Note: Descriptions are shown in the official language in which they were submitted.
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$nes
and hexahydro-2,6-methano-3-bensazocines.
n 7 R2 8 R2-9-R2 -6~oq)-R4-l,2,3,4,5,6-heXa-
hydro-3-R~ ax)-R3-ll~eq)-C~2Z-2,6-methano-3-benzasocines can
be prepared by heating with formic acid in an inert organlc solv-
ont or with a bonzyl-dl-lower-alkyl-ammonium formate or a tri-
lower-alkylammonium formate certain 6-R2n-7-R2-8-R2'-l-Rl-3-Y-
4aa-R3-Sa-R4-l,2,3,4,4a,5,lO,lOa-octahydro-2,5-methanobenzo~g]-
qulnoline-. Sald proaoss als~ prepares certaln 6-R2"-7-R2-8-
R2'-l-Rl-2-Q-4a~-R3-5-R4-l,2,3,4,4a,5,lO,lOa-octahydro-3,5-etheno-
benzo[g]quinol~nes.
2 8 R2 9 R2 -6~eq)-R4-l,2,3,4,5,6-hoxahydro-
3-Rl-ll~ax)-R3-ll~eq)-CH2Z-2,6-methano-3-benzazocine~ of Formula
I and other novel lntermediates u~oful ln their preparation can
be obtained according to the invention by novel reactions, includ-
ing molecular rearrargements involving novel intormedlate~,
according to tho generai reaction ~equence as follows:
1R~89859 ~R
+ ~
4 VII
VIII
~ H2~'
Rl 1 b IRl
~11 S~'
~\8 i8 H, Y i8 COR5) IV ¦
IIIa
tQ i9 RS) \ ~Rl
~ R2~ [,H
A R2--~ R8 II R2~Y
TR (R8 i8 H)
I (Z 1~ Y 18 ~H)
I~
H20
I (Z l~ ~CH~H) I ~Z i~ R5R~)
--3--
H H
h3 R3
R4 ~
IV (R~ H; Y~ is OOORg~ IV H
R n R lH] R2~ R4
IIIa (Q i~l H2; Rl i8 H) \ IIIa ~R~ H, Q i8 COII~)
7~ ~
2 ~ ~H~ Q
IIIb
IIIa ~Q i~l H2) ~
7L '
~Q
IIIa
-` 1089~
In accordance with the present invention there
is provided a process for preparing a compound of the
formula
~Rl
~ ~ IV
which comprises react$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
R5
-C~ - C - OR7
R8 R6
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;
-6- -
.. . . . . . . . .
- 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:
-C - OR7
R6
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,
-7-
.
-- ~... .. ;., . - . ,
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:
- C - OR7
R6
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
- C - OR7
R6
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
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
R5
-C-OR7 , before conversion of the latter to the compound of
R6
~!s
, Formula I where Z is -7H-I-OR7 and R8 18 lowsr-al~yl by heating
R8 R6
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:
R5
7H I OR7
R8 R-6
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,
R8 6 -10-
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
-IH - I - OR7
R8 R6
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
IR5
f
R8 R6
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,
--11--
?~'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 ,
R8 R6
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
-12-
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
R8
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
-13-
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
H 71
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.
-14-
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
2 V
4'
R2 ~f
2 R~ IIIa
-15-
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
-17-
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
- C - OR7
R6
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~
1 5
- C - OR7
R6
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
- C - OR7
R6
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
--1 9 -
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,
-21-
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
-22-
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-
-23-
-" 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
EXAMPLE 1
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
-26-
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
COCH3 H CH3 54
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
-27-
. .
- 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.
-29-
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
F CH3
lAQ CH3 H H
CF3 CH3
lAR CH3 H H
CH3 CH3
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
-30-
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
EXAMPLE 2
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
2F C6H5CH2 CH30 H 10 225-228
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
- 32 -
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-
-33-
- 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
2AC C6H5CH2 CH O H
COOC2H5 H 3 CH3
- 2AD CH H CH3
CO~H3 H ~ CH3
2AE CH3 H CH3
CN H CH3
2AF cyclopropyl-CH2 H H
COOC2H5 H CH3
2AG CH3 H H
C~CH3 Cl CH3
-34-
Example Rl~.y ~2/R2 R3/R4
2AH CH3 H H
COCH3 Br CH3
2AJ CH3 H H
COCH3 F CH3
2AK CH H H
COCH3 CF3 CH3
2AL c~3 H H
COCH3 CH3 CH3
2AM CH~ C H5 H
COCH3 H6 ~ CH3
2AN CH3 CH2 H
COCH3 b CH3
2AP CH3 H H
COCH3 H H
2AQ CH3 H H
COCH3 H CH2CH2Cl
2AR CH3 H ,~
COCH3 H (CH2)
2AS CH H
CO~H3 H (CH2)
2A~ C6Hll CH3S H
COCH3 H CH3
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
COCH3 H CH3
28B 3-CF3C6H4CH2cH2 H CHH3
2BC 3-CH3CONHC H CH CH H H
COCH3 6 4 2 2 H CH3
29D 3,4-0 ~ H3CH2CH2 H H
COCH3 6 H CH3
2BE CH3 H H
COCH3 H CH2CH2ScH3
-35-
59
EXAMPLE 23F
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.
EXAMPLE 3
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.
EXAMPLE 4
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,-
-36-
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.
TABLE 4
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.
EXAMPLE 6
A. A solution of 21.7 g. ~0.06 mole) of 1-benzyl-3~-acetyl-
--37--
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.
TABLE 6
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.
EXAMPLE 7
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.
-39-
--` 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.
EXAMPLE 8
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.
EXAMPLE 9
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,-
-41-
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.
TABLE 9
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
9C CH3 H H 15 256-257
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.
EXAMPLE 10
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.
-42-
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.
-43-
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
H CH2CH2SC6H5
lOK CH3 H H
H CH=CH2
lOL CH3 H H
H CH2CH20H
EXAMPLE 11
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.
-44-
- 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.
TABLE 11
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
--45--
.
~ 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.
TABLE 12
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
EXAMPLE 13
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-
-46-
- 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.
TABLE 13
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-
47-
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.
TABLE 14
Example R7
14C 4-C~3C6H4CO
14D 4 ~C6 4CO
14E 3-ClC6H4CO
14F 3-BrC6H4CO
14G 3 FC6H4CO
14H 3-CF3C6H4CO
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
-48-
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.
-49-
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
-50-
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
-51-
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
-53-
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
18K 6 5 2 H H
CH2CH2COCH3 H C2H5
18L CH3 H CH3
CH2CH2cocH3 H CH3
18M C~HsCH2 H H
CH2CH2COcH3 H CH3
18N C6HsCH2 H0 H
CH2CH2COcH3 H CH3
18P CH3 H H
CH2CH2COC3H~ H C2H5
18Q C6Hll CH3S H
-54-
1~8~9
Table 18b (cont'd)
Example Rl/CH2z R2/R2' R3/R4
_
CH2CH2COCH3 H CH3
18R 4-BrC6H4CH2cH2 CH30 H
CH2CH2COCH3 H CH3
18S 4-clc6H4cH2cH2 CH3CONH H
CH2CH2COCH3 H CH3
18T 4 Fc6H4cH2cH2 C2H50CONH H
CH2CH2COcH3 H CH3
18U 4 Cl 3 CH3C6H3CH2CH2 H H
2CH2COCH3 H CH3
18V 3-CH3COOC6H4cH2cH2 H H
CH2CH2COCH3 H CH3
18W 3,4-(CH30)2C6H3CH2cH2 H H
CH2CH2COCH3 H CH3
18X 4-CH3SC6H4CH2cH2 H H
CH2CH2COCH3 H CH3
18Y 3-CF3C6H4CH2CH~ H H
CH2CH2C~CH3 H CH3
18Z 3-CH3CONHC6H4cH2cH2 H H
CH2CH2COCH3 H CH3
18AA 3,4-~CH20C6H3CH2cH2 H H
CH2CH2COCH3 H CH3
lOAB 3 . H H
2 2 CH3 Cl CH3
18AC C~3 H H
CH2CH2COCH3 ~r c~3
18AD CH3 H H
- CH2CH2COCH3 F CH3
30 18AE CH3 H H
CH2CH2COCH3 CF3 CH3
18~F CH3 H H
2 2 3 CH3 CH3
-55-
Table 18b (cont'd)
Example Rl/CH2z R2/R2' R3/R4
18AG CH3 C6H5 H
2 2COCH3 H CH3
18AH CH3 2~ H
CH2CH2cOcH3 ~ CH3
18AJ CH3 H H
CH2CH2COCH3 H H
18AX CH3 H H
CH2CH2COCH3 H CH2CH2Cl
18AL CH3 H (CH2)3 ~
CH2CH2cOcH3 H
18AM CH3 H (CH2)4 =
CH2CH2COCH3 H
18AN CH3 H H
CH2CH2COCH3 H CH2CH2OCH3
18AP CH3 H H
CH2CH2cOc6H5 H C2H5
18AQ c~3 H H
CH2CH2COCH3 H CH2CH2Sc6H5
18AR CH3 H H
CH2CH2COCH3 CH2CH2SOC6Hs
18AS CH3 H H
CH2CH2COCH3 H CH~CH2
18AT CH3 H H
CH2CH2cOcH3 . H CH2CH2SCH3
18AU CH3 H H
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.
-56-
EXAMPLE 18AW
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.
EXAMPLE 19
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.
EXAMPLE 20
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,-
-57-
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).
EXAMPLE 21
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.
-58-
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.
TABLE 21
~ =
Example
2lE CH2=CHCH2
21F (CH3)2C=cHcH2
21G CH--CCH2
21H CH3CsCCH2
21J C12C=CHcH2
EXAMPLE 22
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.
-59-
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)
-60-
-` 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
22S 4 C6 4CH2C 2 C2H50CONH H CH3 CH3 CH3
22T CH2CH2 H CH3 CH3 CH3
-61-
1'~ 9
Example 1 2 R3 4 5 6
22U 3-CH3COOC6H4- H H CH3 C~3 CH3
CH2CH2
22V 3,4-(CH30)2C6H3- H H CH3 CH3 CH3
CH2CH2
22W 4-CH3SC6H4- H H CH3 CH3 CH3
CH2CH2
22X 3-CF3C6H4CH2CH2 H H CH3 CH3 CH3
22Y 3-CH3CONHC6H4- H H CH3 CH3 CH3
2 2
22Z 3,4-~CH20~6H3- H H CH3 CH3 CH3
CH2CH2
22AA CH3 H H C2H5 C6H5 CH3
22AB CH3 H H C2H5 CH3 C6H5
22AC CH3 H CH3C2H5 ~H3 C6H5-
CE12CH2
EXAMPLE 22AD
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.
EXAMPLE 23
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
-62-
. ~
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~.
EXAMPLE 24
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.
TABLE 24
Exam~le R7
24B C6H5C0
24C 4-CH3C6H4C0
24D 3-CH30C6H4C0
24E 4-ClC6H4C0
24F 4-BrC6H4C0
24G 4-FC6H4C0
24H 3-CF3C6H4C0
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
-63-
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.
-64-
EXAMPLE 26
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
-65-
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
EXAMPLE 27
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-
-66-
- 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).
EXAMPLE 28
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
-67-
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
EXAMPLE 29
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.
EXAMPLE 30
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
-68-
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~-
-69-
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
30C CH3 H H C3H7CH3 CH3
30D CH3 H H C2H5CH3 CH3
30E CH3 H H CH3CH3 CH3
30F CH3 HO H C2H5CH3 CH3
30G cyclopropyl-CH2 H HC2H5 CH3 CH3
30H C6H5CH2CH2 H H C2H5CH3 CH3
30J CH3 H H C2H5, CH3 C3H7
30X CH3 H CH3 C2H5C~3 CH3
30L CH3 H H C2H5CH3 H
EXAMPLE 31
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.
-70-
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
31D C6H5CH2 CH30 H
CH3 H CH3
31E C6H5CH2 H H
CH3 H C2H5
31F CH3 H H
C3H7 H C2H5
31G C6Hll CH3S H
CH3 H CH3
31H C BrC6H4CH2CH2 HH3o CH3
31J 4-clc6H4cH2cH2 CH3CONH H
CH3 H CH3
31K 4-FC6H4CH2cH2 C2HsOCONH H
CH3 H CH3
3lL 4-Cl-3-CH3C6H3CH2CH2 H H
CH3 H CH3
31M 3-CH3CCCC6H4CH2~H2 H H
CH3 H CH3
31N 3,4-(CH30)2C6H3CH2cH2 H H
CH3 H CH3
31P 4-CH3SC6H4CH2cH2 H H
CH3 H CH3
-71-
-` lU89~
Example Rl/Q R2/R2' R3/R4
31Q 3-CF3C6H4CH2cH2 H H
CH3 H CH3
31R 3-cH3coNHc6H4cH2cH2 H H
CH3 H CH3
31S 3~4-ocH2oc6H3cH2cH2 H H
CH3 H CH3
3lT CH3 H H
CH3 Cl CH3
103lU CH3 H H
CH3 Br CH3
31V CH3 H H
CH3 F CH3
31W CH3 H H
CH3 CF3 CH3
31X CH3 H H
CH3 CH3 CH3
31Y CH3 C6H5 H
CH3 H CH3
~D
2031Z CH3 CH ~ H
CH3 , CH3
31AA CH3 H H
CH3 H H
31AB CH3 H H
CH3 H CH2CH2Cl
31AC CH3 H (CH2)3
CH3 H
. 31AD CH3 H (CH2)4
CH3 H
303LAE CH3 H H
CH3 H CH2CH2OCH3
31AF CH3 H H
CH3 H CH2CH2Sc6H5
31AG CH3 H H
CH3 H CH2cH2soc6H5
31AH CH3 H H
CH3 H CH-CH2
31AJ CH3 H H
CH3 H CH2CH2ScH3
-~2-
)89
Example Rl/Q_ R2/R;!' R3/R~
31AK CH3 H H
CH3 H CH2CH2O~
31AL CH3 H H
C6H5 C2H5
EXAMPLE 31AM
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-
--73--
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).
EXAMPLE 33
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.
EXAMPLE 34
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
-74-
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.
EXAMPLE 35
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).
EXAMPLE 36
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.
EXAMPLE 37
A) A mixture of 4.8 g. ~0.02 mole) of 7-hydroxy-S~-methyl-
-75-
~ 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
-76-
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
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'}~
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.
22D 16
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
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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~
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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.
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