. 3,6(eq)-Dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (7.5 g.) was prepared by reductive alkylation of 8.2 g. of 8-methoxy-6(eq)-methyl-1,2,3,-4,5,6-hexahydro-ll(e~)-(3-oxobutyl)-2,6-methano-3-benzazocine hydrochloride (described in Example 20B) with formaldehyde and triethylamine over palladium-on-charcoal in ethanol under about 50 p.s.1. of hydrogen using the procedure described in Example 38.
Following a procedure similar to that described in Example 21A, using the 8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexa-hydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine described in Example 20A and an appropriate alkylating agent, RlHal, there prepared the following compounds of Formula I in Table 21, where ~n each instance R2 is HO; R2', R2" and R3 are each hydrogen; R4 i~ CH3; and CH2z i8 CH2cH2cocH3.

~ =
Example 2lE CH2=CHCH2 21F (CH3)2C=cHcH2 21H CH3CsCCH2 21J C12C=CHcH2 A. A ~olution of 4.7 g. tO.16 mole) of 6(eq)-ethyl-1,2,3,-4,5,6-hexahydro-3-methyl-ll(e~)-(3-oxobutyl)-2,6-methano-3-benza-zoclne (from the hylnx~loride described in Example 18A) in 28 ml.

of diethyl ether was added dropwise with stirrin~ to 28 ml. (0.05 mole) of a 1.8M solution of methyl lithium in diethyl ether. The mixture was stirred under nitrogen for about one hour, poured into an ice/aqueous ammonium chloride solution, and the ether layer separated and washed with water. The organic layer was dried, filtered, and taken to dryness to give 4.9 g. of residue which was converted to the methaY~ulfonate salt in methanol/diethyl ether. The latter was recrystallized from methanol/diethyl ether to give 2.5 g. o~ 3-methyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-ll(eq)-~3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine methanesulfonate, m.p. 173-174C.
Following a procedure similar to that de~cribed in Example 22A, using the 8-R2-6(eq)-R4-1,2,3,4,5,6-hexahydro-3-Rl-ll(e~)-(3-oxobutyl)-2,6-methano-3-benzazocines described in Examples 18B, 18D, 18E, 18G, 18J, 21A, 21C and 21D and an appropriate lower-alkyl lithium (R6Li), there are prepared the 8-R2-6(eg)-R4-1,2,3,4,5,6-hexahydro-3-R1-ll(eq)-~3-methyl-3-hydroxy-lower-alkyl)-2,6-methano-3-benzazocines of Formula I
in Table 22a where, in each instance, R2', R2"~ R3 and R7 are hydrogen and R5 is CH3. Unless noted otherwise, product~ were isolated a~, and melting points recorded for, the free ba~e form.
TABLE 22a Example Rl/R2 R4/R6 Wt. S.M./Wt.Prod. m.p.(C.)/Solv.
~ ..._ 22B CH3 C2H5 3.6 (base) 203-206 HO CH3 1.2 (base) ethyl acotate 22C C3H5-CH2~a) C H5 4.0 (base) 184-186 (b) H C~3 2.2 (b) CH3CN/ether 22D C3Hs-CH2(a~ CH3 11.4 (base) 138-14~
HO CH3 3.3 (base) ethyl acetate 22E C H~CH2 CH 3.78 (base) 252 ~b) C~3 t-~4H9 1.25 (b) ethanol 22F CH3 CH3 4.2 (base) 182-183 HO CH3 2.6 (base) ethyl acetate 22G CH3 CH3 7.5 g. (base) oil CH30 C4H9 11.3 g. (base) -` lV~ g Example Rl/R2 R4/R6 Wt S.M./Wt. Prod. m p.(oc.)/solv.
22H 6 5C 2 CH3 3.78 ~base) oil CH30 C2H5 4.5 (base) 22J C3H5-CH2~a) CH3 13.4 ~base) 184-185 ~c) H0 ~d) C4H9 10.2 ~c) ethanDl/ether 22K 6 5CH2 CH3 20.0 (base) oil CH30 C3H7 21.8 (base) 22L 6 5 2 CH3(e) 11.5 ~base) 223-227 (b) CH30 t-C4H9 2.4 (b) ethu~l/e~
10 2ZM C3H5-CH2(a) C2 5 12.0 (ba~e) CH30 t-C4H9 12.9 (base) 22N C6 5CH2 CH3(e) 18.8 (HCl) 246-248 H t-C4H9 3.6 (HCl) ethanol/ether ~a) Cyclopropyl~ethyl (b) Hydrochloride (c) Methanesulfonate (d) Starting material was methyl ether described in Example 21B, and the product obtained from reaction with butyl lithium was cleaved, without characteriz-ation, to the 8-H0 c~mpound with sodium propanethibl using the procedure described in Example 26A.
~e) R3 ~ CH3 Following a procedure similar to that described in Example 22A, u~ing the 8-R2-6~e~)-R4 1,2,3,4,5,6-hexahydro-3-Rl-ll~ax)-R3-ll~eq)-CH2CH2COR5-2,6-methano-3-benzazocine~ de~cribed in Example~ 18N, 18P, 18Q, 18R, 18S, 18T, 18U, 18V, 18W, 18X, 18Y, 18MM, 18A, and 18C, and an appropriate lower-alkyl, phenyl or phenyl-lower-alkyl lithium, R6~i, there are obtained the re-~pective 8-R2-6~eq)-R4-1,2,3,4,5,6-hexahydro-3-Rl-ll~e~)-CH2CH2-30 C~R5)~R6)0H-2,6-methano-3-benzazocines of Formula I li~ted in Table 20B where, in each in~tance, R2~, R2~ and R7 are ~gen.
Table 22b Example 1 R2 R3 R4 R5 R6 22P C6Hll CH3S H CH3 CH3 CH3 22Q 4-BrC6H4CH2CH2 CH30 H CH3 CH3 CH3 22R 4 ClC6H4CH2CH2 CH3CONH H CH3 CH3 CH3 1'~ 9 Example 1 2 R3 4 5 6 22U 3-CH3COOC6H4- H H CH3 C~3 CH3 22V 3,4-(CH30)2C6H3- H H CH3 CH3 CH3 22Z 3,4-~CH20~6H3- H H CH3 CH3 CH3 22AC CH3 H CH3C2H5 ~H3 C6H5-Reaction of 3,6~eq),7-tr~methyl-1,2,3,4,5,6-hexahydro-ll-(eq)-~3-oxobutyl)-2,6-methano-3-benzazocine ~described in Example 18AV) w~th methyl lithium in diethyl ether using the pro-cedure de~cribed in Example 22A afford~ 3,6(e~),7-trimethyl-1,2,3,4,5,6-hexahydro-ll(eq)-~3-hydroxy-3-methyl-butyl)-2,6-methano-3-benzazocine.

A. Reaction of the 3-[2-~4-fluorQphenyl)ethyll-8-ethoxy-carbonylamino-6~eq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine (described in ExampIo 22S) w~th aqueou~ alkali in ethanol affords 3-t2-(4-fluorophenyl)ethyl~- 8-amino-6(eq)-methyl-1,2,3,4,5,6-hexahydro-ll(aq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine.
Following a procedure similar to that desc~ibed in Example 23A, the following 8-R2-6(eq)-R4-1,2,3,4,5,6-hexahydro-3-Rl-ll~e~)-(3-methyl-3-hydroxy-lower alkyl)-2,6-methano-3-benzazocines of Formula I are al~o prepared:
B. 3-12-(3-~ydroxyphenyl)ethyl3-6~eq)-methyl-1,2,3,4,5,6-hexahydxQ-ll(eq)-(3-methyl-3-hydroxybutyrj2,6-methano-3-benza-zocine ~y alkaline hydroly~is of 3-l2-(3-acetoxyphenyl)ethyl]-6(eq)-m~thyl-1,2,3,4,5,6-hexahydro-il(eq)-(3-methyl-3-hydroxy-butyl)-2,6-methano-3-benzazo~ine (described in Example 22U); and . ~

39~59 C. 3-[2-(3-Aminophenyl)ethyl]-6(eq)-methyl-1,2,3,4,5,6,-hexahydro-ll(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benza-zocine by alkaline hydrolysis of 3-t2-(3-acetylaminophenyl)-ethyl]-6(eq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine (described in Example 22Y~.

A. Reaction of 8-hydroxy-3,6(eq)-dimethyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benza-zocine (described in Example 22F) with acetic anhydride affords 8-acetoxy-3,6(eq)-dimethyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-methyl-3-acetoxybutyl)-2,6-methano-3-benzazocine.
Following a procedure similar to that described in Example 24A, using the 3-methyl-6(eq)-ethyl-1,2,3,4,5,6-hexa-hydro-ll(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazoclne de~cr~bed in Example 22A and an appropriate acid chloride in the presence of pyridine, there are obtained the following 3-methyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-ll(eq)-~3-methyl-3-R70-butyl)-2,6-methano-3-benzazocines of Formula I in Table 24 where, in each instance, Rl, R5 and R6 are CH3; R2~ R2 ~ R2 ~ R3 and R8 20 are each hydrogen; and R4 is C2Hs.

Exam~le R7 24E 4-ClC6H4C0 24F 4-BrC6H4C0 X~MPLE 25 A. The 3,6(eq)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxooctyl)-2,6-methano-3-benzazocine p-toluene~ulfonate (15.9 g., 0.03 mole) aescribed in Example 18H was hydrolyzed to lU89~

the free base, and the la~ter ~10.5 g.) dissolved in diethyl ether was added to a stirred slurry of 600 mg. (0.005 mole) of lithium aluminum hydride in ether. The mixture was refluxed for one hour, quenched by the careful addition of 1.2 ml. of water in 10 ml.
of tetrahydrofuran followed by excess dilute sodium hydroxide, filtered and the filtrate evaporated to dryness. The residue (10 ~.) w~s converted to the p-toluenesulfonate salt which wa~ recq~ llzed from ethanol~ether to give 6.2 g. of 3,6~eq)-dimethyl-8-methoxy-1,2,-3,4,5,6-hexahydro-ll(eq)-(3-hydroxyoctyl)-2,6-methano-3-benzazocine p-toluene-~ulonate, m.p. 135-137C.
B. Reaction of 3-cyclopropylmethyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine ~described in Example 18D) with lithium aluminum hydride in diethyl ether using the procedure described in Example 25A affords3-cyclo-propylmethyl-6~eq)-ethyl-1,2,3,4,5,6-hexahydro-ll(eq)-~3-hydroxy-butyl)-2,6-methano-3-benzazocine.

A) A solution of 4.72 g. (0.01 mole) of 3-benzyl-6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-ll(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine (described in Example 22E) in 50 ml. of DMF was reduced with hydrogen over 0.5 g. of palladium-on-charcoal under a hydrogen pressure of about 50 p.s.i.
using the procedure described in Example 3. When reduction was complete, the catalyst was removed by filtration and the solution, containing 6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-ll(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine wa~
treated with 1.68 g. (0.02 mole) of sodium bicarbonate and 2.0 g. (0.015 mole) of cyclopropylmethyl bromide and the mixture was warmed with stirring on a steam bath for one hour.
The reaction mixture containing crude 3-cyclopropyl-methyl-6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-ll(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine, was distilled at atmospheric pressure, collecting 25 ml. of distil-late and then treated with 2.1 g. (0.05 mole) of a 57% dispersion of sodium hydride in mineral oil and 5 ml. of DMF. The mixture was cooled in an ice bath and treated dropwise with stirring under nitrogen with 4.6 ml. of propanethiol. After refluxing and stirring for about four hours, the reaction mixture was poured into a solution of aqueous ammonium chloride and extracted with 50 ml. of diethyl ether. The product was isolated in the usual manner in the form of the free base which was recrystallized from ethanol to give 2.4 g. of 3-cyclopropylmethyl-6(eq)-methyl-8-hydroxy-1,2,3,4,5.6-hexahydro-ll(eq)-(3-hydroxy-3,4,4-trimethyl-pentyl)-2,6-methano-3-benzazocine, m.p. 195-198C. The methane-sulfonate gave m.p. 232C.
Following a procedure similar to that described in Example 26A, using the 8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexa-hydro-3-benzyl-ll~ax)-R3-ll~eq)-~3-hydroxy-3-methyl-lower-alkyl)-2,6-methano-3-benzazocines described in Examples22E, 22K, 22L and 22M and an appropriate alkylating agent, Rl-Hal, (or reductive alkylation with formaldehyde and formic acid using theproo~hre de-scribed in Example 38), there are obtained the 8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-3-Rl-ll(ax)-R3-ll(eq)-(3-hydroxy-3-methyl-lower-alkyl)-2,6-methano-3-benzazocines of Formula I in Table 26 where, in each instance, R2 is hydroxy;R2', R2n, R7 and R8 are each hydrogen; and R4 and R5 are each CH3. Melting points of the products are given in each case for the methanesulfonate salt and yields are also given for the methanesulfonate unless noted otherwise.
Table 26 Example Rl R3/R6 Wt.S.M./Wt. Prod. m.p.(C.)/Solv.
26B c~3 H 4.72 (HCl) 206-208 t-C4H9 2.7 Methanol/ether 26C CH3 H 10.9 tbase) 144-146 C3H7 7.4 ~base) acetone 26D c3Hs-cH2(a) CH3 2.5 (HCl) 249-252 t-C4H9 1.4 methanol/ether 26E C3H -CH2(a) H 9.2 ~base) 182-183 C3H7 1.8 ethanol/ether 26F C3H -CH2(a) H~b) 12.9 (base) 225-228 t-~4H9 0.42 methanol/ether ~a) cyclopropylmethyl (b) R4 i8 C2H5 Using a procedure similar to that described above in Example 26A, 3.19 g. ~0.007 mole) of 3-benzyl-6(eq),11~ax)-di-methyl-1,2,3,4,5,6-hexahydro-ll~eq)-~3-hydroxy-3,4,4-trimethyl-pentyl)-2,6-methano-3-benzazocine (described in Example 22N) was debenzylated by reduction over 35 g. of palladium-on-charcoal and the resulting 6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-ll(eq)-~3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine reacted with 2.0 g. (0.015 mole) of cyclopropylmethyl bromide and 1.7 g. ~0.020 mole) of sodium bicarbonate and the product isolated in the form of the hydrochloride salt to give 1.5 g. of 3-cyclo-- lV8~

propylmethyl-6(eq),l1(ax)-dimethyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine hydrochloride, m.p. 232-233C. (from ethanol/ether).

A) A solution of 15 g. (0.04 mole) of 3-benzyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (described in Example 18E) was catalytical-ly debenzylated and the resulting nor-base alkylated with cyclo-propylmethyl bromide in the presence of sodium bicarbonate using the procedure described in Example 26A. ~he resulting 3-cyclo-propylmethyl-8-methoxy-6(eq)-methyl-1,2,3,4,~,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (12.9 g.) was dissolved in 125 ml. of toluene and added to 45 ml. of a 2.lM solution of n-butyl lithium in hexane at -65C. using the procedure described in Example 22A. The resulting 3-cyclopropylmethyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocine (13.4 g.) was dissolved in 130 ml. of DMF and the ether group cleaved by treatment with 7.1 g. (0.168 mole) of a 57~ mineral oil dispersion of sodium hydr~de and 12.8 g. (0.168 mole) of propanethiol in the manner described above in Example 26A. The product was converted to the methanesulfonate salt which ~as recrystallized from ethanol/ether to give 10.2 g.
of 3-cyclopropylmethyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexa-hydro-ll(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocine methanesulfona~3, m.p. 184-185C.
Following a procedure similar to that described in Example 28A, using the 3-benzyl-8-methoxy-6(eq~-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine described in Example 18E, ethyl lithium and an appropriate alkylating agent, Rl-Hal, ~or reductive alkylation with formaldehyde and formic acid using the procedure described in Example 38), there are obtained the 8-hydroxy-3-Rl-6(eq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-~3-hydroxy-3-methylpentyl)-2,6-methano-3-benzazocines of Formula I

in Table 28 where, in each instance, R2 is hydroxy; R2', R2n,R3, R7 and R8 are hydrogen; R4 and R5 are CH3; and R6 is C2H5.
In each instance, the melting points are given for the methane-sulfonate salt and the yield of product is give~ for the free base.
Table 28 Example Rl Wt.S.M/Wt. Prod. m.p.(C.)/Solv.
28B cyclopropyl-CH215.0 (~ase) 195-196 8.3 (base) acetone 28C CH3 15.0 (base) 155-157 11.0 (base) ethanol A) A 5.7 g. sample of 3-methyl-8-metho~y-6(eq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocine described in Example 22G in DMF was cleaved with sodium propylsulfide (0.063 mole) using the procedure de-scribed in Example 26A and the product (3.4 g. of crude base) con-verted to the methanesulfonate salt which was recrystallized from ethanol/ether to give 2.6 g. of 3-methyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-ll(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocine methanesulfonate, m.p~ 184-186C.
B~ Proceeding in a manner similar to that described in Example 29A, 6.4 g. (0.018 mole) of ~3,6(eq)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-ll(eq)-(3-hydroxyoctyl)-2,6-methano-3-benzazocine (from the ~-toluenesulfonate descrlbed in Example 25A) was cleaved with 0.09 mole of sodium propylsulfide in DMF using the procedure described in Example 28A and the product isolated in the form of the p-toluenesulfonate to give 1.8 g. of 3,6(eq)-dimethyl-8-hydroxy-l~2~3~4~5~6-hexahydro-ll(eq)-(3-hydroxyoctyl) 2,6-methano-3-benzazocine p-toluenesulfonate, m.p. 176-179~C.

A) A solution of 1.8 g. (0.0046 mole) of 1-benzyl-3~-(2-hydroxy-2-propyl)-5~-methyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzolg]quinoline hydrochloride (described in Example llD) was dissolved in 100 ml. of mesitylene and the solution treated with 3.8 ml. (0.1 mole) of formic acid and re-fluxed and stirred for about twenty-four hours. On cooling, the mixture was extracted with three 5 ml. portions of lM phosphoric acid and the combined aqueous extracts washed twice with diethyl ether and then basified by the cautious addition of 6.~ g. of po~ium hydroxide pellets. The oil which separated was extracted with diethyl ether and the ether extracts worked up in the usual manner to give an oil which was converted to the hydrochloride salt.
The latter was recrystallized from ethanol/ether to give 0.3 g.
of 3-benzyl-6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-ll(eq)-(3-methyl-2-butenyl)-2,6-methano-3-benzazoci~e hydrochloride, m.p. 232-235C.
B) Following a procedure similar to that described in Example 30A, 19.6 g. (0.062 mole) of 1-methyl-3~r(2-hydroxy-2-propyl)-5~-methyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzotg]quinollne described in Example 9F in 1 liter of mesitylene and 38 ml. of formic acid was heated and stirred under reflux for twenty-four hours and worked up in the manner described in Example 30A to give 8.5 g. (0.023 mole) of 3,6(eq)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-ll(eq)-(3-methyl-2-butenyl)-2,6-methano-3-benzazocine as an oil which, without further charac-terization, was cleaved with 0.15 mole of sodium propylsulfide in 75 ml. of DMF using the procedure described in Example 26A. The product was converted to the methanesulfonate salt which wa~ re-crystallized from ethanol to give 1.6 g. of 3,6(eq)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-ll(eq)-(3-methyl-2-butenyl)-2,6-methano-3-benzazocine methanesulfonate, m.p. 226-229~C.
Following a procedure similar to that described in Example 30A, using the 7-R2-1-Rl-3-C(R5)~R6)0R7-4 ~ R3-5~-R4-1,2,3,4,4a,5,10,10a-o~tahydro-2,5-methanobenzolg]quinolines de-scribed in Examples 9A, 9B, 9C, 9D, 9G, 9E, llA, llC and 13A in refluxing mesitylene/formic acid, there are obtained the respec-tive 8-R2-6~eq)-R4-1,2,3,4,5,6-hexahydro-3-Rl-ll~ax)-R3-ll(eq~-lt~
(2-lower-alkenyl)-2,6-methano-3-benzazocines of Formula I in Table 30 where, in each instance, R2' and R2" and R8 are hydrogen.
Table 30 Example Rl R2 R3 R4 R5 R6 30G cyclopropyl-CH2 H HC2H5 CH3 CH3 30J CH3 H H C2H5, CH3 C3H7 30X CH3 H CH3 C2H5C~3 CH3 A) Two grams of the solid hydrochloride salt obtained a~
an initial precipitate from the ethanol/ether crystallization in Example 18A was recrystallized once again from ethanol/ether to give 1.3 g. of 1,2-dimethyl- ~ ethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzolg]quinoline hydrochloride, m.p. 262-264-C.
A solution of 5.3 g. ~0.017 mole) of the latter in 50 ml. of ethanol was reduced with 0.1 g. of platinum oxide. Wh n reaction wa~ complete, the cataly~t was removed by filtration and the product isolated in the form of the hydrochloride salt ln th usual manner to gi~e~2.4 g. of 1,2-dimethyl- ~-ethyl-1,2,3,4,4a,-5~lo~loa-octahydro-3~5-ethano~enzo g]quinoline hydrochloride, m.p. 319-329C.
The following l-Rl-2-methyl-4a~R3-5 ~ethyl-1,2,3,4,4a,-5,10,10a-octahydro-3,5-ethenobenzo[g]quinolines of Formula IIIa in Table 31a where, in each instance, R2, R2' and R2" are hydrogen~
R4 is C2H5 and Q is CH3 were obtained as by-products with the maln productR of Examples 18C and 18D, respectively. The yield~ and melting point~ for the compounds of Examples 31~ and 31C are given for the hydrochloride and p-toluenesulfonate salts, respectively.

Table 31a Example Rl R3 Wt.II/Wt.IIIa m.P.(C.)/Solv.
31B CH3 CH3 10 (base) 234-235 1.2 acetone 31C cyclopropyl-CH2 H 16 (base) 187-189 2.5 ethyl acetate The following l-Rl-2-Q-4a~-R3-5~ R4-7-R2-8-R2'-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo~]quinoline~ of Formula IIIa, where R2" in each instance i~ hydrogen, are obtained as by-products from the preparations described, respectively, in Examples 18E, 18K, 18P, 18Q, 18R, 18S, 18T, 18U, 18V, 18W, 18X, 18Y, 18Z, 18AA, 18AB, 18AC, 18AD, 18AE, 18AF" 18AG, 18AH, 18AJ, 18AK, 18AL, 18AM, 18AN, 18AQ, 18AR, 18AS, 18AT, 18AU and lOD.
Table 3lb Example Rl/Q R2/R2' R3/R4 31G C6Hll CH3S H

31H C BrC6H4CH2CH2 HH3o CH3 31J 4-clc6H4cH2cH2 CH3CONH H

31K 4-FC6H4CH2cH2 C2HsOCONH H

3lL 4-Cl-3-CH3C6H3CH2CH2 H H

31M 3-CH3CCCC6H4CH2~H2 H H

31N 3,4-(CH30)2C6H3CH2cH2 H H

31P 4-CH3SC6H4CH2cH2 H H

-` lU89~

Example Rl/Q R2/R2' R3/R4 31Q 3-CF3C6H4CH2cH2 H H

31R 3-cH3coNHc6H4cH2cH2 H H

31S 3~4-ocH2oc6H3cH2cH2 H H

3lT CH3 H H
CH3 Cl CH3 103lU CH3 H H
CH3 Br CH3 ~D
2031Z CH3 CH ~ H
CH3 , CH3 CH3 H CH2CH2Cl 31AC CH3 H (CH2)3 . 31AD CH3 H (CH2)4 CH3 H CH2CH2Sc6H5 CH3 H CH2cH2soc6H5 CH3 H CH2CH2ScH3 -~2-)89 Example Rl/Q_ R2/R;!' R3/R~

CH3 H CH2CH2O~

Heating the 1,5O~6-trimethyl-3~acetyl-1,2,3,4,4a,5,-10,10a-octahydro-2,5-methanobenzolg]quinoline de~cribed ln Example 2BF with formic acid in mesitylene using the procedure 10 described in Example 18B afford~, in addition to the benz~socine of Formula I described in Example 18AV, 1,2,5~ 6-tetramethyl-1~2~3~4~4a~5~lo~l-oa-octahydro-3~s-ethenobenzolg]quinoline.
Reduction of the compounds di~clo~ed ln Examples 31D-31AM, inclu~ve, with hydrogen over platinum oxide using the pro-cedure deacribed in Example 31A affords the corre~ponding l-Rl-2-Q-4a~R3-5~R4-7-R2-8-R2'-1,2,3,4,4a,5,10,10a-octahydro-3,5-eth~nobenzo tg]quinoline~ of Formula IIIb.
EXA~LE 32 A) E~ydrolysis with aqueou~ alkali in an ethanol ~olvent of 1- 12- (4-chlorophenyl)ethyll-7-acetylamino-2~5ol~dimethyl-l~2~3 4,4a,5,10,10a-octahydro-3,5-ethenobenzofg]quinolino and l-t2-(4-chlorophenyl)ethyl]-7-acetylamino-2,5O~dimethyl-1,2,3,4,4a,S,-10,10a-octahydro-3,5-ethanobenzotg]quinoline (de~cribed in Exa~le 31J afford, respectively, 7 amino-l- 12- (4-chlorophenyl)ethyll-2,5Ot-dimethyl-l~2~3~4~4a~5~lo~loa-octahydro-3~5-ethenobonzolg]-quinoline and 7-amino-1-12- (4-chlorophenyl)ethyl]-2,5~-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobensotg]qulnoline.
Following a procedure ~imilar to that de~cribed in Exan~ple 32A, the following compound~ of Formulas IIIa and IIIb 30 are imilarly prepared:
B) 7-Amino-l- t2- (4-l~uorophenyl)ethyl]-2,5O~dimethyl-1,2,~
3,4,4a,5,10,10a-octahydro-3,5-ethenobenzotg]quinoline and 7-amino-l-t2-(4-fluorophenyl)ethyl]-2,5~dimethyl-1,2,3,4,4a,5,10,1Oa-1~39~

octahydro-3~5-ethanobenzolg~quinoline~ by alkaline saponification, respectively, of 1-[2-(4-fluorophenyl)ethyl]-2,5~ dimethyl-7-èthoxycarbonylamino-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo-[g]quinoline and 1-[2-(4-fluorophenyl)ethyl]-2,5 ~ dimethyl-7-ethoxycarbonylamino-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo-[g]quinoline (described in Example 31K);
C) 1-12-(3-Aminophenyl)ethyl]-2, ~-dimethyl-1,2,3,4,4a,5,-lO,lOa-octahydro-3,5-ethenobenzo[g]quinoline and 1-12-~3-amino-phenyl)ethyl~-2,5 * dimethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g~quinoline, by alkaline saponification, respectively,of l-[2-(3-acetylaminophenyl)ethyl]-2,5d~dimethyl-1,2,3,4,4a,5,-lO,lOa-octahydro-3,5-ethenobenzolg]quinoline and 1-[2-~3-acetyl-aminophenyl)ethyl]-2,5~ dimethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinoline (described in Example 31R).

A ~olution of 88 g. (0.33 mole) of 2-(4-methoxybenzyl)-8-methylene-3-azabicyclo[3.3.1]non-6-en-4-one (described in Example lSA) was dissolved in a solution of 800 ml. of glacial acotic acid and 180 ml. of concentrated sulfuric acid and the m~xture stirred and heated on a steam bath for one hour. The mixture was then poured into four liters of an ice/water mixture.
The gum which separated slowly solidified and wa~ collected and recrystallized three times from DMF to give 4.3 g. of 7-methoxy-5~-methyl-3~4~4a~5~10~10a-hexahydro-3~5-ethenobenzo[gJquinoline-2-~lH)-one, m.p. 268-272C.

A solution of 5.38 g. (0.02 mole) of 7-methoxy-S
nethyl-3~4~4a~s~lo~loa~hexahydro-3~s-ethenobenzotg]quinoline-2 (18)-one (described in Example 33) in 250 ml. of tetrahvdrofuran was added slowly to a stirred suspension of 1.52 g. (0.04 mole) of lithium aluminum hydride in 108 ml. of tetrahydrofuran and the mixture was heated under reflux for one and one half hours and then worked up in the manner described above in Example 12A. The product was isolate~ in the form of the hydrochloride salt which was recrystallized from ethanol/diethyl ether to give 3.08 g. of 7-methoxy-S~ methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo-[g]quinoline hydrochloride, m.p. 254-255C.

A solution of 18.0 g. (0.07 mole) of 7-methoxy-5~-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo~g]quinoline hydro-chloride (described in Example 34) in 200 ml. of ethanol was re-duced with hydrogen over 1.8 g. of palladium-on-charcoal under a hydrogen pressure of about 55 p.s.i. When reduction was complete, the product was worked up in the manner described above in Example 3 to give 3.6 g. of 7-methoxy-5~methyl-1,2,3,4,4a,5,10,-lOa-octahydro-3,5-ethanobenzotg]quinoline, m.p. 82-84C.
(from hexane).

A) A solution of 12.0 g. (0.047 mole) of 7-methoxy-S~-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzolg]quinoline hydrochloride (described in Example 34) in 60 ml. of 48~ hydro-bromic acid was refluxed and stirred for 15 minutes, then cooled and worked up in the manner described above in Example l9A. The produc~ was isolated in the form of the free base to give 5.7 g.
of 7-hydroxy-5~-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-etheno-benzo[g]quinoline, m.p. 298-310C. (from DMF);
B) Following a procedure similar to that described in Example 36A, 12.5 g. (0.049 mole) of 7-methoxy-5~ methyl-1,2,3,4,-4a,5,10,10a-octahydro-3,5-ethanobenzolg]quinoline (described ln Example 35) was reacted with 62 ml. of 48% hydrobromic acid and the product, ~n the form of the hydrobromidesalt, was recrystal-lized from water to give 5.6 g. of 7-hydroxy-~-methyl-1,2,3,4,4a-5,10,10a-octahydro-3,5-ethanobenzo~g]quinoline hydrobromide, m.p. 305-311C.

A) A mixture of 4.8 g. ~0.02 mole) of 7-hydroxy-S~-methyl-~ o~
1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline ~de-scribed in Example 36A), 1.7 g. ~0.02 mole) of sodium bicarbonate and 1.9 ml. (0.022 mole) of allyl bromide in 50 ml. of DMF was heated with stirring under reflux for one hour and then worked up in the manner described above in Example 7A. The product was isolated in the form of the hydrochloride salt which was recrystal-lized from ethanol/diethyl ether to give 2.6 g. of 1-allyl-7-hydroxy-5~ methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo-[g]quinoline hydrochloride, m.p. 246-248C.
Following a procedure similar to that described in Example 37A, using the 7-hydroxy-5~tmethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline or the 7-hydroxy-5~-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzolg]quinoline de-scribed in Examples 36A and 36B, respectively and an appropriate alkylating agent, Rl-Hal, there are prepared the corresponding 1-R1- 7-hydroxy-5~ methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-etheno-benzo[g]quinolines and 1-Rl-7-hydroxy-5d~methyl-1,2,3,4,4a,5,10,-lOa-octahydro-3,5-ethanobenzo[g]quinolines of Formulas IIIa and IIIb, respectively, in Table 37 below where, in each inRtance, R2', R2" and R3 are hydrogen; Q is H2; R2 i8 HO; and R4 i9 CH3.
The yields of products and the melting points are given, in each ca~e, for the hydrochloride salts unles~ noted otherwise. The nature of the starting material and final product, whether the 3,5-etheno compounds of Formula IIIa or the 3,5-ethano compound~
of Formula IIIb, is indicated by the designations IIIa and IIIb, respectively.
Table 37 Example Rl Wt S.M. Wt.Prod. m.p.~C) Solvent 37B tIIIa) C6H5CH2CH2 4.82 (base) 5.4 ether 37C ~IIIb) CH2-CHCH2 6.5 (HBr) 5.3 238-241 ethanol/
ether 37D (IIIb) C6H5CH2CH2 6.49 (HBr) 5.1 259-262 ethanol 37E ~IIIa) C3H7 4.82 (base) 3.8~a) 21~211ta) CH3CN/ether lV~;,9 Example Rl Wt.S M. Wt.Prod. m p.C.) Solvent 37F (IIIb) C3H5-cH2 (b~ 6.49 (HBr) 2.5 252 ethanol/
ether 37G (IIIb) C3H7 6.49 (HBr) 3.1 26~264 ethanol/-ether (a) Methanesulfonate salt (b) Cyclopropylmethyl EL~MPLE 38 A) A mixture of 4.82 g. (0.02 mole) of 7-hydroxy~ -methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzolglquinoline ~de-scribed in Example 36A), 1.6 ml. (0.02 mole) of 37% aqueous formaldehyde and 100 ml. of ethanol was reduced with hydrogen over 2 g. of palladium-on-charcoal using a Parr-shaking apparatus~
When reduction was complete, the mixture was worked up in the manner described above in Example 3 and the product isolated in the form of the hydrochloride salt to give 3.6 g. of l,50~dimethyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzolg~quinol$ne hydrochloride, m.p. 302-305C. (from ethanol/diethyl ether);
B) Following a procedure similar to that described in Example 38A, a mixture of 6.49 g. (0.02 mole) of 7-hydroxy-5~
methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzolglquinoline hydrobromide ~described in Example 36B), 1.6 ml. (0.02 mole) of 37% aqueous formaldehyde and 2.8 ml. (0.02 mole) of triethylamine in 100 ml. of ethanol was reduced with hydrogen over 2 g. of palladium-on-charcoal and the product isolated in the form of the hydrochloride salt to give 2.8 g. of 1,5~-dimethyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzolglquinoline hydro-chloride, m.p. 318C. (from water~.
The compounds of Formula I are generally active in the 30 acetylcholine-induced abdominal constriction test (Ach), a pr~ry analgesic screening test and also in the rat tail flick radiant thermal heat analgesic test ~Tail Flick Agon.). A few species have also been tested and found active in the phenyl-p-quinone-induced writhing ~PPQ) and the anti-bradykinin ~BK) tests, which '}~

are also primary analgesic screening procedures. Data ~o obtained for the compounds, identified by reference to the preceding examples and expre~sed either in terms of the ED50 (mg./kg., subcutaneous administration) or in terms of per cent inhibition, are given below. All doses are expressed in milligrams per kilogram (mg./kg.). Tail Flic~
Example ch PPQ BK Agonist 18A 1.7 _ ~ 14+2 18B 0.3 - - 6.9-0.8 18C 1.1 - - 11+1.0 18D 7.4 64%/50 - Inact.
18H 18 ~ 40%/10 Inact./240 l9B 1.4 _ 0.24 42+21 21A 8.9 - - Inact.
21C 6.9 - - 64+12 22A 1.6 - - 11+2.2 22B 2.1 - - 10%/60 22C 4.7 11 - Inact.

22F 8.2 5.9 25A 2.8 - - 60+6.9 26A >25, < 75 268 40%/75 - - Inact.
26C 2.6 - - 68+14 26~ 67~/i5~ 33%/25 - ~ Inact.
26E 7.6 - - Inact.
26F 34 - - Inact./60 27 33~/75; 13~/25 - - Inact./120 28A 6.5 - - Inact.
28B 7.9 - _ Inact.
28C 3.3 - - 43%/240 29A 2.5 _ _ ~ 60 29B 1.4 - 0.70 The compounds of Examples 18D, 21A, 22D, 26A and 28A
have also been found to be active in the phenazocine tail flick antagonist test, the ED50 (subcutaneous administration) for tho~e species being, respectively, 24, 0.088, 0.046, 0.27 and 0.025 mg./kg.
The compounds of Formulas IIIa and IIIb are generally active in the same primary analge~ic screening test~, the acetyl-choline-induced abdominal constriction and the phenyl-p-quinone-induced writhing tests. Data so-obtained are given below, all doses being expressed in mg./kg.
Example/Formula A PPQ
31A/IIIa 2.7 31A/IIIb 17 31B/IIIa 1.6 20 31C/IIIa 4.1 36 33/IIIa Inact.
34/IIIa 4.6 17 35/IIIb 5.1 13 36A/IIIa 3.5 Inact.
37A/IIIa 11 37B/IIIa 1.4 10 37C/IIIb 12 Inact.
37D/IIIb 16 Inact.
37E/IIIa 4.5 37F/IIIb 3.2 100~/70 43~/35 37G/IIIb 13 43 38A/IIIa 1.9 23 38B/IIIb 3.0 23 Finally, certain species of Formula II, namely the ~pecie~ of Examples 6D and 9H, have been found active in the acetylcholine-induced abdominal constriction test and the anti-brady~inin test, both of which are primary analgesic screenin~

tests, thus indicating usefulness of these two species as analgesics, in addition to their usefulness as intermediate~ for the preparation of the products of Formula I and IIIa. Thus ED50's of the species of Examples 6D and 9H in the acetylcholine induced abdominal constriction test are 18 and 4.4 mg./kg., re-spectively, while the per cent protection of the pain response elicited by intraarterial bradykinin injection (the anti-brady-kinin test) of the species of Example 9H was 40% at 10 mg./kg. of test compound and 20% (inactive) at 100 mg./kg. The 8pecies of Example 6D was also active in the anti-bradykinin test but less active than the species of Example 9H.

Claims (6)

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:

...IV

which comprises reacting a compound of the formula ...VIII

with CH2=CHY', 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-furylmethyl 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 con-sisting of halogen, lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, amino, lower-alkanoylamino or a single methylenedioxy attached to adjacent carbon atoms; R2 and R2' are each hydrogen, or one of them is hydrogen and the other is halogen, lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, nitro, amino, lower-alkanoyl-amino, lower-alkoxycarbonylamino or phenyl, or R2 and R2' 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-alkylsulfinyl-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 3 or 4; and Y' is carboxy, cyano, carbo-lower-alkoxy, COO-lower-alkylene-cycloalkyl, COO-lower-alkylene-phenyl or lower alkanoyl.

2. A process according to claim 1, in which 4-methoxybenzylmagnesium chloride is reacted with a 3,4-dimethylpyridine methhalide and the resultant product is reacted with ethyl acrylate to yield ethyl 3-(4-methoxybenzyl)-2,4,5-trimethyl-2-azabicyclo[2.2.2.]oct-5-ene-7-carboxylate.

3. A process according to claim l, in which 4-methoxybenzylmagnesium chloride is reacted with a 3,4-di-methylpyridine benzhalide and the resultant product is reacted with ethyl acrylate to yield ethyl 2-benzyl-3-(4-methoxybenzyl)-4,5-dimethyl-2-azabicyclo[2.2.2.]oct-5-ene-7-carboxylate.

4. A compound of the Formula IV when prepared by the process according to claim 1 or by an abvious chemical equivalent thereof.

5. Ethyl 3-(4-methoxybenzyl)-2,4,5-trimethyl-2-azabicyclo[2.2.2.]oct-5-ene-7-carboxylate when prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

6. Ethyl 2-benzyl-3-(4-methoxybenzyl)-4,5-dimethyl-2-azabicyclo[2.2.2.]oct-5-ene-7-carboxylate when prepared by the process of claim 3 or by an obvious chemical equivalent thereof.